肥厚型心肌病临床异质性的遗传及环境因素
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摘要
背景：50年来,肥厚型心肌病(hypertrophic cardiomyopathy, HCM)被认为是具有高猝死风险的家族性心脏病,其临床表型、自然病史以及基因突变谱有很大的异质性,而这种异质性源于遗传与环境因素的共同作用。多基因突变作为重要的遗传因素尽管已经常见报道于儿童或者具有严重临床表型的肥厚型心肌病患者,被推测与恶劣预后相关,但是尚没有其提示恶性临床预后的前瞻性研究报道。另外,作为HCM重要的心肌重塑表现,纤维化是近年来备受关注的与恶性预后相关的危险因素,大内皮素-1作为心肌重构的重要生物标记物是否能够影响和提示预后也是尚未解决的问题。
方法：连续纳入552名无亲缘关系的HCM患者,应用多重靶向测序技术对已知的最常见HCM致病基因进行全外显子捕获测序,最终测序质量合格者529人。对于高通量测序所检出的突变致病性的判断遵循如下标准：在已公布的突变数据库或者已发表的文献中报道的与HCM相关的突变；新发现的突变应满足：在本研究纳入的312名健康对照中无此突变,并且生物信息学分析证明该突变引起高保守的氨基酸改变及蛋白结构改变,该突变在其家系中与HCM共分离,如果家系资料对于基因突变与疾病共分离分析不可用(家系过小或无其他家庭成员发病),一定要无义突变或者插入缺失突变,如果是剪切位点突变则需证实突变损伤了剪切位点。根据患者所携带的突变数量分三组：未检出突变组、单突变组及多突变组(携带突变数量≥2个)。通过历时4.7+3.2年的随访,获知心血管死亡等临床事件,并评估多突变与各类事件的相关性。并且我们将多突变组中的4名先证者扩大测序的范围至26个与HCM相关的基因,并对这四个家系的成员进行了详细的临床及遗传筛查,以观察多基因突变对于相同遗传背景者临床表型的影响。其中随机纳入245名患者在入组时进行了血浆大内皮素-1的检测,并进行了历时3(2-5)年的随访,以观察血浆大内皮素与预后的相关性。
结果：我们在232名患者中发现了256个致病突变：38名(7.2%)患者携带了多突变,194名(36.7%)患者携带单突变。携带多突变的患者不论入组年龄、发病年龄还是确诊年龄都更年轻(p<10-6)、具有猝死危险因素患者的比例更高(p=0.002)。随访发现,42名患者发生了心血管死亡,5年、10年的心血管死亡生存率在多突变组分别为65.0%和55.7%,在单突变组分别为95.8%和88.3%,在未检出突变组分别为92.1%和86.5%(p<10-6)。与单突变组相比,多突变组心血管死亡危险显著增加(校正后的风险比[HR]为3.74；95%可信区间[CI]为2.51-12.231.84-7.58；p=0.0003)。并且与携带≤1个突变的患者相比,多突变携带者发生心力衰竭(校正后HR为3.53；95%CI为1.25-9.92；p=0.017)及猝死(校正后HR为3.57；95%CI为1.23-10.35；p=0.019)的危险更高。对于猝死危险预测,具有≥1个传统危险因素的患者较其他患者HR为2.74(95%CI为1.08-6.94；p=0.033),而具有≥1个传统危险因素并且携带多突变的患者较其他患者HR为5.52(95%CI为1.83-16.65；p=0.002)。以生存年龄为时长进行统计分析得到类似结果。在家系筛查中,以家系内基因突变数量不同的携带者之间的临床表型相比较,也提示携带突变数量越多发病年龄相对越早、症状更重,更易出现心衰症状。并且发现某些变异单独存在并不致病而同时共存时却能引起表型,其遗传模式符合隐性遗传。
在进行血浆大内皮素-1检测的患者中发现,血浆大内皮素-1水平高的患者左房内径更大、心功能更差以及伴发房颤的患者比例更高。血浆大内皮素-1水平与N端B型钠尿肽的水平(r=0.291,p<0.001)以及钆延迟增强显像(r=0.222,p=0.016)显著相关。随访发现,高水平的血浆大内皮素水平与全因死亡、心血管死亡以及进展为慢性心力衰竭均有显著的相关性(p=0.020,0.044及0.032)。多因素校正后的回归模型显示,血浆大内皮素-1高水平组比低水平组全因死亡(HR=4.94,95%CI1.07-22.88；p=0.041)及进展为心衰(HR=4.10,95%CI1.32-12.75, p=0.015)的风险均显著增加。
结论：作为遗传因素,多突变是HCM患者心血管死亡以及其他恶性临床事件的独立危险因素,其加入能够提高传统猝死危险因素模型对猝死风险的阳性预测价值。并且在家系内的筛查,家系中有多个患者时应当注意先证者的选择,或者必要时所有发病者均行全面的筛查,以便将整个家系中所携带的相关基因突变查全。并且应当重视单独存在并不致病而共存时却能引起表型的变异,它们可能以隐性遗传模式致病,在以往的基因筛查方式中易被遗漏。
作为重要的生物标记物,高水平的血浆大内皮素-1是全因死亡以及进展为心衰的独立危险因素,可应用于HCM患者危险分层。并且血浆大内皮素-1作为生物标志物可能成为新的干预目标,并且打开一个观察HCM机制的新窗口。
BACKGROUND
For over50years, hypertrophic cardiomyopathy (HCM) has been recognized as a familial cardiac disease with highly visible risk for sudden death and disease progression, characterizedby heterogeneous phenotypic expression, natural history, and genetic profile. Although multiple mutations was often reported in HCM patients at childhood and with severe phenotype and thereby considered with worse prognosis, its predictive value for malignant clinical outcomes had not been well explored. And cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1has been linked to cardiac remodeling. Big endothelin-1is the precursor of endothelin-1. We tested if it can become the marker for predicting the prognosis of HCM..
METHODS
A total of529patients from a prospectively collected HCM cohort were genotyped by screening10disease genes with multiplexing targeted resequencing and were subsequently divided into3groups based on pathogenic mutation dosage:no mutation was detected (no mutation), single mutation and multiple mutation s (≥2mutations). Mutation was considered to be pathogenic if it was absent in312healthy controls, the variant residues are highly conserved throughout evolution and segregated with disease in family. If family co-segregation analysis was unavailable, one of the following additional criteria must be met:previously reported to be pathogenic, nonsense or indels mutations, in silico prediction of damaging effect, and destroyed existing splice site predicted by Human Splicing Finder.The incidence of cardiovascular death and other adverse outcomes were recorded through a follow-up of4.7±3.2years. Correlations of multiple mutations with clinical outcomes were assessed. The families of four probands with multiple mutations were clinically and genetically screened. Twenty-six HCM-related genes were comprehensively screened for mutations in the probands with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and healthy controls. And a total of245consecutive patients with HCM were enrolled from1999to2011and partitioned to low, middle and high level groups according to their plasma big endothelin-1levels.
RESULTS
We identified232mutations from256patients:38(7.2%) with multiple mutations and194(36.7%) with single mutation. Patients with multiple mutations were younger (P<10-6) and higher frequencies of carrying≥1conventional sudden cardiac death (SCD) risk factors (P=0.002). During follow-up,42cardiovascular deaths occurred. The survival rates of free of cardiovascular death at5and10years of follow up were65.0%and55.7%for patients with multiple mutations,95.8%and88.3%for those with single mutation and92.1%and86.5%for those with no mutation, respectively (P<10-6). Multiple mutations significantly increased the risk of cardiovascular death compared with single mutation (adjusted hazard ratio [HR],3.74;95%confidence interval [CI],2.51-12.231; P=0.0003). Patients with multiple mutations had higher risk for heart failure (adjusted HR,3.53;95%CI,1.25-9.92; P=0.017) and SCD (adjusted HR,3.57;95%CI,1.23-10.35; P=0.019) than those with≤1mutation. The HR ratio for SCD prediction was increased from2.74(95%CI,1.08-6.94; P=0.033) by using≥1conventional risk factors to5.52(95%CI,1.83-16.65; P=0.002) by using the presence of≥1conventional risk factors and multiple mutations. Lifelong-time analysis also showed similar associations in various adverse clinical outcomes. In the4families with multiple mutations, compared to the members with single mutation, the members with multiple mutations were younger, with severer symptom and more susceptible to heart failure.
We also found that at baseline, significant associations were found between high levels of big endothelin-1and left atrium size, heart function and atrial fibrillation. Big endothelin-1was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of3(range,2-5) years, big endothelin-1level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to heart failure (p=0.020,0.044and0.032, respectively). After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1with the risk of all-cause mortality (hazard ratio (HR)=4.94,95%confidence interval (CI)1.07-22.88; p=0.041) and progression to heart failure (HR=4.10,95%CI1.32-12.75, p=0.015).
CONCLUSIONS
Multiple mutations in HCM are an independent risk factor for cardiovascular death and other adverse clinical outcomes. The positive rate for SCD prediction can be improved by adding genetic analysis into conventional frisk stratification algorithm. In the screening of a family with more than one patient who presents various phenotypes, there should not be only one proband chosen for genetic screening, for recognize all mutations correlated with HCM in the family. Our study also showed that high level of plasma big endothelin-1predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk. It needs to further explore whether the biomarkers could be used to evaluate the efficacy of intervention and opens a new window to look at the pathogenesis of HCM.
方法：连续纳入552名无亲缘关系的HCM患者,应用多重靶向测序技术对已知的最常见HCM致病基因进行全外显子捕获测序,最终测序质量合格者529人。对于高通量测序所检出的突变致病性的判断遵循如下标准：在已公布的突变数据库或者已发表的文献中报道的与HCM相关的突变；新发现的突变应满足：在本研究纳入的312名健康对照中无此突变,并且生物信息学分析证明该突变引起高保守的氨基酸改变及蛋白结构改变,该突变在其家系中与HCM共分离,如果家系资料对于基因突变与疾病共分离分析不可用(家系过小或无其他家庭成员发病),一定要无义突变或者插入缺失突变,如果是剪切位点突变则需证实突变损伤了剪切位点。根据患者所携带的突变数量分三组：未检出突变组、单突变组及多突变组(携带突变数量≥2个)。通过历时4.7+3.2年的随访,获知心血管死亡等临床事件,并评估多突变与各类事件的相关性。并且我们将多突变组中的4名先证者扩大测序的范围至26个与HCM相关的基因,并对这四个家系的成员进行了详细的临床及遗传筛查,以观察多基因突变对于相同遗传背景者临床表型的影响。其中随机纳入245名患者在入组时进行了血浆大内皮素-1的检测,并进行了历时3(2-5)年的随访,以观察血浆大内皮素与预后的相关性。
结果：我们在232名患者中发现了256个致病突变：38名(7.2%)患者携带了多突变,194名(36.7%)患者携带单突变。携带多突变的患者不论入组年龄、发病年龄还是确诊年龄都更年轻(p<10-6)、具有猝死危险因素患者的比例更高(p=0.002)。随访发现,42名患者发生了心血管死亡,5年、10年的心血管死亡生存率在多突变组分别为65.0%和55.7%,在单突变组分别为95.8%和88.3%,在未检出突变组分别为92.1%和86.5%(p<10-6)。与单突变组相比,多突变组心血管死亡危险显著增加(校正后的风险比[HR]为3.74；95%可信区间[CI]为2.51-12.231.84-7.58；p=0.0003)。并且与携带≤1个突变的患者相比,多突变携带者发生心力衰竭(校正后HR为3.53；95%CI为1.25-9.92；p=0.017)及猝死(校正后HR为3.57；95%CI为1.23-10.35；p=0.019)的危险更高。对于猝死危险预测,具有≥1个传统危险因素的患者较其他患者HR为2.74(95%CI为1.08-6.94；p=0.033),而具有≥1个传统危险因素并且携带多突变的患者较其他患者HR为5.52(95%CI为1.83-16.65；p=0.002)。以生存年龄为时长进行统计分析得到类似结果。在家系筛查中,以家系内基因突变数量不同的携带者之间的临床表型相比较,也提示携带突变数量越多发病年龄相对越早、症状更重,更易出现心衰症状。并且发现某些变异单独存在并不致病而同时共存时却能引起表型,其遗传模式符合隐性遗传。
在进行血浆大内皮素-1检测的患者中发现,血浆大内皮素-1水平高的患者左房内径更大、心功能更差以及伴发房颤的患者比例更高。血浆大内皮素-1水平与N端B型钠尿肽的水平(r=0.291,p<0.001)以及钆延迟增强显像(r=0.222,p=0.016)显著相关。随访发现,高水平的血浆大内皮素水平与全因死亡、心血管死亡以及进展为慢性心力衰竭均有显著的相关性(p=0.020,0.044及0.032)。多因素校正后的回归模型显示,血浆大内皮素-1高水平组比低水平组全因死亡(HR=4.94,95%CI1.07-22.88；p=0.041)及进展为心衰(HR=4.10,95%CI1.32-12.75, p=0.015)的风险均显著增加。
结论：作为遗传因素,多突变是HCM患者心血管死亡以及其他恶性临床事件的独立危险因素,其加入能够提高传统猝死危险因素模型对猝死风险的阳性预测价值。并且在家系内的筛查,家系中有多个患者时应当注意先证者的选择,或者必要时所有发病者均行全面的筛查,以便将整个家系中所携带的相关基因突变查全。并且应当重视单独存在并不致病而共存时却能引起表型的变异,它们可能以隐性遗传模式致病,在以往的基因筛查方式中易被遗漏。
作为重要的生物标记物,高水平的血浆大内皮素-1是全因死亡以及进展为心衰的独立危险因素,可应用于HCM患者危险分层。并且血浆大内皮素-1作为生物标志物可能成为新的干预目标,并且打开一个观察HCM机制的新窗口。
BACKGROUND
For over50years, hypertrophic cardiomyopathy (HCM) has been recognized as a familial cardiac disease with highly visible risk for sudden death and disease progression, characterizedby heterogeneous phenotypic expression, natural history, and genetic profile. Although multiple mutations was often reported in HCM patients at childhood and with severe phenotype and thereby considered with worse prognosis, its predictive value for malignant clinical outcomes had not been well explored. And cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1has been linked to cardiac remodeling. Big endothelin-1is the precursor of endothelin-1. We tested if it can become the marker for predicting the prognosis of HCM..
