低剂量培哚普利和厄贝沙坦联合治疗扩张型心肌病的疗效及相关机制研究
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摘要
第一章低剂量培哚普利和厄贝沙坦联合治疗对扩张型心肌病大鼠心功能及预后的影响
背景：扩张型心肌病(DCM)的主要危害是慢性心力衰竭(CHF)。联合应用血管紧张素转换酶抑制剂(ACEIs)，血管紧张素Ⅱ1型受体阻滞剂(ARBs)治疗CHF可以使患者额外受益。将ACEIs和ARBs的常用治疗心衰剂量减半后，再联合治疗DCM的CHF可否获得更好的近期和远期疗效，值得探讨。本研究通过联合培哚普利和厄贝沙坦治疗DCM大鼠，验证这一设想。
目的：观察低剂量培哚普利和厄贝沙坦联合治疗对DCM大鼠心功能及预后的影响。
方法：腹腔注射阿霉素建立SD大鼠DCM模型。然后将大鼠分为4组进行干预：正常大鼠组(n=14)，予蒸馏水灌胃。DCM大鼠随机分为DCM对照组(n=26)，予蒸馏水灌胃；单用培哚普利组(n=24)，予培哚普利2mg.kg~(-1).d~(-1)灌胃；培哚普利联合厄贝沙坦组(n=24)，予以培哚普利1mg.kg~(-1).d~(-1)及厄贝沙坦25mg.kg~(-1).d~(-1)灌胃。全自动生化分析仪检测血钾、血肌酐；ELISA方法检测血浆脑利钠肽(BNP)水平；彩色超声心动图测定左室射血分数(LVEF)，记录每只大鼠的生存时间。
结果：(1)各组干预前后血钾、血肌酐水平差异无统计学意义(P＞0.05)。(2)干预前各个DCM组血浆BNP水平均高于正常组(P＜0.05)。与干预前比较，单用培哚普利组、联合治疗组干预后血浆BNP水平均明显下降(P＜0.01)。与单用培哚普利组比较，联合治疗组血浆BNP水平下降更明显(P＜0.01)。(3)干预前各个DCM组LVEF均低于正常组(P＜0.05)。与干预前比较，单用培哚普利组、联合治疗组干预后LVEF均明显升高(P＜0.01)。与单用培哚普利组比较，联合治疗组LVEF升高更明显(P＜0.05)。(4)对数秩检验显示：单用培哚普利组存活期长于DCM对照组(P＜0.05)，而短于联合治疗组(P＜0.05)；Cox回归分析显示：联合治疗或单用培哚普利为延长生存期因素，联合治疗作用更明显。
结论：(1)DCM大鼠血浆BNP水平增高，LVEF下降。(2)单用培哚普利或培哚普利和厄贝沙坦各减半常用抗心衰剂量联合治疗DCM大鼠，均可降低血浆BNP水平，升高LVEF，延长存活期。(3)联合治疗在改善左室功能及远期预后方面优于单用培哚普利。
第二章培哚普利联合厄贝沙坦对扩张型心肌病大鼠心肌AT_1受体、lamin A及NF-κB表达的影响
背景：联合ACEIs和ARBs治疗CHF的临床试验较多，但是二者合用的作用机制报道不多。CHF患者存在肾素-血管紧张素系统(RAS)激活；而A型核纤层蛋白(lamin A／C，LMNA)突变或表达缺失可以导致DCM；CHF患者心肌核因子-κB(NF-κB)表达增加。提示心肌血管紧张素Ⅱ1型受体(AT_1Rs)、lamin A／C和NF-κB的表达量改变可能参与DCM的发病机制。ACEIs和ARBs治疗DCM的CHF，是否通过影响上述指标，达到更好疗效，本文就此进行初步探讨。
目的：探讨培哚普利联合厄贝沙坦对DCM大鼠心肌AT_1Rs，lamin A的mRNA及NF-κB蛋白表达的调节。
方法：DCM动物模型的制备、药物干预分组、LVEF和BNP检测见第一章。RT-PCR方法检测心肌AT_1Rs、lamin A的mRNA表达；心肌切片HE染色后进行病理评分：免疫组化方法检测心肌NF-κB蛋白的表达。
结果：(1)与正常组比较，DCM对照组AT_1Rs表达下调(P＜0.05)。与DCM对照组比较，单用培哚普利组、联合治疗组AT_1Rs表达均上调(P＜0.05)。与单用培哚普利组比较，联合治疗组AT_1Rs表达上调更明显(P＜0.01)。(2)与正常组比较，DCM对照组lamin A表达下调(P＜0.05)；联合治疗组lamin A表达水平高于DCM对照组(P＜0.05)。(3)与正常组比较，DCM对照组存在明显心肌病理损害；与DCM对照组比较，单用培哚普利组、联合治疗组心肌病理损害均减轻(P＜0.01)。(4)与正常组比较，DCM对照组心肌NF-κB表达增加(P＜0.05)。与DCM对照组比较，单用培哚普利组、联合治疗组NF-κB表达均减弱(P＜0.05)。与单用培哚普利组比较，联合治疗组NF-κB表达减弱更明显(P＜0.05)。
