射血分数保留型心衰:机制与治疗的新视点
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摘要
射血分数保留型心衰是最常见的心衰形式,其治疗仍是临床面临的重大挑战。本文综述了射血分数保留型心衰的三种血流动力学机制和三种潜在的分子机制,前者包括左心室充血/舒张功能障碍/左心房高压、肺血管病/右心室功能障碍、血浆容量扩大,后者则包括全身微血管炎症、心脏代谢功能异常、细胞(肌联蛋白)/细胞外(纤维化)结构异常。结合已经完成或正在进行的相关药物治疗试验结果,介绍了基于上述发病机制的治疗策略。最后,简要介绍了这类心衰的常见并发症(如心肌缺血、心房颤动、高血压等)的管理措施。
Heart failure with preserved ejection fraction(HFpEF) is the most common form of heart failure,and its treatment is still a big challenge in clinic. This paper reviews three hemodynamic mechanisms and three potential molecular mechanisms,respectively. The former includes left ventricular hyperemia(diastolic dysfunction or left atrial hypertension),pulmonary vascular disease(right ventricular dysfunction) and plasma volume expansion. The latter includes systemic microvascular inflammation,cardiac metabolic dysfunction,and cellular(titin) or extracellular(fibrosis) structural abnormalities. In combination with the test results of related drug therapy being completed or in progress,this paper also introduces corresponding therapeutic strategies based on the above pathogenesises.Finally,managerial measures of complications of HFpEF(including myocardial ischemia,atrial fibrillation and hypertension) are briefly introduced.
Heart failure with preserved ejection fraction(HFpEF) is the most common form of heart failure,and its treatment is still a big challenge in clinic. This paper reviews three hemodynamic mechanisms and three potential molecular mechanisms,respectively. The former includes left ventricular hyperemia(diastolic dysfunction or left atrial hypertension),pulmonary vascular disease(right ventricular dysfunction) and plasma volume expansion. The latter includes systemic microvascular inflammation,cardiac metabolic dysfunction,and cellular(titin) or extracellular(fibrosis) structural abnormalities. In combination with the test results of related drug therapy being completed or in progress,this paper also introduces corresponding therapeutic strategies based on the above pathogenesises.Finally,managerial measures of complications of HFpEF(including myocardial ischemia,atrial fibrillation and hypertension) are briefly introduced.
引文
[1]Lam CSP,Voors AA,de Boer RA,et al.Heart failure with preserved ejection fraction:from mechanisms to therapies[J].Eur Heart J,2018,39(30):2780-2792.
[2]Ponikowski P,Voors AA,Anker SD,et al.2016 ESCguidelines for the diagnosis and treatment of acute and chronic heart failure:the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology(ESC).Developed with the special contribution of the Heart Failure Association(HFA)of the ESC[J].Eur Heart J,2016,37(27):2129-2200.
[3]Bamaiyi AJ,Woodiwiss AJ,Peterson V,et al.Insulin resistance influences the impact of hypertension on left ventricular diastolic dysfunction in a community sample[J].Clin Cardiol,2019,42(2):305-311.
[4]Varga ZV,Giricz Z,Liaudet L,et al.Interplay of oxidative,nitrosative/nitrative stress,inflammation,cell death and autophagy in diabetic cardiomyopathy[J].Biochim Biophys Acta,2015,1852(2):232-242.
[5]Zhang X,Zhang Z,Yang Y,et al.Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits[J].Cardiovasc Diabetol,2018,17(1):160.
[6]Zile MR,Baicu CF,Gaasch WH.Diastolic heart failureabnormalities in active relaxation and passive stiffness of the left ventricle[J].N Engl J Med,2004,350(19):1953-1959.
[7]Reddy YNV,Andersen MJ,Obokata M,et al.Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction[J].J Am Coll Cardiol,2017,70(2):136-148.
[8]Sanchis L,Gabrielli L,Andrea R,et al.Left atrial dysfunction relates to symptom onset in patients with heart failure and preserved left ventricular ejection fraction[J].Eur Heart J Cardiovasc Imaging,2015,16(1):62-67.
[9]Freed BH,Daruwalla V,Cheng JY,et al.Prognostic utility and clinical significance of cardiac mechanics in heart failure with preserved ejection fraction:Importance of left atrial strain[J].Circ Cardiovasc Imaging,2016,9(3):1-10.