METHODS
A total of529patients from a prospectively collected HCM cohort were genotyped by screening10disease genes with multiplexing targeted resequencing and were subsequently divided into3groups based on pathogenic mutation dosage:no mutation was detected (no mutation), single mutation and multiple mutation s (≥2mutations). Mutation was considered to be pathogenic if it was absent in312healthy controls, the variant residues are highly conserved throughout evolution and segregated with disease in family. If family co-segregation analysis was unavailable, one of the following additional criteria must be met:previously reported to be pathogenic, nonsense or indels mutations, in silico prediction of damaging effect, and destroyed existing splice site predicted by Human Splicing Finder.The incidence of cardiovascular death and other adverse outcomes were recorded through a follow-up of4.7±3.2years. Correlations of multiple mutations with clinical outcomes were assessed. The families of four probands with multiple mutations were clinically and genetically screened. Twenty-six HCM-related genes were comprehensively screened for mutations in the probands with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and healthy controls. And a total of245consecutive patients with HCM were enrolled from1999to2011and partitioned to low, middle and high level groups according to their plasma big endothelin-1levels.
RESULTS
We identified232mutations from256patients:38(7.2%) with multiple mutations and194(36.7%) with single mutation. Patients with multiple mutations were younger (P<10-6) and higher frequencies of carrying≥1conventional sudden cardiac death (SCD) risk factors (P=0.002). During follow-up,42cardiovascular deaths occurred. The survival rates of free of cardiovascular death at5and10years of follow up were65.0%and55.7%for patients with multiple mutations,95.8%and88.3%for those with single mutation and92.1%and86.5%for those with no mutation, respectively (P<10-6). Multiple mutations significantly increased the risk of cardiovascular death compared with single mutation (adjusted hazard ratio [HR],3.74;95%confidence interval [CI],2.51-12.231; P=0.0003). Patients with multiple mutations had higher risk for heart failure (adjusted HR,3.53;95%CI,1.25-9.92; P=0.017) and SCD (adjusted HR,3.57;95%CI,1.23-10.35; P=0.019) than those with≤1mutation. The HR ratio for SCD prediction was increased from2.74(95%CI,1.08-6.94; P=0.033) by using≥1conventional risk factors to5.52(95%CI,1.83-16.65; P=0.002) by using the presence of≥1conventional risk factors and multiple mutations. Lifelong-time analysis also showed similar associations in various adverse clinical outcomes. In the4families with multiple mutations, compared to the members with single mutation, the members with multiple mutations were younger, with severer symptom and more susceptible to heart failure.
We also found that at baseline, significant associations were found between high levels of big endothelin-1and left atrium size, heart function and atrial fibrillation. Big endothelin-1was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of3(range,2-5) years, big endothelin-1level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to heart failure (p=0.020,0.044and0.032, respectively). After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1with the risk of all-cause mortality (hazard ratio (HR)=4.94,95%confidence interval (CI)1.07-22.88; p=0.041) and progression to heart failure (HR=4.10,95%CI1.32-12.75, p=0.015).
CONCLUSIONS
Multiple mutations in HCM are an independent risk factor for cardiovascular death and other adverse clinical outcomes. The positive rate for SCD prediction can be improved by adding genetic analysis into conventional frisk stratification algorithm. In the screening of a family with more than one patient who presents various phenotypes, there should not be only one proband chosen for genetic screening, for recognize all mutations correlated with HCM in the family. Our study also showed that high level of plasma big endothelin-1predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk. It needs to further explore whether the biomarkers could be used to evaluate the efficacy of intervention and opens a new window to look at the pathogenesis of HCM.
引文
1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the cardia study. Coronary artery risk development in (young) adults. Circulation. 1995;92:785-789
2. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china:A population-based echocardiographic analysis of 8080 adults. Am J Med.2004; 116:14-18
3. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
4. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
5. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, Dooijes D, van Tintelen JP, van den Berg MP, Volders PG, Arens YH, van den Wijngaard A, Atsma DE, Helderman-van den Enden AT, Houweling AC, de Boer K, van der Smagt JJ, Hauer RN, Marcelis CL, Timmermans J, van Langen IM, Wilde AA. Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers:Determining the best cardiological screening strategy. Eur Heart J.2011;32:1161-1170
6. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:e783-831
7. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MY, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
8. Seggewiss H, Rigopoulos A. Management of hypertrophic cardiomyopathy in children. Paediatr Drugs.2003;5:663-672
9. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ.2006;332:1251-1255
10. Prinz C, Schwarz M, Hic I, Laser KT, Lehmann R, Prinz EM, Bitter T, Vogt J, van Buuren F, Bogunovic N, Horstkotte D, Faber L. Myocardial fibrosis severity on cardiac magnetic resonance imaging predicts sustained arrhythmic events in hypertrophic cardiomyopathy. Can J Cardiol. 2013;29:358-363
11. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation.2008;118:1541-1549
12. Ho CY. Genetics and clinical destiny:Improving care in hypertrophic cardiomyopathy. Circulation.2010;122:2430-2440; discussion 2440
13. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, et al. Mutations in the genes for cardiac troponin t and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med.1995;332:1058-1064
14. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy:A beta cardiac myosin heavy chain gene missense mutation. Cell.1990;62:999-1006
15. Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin t gene. Circ Cardiovasc Genet.2012;5:10-17
16. Michels M, Soliman 01, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, Majoor-Krakauer D, Ten Cate FJ. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur Heart J. 2009;30:2593-2598
17. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation.2010;122:2441-2449; discussion 2450
18. Saltzman AJ, Mancini-DiNardo D, Li C, Chung WK, Ho CY, Hurst S, Wynn J, Care M, Hamilton RM, Seidman GW, Gorham J, McDonough B, Sparks E, Seidman JG, Seidman CE, Rehm HL. Short communication:The cardiac myosin binding protein c arg502trp mutation:A common cause of hypertrophic cardiomyopathy. Circ Res.2010;106:1549-1552
19. Zou Y, Wang J, Liu X, Wang Y, Chen Y, Sun K, Gao S, Zhang C, Wang Z, Zhang Y, Feng X, Song Y, Wu Y, Zhang H, Jia L, Wang H, Wang D, Yan C, Lu M, Zhou X, Song L, Hui R. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep.2013
20. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
21. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic cardiomyopathy:Report of a working group of the national heart, lung, and blood institute. Circulation.2010;122:1130-1133
22. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. J Med Genet.2005;42:e59
23. Richard P, Isnard R, Carrier L, Dubourg O, Donatien Y, Mathieu B, Bonne G, Gary F, Charron P, Hagege M, Komajda M, Schwartz K, Hainque B. Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein c genes in a family with hypertrophic cardiomyopathy. J Med Genet.1999;36:542-545
24. Mohiddin SA, Begley DA, McLam E, Cardoso JP, Winkler JB, Sellers JR, Fananapazir L. Utility of genetic screening in hypertrophic cardiomyopathy:Prevalence and significance of novel and double (homozygous and heterozygous) beta-myosin mutations. Genet Test 1.648.2003;7:21-27
25. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003; 107:2227-2232
26. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein c mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol.2004;44:1903-1910
27. Girolami F, Ho CY, Semsarian C, Baldi M, Will ML, Baldini K, Torricelli F, Yeates L, Cecchi F, Ackerman MJ, Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol.2010;55:1444-1453
28. Garcia-Pavia P, Vazquez ME, Segovia J, Salas C, Avellana P, Gomez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L. Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail.2011; 13:1193-1201
29. Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE. Homozygous mutation in cardiac troponin t:Implications for hypertrophic cardiomyopathy. Circulation. 2000;102:1950-1955
30. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V, Scharfenberger-Schmeer M, Stahler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet.2011;4:110-122
31. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med.2012;366:619-628
32. Harakalova M, Mokry M, Hrdlickova B, Renkens I, Duran K, van Roekel H, Lansu N, van Roosmalen M, de Bruijn E, Nijman IJ, Kloosterman WP, Cuppen E. Multiplexed array-based and in-solution genomic enrichment for flexible and cost-effective targeted next-generation sequencing. Nat Protoc.2011;6:1870-1886
33. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med.2008;358:1899-1908
34. Ho CY, MacRae CA. Defining the pathogenicity of DNA sequence variation. Circ Cardiovasc Genet.2009;2:95-97
35. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:Executive summary:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:2761-2796
36. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR. Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. Am J Hum Genet. 2011;88:183-192
37. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248-249
38. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease:A marker of disease severity? Circ Cardiovasc Genet.2009;2:182-190
39. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98:625-630
40. Wordsworth S, Leal J, Blair E, Legood R, Thomson K, Seller A, Taylor J, Watkins H. DNA testing for hypertrophic cardiomyopathy:A cost-effectiveness model. Eur Heart J.2010;31:926-935
1. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
2. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:e783-831
3. Brito D, Richard P, Komajda M, Madeira H. Familial and sporadic hypertrophic myopathy: Differences and similarities in a genotyped population. A long follow-up study. Rev Port Cardiol. 2008;27:147-173
4. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98:625-630
5. Goldenberg I, Moss AJ, Maron BJ, Dick AW, Zareba W. Cost-effectiveness of implanted defibrillators in young people with inherited cardiac arrhythmias. Ann Noninvasive Electrocardiol. 2005;10:67-83
6. Garcia-Pavia P, Vazquez ME, Segovia J, Salas C, Avellana P, Gomez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L. Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail.2011; 13:1193-1201
7. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
8. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. JMed Genet.2005;42:e59
9. Girolami F, Ho CY, Semsarian C, Baldi M, Will ML, Baldini K, Torricelli F, Yeates L, Cecchi F, Ackerman MJ, Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol.2010;55:1444-1453
10. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation.2011;123:1021-1037
11. Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE. Homozygous mutation in cardiac troponin t:Implications for hypertrophic cardiomyopathy. Circulation. 2000;102:1950-1955
12. Ortiz MF, Rodriguez-Garcia MI, Hermida-Prieto M, Fernandez X, Veira E, Barriales-Villa R, Castro-Beiras A, Monserrat L. A homozygous mybpc3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy. Rev Esp Cardiol.2009;62:572-575
13. Olson TM, Karst ML, Whitby FG, Driscoll DJ. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation. 2002;105:2337-2340
14. Gray B, Yeates L, Medi C, Ingles J, Semsarian C. Homozygous mutation in the cardiac troponin i gene:Clinical heterogeneity in hypertrophic cardiomyopathy. Int J Cardiol.2012
15. Marston SB. How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res.2011;4:245-255
16. Schlossarek S, Mearini G, Carrier L. Cardiac myosin-binding protein c in hypertrophic cardiomyopathy:Mechanisms and therapeutic opportunities. J Mol Cell Cardiol.2011;50:613-620
17. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003;107:2227-2232
18. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein c and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248-1257
19. Wang S, Zou Y, Fu C, Xu X, Wang J, Song L, Wang H, Chen J, Huan T, Hui R. Worse prognosis with gene mutations of beta-myosin heavy chain than myosin-binding protein c in chinese patients with hypertrophic cardiomyopathy. Clin Cardiol.2008;31:114-118
20. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein c mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol.2004;44:1903-1910
21. Moolman-Smook J, Flashman E, de Lange W, Li Z, Corfield V, Redwood C, Watkins H. Identification of novel interactions between domains of myosin binding protein-c that are modulated by hypertrophic cardiomyopathy missense mutations. Circ Res.2002;91:704-711
22. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. J Am Coll Cardiol.2012;60:705-715
23. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet.2013;381:242-255
1. Saura D, Marin F, Climent V, Gonzalez J, Roldan V, Hernandez-Romero D, Oliva MJ, Sabater M, de la Morena G, Lip GY, Valdes M. Left atrial remodelling in hypertrophic cardiomyopathy:Relation with exercise capacity and biochemical markers of tissue strain and remodelling. Int J Clin Pract. 2009;63:1465-1471
2. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china:A population-based echocardiographic analysis of 8080 adults. Am J Med.2004;116:14-18
3. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
4. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
5. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, Dooijes D, van Tintelen JP, van den Berg MP, Volders PG, Arens YH, van den Wijngaard A, Atsma DE, Helderman-van den Enden AT, Houweling AC, de Boer K, van der Smagt JJ, Hauer RN, Marcelis CL, Timmermans J, van Langen IM, Wilde AA. Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers:Determining the best cardiological screening strategy. Eur Heart J.2011;32:1161-1170
6. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;124:e783-831
7. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
8. Anderson KR, Sutton MG, Lie JT. Histopathological types of cardiac fibrosis in myocardial disease. J Pathol.1979;128:79-85