结论：(1)DCM大鼠心肌AT_1Rs及lamin A的表达下调，NF-κB的表达增加，可能参与了DCM的发病机制。(2)单用培哚普利或培哚普利联合厄贝沙坦均能减轻心肌病理损害。(3)单用培哚普利或联合治疗均上调AT_1Rs表达，减弱NF-κB表达；而联合治疗作用更明显伴上调lamin A的表达。联合治疗可能通过影响AT_1Rs、lamin A、NF-κB的表达实现更好的抗心衰疗效。
第三章低剂量培哚普利和厄贝沙坦联合治疗扩张型心肌病患者的疗效分析
背景：扩张型心肌病(DCM)的预后很差，国内报道症状出现后5年的存活率在65.3％左右。虽然目前治疗DCM有心脏移植、左心室减容术、心脏再同步治疗，但是因为费用昂贵，并不能广泛应用。自上世纪90年代开始，就有临床试验探讨联合应用ACEIs，ARBs治疗CHF是否可以使患者额外受益。至2005年将联合应用ACEIs，ARBs治疗CHF列入治疗心衰指南。但是，至今尚未阐明联合应用ACEIs，ARBs治疗DCM患者的合适剂量。
目的：探讨低剂量培哚普利和厄贝沙坦联合治疗DCM患者的疗效及不良反应。
方法：选择住院或门诊的DCM患者60例，随机分为常规治疗组(n=30)和联合治疗组(n=30)。两组性别、年龄、病情、病程无差异。常规治疗组治疗方案包括培哚普利4mg／d，联合治疗组治疗方案包括培哚普利2mg／d和厄贝沙坦75mg／d，其余的治疗措施2组一致。全自动生化分析仪检测血钾、血肌酐；ELISA方法检测血浆BNP水平；彩色超声心动图测定LVEF。
结果：(1)2组干预后心功能均改善(P＜0.05；P＜0.01)，且联合治疗组较常规治疗组心功能改善更明显(P＜0.05)。(2)2组干预后血浆BNP水平均明显下降(P＜0.01)，且联合治疗组BNP水平低于常规治疗组(P＜0.05)。(3)2组干预后LVEF均明显升高(P＜0.01)，且联合治疗组LVEF高于常规治疗组(P＜0.05)。(4)2组干预前后血钾、血肌酐水平差异无统计学意义(P＞0.05)。
结论：(1)单用培哚普利或培哚普利和厄贝沙坦各减半常用抗心衰剂量联合治疗DCM患者，均改善DCM患者心功能，降低血浆BNP水平、升高LVEF。(2)培哚普利联合厄贝沙坦治疗DCM患者，在改善心功能，降低血浆BNP水平、升高LVEF方面优于单用培哚普利，且不增加不良反应。
Chapter 1The effects of combination therapy with low dose of perindopril andirbesartan on cardiac function and prognosis in a rat modelof dilated cardiomyopathy
Background The main hazard of dilated cardiomyopathy (DCM)is chronic heart failure (CHF). It has been reported that combinationtherapy with ACEIs and ARBs would produce better therapeutic effectsto patients with CHF. It is not well known if half of the conventionaldosage of ACEIs for heart failure combined with half of the conventionaldosage of ARBs for heart failure would also bring better short-term andlong-term therapeutic effects to CHF induced by DCM. This studyconfirmed this hypothesis by combination therapy with perindopril andirbesartan in a rat model of DCM.
Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on cardiac function and prognosis in arat model of DCM.
Methods For inducing DCM, adriamycin was administeredintraperitoneally in Sprague-Dawley rats. Then the rats were divided into4 groups. Normal group (n=14), which was administered distilled water.Rats with DCM were randomly divided into DCM-control group (n=26),perindopril group (n=24) and combination therapy (combination therapywith perindopril and irbesartan ) group (n=24). The DCM-control groupwas administered distilled water. The perindopril group was administeredperindopril 2mg.kg~(-1).d~(-1). The combination therapy group wasadministered perindopril 1mg.kg~(-1).d~(-1) and irbesartan 25mg.kg~(-1).d~(-1). All thedrugs were given orally by gastric gavage once a day. Plasma potassiumand creatinine were measured by automatic biochemistry analyzer; brainnatriuretic peptide (BNP) was assessed by ELISA; LVEF weredetermined by ultrasonic cardiogram. Each rat's survival time duringintervention was recorded.
Results (1) Each group plasma concentrations of potassium andcreatinine showed no significant differences between pre-intervention andpost-intervention (P＞0.05). (2) Before intervention, plasmaconcentrations of BNP of each DCM group were higher than those of thenormal group (P＜0.05). In both perindopril group and combinationtherapy group, plasma concentrations of BNP were much lower afterintervention compared with those before intervention (P＜0.01).However, plasma concentrations of BNP decreased more in thecombination therapy group than in the perindopril group (P＜0.01). (3)Before intervention, LVEF of each DCM group was lower than that of thenormal group (P＜0.05). LVEF in both perindopril group andcombination therapy group was much higher after intervention comparedwith that before intervention (P＜0.01). However, LVEF increased morein the combination therapy group than in the perindopril group (P＜0.05). (4) Log rank test showed that the life span of perindopril groupwas longer than that of the DCM-control group (P＜0.05), but wasshorter than that of the combination therapy group (P＜0.05). Coxregression analysis showed that combination therapy or onlyadministering perindopril could prolong the survival time, butcombination therapy's contribution was bigger.
Conclusions (1) Rats with DCM have elevated plasmaconcentrations of BNP and decreased LVEF. (2) Both monotherapy withperindopril and combination therapy with half of the conventional dosagefor CHF of perindopril and half of the conventional dosage for CHF ofirbesartan in a rat model of DCM can reduce the plasma concentrations ofBNP, increase LVEF and prolong survival time. (3) Combinationtherapy can more effectively improve left ventricular function andprognosis in rats with DCM than monotherapy with perindopril.
Chapter 2The effects of combination therapy with perindopril and irbesartanon the expression of AT_1 receptor and lamin A and NF-κB in themyocardium of a rat model of dilated cardiomyopathy
Background Many clinical trials about combination therapy withACEIs and ARBs in CHF have been reported, but the related mechanismshave not been fully illuminated. The renin-angiotensin system (RAS) isactivated in patients with CHF; the mutation or deficiency of theexpression of lamin A/C may induce DCM; and the NF-kappa B(NF-κB)is over activated in the myocardium of patients with CHF. All thesefindings imply that the changes of expression of angiotensinⅡtype 1receptors (AT_1Rs) and lamin A/C and NF-κB might participate in thepathogenesis of DCM. It is worth investigating if combination therapywith ACEIs and ARBs might more obviously affect these factors toachieve better therapeutic effects on CHF of DCM.
Objective To evaluate the effects of combination therapy withperindopril and irbesartan on the mRNA expression of AT_1Rs and laminA and on the protein expression of NF-κB in the myocardium of the ratswith DCM.
Methods The methods of inducing an animal model of DCM,grouping for drug treatment, and measuring LVEF and BNP have beenmentioned in the chapter one. The mRNA expression of AT_1Rs and laminA in the myocardium was detected by reverse transcription-polymerasechain reaction (RT-PCR); the pathological lesions of cardiac muscletissues after HE staining were evaluated by light microscope; and theprotein expression of NF-κB was assessed by immunohistochemistry.