[10]Hasenfu G,Hayward C,Burkhoff D,et al.A transcatheter intracardiac shunt device for heart failure with preserved ejectionfraction(REDUCE LAP-HF):a multicentre,open-label,single-arm,phase 1 trial[J].Lancet,2016,387(10025):1298-1304.
[11]Adamson PB,Abraham WT,Bourge RC,et al.Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction[J].Circ Heart Fail,2014,7(6):935-944.
[12]Gorter TM,Hoendermis ES,van Veldhuisen DJ,et al.Right ventricular dysfunction in heart failure with preserved ejection fraction:a systematic review and meta-analysis[J].Eur J Heart Fail,2016,18(12):1472-1487.
[13]Gorter TM,van Veldhuisen DJ,Bauersachs J,et al.Right heart dysfunction and failure in heart failure with preserved ejection fraction:Mechanisms and management.Position statement on behalf of the heart failure association of the European Society of Cardiology[J].Eur JHeart Fail,2018,20(1):16-37.
[14]Borlaug BA,Kane GC,Melenovsky V,et al.Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction[J].Eur Heart J,2016,37(43):3293-3302.
[15]Borlaug BA,Obokata M.Is it time to recognize a new phenotype Heart failure with preserved ejection fraction with pulmonary vascular disease[J].Eur Heart J,2017,38(38):2874-2878.
[16]Olson TP,Johnson BD,Borlaug BA.Impaired pulmonary diffusion in heart failure with preserved ejection fraction[J].JACC Heart Fail,2016,4(6):490-498.
[17]Hoeper MM,Meyer K,Rademacher J,et al.Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction[J].JACC Heart Fail,2016,4(6):441-449.
[18]Fayyaz AU,Edwards WD,Maleszewski JJ,et al.Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction[J].Circulation,2018,137(17):1796-1810.
[19]Hoendermis ES,Liu LC,Hummel YM,et al.Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension:a randomized controlled trial[J].Eur Heart J,2015,36(38):2565-2573.
[20]Andersen MJ,Hwang SJ,Kane GC,et al.Enhanced pulmonary vasodilator reserve and abnormal right ventricular:Pulmonary artery coupling in heart failure with preserved ejection fraction[J].Circ Heart Fail,2015,8(3):542-550.
[21]Obokata M,Reddy YNV,Pislaru SV,et al.Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction[J].Circulation,2017,136(1):6-19.
[22]Borlaug BA,Carter RE,Melenovsky V,et al.Percutaneous pericardial resection:A novel potential treatment for heart failure with preserved ejection fraction[J].Circ Heart Fail,2017,10(4):1-8.
[23]Heise T,Jordan J,Wanner C,et al.Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes[J].Clin Ther,2016,38(10):2265-2276.
[24]Inzucchi SE,Zinman B,Wanner C,et al.Sglt-2 inhibitors and cardiovascular risk:Proposed pathways and review of ongoing outcome trials[J].Diab Vasc Dis Res,2015,12(2):90-100.
[25]Bouchi R,Terashima M,Sasahara Y,et al.Luseogliflozin reduces epicardial fat accumulation in patients with type2 diabetes:a pilot study[J].Cardiovasc Diabetol,2017,16(1):32.
[26]Glezeva N,Baugh JA.Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target[J].Heart Fail Rev,2014,19(5):681-694.
[27]van Tassell BW,Buckley LF,Carbone S,et al.Interleukin-1 blockade in heart failure with preserved ejection fraction:Rationale and design of the diastolic heart failure anakinra response trial 2(d-hart2)[J].Clin Cardiol,2017,40(9):626-632.
[28]Redfield MM,Anstrom KJ,Levine JA,et al.Isosorbide mononitrate in heart failure with preserved ejection fraction[J].N Engl J Med,2015,373(24):2314-2324.
[29]Borlaug BA,Koepp KE,Melenovsky V.Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction[J].J Am Coll Cardiol,2015,66(15):1672-1682.
[30]Borlaug BA,Melenovsky V,Koepp KE.Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction[J].Circ Res,2016,119(7):880-886.
[31]Molina AJ,Bharadwaj MS,van Horn C,et al.Skeletal muscle mitochondrial content,oxidative capacity,and mfn2 expression are reduced in older patients with heart failure and preserved ejection fraction and are related to exercise intolerance[J].JACC Heart Fail,2016,4(8):636-645.
[32]Zile MR,Baicu CF,Ikonomidis JS,et al.Myocardial stiffness in patients with heart failure and a preserved ejection fraction:contributions of collagen and titin[J].Circulation,2015,131(14):1247-1259.