9. Arteaga E, de Araujo AQ, Bernstein M, Ramires FJ, lanni BM, Fernandes F, Mady C. Prognostic value of the collagen volume fraction in hypertrophic cardiomyopathy. Arq Bras Cardiol. 2009;92:210-214,216-220
10. Sepp R, Severs NJ, Gourdie RG. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart.1996;76:412-417
11. Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side-to-side cell connections:A major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol.1997;20:397-413
12. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Oirc Res.1986;58:356-371
13. de Bakker JM, van Capelle FJ, Janse MJ, Tasseron S, Vermeulen JT, de Jonge N, Lahpor JR. Slow conduction in the infarcted human heart.'Zigzag' course of activation. Circulation. 1993;88:915-926
14. Spach MS, Heidlage JF, Dolber PC, Barr RC. Mechanism of origin of conduction disturbances in aging human atrial bundles:Experimental and model study. Heart Rhythm.2007;4:175-185
15. Gaudesius G, Miragoli M, Thomas SP, Rohr S. Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res.2003;93:421-428
16. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res.1989;65:1612-1631
17. Morita N, Sovari AA, Xie Y, Fishbein MC, Mandel WJ, Garfinkel A, Lin SF, Chen PS, Xie LH, Chen F, Qu Z, Weiss JN, Karagueuzian HS. Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. Am J Physiol Heart Circ Physiol.2009;297:H1594-1605
18. Ono N, Hayashi H, Kawase A, Lin SF, Li H, Weiss JN, Chen PS, Karagueuzian HS. Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition. Am J Physiol Heart Circ Physiol.2007;292:H639-648
19. Morita N, Lee JH, Xie Y, Sovari A, Qu Z, Weiss JN, Karagueuzian HS. Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine. J Am Coll Cardiol. 2011;57:366-375
20. Morita N, Lee JH, Bapat A, Fishbein MC, Mandel WJ, Chen PS, Weiss JN, Karagueuzian HS. Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts. Am J Physiol Heart Circ Physiol.2011;301:H180-191
21. Lakatta EG, Levy D. Arterial and cardiac aging:Major shareholders in cardiovascular disease enterprises:Part ii:The aging heart in health:Links to heart disease. Circulation. 2003;107:346-354
22. Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL. Importance of heart failure with preserved systolic function in patients> or= 65 years of age. Chs research group. Cardiovascular health study. Am J Cardiol. 2001;87:413-419
23. Luscher TF. Endothelin. Key to coronary vasospasm? Circulation.1991;83:701-703
24. Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH, Chien KR Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem.1990;265:20555-20562
25. Van Beneden R, Gurne O, Selvais PL, Ahn SA, Robert AR, Ketelslegers JM, Pouleur HG, Rousseau MF. Superiority of big endothelin-1 and endothelin-1 over natriuretic peptides in predicting survival in severe congestive heart failure:A 7-year follow-up study. J Card Fail.2004; 10:490-495
26. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F. Protective effect of long-term angiotensin ii inhibition. Am J Physiol Heart Circ Physiol.2007;293:H1351-1358
27. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G. Disruption of the ang ii type 1 receptor promotes longevity in mice. J Clin Invest.2009; 119:524-530
28. Rosenkranz S. Tgf-betal and angiotensin networking in cardiac remodeling. Cardiovasc Res. 2004;63:423-432
29. Weber KT, Swamynathan SK, Guntaka RV, Sun Y. Angiotensin ii and extracellular matrix homeostasis. IntJ Biochem Cell Biol.1999;31:395-403
30. Rubin SA, Levin ER. Clinical review 53:The endocrinology of vasoactive peptides:Synthesis to function. J Clin Endocrinol Metab.1994;78:6-10
31. Hemsen A, Ahlborg G, Ottosson-Seeberger A, Lundberg JM. Metabolism of big endothelin-1 (1-38) and (22-38) in the human circulation in relation to production of endothelin-1 (1-21). Regul Pept. 1995;55:287-297
32. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A. Esc guidelines for the diagnosis and treatment of acute and chronic heart failure 2012:The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology. Developed in collaboration with the heart failure association (hfa) of the esc. Eur Heart J.2012;33:1787-1847
33. Pacileo G, Salerno G, Gravino R, Calabro R, Elliott PM. Risk stratification in hypertrophic cardiomyopathy:Time for renewal? J Cardiovasc Med (Hagerstown).2012
34. Bellien J, lacob M, Remy-Jouet I, Lucas D, Monteil C, Gutierrez L, Vendeville C, Dreano Y, Mercier A, Thuillez C, Joannides R. Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation.2012;125:1266-1275
35. Kakinuma Y, Miyauchi T, Yuki K, Murakoshi N, Goto K, Yamaguchi I. Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-lalpha induced for impaired myocardial energy metabolism. Circulation.2001;103:2387-2394
36. Coats CJ, Gallagher MJ, Foley M, O'Mahony C, Critoph C, Gimeno J, Dawnay A, McKenna WJ, Elliott PM. Relation between serum n-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy. Eur Heart J.2013
37. Luchner A, Mockel M, Spanuth E, Mocks J, Peetz D, Baum H, Spes C, Wrede CE, Vollert J, Muller R, Katus H, Giannitsis E. N-terminal pro brain natriuretic peptide in the management of patients in the medical emergency department (prompt):Correlation with disease severity, utilization of hospital resources, and prognosis in a large, prospective, randomized multicentre trial. Eur J Heart Fail.2012;14:259-267
38. Scheuer J, Malhotra A, Hirsch C, Capasso J, Schaible TF. Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats. J Clin Invest. 1982;70:1300-1305
39. Wakatsuki T, Schlessinger J, Elson EL. The biochemical response of the heart to hypertension and exercise. Trends Biochem Sci.2004;29:609-617
40. Barry SP, Davidson SM, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol.2008;40:2023-2039
41. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med. 1999;341:1276-1283
42. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications:A consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol.2000;35:569-582
43. Kajstura J, Liu Y, Baldini A, Li B, Olivetti G, Leri A, Anversa P. Coronary artery constriction in rats: Necrotic and apoptotic myocyte death. Am J Cardiol.1998;82:30K-41K
44. Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A.1998;95:8801-8805
45. Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res.2011;89:265-272
46. Prinz C, Schwarz M, Ilic I, Laser KT, Lehmann R, Prinz EM, Bitter T, Vogt J, van Buuren F, Bogunovic N, Horstkotte D, Faber L. Myocardial fibrosis severity on cardiac magnetic resonance imaging predicts sustained arrhythmic events in hypertrophic cardiomyopathy. Can J Cardiol. 2013;29:358-363
47. Luscher TF. Endothelin. J Cardiovasc Pharmacol.1991;18 Suppl 10-:S15-22
48. Marian AJ. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet.2000;355:58-60
49. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Pharmacol Rep.2007;59:715-720
50. Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res.1991;69:209-215
51. Hasegawa K, Fujiwara H, Koshiji M, Inada T, Ohtani S, Doyama K, Tanaka M, Matsumori A, Fujiwara T, Shirakami G, Hosoda K, Nakao K, Sasayama S. Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension.1996;27:259-264
52. Ogino K, Ogura K, Kinugawa T, Osaki S, Kato M, Furuse Y, Kinugasa Y, Tomikura Y, Igawa O, Hisatome I, Shigemasa C. Neurohumoral profiles in patients with hypertrophic cardiomyopathy: Differences to hypertensive left ventricular hypertrophy. CircJ.2004;68:444-450
53. Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto H, Ohta Y, Marumo F. Endothelin eta receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation. 1994;89:2198-2203
54. Yorikane R, Sakai S, Miyauchi T, Sakurai T, Sugishita Y, Goto K. Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett.1993;332:31-34
55. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy:The interrelation of disarray, fibrosis, and small vessel disease. Heart.2000;84:476-482
1. Braunwald E, Lambrew CT, Rockoff SD, Ross J, Jr., Morrow AG. Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients. Circulation. 1964;30:SUPPL 4:3-119
2. Pokorski RJ. Hypertrophic cardiomyopathy:Risk factors for life and living benefits insurance. J Insur Med.2002;34:43-60
3. Maron BJ. Hypertrophic cardiomyopathy:An important global disease. Am J Med.2004;116:63-65
4. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
5. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy:From bench to the clinics. JCardiovasc Electrophysiol.2008;19:104-110
6. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation.2010;121:445-456
7. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH,3rd, Spirito P, Ten Cate FJ, Wigle ED. American college of cardiology/european society of cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the american college of cardiology foundation task force on clinical expert consensus documents and the european society of cardiology committee for practice guidelines. J Am Coll Cardiol. 2003;42:1687-1713
8. Seidman CE, Seidman JG.Identifying sarcomere gene mutations in hypertrophic cardiomyopathy:A personal history. Circ Res.2011; 108:743-750
9. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. JAm Coll Cardiol.2012;60:705-715
10. Kittle CF, Reed WA, Crockett JE. Infundibulectomy for subaortic hypertrophic stenosis. Circulation. 1964;29:SUPPL:119-124
11. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol.2009;54:220-228
12. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic cardiomyopathy:Report of a working group of the national heart, lung, and blood institute. Circulation.2010;122:1130-1133
13. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1.N Engl J Med.1989;321:1372-1378
14. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy:A beta cardiac myosin heavy chain gene missense mutation. Cell.1990;62:999-1006
15. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med.1992;326:1108-1114
16. Ho CY. Genetics and clinical destiny:Improving care in hypertrophic cardiomyopathy. Circulation. 2010;122:2430-2440; discussion 2440
17. Watkins H. Sudden death in hypertrophic cardiomyopathy. N Engl J Med.2000;342:422-424
18. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet.2013;381:242-255
19. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation.2010;122:2441-2449; discussion 2450
20. Ackerman MJ, VanDriest SL, Ommen SR, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin t genes in hypertrophic cardiomyopathy:A comprehensive outpatient perspective. J Am Coll Cardiol. 2002;39:2042-2048
21. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein c and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248-1257
22. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003;107:2227-2232
23. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N, Weil J, Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation.2005; 112:855-861
24. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging.2012;5:370-377
25. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004;90:645-649
26. Maron BJ, Seidman CE, Ackerman MJ, Towbin JA, Maron MS, Ommen SR, Nishimura RA, Gersh BJ. How should hypertrophic cardiomyopathy be classified?:What's in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy. Circ Cardiovasc Genet.2009;2:81-85; discussion 86
27. Maron BJ. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation.2007; 116:196-206; discussion 206
28. Olivotto I, Ommen SR, Maron MS, Cecchi F, Maron BJ. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol.2007;50:831-834
29. Nishimura RA, Ommen SR. Septal reduction therapy for obstructive hypertrophic cardiomyopathy and sudden death:What statistics cannot tell you. Circ Cardiovasc Intern.2010;3:91-93
30. ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy:A word of caution. Circ Heart Fail.2010;3:362-369
31. Maron BJ, Maron MS, Wigle ED, Braunwald E. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy:From idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:191-200
32. Agarwal S, Tuzcu EM, Desai MY, Smedira N, Lever HM, Lytle BW, Kapadia SR. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol.2010;55:823-834
33. Maron BJ, Yacoub M, Dearani JA. Controversies in cardiovascular medicine. Benefits of surgery in obstructive hypertrophic cardiomyopathy:Bring septal myectomy back for european patients. Eur Heart J.2011;32:1055-1058
34. Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE, Cecchi F, Maron BJ. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. JAm Coll Cardiol.2005;46:480-487
35. Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;41:974-980
36. Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Comparison of prevalence of apical hypertrophic cardiomyopathy in japan and the united states. Am J Cardiol.2003;92:1183-1186
37. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echo card iographic analysis of 4111 subjects in the cardia study. Coronary artery risk development in (young) adults. Circulation.1995;92:785-789
38. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-related death:Revisited in a large non-referral-based patient population. Circulation.2000; 102:858-864
39. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein c gene mutations. JAm Coll Cardiol.2001;38:315-321
40. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation.2006;114:2232-2239
41. Biagini E, Berardini A, Graziosi M, Rosmini S, Pazzi C, Rapezzi C. [gender effect on cardiomyopathy]. G Ital Cardiol (Rome).2012;13:424-431
42. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china: A population-based echocardiographic analysis of 8080 adults. Am J Med.2004; 116:14-18
43. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:Executive summary:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011; 124:2761-2796
44. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy. Echocardiographic identification of the pathognomonic anatomic abnormality of ihss. Circulation.1973;47:225-233
45. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation.2011;123:1021-1037
46. Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin t, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation.2002;106:3085-3090
47. Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet.2003;64:339-349
48. Andersen PS, Havndrup O, Hougs L, Sorensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in danish hypertrophic cardiomyopathy patients and relatives. Hum Mutat.2009;30:363-370
49. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:201-211
50. Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation.1992;85:1651-1660
51. Maron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Maron BJ. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011; 124:40-47
52. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N EnglJMed.2003;349:1027-1035
53. Maron MS, Olivotto I, Maron BJ, Prasad SK, Cecchi F, Udelson JE, Camici PG. The case for myocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:866-875
54. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy:Morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol.1995;26:1699-1708
55. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc.2008;83:630-638
56. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation.2002; 105:446-451
57. Walsh R, Rutland C, Thomas R, Loughna S. Cardiomyopathy:A systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations. Cardiology.2010;115:49-60
58. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, Prieur F, Bresson JL, Faivre L, Eicher JC, Chassaing N, Crehalet H, Porcher R, Rodriguez-Lafrasse C, Rousson R. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet.2010;53:261-267
59. Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires tgf-beta. J Clin Invest.2010; 120:3520-3529
60. Konno T, Chen D, Wang L, Wakimoto H, Teekakirikul P, Nayor M, Kawana M, Eminaga S, Gorham JM, Pandya K, Smithies O, Naya FJ, Olson EN, Seidman JG Seidman CE. Heterogeneous myocyte enhancer factor-2 (mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A.2010;107:18097-18102
61. Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L. Nonsense-mediated mrna decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein c mutant levels in cardiomyopathic mice. Circ Res.2009;105:239-248
62. Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H. Evidence from human myectomy samples that mybpc3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res.2009; 105:219-222
63. Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G, Ahmed I, Maher AR, Kaur K, Taylor J, Henning A, Ashrafian H, Watkins H, Frenneaux M. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation. 2010;122:1562-1569
64. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE. Acmg recommendations for standards for interpretation and reporting of sequence variations:Revisions 2007. Genet Med.2008;10:294-300
65. Mestroni L, Taylor MR. Hearing the noise the challenges of human genome variation in genetic testing. JAm Coll Cardiol.2011;57:2328-2329
66. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V, Scharfenberger-Schmeer M, Stahler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet.2011;4:110-122
67. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature.2010;467:1061-1073
68. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation.1995;92:1680-1692
69. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional united states cohort. JAMA.1999;281:650-655
70. Decker JA, Rossano JW, Smith EO, Cannon B, Clunie SK, Gates C, Jefferies JL, Kim JJ, Price JF, Dreyer WJ, Towbin JA, Denfield SW. Risk factors and mode of death in isolated hypertrophic cardiomyopathy in children. JAm Coll Cardiol.2009;54:250-254
71. Maron BJ, Casey SA, Hauser RG, Aeppli DM. Clinical course of hypertrophic cardiomyopathy with survival to advanced age. JAm Coll Cardiol.2003;42:882-888
72. Maron BJ, Casey SA, Haas TS, Kitner CL, Garberich RF, Lesser JR. Hypertrophic cardiomyopathy with longevity to 90 years or older. Am J Cardiol.2012;109:1341-1347
73. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358:1899-1908
74. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA,3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365-373
75. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
76. Noseworthy PA, Rosenberg MA, Fifer MA, Palacios IF, Lowry PA, Ruskin JN, Sanborn DM, Picard MH, Vlahakes GJ, Mela T, Das S. Ventricular arrhythmia following alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol.2009;104:128-132
77. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol.2005;46:470-476
78. McKenna WJ, Deanfield JE. Hypertrophic cardiomyopathy:An important cause of sudden death. Arch Dis Child.1984;59:971-975
79. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med.1997;336:775-785
80. Maron BJ, Braunwald E. Evolution of hypertrophic cardiomyopathy to a contemporary treatable disease. Circulation.2012; 126:1640-1644
81. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation.2006;114:216-225
82. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation.2001;104:2517-2524
83. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, Casey SA, Gohman TE, Bongioanni S, Spirito P. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. JAm Coll Cardiol.2002;39:301-307
84. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med.1986;315:610-614
85. Adabag AS, Kuskowski MA, Maron BJ. Determinants for clinical diagnosis of hypertrophic cardiomyopathy. Am J Cardiol.2006;98:1507-1511
86. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. NEngl J Med.1998;339:364-369
87. Mozaffarian D, Caldwell JH. Right ventricular involvement in hypertrophic cardiomyopathy:A case report and literature review. Clin Cardiol.2001;4:2-8
88. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;124:e783-831
89. Maron MS, Lesser JR, Maron B J. Management implications of massive left ventricular hypertrophy in hypertrophic cardiomyopathy significantly underestimated by echocardiography but identified by cardiovascular magnetic resonance. Am J Cardiol.2010; 105:1842-1843
90. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation.2008;118:1541-1549
91. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy. Significance in producing left ventricular outflow obstruction. Circulation.1991;84:1188-1197
92. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778-1785
93. Olivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, De Santis M, Quarta G, Nistri S, Cecchi F, Salton CJ, Udelson JE, Manning WJ, Maron BJ. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol.2008;52:559-566
94. Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY, Barr S, Karim A, Olson TM, Kamisago M, Seidman JG, Seidman CE. Gene mutations in apical hypertrophic cardiomyopathy. Circulation.2005;112:2805-2811
95. Maron BJ, Pelliccia A. The heart of trained athletes:Cardiac remodeling and the risks of sports, including sudden death. Circulation.2006;114:1633-1644
96. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene G. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA.2006;296:1593-1601
97. Maron BJ. The electrocardiogram as a diagnostic tool for hypertrophic cardiomyopathy:Revisited. Ann Noninvasive Electrocardiol.2001;6:277-279
98. McLeod CJ, Ackerman MJ, Nishimura RA, Tajik AJ, Gersh BJ, Ommen SR. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J Am Coll Cardiol. 2009;54:229-233
99. Rowin EJ, Maron BJ, Appelbaum E, Link MS, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Maron MS. Significance of false negative electrocardiograms in preparticipation screening of athletes for hypertrophic cardiomyopathy. Am J Cardiol.2012; 110:1027-1032
100. Maron BJ, Haas TS, Kitner C, Lesser JR. Onset of apical hypertrophic cardiomyopathy in adulthood. Am J Cardiol.2011;108:1783-1787
101. Maron BJ, Rowin EJ, Casey SA, Haas TS, Chan RH, Udelson JE, Garberich RF, Lesser JR, Appelbaum E, Manning WJ, Maron MS. Risk stratification and outcome of patients with hypertrophic cardiomyopathy>=60 years of age. Circulation.2013;127:585-593
102. Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamasaki N, Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL. Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein c gene among japanese. JAm Coll Cardiol.2005;46:1737-1743
103. Anan R, Niimura H, Takenaka T, Hamasaki S, Tei C. Mutations in the genes for sarcomeric proteins in japanese patients with onset sporadic hypertrophic cardiomyopathy after age 40 years. Am J Cardiol.2007;99:1750-1754
104. Binder J, Ommen SR, Gersh BJ, Van Driest SL, Tajik AJ, Nishimura RA, Ackerman MJ. Echocardiography-guided genetic testing in hypertrophic cardiomyopathy:Septal morphological features predict the presence of myofilament mutations. Mayo Clin Proc.2006;81:459-467
105. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy:Identification of high risk patients. J Am Coll Cardiol. 2000;36:2212-2218
106. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes:Analysis of 1866 deaths in the united states,1980-2006. Circulation.2009;119:1085-1092
107. Maron BJ, Maron MS, Lesser JR, Hauser RG, Haas TS, Harrigan CJ, Appelbaum E, Main ML, Roberts WC. Sudden cardiac arrest in hypertrophic cardiomyopathy in the absence of conventional criteria for high risk status. Am J Cardiol.2008;101:544-547
108. Maron BJ, Semsarian C, Shen WK, Link MS, Epstein AE, Estes NA,3rd, Almquist A, Giudici MC, Haas TS, Hodges JS, Spirito P. Circadian patterns in the occurrence of malignant ventricular tachyarrhythmias triggering defibrillator interventions in patients with hypertrophic cardiomyopathy. Heart Rhythm.2009;6:599-602
109. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS, Bongioanni S, Coccolo F, Estes NA, Barilla CS, Biagini E, Quarta G, Conte MR, Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation.2009; 119:1703-1710
110. Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation.1979;59:689-706
111. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young:Pathologic evidence of myocardial ischemia. Hum Pathol. 2000;31:988-998
112. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol.2000;35:36-44
113. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol.1986;8:545-557
114. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001;357:420-424
115. Elliott PM, Gimeno JR, Tome MT, Shah J, Ward D, Thaman R, Mogensen J, McKenna WJ. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J.2006;27:1933-1941
116. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol.2008;19:1118-1126
117. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA,3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Riegel B, Tarkington LG, Yancy CW. Acc/aha/hrs 2008 guidelines for device-based therapy of cardiac rhythm abnormalities:A report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the acc/aha/naspe 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the american association for thoracic surgery and society of thoracic surgeons. J Am Coll Cardiol.2008;51:e1-62
118. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
119. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation. 2003; 108:2342-2348
120. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol.2008;51:1369-1374
121. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task force 4:Hcm and other cardiomyopathies, mitral valve prolapse, myocarditis, and marfan syndrome. J Am Coll Cardiol. 2005;45:1340-1345
122. Pelliccia A, Fagard R, Bjornstad HH, Anastassakis A, Arbustini E, Assanelli D, Biffi A, Borjesson M, Carre F, Corrado D, Delise P, Dorwarth U, Hirth A, Heidbuchel H, Hoffmann E, Mellwig KP, Panhuyzen-Goedkoop N, Pisani A, Solberg EE, van-Buuren F, Vanhees L, Blomstrom-Lundqvist C, Deligiannis A, Dugmore D, Glikson M, Hoff PI, Hoffmann A, Horstkotte D, Nordrehaug JE, Oudhof J, McKenna WJ, Penco M, Priori S, Reybrouck T, Senden J, Spataro A, Thiene G. Recommendations for competitive sports participation in athletes with cardiovascular disease:A consensus document from the study group of sports cardiology of the working group of cardiac rehabilitation and exercise physiology and the working group of myocardial and pericardial diseases of the european society of cardiology. Eur Heart J.2005;26:1422-1445
123. Basso C, Thiene G, Mackey-Bojack S, Frigo AC, Corrado D, Maron BJ. Myocardial bridging, a frequent component of the hypertrophic cardiomyopathy phenotype, lacks systematic association with sudden cardiac death. Eur Heart J 10.046.2009;30:1627-1634
124. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy:An independent marker of sudden death risk in young patients. J Am Coll Cardiol.2003;42:873-879
125. Melacini P, Maron BJ, Bobbo F, Basso C, Tokajuk B, Zucchetto M, Thiene G, Iliceto S. Evidence that pharmacological strategies lack efficacy for the prevention of sudden death in hypertrophic cardiomyopathy. Heart.2007;93:708-710
126. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK, Cannon BC, Alexander ME, Triedman JK, Walsh EP, Friedman RA. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol. 2008;51:1685-1691
127. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, Almquist AK, Baffa JM, Saul JP, Ho CY, Seidman J, Seidman CE. Clinical outcome and phenotypic expression in lamp2 cardiomyopathy. JAMA.2009;301:1253-1259
128. Dukkipati SR, d'Avila A, Soejima K, Bala R, Inada K, Singh S, Stevenson WG, Marchlinski FE, Reddy VY. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Oirc Arrhythm Electrophysiol 4.78. 2011;4:185-194
129. Maron BJ, Haas TS, Shannon KM, Almquist AK, Hodges JS. Long-term survival after cardiac arrest in hypertrophic cardiomyopathy. Heart Rhythm.2009;6:993-997
130. Hauser RG, Maron BJ. Lessons from the failure and recall of an implantable cardioverter-defibrillator. Circulation.2005;112:2040-2042
131. Melacini P, Basso C, Angelini A, Calore C, Bobbo F, Tokajuk B, Bellini N, Smaniotto G, Zucchetto M, Iliceto S, Thiene G, Maron BJ. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J.2010;31:2111-2123
132. Maron BJ, Tholakanahalli VN, Zenovich AG, Casey SA, Duprez D, Aeppli DM, Cohn JN. Usefulness of b-type natriuretic peptide assay in the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation.2004; 109:984-989
133. Coats CJ, Gallagher MJ, Foley M,O'Mahony C, Critoph C, Gimeno J, Dawnay A, McKenna WJ, Elliott PM. Relation between serum n-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy. Eur Heart J.2013
134. Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol.2005;45:1076-1080
135. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J. Noninvasive assessment of left ventricular diastolic function by pulsed doppler echocardiography in patients with hypertrophic cardiomyopathy. JAm Coll Cardiol.1987;10:733-742
136. Maron MS, Zenovich AG, Casey SA, Link MS, Udelson JE, Aeppli DM, Maron BJ. Significance and relation between magnitude of left ventricular hypertrophy and heart failure symptoms in hypertrophic cardiomyopathy. Am J Cardiol.2005;95:1329-1333
137. Shah PM, Taylor RD, Wong M. Abnormal mitral valve coaptation in hypertrophic obstructive cardiomyopathy:Proposed role in systolic anterior motion of mitral valve. Am J Cardiol. 1981;48:258-262
138. Maron BJ, Harding AM, Spirito P, Roberts WC, Waller BF. Systolic anterior motion of the posterior mitral leaflet:A previously unrecognized cause of dynamic subaortic obstruction in patients with hypertrophic cardiomyopathy. Circulation.1983;68:282-293
139. Paz R, Jortner R, Tunick PA, Sclarovsky S, Eilat B, Perez JL, Kronzon 1. The effect of the ingestion of ethanol on obstruction of the left ventricular outflow tract in hypertrophic cardiomyopathy. N Engl J Med.1996;335:938-941
140. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol.2005;45:1251-1258