Results (1) Compared with those in the normal group, expressionlevels of AT_1Rs in the DCM-control group were down-regulated (P＜0.05). Compared with those in the DCM-control group, expression levelsof AT_1Rs in both perindopril group and combination therapy group wereup-regulated (P＜0.05). Expression levels of AT_1Rs were more obviously up-regulated in the combination therapy group than in theperindopril group (P＜0.01). (2) Compared with those in the normalgroup, expression levels of lamin A in the DCM-control group weredown-regulated (P＜0.05). Expression levels of lamin A in thecombination therapy group were higher than those in the DCM-controlgroup (P＜0.05). (3) Compared with those in the normal group,cardiac muscle tissues in the DCM-control group were obviouslydamaged. Compared with those in the DCM-control group, pathologicallesions of cardiac muscle tissues in both perindopril group andcombination therapy group were attenuated (P＜0.01). (4) Comparedwith that in the normal group, NF-κB in the DCM-control group wasmore obviously expressed (P＜0.05). Compared with that in theDCM-control group, obviously expressed NF-κB was attenuated in bothperindopril group and combination therapy group (P＜0.05). Obviouslyexpressed NF-κB was attenuated more in the combination therapy groupthan in the perindopril group (P＜0.05).
Conclusions (1) Down-regulation of the expression of AT_1Rsand lamin A, and the over-expression of NF-κB might participate in thepathogenesis of DCM. (2) Both monotherapy with perindopril andcombination therapy with perindopril and irbesartan can attenuatepathological lesions of cardiac muscle tissues. (3) Both monotherapywith perindopril and combination therapy can up-regulate the expressionof AT_1Rs and attenuate the expression of NF-κB, and the combinationtherapy's effects are more obvious. Furthermore, combination therapy canup-regulate the expression of lamin A. The effects of combination therapyon the expression of AT_1Rs, lamin A and NF-κB may contribute to thebetter therapeutic effects on heart failure.
Chapter 3The therapeutic effects of combination therapy with low dose ofperindopril and irbesartan in patientswith dilated cardiomyopathy
Background The prognosis of DCM is very poor, and in China,the 5-year survival rate is about 65.3％after the symptom occurs.Nowadays, therapeutic measures, such as heart transplantation, leftventricular reconstruction operation and cardiac resynchronizationtherapy are used in clinic, but these measures are too expensive to bewidely used. Since 1990s, there were clinical trials investigating ifcombination therapy with ACEIs and ARBs could produce better effectson patients with CHF. In 2005, combination therapy with ACEIs andARBs was suggested in the guideline of CHF. But until now, it is notclear what is the appropriate dose of combination therapy with ACEIs andARBs in treating patients with DCM.
Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on patients with DCM and the relatedadverse reactions.
Methods 60 hospitalized patients or outpatients with DCM wereenrolled, and the patients were randomly divided into two groups,conventional therapy group (n=30) and combination therapy group (n=30). The age, sex, patient's condition, and course of disease showed nosignificant differences between the conventional therapy group and thecombination therapy group. The conventional therapy group wasadministered perindopril 4mg/d and the combination therapy group wasadministered perindopril 2mg/d and irbesartan 75mg/d. The othertherapeutic measures in these two groups were just the same. Plasmapotassium and creatinine were studied by automatic biochemistryanalyzer; brain natriuretic peptide (BNP) was assessed by ELISA; leftventricular ejection fraction (LVEF) were measured by ultrasoniccardiogram.
Results (1) In both groups, cardiac function was improved afterdrug treatment (P＜0.05; P＜0.01); cardiac function was moremarkedly improved in the combination therapy group than in theconventional therapy group (P＜0.05). (2) In both groups, plasmaconcentrations of BNP were much lower after drug treatment (P＜0.01),however, plasma concentrations of BNP in the combination therapygroup was lower than those in the conventional therapy group (P＜0.05).(3) In both groups, LVEF was much higher after drug treatment (P＜0.01), but LVEF in the combination therapy group was higher than thatin the conventional therapy group (P＜0.05). (4) In each group, plasmaconcentrations of potassium and creatinine showed no significantdifferences between pre-intervention and post-intervention (P＞0.05).
Conclusions (1) Both monotherapy with pedndopril andcombination therapy with half of the conventional dosage for CHF ofperindopril and half of the conventional dosage for CHF of irbesartan inpatients with DCM can improve cardiac function, reduce the plasmaconcentrations of BNP and increase LVEF. (2) Combination therapywith perindopril and irbesartan in patients with DCM can moreeffectively improve cardiac function, reduce the plasma concentrations ofBNP and increase LVEF than monotherapy with perindopril, withoutincreased adverse reactions.