[33]Methawasin M,Strom JG,Slater RE,et al.Experimentally increasing the compliance of titin through rna binding motif-20(rbm20)inhibition improves diastolic function in a mouse model of heart failure with preserved ejection fraction[J].Circulation,2016,134(15):1085-1099.
[34]Hwang SJ,Melenovsky V,Borlaug BA.Implications of coronary artery disease in heart failure with preserved ejection fraction[J].J Am Coll Cardiol,2014,63(25 Pt A):2817-2827.
[35]Rusinaru D,Houpe D,Szymanski C,et al.Coronary artery disease and 10-year outcome after hospital admission for heart failure with preserved and with reduced ejection fraction[J].Eur J Heart Fail,2014,16(9):967-976.
[36]Mohammed SF,Hussain S,Mirzoyev SA,et al.Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction[J].Circulation,2015,131(6):550-559.
[37]Zakeri R,Borlaug BA,McNulty SE,et al.Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction:a relax trial ancillary study[J].Circ Heart Fail,2014,7(1):123-130.
[38]Morawietz H,Bornstein SR.Spironolactone for heart failure with preserved ejection fraction[J].N Engl J Med,2014,371(2):179-182.
[2]Ponikowski P,Voors AA,Anker SD,et al.2016 ESCguidelines for the diagnosis and treatment of acute and chronic heart failure:the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology(ESC).Developed with the special contribution of the Heart Failure Association(HFA)of the ESC[J].Eur Heart J,2016,37(27):2129-2200.
[3]Bamaiyi AJ,Woodiwiss AJ,Peterson V,et al.Insulin resistance influences the impact of hypertension on left ventricular diastolic dysfunction in a community sample[J].Clin Cardiol,2019,42(2):305-311.
[4]Varga ZV,Giricz Z,Liaudet L,et al.Interplay of oxidative,nitrosative/nitrative stress,inflammation,cell death and autophagy in diabetic cardiomyopathy[J].Biochim Biophys Acta,2015,1852(2):232-242.
[5]Zhang X,Zhang Z,Yang Y,et al.Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits[J].Cardiovasc Diabetol,2018,17(1):160.
[6]Zile MR,Baicu CF,Gaasch WH.Diastolic heart failureabnormalities in active relaxation and passive stiffness of the left ventricle[J].N Engl J Med,2004,350(19):1953-1959.
[7]Reddy YNV,Andersen MJ,Obokata M,et al.Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction[J].J Am Coll Cardiol,2017,70(2):136-148.
[8]Sanchis L,Gabrielli L,Andrea R,et al.Left atrial dysfunction relates to symptom onset in patients with heart failure and preserved left ventricular ejection fraction[J].Eur Heart J Cardiovasc Imaging,2015,16(1):62-67.
[9]Freed BH,Daruwalla V,Cheng JY,et al.Prognostic utility and clinical significance of cardiac mechanics in heart failure with preserved ejection fraction:Importance of left atrial strain[J].Circ Cardiovasc Imaging,2016,9(3):1-10.
[10]Hasenfu G,Hayward C,Burkhoff D,et al.A transcatheter intracardiac shunt device for heart failure with preserved ejectionfraction(REDUCE LAP-HF):a multicentre,open-label,single-arm,phase 1 trial[J].Lancet,2016,387(10025):1298-1304.
[11]Adamson PB,Abraham WT,Bourge RC,et al.Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction[J].Circ Heart Fail,2014,7(6):935-944.
[12]Gorter TM,Hoendermis ES,van Veldhuisen DJ,et al.Right ventricular dysfunction in heart failure with preserved ejection fraction:a systematic review and meta-analysis[J].Eur J Heart Fail,2016,18(12):1472-1487.
[13]Gorter TM,van Veldhuisen DJ,Bauersachs J,et al.Right heart dysfunction and failure in heart failure with preserved ejection fraction:Mechanisms and management.Position statement on behalf of the heart failure association of the European Society of Cardiology[J].Eur JHeart Fail,2018,20(1):16-37.
[14]Borlaug BA,Kane GC,Melenovsky V,et al.Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction[J].Eur Heart J,2016,37(43):3293-3302.
[15]Borlaug BA,Obokata M.Is it time to recognize a new phenotype Heart failure with preserved ejection fraction with pulmonary vascular disease[J].Eur Heart J,2017,38(38):2874-2878.