141. Nistri S, Olivotto I, Maron MS, Ferrantini C, Coppini R, Grifoni C, Baldini K, Sgalambro A, Cecchi F, Maron BJ. Beta blockers for prevention of exercise-induced left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J Cardiol.2012;110:715-719
142. Morrow AG, Brockenbrough EC. Surgical treatment of idiopathic hypertrophic subaortic stenosis: Technic and hemodynamic results of subaortic ventriculomyotomy. Ann Surg.1961;154:181-189
143. Woo A, Williams WG, Choi R, Wigle ED, Rozenblyum E, Fedwick K, Siu S, Ralph-Edwards A, Rakowski H. Clinical and echocardiographic determinants of long-term survival after surgical myectomy in obstructive hypertrophic cardiomyopathy. Circulation.2005;111:2033-2041
144. Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, Williams WG, Schwartz L, Guttman A, Woo A. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol. 2011;58:2313-2321
145. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF, Breen JF, Ommen SR, Gersh BJ, Tajik AJ, Rihal CS, Schaff HV, Maron BJ. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol.2007;49:350-357
146. Firoozi S, Elliott PM, Sharma S, Murday A, Brecker SJ, Hamid MS, Sachdev B, Thaman R, McKenna WJ. Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J.2002;23:1617-1624
147. Sorajja P, Valeti U, Nishimura RA, Ommen SR, Rihal CS, Gersh BJ, Hodge DO, Schaff HV, Holmes DR, Jr. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation. 2008;118:131-139
148. Cuoco FA, Spencer WH,3rd, Fernandes VL, Nielsen CD, Nagueh S, Sturdivant JL, Leman RB, Wharton JM, Gold MR. Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;52:1718-1723
149. Nagueh SF, Groves BM, Schwartz L, Smith KM, Wang A, Bach RG, Nielsen C, Leya F, Buergler JM, Rowe SK, Woo A, Maldonado YM, Spencer WH,3rd. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter north american registry. J Am Coll Cardiol. 2011;58:2322-2328
150. Nagueh SF, Ommen SR, Lakkis NM, Killip D, Zoghbi WA, Schaff HV, Danielson GK, Quinones MA, Tajik AJ, Spencer WH. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol.2001;38:1701-1706
151. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (m-pathy). Circulation.1999;99:2927-2933
152. Maron BJ, Lever H. In defense of antimicrobial prophylaxis for prevention of infective endocarditis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:2339-2340; author reply 2340
153. Spirito P, Rapezzi C, Bellone P, Betocchi S, Autore C, Conte MR, Bezante GP, Bruzzi P. Infective endocarditis in hypertrophic cardiomyopathy:Prevalence, incidence, and indications for antibiotic prophylaxis. Circulation.1999;99:2132-2137
154. Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling pressures by doppler echocardiography in patients with hypertrophic cardiomyopathy:Correlation with direct left atrial pressure measurement at cardiac catheterization. Circulation.2007; 116:2702-2708
155. Olivotto I, Maron BJ, Appelbaum E, Harrigan CJ, Salton C, Gibson CM, Udelson JE, O'Donnell C, Lesser JR, Manning WJ, Maron MS. Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol 3.68.2010;106:261-267
156. Maron MS, Kalsmith BM, Udelson JE, Li W, DeNofrio D. Survival after cardiac transplantation in patients with hypertrophic cardiomyopathy. Circ Heart Fail.2010;3:574-579
157. Topilsky Y, Pereira NL, Shah DK, Boilson B, Schirger JA, Kushwaha SS, Joyce LD, Park SJ. Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. Circ Heart Fail 4.315.2011;4:266-275
158. Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami F, Torricelli F, Camici PG. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol.2006;47:1043-1048
159. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol.2008;51:810-815
160. Di Donna P, Olivotto I, Delcre SD, Caponi D, Scaglione M, Nault I, Montefusco A, Girolami F, Cecchi F, Haissaguerre M, Gaita F. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy:Impact of age, atrial remodelling, and disease progression. Europace. 2010;12:347-355
161. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
162. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. Hrs/ehra expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the heart rhythm society (hrs) and the european heart rhythm association (ehra). Heart Rhythm.2011;8:1308-1339
163. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. JAm Coll Cardiol.2004;44:2125-2132
164. Maron BJ, Zipes DP. Introduction:Eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol.2005;45:1318-1321
165. Germans T, Wilde AA, Dijkmans PA, Chai W, Kamp O, Pinto YM, van Rossum AC. Structural abnormalities of the inferoseptal left ventricular wall detected by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am Coll Cardiol.2006;48:2518-2523
166. Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (+)-phenotype negative (-) family members in hypertrophic cardiomyopathy. Am J Cardiol.2011;107:604-608
167. Christiaans I, Lekanne dit Deprez RH, van Langen IM, Wilde AA. Ventricular fibrillation in myh7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy. Heart Rhythm. 2009;6:1366-1369
168. Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG The 1-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. JClin Invest.2002; 109:1013-1020
169. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation.2001;104:317-324
170. Arad M, Maron BJ, Gorham JM, Johnson WH, Jr., Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med.2005;352:362-372
171. Maron BJ, Roberts WC, Ho CY, Kitner C, Haas TS, Wright GB, Moazami N, Feldman DS. Profound left ventricular remodeling associated with lamp2 cardiomyopathy. Am J Cardiol. 2010;106:1194-1196
172. Patel MR, Cecchi F, Cizmarik M, Kantola I, Linhart A, Nicholls K, Strotmann J, Tallaj J, Tran TC, West ML, Beitner-Johnson D, Abiose A. Cardiovascular events in patients with fabry disease natural history data from the fabry registry. J Am Coll Cardiol.2011;57:1093-1099
173. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Stork S, Voelker W, Ertl G, Wanner C, Strotmann J. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy:Evidence for a better outcome with early treatment. Circulation.2009;119:524-529
174. Kubo T, Gimeno JR, Bahl A, Steffensen U, Steffensen M, Osman E, Thaman R, Mogensen J, Elliott PM, Doi Y, McKenna WJ. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol.2007;49:2419-2426
175. Ciro E, Nichols PF,3rd, Maron BJ. Heterogeneous morphologic expression of genetically transmitted hypertrophic cardiomyopathy. Two-dimensional echocardiographic analysis. Circulation. 1983;67:1227-1233
176. Wang S, Zou Y, Fu C, Xu X, Wang J, Song L, Wang H, Chen J, Huan T, Hui R. Worse prognosis with gene mutations of beta-myosin heavy chain than myosin-binding protein c in chinese patients with hypertrophic cardiomyopathy. Clin Cardiol.2008;31:114-118
177. van der Merwe L, Cloete R, Revera M, Heradien M, Goosen A, Corfield VA, Brink PA, Moolman-Smook JC. Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Hum Genet.2008; 124:57-61
178. Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in tnncl-encoded troponin c. J Mol Cell Cardiol.2008;45:281-288
179. Friedrich FW, Bausero P, Sun Y, Treszl A, Kramer E, Juhr D, Richard P, Wegscheider K, Schwartz K, Brito D, Arbustini E, Waldenstrom A, Isnard R, Komajda M, Eschenhagen T, Carrier L. A new polymorphism in human calmodulin iii gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. Eur Heart J.2009;30:1648-1655
180. Palacin M, Reguero JR, Martin M, Diaz Molina B, Moris C, Alvarez V, Coto E. Profile of micrornas differentially produced in hearts from patients with hypertrophic cardiomyopathy and sarcomeric mutations. Clin Chem.2011;57:1614-1616
181. Saltzman AJ, Mancini-DiNardo D, Li C, Chung WK, Ho CY, Hurst S, Wynn J, Care M, Hamilton RM, Seidman GW, Gorham J, McDonough B, Sparks E, Seidman JG, Seidman CE, Rehm HL. Short communication:The cardiac myosin binding protein c arg502trp mutation:A common cause of hypertrophic cardiomyopathy. Circ Res.2010;106:1549-1552
182. Semsarian C, Yu B, Ryce C, Lawrence C, Washington H, Trent RJ. Sudden cardiac death in familial hypertrophic cardiomyopathy:Are "benign" mutations really benign? Pathology.1997;29:305-308
183. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. J Med Genet.2005;42:e59
184. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease:A marker of disease severity? Circ Cardiovasc Genet.2009;2:182-190
185. Basille C, Frydman R, El Aly A, Hesters L, Fanchin R, Tachdjian G, Steffann J, LeLorc'h M, Achour-Frydman N. Preimplantation genetic diagnosis:State of the art. Eur J Obstet Gynecol Reprod Biol.2009;145:9-13
186. Ingles J, Yeates L, Semsarian C. The emerging role of the cardiac genetic counselor. Heart Rhythm. 2011;8:1958-1962
187. Abiola S. Recent developments in health law. The genetic information nondiscrimination act of 2008: "First major civil rights bill of the century" bars misuse of genetic test results. J Law Med Ethics. 2008;36:856-860
188. Bagnall RD, Ingles J, Semsarian C. Molecular diagnostics of cardiomyopathies:The future is here. Circ Cardiovasc Genet.2011;4:103-104
2. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china:A population-based echocardiographic analysis of 8080 adults. Am J Med.2004; 116:14-18
3. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
4. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
5. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, Dooijes D, van Tintelen JP, van den Berg MP, Volders PG, Arens YH, van den Wijngaard A, Atsma DE, Helderman-van den Enden AT, Houweling AC, de Boer K, van der Smagt JJ, Hauer RN, Marcelis CL, Timmermans J, van Langen IM, Wilde AA. Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers:Determining the best cardiological screening strategy. Eur Heart J.2011;32:1161-1170
6. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:e783-831
7. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MY, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
8. Seggewiss H, Rigopoulos A. Management of hypertrophic cardiomyopathy in children. Paediatr Drugs.2003;5:663-672
9. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ.2006;332:1251-1255
10. Prinz C, Schwarz M, Hic I, Laser KT, Lehmann R, Prinz EM, Bitter T, Vogt J, van Buuren F, Bogunovic N, Horstkotte D, Faber L. Myocardial fibrosis severity on cardiac magnetic resonance imaging predicts sustained arrhythmic events in hypertrophic cardiomyopathy. Can J Cardiol. 2013;29:358-363
11. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation.2008;118:1541-1549
12. Ho CY. Genetics and clinical destiny:Improving care in hypertrophic cardiomyopathy. Circulation.2010;122:2430-2440; discussion 2440
13. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, et al. Mutations in the genes for cardiac troponin t and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med.1995;332:1058-1064
14. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy:A beta cardiac myosin heavy chain gene missense mutation. Cell.1990;62:999-1006
15. Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin t gene. Circ Cardiovasc Genet.2012;5:10-17
16. Michels M, Soliman 01, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, Majoor-Krakauer D, Ten Cate FJ. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur Heart J. 2009;30:2593-2598
17. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation.2010;122:2441-2449; discussion 2450
18. Saltzman AJ, Mancini-DiNardo D, Li C, Chung WK, Ho CY, Hurst S, Wynn J, Care M, Hamilton RM, Seidman GW, Gorham J, McDonough B, Sparks E, Seidman JG, Seidman CE, Rehm HL. Short communication:The cardiac myosin binding protein c arg502trp mutation:A common cause of hypertrophic cardiomyopathy. Circ Res.2010;106:1549-1552
19. Zou Y, Wang J, Liu X, Wang Y, Chen Y, Sun K, Gao S, Zhang C, Wang Z, Zhang Y, Feng X, Song Y, Wu Y, Zhang H, Jia L, Wang H, Wang D, Yan C, Lu M, Zhou X, Song L, Hui R. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep.2013
20. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
21. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic cardiomyopathy:Report of a working group of the national heart, lung, and blood institute. Circulation.2010;122:1130-1133
22. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. J Med Genet.2005;42:e59
23. Richard P, Isnard R, Carrier L, Dubourg O, Donatien Y, Mathieu B, Bonne G, Gary F, Charron P, Hagege M, Komajda M, Schwartz K, Hainque B. Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein c genes in a family with hypertrophic cardiomyopathy. J Med Genet.1999;36:542-545
24. Mohiddin SA, Begley DA, McLam E, Cardoso JP, Winkler JB, Sellers JR, Fananapazir L. Utility of genetic screening in hypertrophic cardiomyopathy:Prevalence and significance of novel and double (homozygous and heterozygous) beta-myosin mutations. Genet Test 1.648.2003;7:21-27
25. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003; 107:2227-2232
26. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein c mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol.2004;44:1903-1910
27. Girolami F, Ho CY, Semsarian C, Baldi M, Will ML, Baldini K, Torricelli F, Yeates L, Cecchi F, Ackerman MJ, Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol.2010;55:1444-1453
28. Garcia-Pavia P, Vazquez ME, Segovia J, Salas C, Avellana P, Gomez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L. Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail.2011; 13:1193-1201
29. Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE. Homozygous mutation in cardiac troponin t:Implications for hypertrophic cardiomyopathy. Circulation. 2000;102:1950-1955
30. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V, Scharfenberger-Schmeer M, Stahler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet.2011;4:110-122
31. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE. Truncations of titin causing dilated cardiomyopathy. N Engl J Med.2012;366:619-628
32. Harakalova M, Mokry M, Hrdlickova B, Renkens I, Duran K, van Roekel H, Lansu N, van Roosmalen M, de Bruijn E, Nijman IJ, Kloosterman WP, Cuppen E. Multiplexed array-based and in-solution genomic enrichment for flexible and cost-effective targeted next-generation sequencing. Nat Protoc.2011;6:1870-1886
33. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med.2008;358:1899-1908
34. Ho CY, MacRae CA. Defining the pathogenicity of DNA sequence variation. Circ Cardiovasc Genet.2009;2:95-97
35. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:Executive summary:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:2761-2796
36. Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR. Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. Am J Hum Genet. 2011;88:183-192
37. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248-249
38. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease:A marker of disease severity? Circ Cardiovasc Genet.2009;2:182-190
39. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98:625-630