背景：扩张型心肌病(DCM)的主要危害是慢性心力衰竭(CHF)。联合应用血管紧张素转换酶抑制剂(ACEIs)，血管紧张素Ⅱ1型受体阻滞剂(ARBs)治疗CHF可以使患者额外受益。将ACEIs和ARBs的常用治疗心衰剂量减半后，再联合治疗DCM的CHF可否获得更好的近期和远期疗效，值得探讨。本研究通过联合培哚普利和厄贝沙坦治疗DCM大鼠，验证这一设想。
目的：观察低剂量培哚普利和厄贝沙坦联合治疗对DCM大鼠心功能及预后的影响。
方法：腹腔注射阿霉素建立SD大鼠DCM模型。然后将大鼠分为4组进行干预：正常大鼠组(n=14)，予蒸馏水灌胃。DCM大鼠随机分为DCM对照组(n=26)，予蒸馏水灌胃；单用培哚普利组(n=24)，予培哚普利2mg.kg~(-1).d~(-1)灌胃；培哚普利联合厄贝沙坦组(n=24)，予以培哚普利1mg.kg~(-1).d~(-1)及厄贝沙坦25mg.kg~(-1).d~(-1)灌胃。全自动生化分析仪检测血钾、血肌酐；ELISA方法检测血浆脑利钠肽(BNP)水平；彩色超声心动图测定左室射血分数(LVEF)，记录每只大鼠的生存时间。
结果：(1)各组干预前后血钾、血肌酐水平差异无统计学意义(P＞0.05)。(2)干预前各个DCM组血浆BNP水平均高于正常组(P＜0.05)。与干预前比较，单用培哚普利组、联合治疗组干预后血浆BNP水平均明显下降(P＜0.01)。与单用培哚普利组比较，联合治疗组血浆BNP水平下降更明显(P＜0.01)。(3)干预前各个DCM组LVEF均低于正常组(P＜0.05)。与干预前比较，单用培哚普利组、联合治疗组干预后LVEF均明显升高(P＜0.01)。与单用培哚普利组比较，联合治疗组LVEF升高更明显(P＜0.05)。(4)对数秩检验显示：单用培哚普利组存活期长于DCM对照组(P＜0.05)，而短于联合治疗组(P＜0.05)；Cox回归分析显示：联合治疗或单用培哚普利为延长生存期因素，联合治疗作用更明显。
结论：(1)DCM大鼠血浆BNP水平增高，LVEF下降。(2)单用培哚普利或培哚普利和厄贝沙坦各减半常用抗心衰剂量联合治疗DCM大鼠，均可降低血浆BNP水平，升高LVEF，延长存活期。(3)联合治疗在改善左室功能及远期预后方面优于单用培哚普利。
第二章培哚普利联合厄贝沙坦对扩张型心肌病大鼠心肌AT_1受体、lamin A及NF-κB表达的影响
背景：联合ACEIs和ARBs治疗CHF的临床试验较多，但是二者合用的作用机制报道不多。CHF患者存在肾素-血管紧张素系统(RAS)激活；而A型核纤层蛋白(lamin A／C，LMNA)突变或表达缺失可以导致DCM；CHF患者心肌核因子-κB(NF-κB)表达增加。提示心肌血管紧张素Ⅱ1型受体(AT_1Rs)、lamin A／C和NF-κB的表达量改变可能参与DCM的发病机制。ACEIs和ARBs治疗DCM的CHF，是否通过影响上述指标，达到更好疗效，本文就此进行初步探讨。
目的：探讨培哚普利联合厄贝沙坦对DCM大鼠心肌AT_1Rs，lamin A的mRNA及NF-κB蛋白表达的调节。
方法：DCM动物模型的制备、药物干预分组、LVEF和BNP检测见第一章。RT-PCR方法检测心肌AT_1Rs、lamin A的mRNA表达；心肌切片HE染色后进行病理评分：免疫组化方法检测心肌NF-κB蛋白的表达。
结果：(1)与正常组比较，DCM对照组AT_1Rs表达下调(P＜0.05)。与DCM对照组比较，单用培哚普利组、联合治疗组AT_1Rs表达均上调(P＜0.05)。与单用培哚普利组比较，联合治疗组AT_1Rs表达上调更明显(P＜0.01)。(2)与正常组比较，DCM对照组lamin A表达下调(P＜0.05)；联合治疗组lamin A表达水平高于DCM对照组(P＜0.05)。(3)与正常组比较，DCM对照组存在明显心肌病理损害；与DCM对照组比较，单用培哚普利组、联合治疗组心肌病理损害均减轻(P＜0.01)。(4)与正常组比较，DCM对照组心肌NF-κB表达增加(P＜0.05)。与DCM对照组比较，单用培哚普利组、联合治疗组NF-κB表达均减弱(P＜0.05)。与单用培哚普利组比较，联合治疗组NF-κB表达减弱更明显(P＜0.05)。