[16]Olson TP,Johnson BD,Borlaug BA.Impaired pulmonary diffusion in heart failure with preserved ejection fraction[J].JACC Heart Fail,2016,4(6):490-498.
[17]Hoeper MM,Meyer K,Rademacher J,et al.Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction[J].JACC Heart Fail,2016,4(6):441-449.
[18]Fayyaz AU,Edwards WD,Maleszewski JJ,et al.Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction[J].Circulation,2018,137(17):1796-1810.
[19]Hoendermis ES,Liu LC,Hummel YM,et al.Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension:a randomized controlled trial[J].Eur Heart J,2015,36(38):2565-2573.
[20]Andersen MJ,Hwang SJ,Kane GC,et al.Enhanced pulmonary vasodilator reserve and abnormal right ventricular:Pulmonary artery coupling in heart failure with preserved ejection fraction[J].Circ Heart Fail,2015,8(3):542-550.
[21]Obokata M,Reddy YNV,Pislaru SV,et al.Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction[J].Circulation,2017,136(1):6-19.
[22]Borlaug BA,Carter RE,Melenovsky V,et al.Percutaneous pericardial resection:A novel potential treatment for heart failure with preserved ejection fraction[J].Circ Heart Fail,2017,10(4):1-8.
[23]Heise T,Jordan J,Wanner C,et al.Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes[J].Clin Ther,2016,38(10):2265-2276.
[24]Inzucchi SE,Zinman B,Wanner C,et al.Sglt-2 inhibitors and cardiovascular risk:Proposed pathways and review of ongoing outcome trials[J].Diab Vasc Dis Res,2015,12(2):90-100.
[25]Bouchi R,Terashima M,Sasahara Y,et al.Luseogliflozin reduces epicardial fat accumulation in patients with type2 diabetes:a pilot study[J].Cardiovasc Diabetol,2017,16(1):32.
[26]Glezeva N,Baugh JA.Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target[J].Heart Fail Rev,2014,19(5):681-694.
[27]van Tassell BW,Buckley LF,Carbone S,et al.Interleukin-1 blockade in heart failure with preserved ejection fraction:Rationale and design of the diastolic heart failure anakinra response trial 2(d-hart2)[J].Clin Cardiol,2017,40(9):626-632.
[28]Redfield MM,Anstrom KJ,Levine JA,et al.Isosorbide mononitrate in heart failure with preserved ejection fraction[J].N Engl J Med,2015,373(24):2314-2324.
[29]Borlaug BA,Koepp KE,Melenovsky V.Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction[J].J Am Coll Cardiol,2015,66(15):1672-1682.
[30]Borlaug BA,Melenovsky V,Koepp KE.Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction[J].Circ Res,2016,119(7):880-886.
[31]Molina AJ,Bharadwaj MS,van Horn C,et al.Skeletal muscle mitochondrial content,oxidative capacity,and mfn2 expression are reduced in older patients with heart failure and preserved ejection fraction and are related to exercise intolerance[J].JACC Heart Fail,2016,4(8):636-645.
[32]Zile MR,Baicu CF,Ikonomidis JS,et al.Myocardial stiffness in patients with heart failure and a preserved ejection fraction:contributions of collagen and titin[J].Circulation,2015,131(14):1247-1259.
[33]Methawasin M,Strom JG,Slater RE,et al.Experimentally increasing the compliance of titin through rna binding motif-20(rbm20)inhibition improves diastolic function in a mouse model of heart failure with preserved ejection fraction[J].Circulation,2016,134(15):1085-1099.
[34]Hwang SJ,Melenovsky V,Borlaug BA.Implications of coronary artery disease in heart failure with preserved ejection fraction[J].J Am Coll Cardiol,2014,63(25 Pt A):2817-2827.
[35]Rusinaru D,Houpe D,Szymanski C,et al.Coronary artery disease and 10-year outcome after hospital admission for heart failure with preserved and with reduced ejection fraction[J].Eur J Heart Fail,2014,16(9):967-976.
[36]Mohammed SF,Hussain S,Mirzoyev SA,et al.Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction[J].Circulation,2015,131(6):550-559.
[37]Zakeri R,Borlaug BA,McNulty SE,et al.Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction:a relax trial ancillary study[J].Circ Heart Fail,2014,7(1):123-130.
[38]Morawietz H,Bornstein SR.Spironolactone for heart failure with preserved ejection fraction[J].N Engl J Med,2014,371(2):179-182.