40. Wordsworth S, Leal J, Blair E, Legood R, Thomson K, Seller A, Taylor J, Watkins H. DNA testing for hypertrophic cardiomyopathy:A cost-effectiveness model. Eur Heart J.2010;31:926-935
1. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
2. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011;124:e783-831
3. Brito D, Richard P, Komajda M, Madeira H. Familial and sporadic hypertrophic myopathy: Differences and similarities in a genotyped population. A long follow-up study. Rev Port Cardiol. 2008;27:147-173
4. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart. 2012;98:625-630
5. Goldenberg I, Moss AJ, Maron BJ, Dick AW, Zareba W. Cost-effectiveness of implanted defibrillators in young people with inherited cardiac arrhythmias. Ann Noninvasive Electrocardiol. 2005;10:67-83
6. Garcia-Pavia P, Vazquez ME, Segovia J, Salas C, Avellana P, Gomez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L. Genetic basis of end-stage hypertrophic cardiomyopathy. Eur J Heart Fail.2011; 13:1193-1201
7. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
8. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. JMed Genet.2005;42:e59
9. Girolami F, Ho CY, Semsarian C, Baldi M, Will ML, Baldini K, Torricelli F, Yeates L, Cecchi F, Ackerman MJ, Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol.2010;55:1444-1453
10. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation.2011;123:1021-1037
11. Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE. Homozygous mutation in cardiac troponin t:Implications for hypertrophic cardiomyopathy. Circulation. 2000;102:1950-1955
12. Ortiz MF, Rodriguez-Garcia MI, Hermida-Prieto M, Fernandez X, Veira E, Barriales-Villa R, Castro-Beiras A, Monserrat L. A homozygous mybpc3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy. Rev Esp Cardiol.2009;62:572-575
13. Olson TM, Karst ML, Whitby FG, Driscoll DJ. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation. 2002;105:2337-2340
14. Gray B, Yeates L, Medi C, Ingles J, Semsarian C. Homozygous mutation in the cardiac troponin i gene:Clinical heterogeneity in hypertrophic cardiomyopathy. Int J Cardiol.2012
15. Marston SB. How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res.2011;4:245-255
16. Schlossarek S, Mearini G, Carrier L. Cardiac myosin-binding protein c in hypertrophic cardiomyopathy:Mechanisms and therapeutic opportunities. J Mol Cell Cardiol.2011;50:613-620
17. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003;107:2227-2232
18. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein c and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248-1257
19. Wang S, Zou Y, Fu C, Xu X, Wang J, Song L, Wang H, Chen J, Huan T, Hui R. Worse prognosis with gene mutations of beta-myosin heavy chain than myosin-binding protein c in chinese patients with hypertrophic cardiomyopathy. Clin Cardiol.2008;31:114-118
20. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein c mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol.2004;44:1903-1910
21. Moolman-Smook J, Flashman E, de Lange W, Li Z, Corfield V, Redwood C, Watkins H. Identification of novel interactions between domains of myosin binding protein-c that are modulated by hypertrophic cardiomyopathy missense mutations. Circ Res.2002;91:704-711
22. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. J Am Coll Cardiol.2012;60:705-715
23. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet.2013;381:242-255
1. Saura D, Marin F, Climent V, Gonzalez J, Roldan V, Hernandez-Romero D, Oliva MJ, Sabater M, de la Morena G, Lip GY, Valdes M. Left atrial remodelling in hypertrophic cardiomyopathy:Relation with exercise capacity and biochemical markers of tissue strain and remodelling. Int J Clin Pract. 2009;63:1465-1471
2. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china:A population-based echocardiographic analysis of 8080 adults. Am J Med.2004;116:14-18
3. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
4. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
5. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, Dooijes D, van Tintelen JP, van den Berg MP, Volders PG, Arens YH, van den Wijngaard A, Atsma DE, Helderman-van den Enden AT, Houweling AC, de Boer K, van der Smagt JJ, Hauer RN, Marcelis CL, Timmermans J, van Langen IM, Wilde AA. Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers:Determining the best cardiological screening strategy. Eur Heart J.2011;32:1161-1170
6. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;124:e783-831
7. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
8. Anderson KR, Sutton MG, Lie JT. Histopathological types of cardiac fibrosis in myocardial disease. J Pathol.1979;128:79-85
9. Arteaga E, de Araujo AQ, Bernstein M, Ramires FJ, lanni BM, Fernandes F, Mady C. Prognostic value of the collagen volume fraction in hypertrophic cardiomyopathy. Arq Bras Cardiol. 2009;92:210-214,216-220
10. Sepp R, Severs NJ, Gourdie RG. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart.1996;76:412-417
11. Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side-to-side cell connections:A major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol.1997;20:397-413
12. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Oirc Res.1986;58:356-371
13. de Bakker JM, van Capelle FJ, Janse MJ, Tasseron S, Vermeulen JT, de Jonge N, Lahpor JR. Slow conduction in the infarcted human heart.'Zigzag' course of activation. Circulation. 1993;88:915-926
14. Spach MS, Heidlage JF, Dolber PC, Barr RC. Mechanism of origin of conduction disturbances in aging human atrial bundles:Experimental and model study. Heart Rhythm.2007;4:175-185
15. Gaudesius G, Miragoli M, Thomas SP, Rohr S. Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res.2003;93:421-428
16. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res.1989;65:1612-1631
17. Morita N, Sovari AA, Xie Y, Fishbein MC, Mandel WJ, Garfinkel A, Lin SF, Chen PS, Xie LH, Chen F, Qu Z, Weiss JN, Karagueuzian HS. Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. Am J Physiol Heart Circ Physiol.2009;297:H1594-1605
18. Ono N, Hayashi H, Kawase A, Lin SF, Li H, Weiss JN, Chen PS, Karagueuzian HS. Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition. Am J Physiol Heart Circ Physiol.2007;292:H639-648
19. Morita N, Lee JH, Xie Y, Sovari A, Qu Z, Weiss JN, Karagueuzian HS. Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine. J Am Coll Cardiol. 2011;57:366-375
20. Morita N, Lee JH, Bapat A, Fishbein MC, Mandel WJ, Chen PS, Weiss JN, Karagueuzian HS. Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts. Am J Physiol Heart Circ Physiol.2011;301:H180-191
21. Lakatta EG, Levy D. Arterial and cardiac aging:Major shareholders in cardiovascular disease enterprises:Part ii:The aging heart in health:Links to heart disease. Circulation. 2003;107:346-354
22. Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL. Importance of heart failure with preserved systolic function in patients> or= 65 years of age. Chs research group. Cardiovascular health study. Am J Cardiol. 2001;87:413-419
23. Luscher TF. Endothelin. Key to coronary vasospasm? Circulation.1991;83:701-703
24. Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH, Chien KR Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. J Biol Chem.1990;265:20555-20562
25. Van Beneden R, Gurne O, Selvais PL, Ahn SA, Robert AR, Ketelslegers JM, Pouleur HG, Rousseau MF. Superiority of big endothelin-1 and endothelin-1 over natriuretic peptides in predicting survival in severe congestive heart failure:A 7-year follow-up study. J Card Fail.2004; 10:490-495
26. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F. Protective effect of long-term angiotensin ii inhibition. Am J Physiol Heart Circ Physiol.2007;293:H1351-1358
27. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G. Disruption of the ang ii type 1 receptor promotes longevity in mice. J Clin Invest.2009; 119:524-530
28. Rosenkranz S. Tgf-betal and angiotensin networking in cardiac remodeling. Cardiovasc Res. 2004;63:423-432
29. Weber KT, Swamynathan SK, Guntaka RV, Sun Y. Angiotensin ii and extracellular matrix homeostasis. IntJ Biochem Cell Biol.1999;31:395-403
30. Rubin SA, Levin ER. Clinical review 53:The endocrinology of vasoactive peptides:Synthesis to function. J Clin Endocrinol Metab.1994;78:6-10
31. Hemsen A, Ahlborg G, Ottosson-Seeberger A, Lundberg JM. Metabolism of big endothelin-1 (1-38) and (22-38) in the human circulation in relation to production of endothelin-1 (1-21). Regul Pept. 1995;55:287-297
32. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A. Esc guidelines for the diagnosis and treatment of acute and chronic heart failure 2012:The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology. Developed in collaboration with the heart failure association (hfa) of the esc. Eur Heart J.2012;33:1787-1847
33. Pacileo G, Salerno G, Gravino R, Calabro R, Elliott PM. Risk stratification in hypertrophic cardiomyopathy:Time for renewal? J Cardiovasc Med (Hagerstown).2012
34. Bellien J, lacob M, Remy-Jouet I, Lucas D, Monteil C, Gutierrez L, Vendeville C, Dreano Y, Mercier A, Thuillez C, Joannides R. Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation.2012;125:1266-1275
35. Kakinuma Y, Miyauchi T, Yuki K, Murakoshi N, Goto K, Yamaguchi I. Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-lalpha induced for impaired myocardial energy metabolism. Circulation.2001;103:2387-2394
36. Coats CJ, Gallagher MJ, Foley M, O'Mahony C, Critoph C, Gimeno J, Dawnay A, McKenna WJ, Elliott PM. Relation between serum n-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy. Eur Heart J.2013
37. Luchner A, Mockel M, Spanuth E, Mocks J, Peetz D, Baum H, Spes C, Wrede CE, Vollert J, Muller R, Katus H, Giannitsis E. N-terminal pro brain natriuretic peptide in the management of patients in the medical emergency department (prompt):Correlation with disease severity, utilization of hospital resources, and prognosis in a large, prospective, randomized multicentre trial. Eur J Heart Fail.2012;14:259-267
38. Scheuer J, Malhotra A, Hirsch C, Capasso J, Schaible TF. Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats. J Clin Invest. 1982;70:1300-1305
39. Wakatsuki T, Schlessinger J, Elson EL. The biochemical response of the heart to hypertension and exercise. Trends Biochem Sci.2004;29:609-617
40. Barry SP, Davidson SM, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol.2008;40:2023-2039
41. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med. 1999;341:1276-1283
42. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications:A consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol.2000;35:569-582
43. Kajstura J, Liu Y, Baldini A, Li B, Olivetti G, Leri A, Anversa P. Coronary artery constriction in rats: Necrotic and apoptotic myocyte death. Am J Cardiol.1998;82:30K-41K
44. Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A.1998;95:8801-8805
45. Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res.2011;89:265-272
46. Prinz C, Schwarz M, Ilic I, Laser KT, Lehmann R, Prinz EM, Bitter T, Vogt J, van Buuren F, Bogunovic N, Horstkotte D, Faber L. Myocardial fibrosis severity on cardiac magnetic resonance imaging predicts sustained arrhythmic events in hypertrophic cardiomyopathy. Can J Cardiol. 2013;29:358-363
47. Luscher TF. Endothelin. J Cardiovasc Pharmacol.1991;18 Suppl 10-:S15-22
48. Marian AJ. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet.2000;355:58-60
49. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Pharmacol Rep.2007;59:715-720
50. Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res.1991;69:209-215
51. Hasegawa K, Fujiwara H, Koshiji M, Inada T, Ohtani S, Doyama K, Tanaka M, Matsumori A, Fujiwara T, Shirakami G, Hosoda K, Nakao K, Sasayama S. Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension.1996;27:259-264
52. Ogino K, Ogura K, Kinugawa T, Osaki S, Kato M, Furuse Y, Kinugasa Y, Tomikura Y, Igawa O, Hisatome I, Shigemasa C. Neurohumoral profiles in patients with hypertrophic cardiomyopathy: Differences to hypertensive left ventricular hypertrophy. CircJ.2004;68:444-450
53. Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto H, Ohta Y, Marumo F. Endothelin eta receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation. 1994;89:2198-2203
54. Yorikane R, Sakai S, Miyauchi T, Sakurai T, Sugishita Y, Goto K. Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett.1993;332:31-34
55. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy:The interrelation of disarray, fibrosis, and small vessel disease. Heart.2000;84:476-482
1. Braunwald E, Lambrew CT, Rockoff SD, Ross J, Jr., Morrow AG. Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients. Circulation. 1964;30:SUPPL 4:3-119
2. Pokorski RJ. Hypertrophic cardiomyopathy:Risk factors for life and living benefits insurance. J Insur Med.2002;34:43-60
3. Maron BJ. Hypertrophic cardiomyopathy:An important global disease. Am J Med.2004;116:63-65
4. Maron BJ. Hypertrophic cardiomyopathy:A systematic review. JAMA.2002;287:1308-1320
5. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy:From bench to the clinics. JCardiovasc Electrophysiol.2008;19:104-110
6. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation.2010;121:445-456
7. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH,3rd, Spirito P, Ten Cate FJ, Wigle ED. American college of cardiology/european society of cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the american college of cardiology foundation task force on clinical expert consensus documents and the european society of cardiology committee for practice guidelines. J Am Coll Cardiol. 2003;42:1687-1713
8. Seidman CE, Seidman JG.Identifying sarcomere gene mutations in hypertrophic cardiomyopathy:A personal history. Circ Res.2011; 108:743-750
9. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: Clinical perspectives. JAm Coll Cardiol.2012;60:705-715
10. Kittle CF, Reed WA, Crockett JE. Infundibulectomy for subaortic hypertrophic stenosis. Circulation. 1964;29:SUPPL:119-124
11. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol.2009;54:220-228
12. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic cardiomyopathy:Report of a working group of the national heart, lung, and blood institute. Circulation.2010;122:1130-1133
13. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, Levi T, Donis-Keller H, Seidman JG, Seidman CE. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1.N Engl J Med.1989;321:1372-1378
14. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy:A beta cardiac myosin heavy chain gene missense mutation. Cell.1990;62:999-1006
15. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med.1992;326:1108-1114
16. Ho CY. Genetics and clinical destiny:Improving care in hypertrophic cardiomyopathy. Circulation. 2010;122:2430-2440; discussion 2440