结论：(1)DCM大鼠心肌AT_1Rs及lamin A的表达下调，NF-κB的表达增加，可能参与了DCM的发病机制。(2)单用培哚普利或培哚普利联合厄贝沙坦均能减轻心肌病理损害。(3)单用培哚普利或联合治疗均上调AT_1Rs表达，减弱NF-κB表达；而联合治疗作用更明显伴上调lamin A的表达。联合治疗可能通过影响AT_1Rs、lamin A、NF-κB的表达实现更好的抗心衰疗效。
第三章低剂量培哚普利和厄贝沙坦联合治疗扩张型心肌病患者的疗效分析
背景：扩张型心肌病(DCM)的预后很差，国内报道症状出现后5年的存活率在65.3％左右。虽然目前治疗DCM有心脏移植、左心室减容术、心脏再同步治疗，但是因为费用昂贵，并不能广泛应用。自上世纪90年代开始，就有临床试验探讨联合应用ACEIs，ARBs治疗CHF是否可以使患者额外受益。至2005年将联合应用ACEIs，ARBs治疗CHF列入治疗心衰指南。但是，至今尚未阐明联合应用ACEIs，ARBs治疗DCM患者的合适剂量。
目的：探讨低剂量培哚普利和厄贝沙坦联合治疗DCM患者的疗效及不良反应。
方法：选择住院或门诊的DCM患者60例，随机分为常规治疗组(n=30)和联合治疗组(n=30)。两组性别、年龄、病情、病程无差异。常规治疗组治疗方案包括培哚普利4mg／d，联合治疗组治疗方案包括培哚普利2mg／d和厄贝沙坦75mg／d，其余的治疗措施2组一致。全自动生化分析仪检测血钾、血肌酐；ELISA方法检测血浆BNP水平；彩色超声心动图测定LVEF。
结果：(1)2组干预后心功能均改善(P＜0.05；P＜0.01)，且联合治疗组较常规治疗组心功能改善更明显(P＜0.05)。(2)2组干预后血浆BNP水平均明显下降(P＜0.01)，且联合治疗组BNP水平低于常规治疗组(P＜0.05)。(3)2组干预后LVEF均明显升高(P＜0.01)，且联合治疗组LVEF高于常规治疗组(P＜0.05)。(4)2组干预前后血钾、血肌酐水平差异无统计学意义(P＞0.05)。
结论：(1)单用培哚普利或培哚普利和厄贝沙坦各减半常用抗心衰剂量联合治疗DCM患者，均改善DCM患者心功能，降低血浆BNP水平、升高LVEF。(2)培哚普利联合厄贝沙坦治疗DCM患者，在改善心功能，降低血浆BNP水平、升高LVEF方面优于单用培哚普利，且不增加不良反应。
Chapter 1The effects of combination therapy with low dose of perindopril andirbesartan on cardiac function and prognosis in a rat modelof dilated cardiomyopathy
Background The main hazard of dilated cardiomyopathy (DCM)is chronic heart failure (CHF). It has been reported that combinationtherapy with ACEIs and ARBs would produce better therapeutic effectsto patients with CHF. It is not well known if half of the conventionaldosage of ACEIs for heart failure combined with half of the conventionaldosage of ARBs for heart failure would also bring better short-term andlong-term therapeutic effects to CHF induced by DCM. This studyconfirmed this hypothesis by combination therapy with perindopril andirbesartan in a rat model of DCM.
Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on cardiac function and prognosis in arat model of DCM.