17. Watkins H. Sudden death in hypertrophic cardiomyopathy. N Engl J Med.2000;342:422-424
18. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet.2013;381:242-255
19. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation.2010;122:2441-2449; discussion 2450
20. Ackerman MJ, VanDriest SL, Ommen SR, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin t genes in hypertrophic cardiomyopathy:A comprehensive outpatient perspective. J Am Coll Cardiol. 2002;39:2042-2048
21. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein c and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248-1257
22. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy:Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation.2003;107:2227-2232
23. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N, Weil J, Zenovich AG, Maron BJ. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation.2005; 112:855-861
24. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging.2012;5:370-377
25. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004;90:645-649
26. Maron BJ, Seidman CE, Ackerman MJ, Towbin JA, Maron MS, Ommen SR, Nishimura RA, Gersh BJ. How should hypertrophic cardiomyopathy be classified?:What's in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy. Circ Cardiovasc Genet.2009;2:81-85; discussion 86
27. Maron BJ. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation.2007; 116:196-206; discussion 206
28. Olivotto I, Ommen SR, Maron MS, Cecchi F, Maron BJ. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol.2007;50:831-834
29. Nishimura RA, Ommen SR. Septal reduction therapy for obstructive hypertrophic cardiomyopathy and sudden death:What statistics cannot tell you. Circ Cardiovasc Intern.2010;3:91-93
30. ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy:A word of caution. Circ Heart Fail.2010;3:362-369
31. Maron BJ, Maron MS, Wigle ED, Braunwald E. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy:From idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:191-200
32. Agarwal S, Tuzcu EM, Desai MY, Smedira N, Lever HM, Lytle BW, Kapadia SR. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol.2010;55:823-834
33. Maron BJ, Yacoub M, Dearani JA. Controversies in cardiovascular medicine. Benefits of surgery in obstructive hypertrophic cardiomyopathy:Bring septal myectomy back for european patients. Eur Heart J.2011;32:1055-1058
34. Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE, Cecchi F, Maron BJ. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. JAm Coll Cardiol.2005;46:480-487
35. Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;41:974-980
36. Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Comparison of prevalence of apical hypertrophic cardiomyopathy in japan and the united states. Am J Cardiol.2003;92:1183-1186
37. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echo card iographic analysis of 4111 subjects in the cardia study. Coronary artery risk development in (young) adults. Circulation.1995;92:785-789
38. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-related death:Revisited in a large non-referral-based patient population. Circulation.2000; 102:858-864
39. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein c gene mutations. JAm Coll Cardiol.2001;38:315-321
40. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation.2006;114:2232-2239
41. Biagini E, Berardini A, Graziosi M, Rosmini S, Pazzi C, Rapezzi C. [gender effect on cardiomyopathy]. G Ital Cardiol (Rome).2012;13:424-431
42. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in china: A population-based echocardiographic analysis of 8080 adults. Am J Med.2004; 116:14-18
43. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:Executive summary:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation.2011; 124:2761-2796
44. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy. Echocardiographic identification of the pathognomonic anatomic abnormality of ihss. Circulation.1973;47:225-233
45. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation.2011;123:1021-1037
46. Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ. Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin t, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation.2002;106:3085-3090
47. Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet.2003;64:339-349
48. Andersen PS, Havndrup O, Hougs L, Sorensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in danish hypertrophic cardiomyopathy patients and relatives. Hum Mutat.2009;30:363-370
49. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:201-211
50. Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation.1992;85:1651-1660
51. Maron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Maron BJ. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011; 124:40-47
52. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N EnglJMed.2003;349:1027-1035
53. Maron MS, Olivotto I, Maron BJ, Prasad SK, Cecchi F, Udelson JE, Camici PG. The case for myocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:866-875
54. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy:Morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol.1995;26:1699-1708
55. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, Ommen SR, Theis JL, Vaubel RA, Re F, Armentano C, Poggesi C, Torricelli F, Cecchi F. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc.2008;83:630-638
56. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation.2002; 105:446-451
57. Walsh R, Rutland C, Thomas R, Loughna S. Cardiomyopathy:A systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations. Cardiology.2010;115:49-60
58. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, Prieur F, Bresson JL, Faivre L, Eicher JC, Chassaing N, Crehalet H, Porcher R, Rodriguez-Lafrasse C, Rousson R. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet.2010;53:261-267
59. Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires tgf-beta. J Clin Invest.2010; 120:3520-3529
60. Konno T, Chen D, Wang L, Wakimoto H, Teekakirikul P, Nayor M, Kawana M, Eminaga S, Gorham JM, Pandya K, Smithies O, Naya FJ, Olson EN, Seidman JG Seidman CE. Heterogeneous myocyte enhancer factor-2 (mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A.2010;107:18097-18102
61. Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L. Nonsense-mediated mrna decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein c mutant levels in cardiomyopathic mice. Circ Res.2009;105:239-248
62. Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H. Evidence from human myectomy samples that mybpc3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res.2009; 105:219-222
63. Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G, Ahmed I, Maher AR, Kaur K, Taylor J, Henning A, Ashrafian H, Watkins H, Frenneaux M. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation. 2010;122:1562-1569
64. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE. Acmg recommendations for standards for interpretation and reporting of sequence variations:Revisions 2007. Genet Med.2008;10:294-300
65. Mestroni L, Taylor MR. Hearing the noise the challenges of human genome variation in genetic testing. JAm Coll Cardiol.2011;57:2328-2329
66. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, Boisguerin V, Scharfenberger-Schmeer M, Stahler P, Beier M, Weichenhan D, Strom TM, Pfeufer A, Korn B, Katus HA, Rottbauer W. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet.2011;4:110-122
67. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature.2010;467:1061-1073
68. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation.1995;92:1680-1692
69. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional united states cohort. JAMA.1999;281:650-655
70. Decker JA, Rossano JW, Smith EO, Cannon B, Clunie SK, Gates C, Jefferies JL, Kim JJ, Price JF, Dreyer WJ, Towbin JA, Denfield SW. Risk factors and mode of death in isolated hypertrophic cardiomyopathy in children. JAm Coll Cardiol.2009;54:250-254
71. Maron BJ, Casey SA, Hauser RG, Aeppli DM. Clinical course of hypertrophic cardiomyopathy with survival to advanced age. JAm Coll Cardiol.2003;42:882-888
72. Maron BJ, Casey SA, Haas TS, Kitner CL, Garberich RF, Lesser JR. Hypertrophic cardiomyopathy with longevity to 90 years or older. Am J Cardiol.2012;109:1341-1347
73. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358:1899-1908
74. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA,3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365-373
75. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA,3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA.2007;298:405-412
76. Noseworthy PA, Rosenberg MA, Fifer MA, Palacios IF, Lowry PA, Ruskin JN, Sanborn DM, Picard MH, Vlahakes GJ, Mela T, Das S. Ventricular arrhythmia following alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol.2009;104:128-132
77. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol.2005;46:470-476
78. McKenna WJ, Deanfield JE. Hypertrophic cardiomyopathy:An important cause of sudden death. Arch Dis Child.1984;59:971-975
79. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med.1997;336:775-785
80. Maron BJ, Braunwald E. Evolution of hypertrophic cardiomyopathy to a contemporary treatable disease. Circulation.2012; 126:1640-1644
81. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation.2006;114:216-225
82. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation.2001;104:2517-2524
83. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, Casey SA, Gohman TE, Bongioanni S, Spirito P. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. JAm Coll Cardiol.2002;39:301-307
84. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med.1986;315:610-614
85. Adabag AS, Kuskowski MA, Maron BJ. Determinants for clinical diagnosis of hypertrophic cardiomyopathy. Am J Cardiol.2006;98:1507-1511
86. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. NEngl J Med.1998;339:364-369
87. Mozaffarian D, Caldwell JH. Right ventricular involvement in hypertrophic cardiomyopathy:A case report and literature review. Clin Cardiol.2001;4:2-8
88. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW.2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;124:e783-831
89. Maron MS, Lesser JR, Maron B J. Management implications of massive left ventricular hypertrophy in hypertrophic cardiomyopathy significantly underestimated by echocardiography but identified by cardiovascular magnetic resonance. Am J Cardiol.2010; 105:1842-1843
90. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, Lesser JR, Udelson JE, Ackerman MJ, Maron BJ. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation.2008;118:1541-1549
91. Klues HG, Roberts WC, Maron BJ. Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy. Significance in producing left ventricular outflow obstruction. Circulation.1991;84:1188-1197
92. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778-1785
93. Olivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, De Santis M, Quarta G, Nistri S, Cecchi F, Salton CJ, Udelson JE, Manning WJ, Maron BJ. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol.2008;52:559-566
94. Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY, Barr S, Karim A, Olson TM, Kamisago M, Seidman JG, Seidman CE. Gene mutations in apical hypertrophic cardiomyopathy. Circulation.2005;112:2805-2811
95. Maron BJ, Pelliccia A. The heart of trained athletes:Cardiac remodeling and the risks of sports, including sudden death. Circulation.2006;114:1633-1644
96. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene G. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA.2006;296:1593-1601
97. Maron BJ. The electrocardiogram as a diagnostic tool for hypertrophic cardiomyopathy:Revisited. Ann Noninvasive Electrocardiol.2001;6:277-279
98. McLeod CJ, Ackerman MJ, Nishimura RA, Tajik AJ, Gersh BJ, Ommen SR. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J Am Coll Cardiol. 2009;54:229-233
99. Rowin EJ, Maron BJ, Appelbaum E, Link MS, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Maron MS. Significance of false negative electrocardiograms in preparticipation screening of athletes for hypertrophic cardiomyopathy. Am J Cardiol.2012; 110:1027-1032
100. Maron BJ, Haas TS, Kitner C, Lesser JR. Onset of apical hypertrophic cardiomyopathy in adulthood. Am J Cardiol.2011;108:1783-1787
101. Maron BJ, Rowin EJ, Casey SA, Haas TS, Chan RH, Udelson JE, Garberich RF, Lesser JR, Appelbaum E, Manning WJ, Maron MS. Risk stratification and outcome of patients with hypertrophic cardiomyopathy>=60 years of age. Circulation.2013;127:585-593
102. Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamasaki N, Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL. Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein c gene among japanese. JAm Coll Cardiol.2005;46:1737-1743
103. Anan R, Niimura H, Takenaka T, Hamasaki S, Tei C. Mutations in the genes for sarcomeric proteins in japanese patients with onset sporadic hypertrophic cardiomyopathy after age 40 years. Am J Cardiol.2007;99:1750-1754
104. Binder J, Ommen SR, Gersh BJ, Van Driest SL, Tajik AJ, Nishimura RA, Ackerman MJ. Echocardiography-guided genetic testing in hypertrophic cardiomyopathy:Septal morphological features predict the presence of myofilament mutations. Mayo Clin Proc.2006;81:459-467
105. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy:Identification of high risk patients. J Am Coll Cardiol. 2000;36:2212-2218
106. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes:Analysis of 1866 deaths in the united states,1980-2006. Circulation.2009;119:1085-1092
107. Maron BJ, Maron MS, Lesser JR, Hauser RG, Haas TS, Harrigan CJ, Appelbaum E, Main ML, Roberts WC. Sudden cardiac arrest in hypertrophic cardiomyopathy in the absence of conventional criteria for high risk status. Am J Cardiol.2008;101:544-547
108. Maron BJ, Semsarian C, Shen WK, Link MS, Epstein AE, Estes NA,3rd, Almquist A, Giudici MC, Haas TS, Hodges JS, Spirito P. Circadian patterns in the occurrence of malignant ventricular tachyarrhythmias triggering defibrillator interventions in patients with hypertrophic cardiomyopathy. Heart Rhythm.2009;6:599-602
109. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS, Bongioanni S, Coccolo F, Estes NA, Barilla CS, Biagini E, Quarta G, Conte MR, Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation.2009; 119:1703-1710
110. Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation.1979;59:689-706
111. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young:Pathologic evidence of myocardial ischemia. Hum Pathol. 2000;31:988-998
112. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol.2000;35:36-44
113. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural ("small vessel") coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol.1986;8:545-557
114. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001;357:420-424