Methods For inducing DCM, adriamycin was administeredintraperitoneally in Sprague-Dawley rats. Then the rats were divided into4 groups. Normal group (n=14), which was administered distilled water.Rats with DCM were randomly divided into DCM-control group (n=26),perindopril group (n=24) and combination therapy (combination therapywith perindopril and irbesartan ) group (n=24). The DCM-control groupwas administered distilled water. The perindopril group was administeredperindopril 2mg.kg~(-1).d~(-1). The combination therapy group wasadministered perindopril 1mg.kg~(-1).d~(-1) and irbesartan 25mg.kg~(-1).d~(-1). All thedrugs were given orally by gastric gavage once a day. Plasma potassiumand creatinine were measured by automatic biochemistry analyzer; brainnatriuretic peptide (BNP) was assessed by ELISA; LVEF weredetermined by ultrasonic cardiogram. Each rat's survival time duringintervention was recorded.
Results (1) Each group plasma concentrations of potassium andcreatinine showed no significant differences between pre-intervention andpost-intervention (P＞0.05). (2) Before intervention, plasmaconcentrations of BNP of each DCM group were higher than those of thenormal group (P＜0.05). In both perindopril group and combinationtherapy group, plasma concentrations of BNP were much lower afterintervention compared with those before intervention (P＜0.01).However, plasma concentrations of BNP decreased more in thecombination therapy group than in the perindopril group (P＜0.01). (3)Before intervention, LVEF of each DCM group was lower than that of thenormal group (P＜0.05). LVEF in both perindopril group andcombination therapy group was much higher after intervention comparedwith that before intervention (P＜0.01). However, LVEF increased morein the combination therapy group than in the perindopril group (P＜0.05). (4) Log rank test showed that the life span of perindopril groupwas longer than that of the DCM-control group (P＜0.05), but wasshorter than that of the combination therapy group (P＜0.05). Coxregression analysis showed that combination therapy or onlyadministering perindopril could prolong the survival time, butcombination therapy's contribution was bigger.
Conclusions (1) Rats with DCM have elevated plasmaconcentrations of BNP and decreased LVEF. (2) Both monotherapy withperindopril and combination therapy with half of the conventional dosagefor CHF of perindopril and half of the conventional dosage for CHF ofirbesartan in a rat model of DCM can reduce the plasma concentrations ofBNP, increase LVEF and prolong survival time. (3) Combinationtherapy can more effectively improve left ventricular function andprognosis in rats with DCM than monotherapy with perindopril.
Chapter 2The effects of combination therapy with perindopril and irbesartanon the expression of AT_1 receptor and lamin A and NF-κB in themyocardium of a rat model of dilated cardiomyopathy
Background Many clinical trials about combination therapy withACEIs and ARBs in CHF have been reported, but the related mechanismshave not been fully illuminated. The renin-angiotensin system (RAS) isactivated in patients with CHF; the mutation or deficiency of theexpression of lamin A/C may induce DCM; and the NF-kappa B(NF-κB)is over activated in the myocardium of patients with CHF. All thesefindings imply that the changes of expression of angiotensinⅡtype 1receptors (AT_1Rs) and lamin A/C and NF-κB might participate in thepathogenesis of DCM. It is worth investigating if combination therapywith ACEIs and ARBs might more obviously affect these factors toachieve better therapeutic effects on CHF of DCM.
Objective To evaluate the effects of combination therapy withperindopril and irbesartan on the mRNA expression of AT_1Rs and laminA and on the protein expression of NF-κB in the myocardium of the ratswith DCM.
Methods The methods of inducing an animal model of DCM,grouping for drug treatment, and measuring LVEF and BNP have beenmentioned in the chapter one. The mRNA expression of AT_1Rs and laminA in the myocardium was detected by reverse transcription-polymerasechain reaction (RT-PCR); the pathological lesions of cardiac muscletissues after HE staining were evaluated by light microscope; and theprotein expression of NF-κB was assessed by immunohistochemistry.
Results (1) Compared with those in the normal group, expressionlevels of AT_1Rs in the DCM-control group were down-regulated (P＜0.05). Compared with those in the DCM-control group, expression levelsof AT_1Rs in both perindopril group and combination therapy group wereup-regulated (P＜0.05). Expression levels of AT_1Rs were more obviously up-regulated in the combination therapy group than in theperindopril group (P＜0.01). (2) Compared with those in the normalgroup, expression levels of lamin A in the DCM-control group weredown-regulated (P＜0.05). Expression levels of lamin A in thecombination therapy group were higher than those in the DCM-controlgroup (P＜0.05). (3) Compared with those in the normal group,cardiac muscle tissues in the DCM-control group were obviouslydamaged. Compared with those in the DCM-control group, pathologicallesions of cardiac muscle tissues in both perindopril group andcombination therapy group were attenuated (P＜0.01). (4) Comparedwith that in the normal group, NF-κB in the DCM-control group wasmore obviously expressed (P＜0.05). Compared with that in theDCM-control group, obviously expressed NF-κB was attenuated in bothperindopril group and combination therapy group (P＜0.05). Obviouslyexpressed NF-κB was attenuated more in the combination therapy groupthan in the perindopril group (P＜0.05).
Conclusions (1) Down-regulation of the expression of AT_1Rsand lamin A, and the over-expression of NF-κB might participate in thepathogenesis of DCM. (2) Both monotherapy with perindopril andcombination therapy with perindopril and irbesartan can attenuatepathological lesions of cardiac muscle tissues. (3) Both monotherapywith perindopril and combination therapy can up-regulate the expressionof AT_1Rs and attenuate the expression of NF-κB, and the combinationtherapy's effects are more obvious. Furthermore, combination therapy canup-regulate the expression of lamin A. The effects of combination therapyon the expression of AT_1Rs, lamin A and NF-κB may contribute to thebetter therapeutic effects on heart failure.
Chapter 3The therapeutic effects of combination therapy with low dose ofperindopril and irbesartan in patientswith dilated cardiomyopathy
Background The prognosis of DCM is very poor, and in China,the 5-year survival rate is about 65.3％after the symptom occurs.Nowadays, therapeutic measures, such as heart transplantation, leftventricular reconstruction operation and cardiac resynchronizationtherapy are used in clinic, but these measures are too expensive to bewidely used. Since 1990s, there were clinical trials investigating ifcombination therapy with ACEIs and ARBs could produce better effectson patients with CHF. In 2005, combination therapy with ACEIs andARBs was suggested in the guideline of CHF. But until now, it is notclear what is the appropriate dose of combination therapy with ACEIs andARBs in treating patients with DCM.
Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on patients with DCM and the relatedadverse reactions.
Methods 60 hospitalized patients or outpatients with DCM wereenrolled, and the patients were randomly divided into two groups,conventional therapy group (n=30) and combination therapy group (n=30). The age, sex, patient's condition, and course of disease showed nosignificant differences between the conventional therapy group and thecombination therapy group. The conventional therapy group wasadministered perindopril 4mg/d and the combination therapy group wasadministered perindopril 2mg/d and irbesartan 75mg/d. The othertherapeutic measures in these two groups were just the same. Plasmapotassium and creatinine were studied by automatic biochemistryanalyzer; brain natriuretic peptide (BNP) was assessed by ELISA; leftventricular ejection fraction (LVEF) were measured by ultrasoniccardiogram.
Results (1) In both groups, cardiac function was improved afterdrug treatment (P＜0.05; P＜0.01); cardiac function was moremarkedly improved in the combination therapy group than in theconventional therapy group (P＜0.05). (2) In both groups, plasmaconcentrations of BNP were much lower after drug treatment (P＜0.01),however, plasma concentrations of BNP in the combination therapygroup was lower than those in the conventional therapy group (P＜0.05).(3) In both groups, LVEF was much higher after drug treatment (P＜0.01), but LVEF in the combination therapy group was higher than thatin the conventional therapy group (P＜0.05). (4) In each group, plasmaconcentrations of potassium and creatinine showed no significantdifferences between pre-intervention and post-intervention (P＞0.05).
Conclusions (1) Both monotherapy with pedndopril andcombination therapy with half of the conventional dosage for CHF ofperindopril and half of the conventional dosage for CHF of irbesartan inpatients with DCM can improve cardiac function, reduce the plasmaconcentrations of BNP and increase LVEF. (2) Combination therapywith perindopril and irbesartan in patients with DCM can moreeffectively improve cardiac function, reduce the plasma concentrations ofBNP and increase LVEF than monotherapy with perindopril, withoutincreased adverse reactions.
引文
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