115. Elliott PM, Gimeno JR, Tome MT, Shah J, Ward D, Thaman R, Mogensen J, McKenna WJ. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J.2006;27:1933-1941
116. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol.2008;19:1118-1126
117. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA,3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Riegel B, Tarkington LG, Yancy CW. Acc/aha/hrs 2008 guidelines for device-based therapy of cardiac rhythm abnormalities:A report of the american college of cardiology/american heart association task force on practice guidelines (writing committee to revise the acc/aha/naspe 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the american association for thoracic surgery and society of thoracic surgeons. J Am Coll Cardiol.2008;51:e1-62
118. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med.2003;348:295-303
119. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation. 2003; 108:2342-2348
120. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol.2008;51:1369-1374
121. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task force 4:Hcm and other cardiomyopathies, mitral valve prolapse, myocarditis, and marfan syndrome. J Am Coll Cardiol. 2005;45:1340-1345
122. Pelliccia A, Fagard R, Bjornstad HH, Anastassakis A, Arbustini E, Assanelli D, Biffi A, Borjesson M, Carre F, Corrado D, Delise P, Dorwarth U, Hirth A, Heidbuchel H, Hoffmann E, Mellwig KP, Panhuyzen-Goedkoop N, Pisani A, Solberg EE, van-Buuren F, Vanhees L, Blomstrom-Lundqvist C, Deligiannis A, Dugmore D, Glikson M, Hoff PI, Hoffmann A, Horstkotte D, Nordrehaug JE, Oudhof J, McKenna WJ, Penco M, Priori S, Reybrouck T, Senden J, Spataro A, Thiene G. Recommendations for competitive sports participation in athletes with cardiovascular disease:A consensus document from the study group of sports cardiology of the working group of cardiac rehabilitation and exercise physiology and the working group of myocardial and pericardial diseases of the european society of cardiology. Eur Heart J.2005;26:1422-1445
123. Basso C, Thiene G, Mackey-Bojack S, Frigo AC, Corrado D, Maron BJ. Myocardial bridging, a frequent component of the hypertrophic cardiomyopathy phenotype, lacks systematic association with sudden cardiac death. Eur Heart J 10.046.2009;30:1627-1634
124. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy:An independent marker of sudden death risk in young patients. J Am Coll Cardiol.2003;42:873-879
125. Melacini P, Maron BJ, Bobbo F, Basso C, Tokajuk B, Zucchetto M, Thiene G, Iliceto S. Evidence that pharmacological strategies lack efficacy for the prevention of sudden death in hypertrophic cardiomyopathy. Heart.2007;93:708-710
126. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK, Cannon BC, Alexander ME, Triedman JK, Walsh EP, Friedman RA. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol. 2008;51:1685-1691
127. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, Almquist AK, Baffa JM, Saul JP, Ho CY, Seidman J, Seidman CE. Clinical outcome and phenotypic expression in lamp2 cardiomyopathy. JAMA.2009;301:1253-1259
128. Dukkipati SR, d'Avila A, Soejima K, Bala R, Inada K, Singh S, Stevenson WG, Marchlinski FE, Reddy VY. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Oirc Arrhythm Electrophysiol 4.78. 2011;4:185-194
129. Maron BJ, Haas TS, Shannon KM, Almquist AK, Hodges JS. Long-term survival after cardiac arrest in hypertrophic cardiomyopathy. Heart Rhythm.2009;6:993-997
130. Hauser RG, Maron BJ. Lessons from the failure and recall of an implantable cardioverter-defibrillator. Circulation.2005;112:2040-2042
131. Melacini P, Basso C, Angelini A, Calore C, Bobbo F, Tokajuk B, Bellini N, Smaniotto G, Zucchetto M, Iliceto S, Thiene G, Maron BJ. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J.2010;31:2111-2123
132. Maron BJ, Tholakanahalli VN, Zenovich AG, Casey SA, Duprez D, Aeppli DM, Cohn JN. Usefulness of b-type natriuretic peptide assay in the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation.2004; 109:984-989
133. Coats CJ, Gallagher MJ, Foley M,O'Mahony C, Critoph C, Gimeno J, Dawnay A, McKenna WJ, Elliott PM. Relation between serum n-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy. Eur Heart J.2013
134. Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol.2005;45:1076-1080
135. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J. Noninvasive assessment of left ventricular diastolic function by pulsed doppler echocardiography in patients with hypertrophic cardiomyopathy. JAm Coll Cardiol.1987;10:733-742
136. Maron MS, Zenovich AG, Casey SA, Link MS, Udelson JE, Aeppli DM, Maron BJ. Significance and relation between magnitude of left ventricular hypertrophy and heart failure symptoms in hypertrophic cardiomyopathy. Am J Cardiol.2005;95:1329-1333
137. Shah PM, Taylor RD, Wong M. Abnormal mitral valve coaptation in hypertrophic obstructive cardiomyopathy:Proposed role in systolic anterior motion of mitral valve. Am J Cardiol. 1981;48:258-262
138. Maron BJ, Harding AM, Spirito P, Roberts WC, Waller BF. Systolic anterior motion of the posterior mitral leaflet:A previously unrecognized cause of dynamic subaortic obstruction in patients with hypertrophic cardiomyopathy. Circulation.1983;68:282-293
139. Paz R, Jortner R, Tunick PA, Sclarovsky S, Eilat B, Perez JL, Kronzon 1. The effect of the ingestion of ethanol on obstruction of the left ventricular outflow tract in hypertrophic cardiomyopathy. N Engl J Med.1996;335:938-941
140. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol.2005;45:1251-1258
141. Nistri S, Olivotto I, Maron MS, Ferrantini C, Coppini R, Grifoni C, Baldini K, Sgalambro A, Cecchi F, Maron BJ. Beta blockers for prevention of exercise-induced left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J Cardiol.2012;110:715-719
142. Morrow AG, Brockenbrough EC. Surgical treatment of idiopathic hypertrophic subaortic stenosis: Technic and hemodynamic results of subaortic ventriculomyotomy. Ann Surg.1961;154:181-189
143. Woo A, Williams WG, Choi R, Wigle ED, Rozenblyum E, Fedwick K, Siu S, Ralph-Edwards A, Rakowski H. Clinical and echocardiographic determinants of long-term survival after surgical myectomy in obstructive hypertrophic cardiomyopathy. Circulation.2005;111:2033-2041
144. Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, Williams WG, Schwartz L, Guttman A, Woo A. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol. 2011;58:2313-2321
145. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF, Breen JF, Ommen SR, Gersh BJ, Tajik AJ, Rihal CS, Schaff HV, Maron BJ. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol.2007;49:350-357
146. Firoozi S, Elliott PM, Sharma S, Murday A, Brecker SJ, Hamid MS, Sachdev B, Thaman R, McKenna WJ. Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J.2002;23:1617-1624
147. Sorajja P, Valeti U, Nishimura RA, Ommen SR, Rihal CS, Gersh BJ, Hodge DO, Schaff HV, Holmes DR, Jr. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation. 2008;118:131-139
148. Cuoco FA, Spencer WH,3rd, Fernandes VL, Nielsen CD, Nagueh S, Sturdivant JL, Leman RB, Wharton JM, Gold MR. Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;52:1718-1723
149. Nagueh SF, Groves BM, Schwartz L, Smith KM, Wang A, Bach RG, Nielsen C, Leya F, Buergler JM, Rowe SK, Woo A, Maldonado YM, Spencer WH,3rd. Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter north american registry. J Am Coll Cardiol. 2011;58:2322-2328
150. Nagueh SF, Ommen SR, Lakkis NM, Killip D, Zoghbi WA, Schaff HV, Danielson GK, Quinones MA, Tajik AJ, Spencer WH. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol.2001;38:1701-1706
151. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (m-pathy). Circulation.1999;99:2927-2933
152. Maron BJ, Lever H. In defense of antimicrobial prophylaxis for prevention of infective endocarditis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol.2009;54:2339-2340; author reply 2340
153. Spirito P, Rapezzi C, Bellone P, Betocchi S, Autore C, Conte MR, Bezante GP, Bruzzi P. Infective endocarditis in hypertrophic cardiomyopathy:Prevalence, incidence, and indications for antibiotic prophylaxis. Circulation.1999;99:2132-2137
154. Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling pressures by doppler echocardiography in patients with hypertrophic cardiomyopathy:Correlation with direct left atrial pressure measurement at cardiac catheterization. Circulation.2007; 116:2702-2708
155. Olivotto I, Maron BJ, Appelbaum E, Harrigan CJ, Salton C, Gibson CM, Udelson JE, O'Donnell C, Lesser JR, Manning WJ, Maron MS. Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol 3.68.2010;106:261-267
156. Maron MS, Kalsmith BM, Udelson JE, Li W, DeNofrio D. Survival after cardiac transplantation in patients with hypertrophic cardiomyopathy. Circ Heart Fail.2010;3:574-579
157. Topilsky Y, Pereira NL, Shah DK, Boilson B, Schirger JA, Kushwaha SS, Joyce LD, Park SJ. Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. Circ Heart Fail 4.315.2011;4:266-275
158. Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami F, Torricelli F, Camici PG. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol.2006;47:1043-1048
159. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol.2008;51:810-815
160. Di Donna P, Olivotto I, Delcre SD, Caponi D, Scaglione M, Nault I, Montefusco A, Girolami F, Cecchi F, Haissaguerre M, Gaita F. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy:Impact of age, atrial remodelling, and disease progression. Europace. 2010;12:347-355
161. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy:A potential link to sudden death in the absence of conventional risk factors. Heart Rhythm.2012;9:57-63
162. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. Hrs/ehra expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the heart rhythm society (hrs) and the european heart rhythm association (ehra). Heart Rhythm.2011;8:1308-1339
163. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. JAm Coll Cardiol.2004;44:2125-2132
164. Maron BJ, Zipes DP. Introduction:Eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol.2005;45:1318-1321
165. Germans T, Wilde AA, Dijkmans PA, Chai W, Kamp O, Pinto YM, van Rossum AC. Structural abnormalities of the inferoseptal left ventricular wall detected by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am Coll Cardiol.2006;48:2518-2523
166. Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (+)-phenotype negative (-) family members in hypertrophic cardiomyopathy. Am J Cardiol.2011;107:604-608
167. Christiaans I, Lekanne dit Deprez RH, van Langen IM, Wilde AA. Ventricular fibrillation in myh7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy. Heart Rhythm. 2009;6:1366-1369
168. Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG The 1-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. JClin Invest.2002; 109:1013-1020
169. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation.2001;104:317-324
170. Arad M, Maron BJ, Gorham JM, Johnson WH, Jr., Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med.2005;352:362-372
171. Maron BJ, Roberts WC, Ho CY, Kitner C, Haas TS, Wright GB, Moazami N, Feldman DS. Profound left ventricular remodeling associated with lamp2 cardiomyopathy. Am J Cardiol. 2010;106:1194-1196
172. Patel MR, Cecchi F, Cizmarik M, Kantola I, Linhart A, Nicholls K, Strotmann J, Tallaj J, Tran TC, West ML, Beitner-Johnson D, Abiose A. Cardiovascular events in patients with fabry disease natural history data from the fabry registry. J Am Coll Cardiol.2011;57:1093-1099
173. Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Stork S, Voelker W, Ertl G, Wanner C, Strotmann J. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy:Evidence for a better outcome with early treatment. Circulation.2009;119:524-529
174. Kubo T, Gimeno JR, Bahl A, Steffensen U, Steffensen M, Osman E, Thaman R, Mogensen J, Elliott PM, Doi Y, McKenna WJ. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol.2007;49:2419-2426
175. Ciro E, Nichols PF,3rd, Maron BJ. Heterogeneous morphologic expression of genetically transmitted hypertrophic cardiomyopathy. Two-dimensional echocardiographic analysis. Circulation. 1983;67:1227-1233
176. Wang S, Zou Y, Fu C, Xu X, Wang J, Song L, Wang H, Chen J, Huan T, Hui R. Worse prognosis with gene mutations of beta-myosin heavy chain than myosin-binding protein c in chinese patients with hypertrophic cardiomyopathy. Clin Cardiol.2008;31:114-118
177. van der Merwe L, Cloete R, Revera M, Heradien M, Goosen A, Corfield VA, Brink PA, Moolman-Smook JC. Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Hum Genet.2008; 124:57-61
178. Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in tnncl-encoded troponin c. J Mol Cell Cardiol.2008;45:281-288
179. Friedrich FW, Bausero P, Sun Y, Treszl A, Kramer E, Juhr D, Richard P, Wegscheider K, Schwartz K, Brito D, Arbustini E, Waldenstrom A, Isnard R, Komajda M, Eschenhagen T, Carrier L. A new polymorphism in human calmodulin iii gene promoter is a potential modifier gene for familial hypertrophic cardiomyopathy. Eur Heart J.2009;30:1648-1655
180. Palacin M, Reguero JR, Martin M, Diaz Molina B, Moris C, Alvarez V, Coto E. Profile of micrornas differentially produced in hearts from patients with hypertrophic cardiomyopathy and sarcomeric mutations. Clin Chem.2011;57:1614-1616
181. Saltzman AJ, Mancini-DiNardo D, Li C, Chung WK, Ho CY, Hurst S, Wynn J, Care M, Hamilton RM, Seidman GW, Gorham J, McDonough B, Sparks E, Seidman JG, Seidman CE, Rehm HL. Short communication:The cardiac myosin binding protein c arg502trp mutation:A common cause of hypertrophic cardiomyopathy. Circ Res.2010;106:1549-1552
182. Semsarian C, Yu B, Ryce C, Lawrence C, Washington H, Trent RJ. Sudden cardiac death in familial hypertrophic cardiomyopathy:Are "benign" mutations really benign? Pathology.1997;29:305-308
183. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy:Implications for genetic testing and counselling. J Med Genet.2005;42:e59
184. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease:A marker of disease severity? Circ Cardiovasc Genet.2009;2:182-190
185. Basille C, Frydman R, El Aly A, Hesters L, Fanchin R, Tachdjian G, Steffann J, LeLorc'h M, Achour-Frydman N. Preimplantation genetic diagnosis:State of the art. Eur J Obstet Gynecol Reprod Biol.2009;145:9-13
186. Ingles J, Yeates L, Semsarian C. The emerging role of the cardiac genetic counselor. Heart Rhythm. 2011;8:1958-1962
187. Abiola S. Recent developments in health law. The genetic information nondiscrimination act of 2008: "First major civil rights bill of the century" bars misuse of genetic test results. J Law Med Ethics. 2008;36:856-860
188. Bagnall RD, Ingles J, Semsarian C. Molecular diagnostics of cardiomyopathies:The future is here. Circ Cardiovasc Genet.2011;4:103-104