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  • Review Article
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Cellular and molecular pathobiology of heart failure with preserved ejection fraction

Nature Reviews Cardiology volume 18, pages 400–423 (2021)Cite this article

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A Publisher Correction to this article was published on 21 January 2021

This article has been updated

Abstract

Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments. HFpEF is arguably the greatest unmet medical need in cardiovascular disease. Although HFpEF was initially considered to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have modified the HFpEF syndrome, which is now recognized to be a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, and immune and inflammatory signalling. This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. However, new animal models involving both haemodynamic and metabolic disease, and increasing efforts to examine human pathophysiology, are revealing new signalling pathways and potential therapeutic targets. In this Review, we discuss the cellular and molecular pathobiology of HFpEF, with the major focus being on mechanisms relevant to the heart, because most research has focused on this organ. We also highlight the involvement of other important organ systems, including the lungs, kidneys and skeletal muscle, efforts to characterize patients with the use of systemic biomarkers, and ongoing therapeutic efforts. Our objective is to provide a roadmap of the signalling pathways and mechanisms of HFpEF that are being characterized and which might lead to more patient-specific therapies and improved clinical outcomes.

Key points

  • The historical focus of studies into the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has been on diastolic dysfunction, cardiac hypertrophy and myocardial fibrosis.

  • However, HFpEF actually involves many different components affecting both systolic and diastolic heart function and also other organs and systems, including the lungs, kidneys, vasculature, adipose tissue and skeletal muscle.

  • Preclinical studies, particularly those combining obesity and metabolic defects with haemodynamic and cardiac disease as occurs in the majority of patients with HFpEF, are beginning to reveal novel molecular mechanisms and therapeutic targets.

  • The proposed molecular and cellular abnormalities in HFpEF and those observed in diabetes mellitus and obesity overlap substantially, including metabolic defects in fuel utilization and efficiency, inflammatory responses, lipotoxicity, pathological growth of myocytes and loss of cytoprotective signalling.

  • In addition to exploring novel haemodynamic interventions with drugs and devices, new therapies are targeting pleiotropic signalling cascades to counteract changes in metabolic, inflammatory and pathological stress pathways.

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Fig. 1: Signalling pathways in cardiac hypertrophy.
Fig. 2: Fibrotic–inflammatory remodelling in heart failure with preserved ejection fraction.
Fig. 3: Components of the cGMP–PKG signalling systems and their cellular effectors.
Fig. 4: Dysregulated oxidative and nitrosative stress in HFpEF pathogenesis.
Fig. 5: Metabolic flexibility and HFpEF.

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References

  1. Gladden, J. D., Chaanine, A. H. & Redfield, M. M. Heart failure with preserved ejection fraction. Ann. Rev. Med. 69, 65–79 (2018).

    CAS  PubMed  Google Scholar 

  2. Lam, C. S. P. et al. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study. Eur. Heart J. 39, 1770–1780 (2018).

    CAS  PubMed  Google Scholar 

  3. Zakeri, R. & Cowie, M. R. Heart failure with preserved ejection fraction: controversies, challenges and future directions. Heart 104, 377–384 (2018).

    CAS  PubMed  Google Scholar 

  4. Shah, S. J. et al. Research priorities for heart failure with preserved ejection fraction: National Heart, Lung, and Blood Institute working group summary. Circulation 141, 1001–1026 (2020).

    PubMed  PubMed Central  Google Scholar 

  5. Dodek, A., Kassebaum, D. G. & Bristow, J. D. Pulmonary edema in coronary-artery disease without cardiomegaly. Paradox of the stiff heart. N. Engl. J. Med. 286, 1347–1350 (1972).

    CAS  PubMed  Google Scholar 

  6. Dougherty, A. H., Naccarelli, G. V., Gray, E. L., Hicks, C. H. & Goldstein, R. A. Congestive heart failure with normal systolic function. Am. J. Cardiol. 54, 778–782 (1984).

    CAS  PubMed  Google Scholar 

  7. Soufer, R. et al. Intact systolic left ventricular function in clinical congestive heart failure. Am. J. Cardiol. 55, 1082–1086 (1985).

    Google Scholar 

  8. Topol, E. J., Traill, T. A. & Fortuin, N. J. Hypertensive hypertrophic cardiomyopathy of the elderly. N. Engl. J. Med. 312, 277–283 (1985).

    CAS  PubMed  Google Scholar 

  9. Vasan, R. S. et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J. Am. Coll. Cardiol. 33, 1948–1955 (1999).

    CAS  PubMed  Google Scholar 

  10. Owan, T. E. et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N. Engl. J. Med. 355, 251–259 (2006).

    CAS  PubMed  Google Scholar 

  11. Melenovsky, V. et al. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J. Am. Coll. Cardiol. 49, 198–207 (2007).

    PubMed  Google Scholar 

  12. Kawaguchi, M., Hay, I., Fetics, B. & Kass, D. A. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 107, 714–720 (2003).

    PubMed  Google Scholar 

  13. Borlaug, B. A., Lam, C. S., Roger, V. L., Rodeheffer, R. J. & Redfield, M. M. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 54, 410–418 (2009).

    PubMed  PubMed Central  Google Scholar 

  14. Borlaug, B. A. et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 114, 2138–2147 (2006).

    PubMed  Google Scholar 

  15. Phan, T. T. et al. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ. Heart Fail. 3, 29–34 (2010).

    PubMed  Google Scholar 

  16. Dominguez, E. et al. Heart rate response and functional capacity in patients with chronic heart failure with preserved ejection fraction. ESC. Heart Fail. 5, 579–585 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Lam, C. S. et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J. Am. Coll. Cardiol. 53, 1119–1126 (2009).

    PubMed  PubMed Central  Google Scholar 

  18. Thenappan, T., Prins, K. W., Cogswell, R. & Shah, S. J. Pulmonary hypertension secondary to heart failure with preserved ejection fraction. Can. J. Cardiol. 31, 430–439 (2015).

    PubMed  Google Scholar 

  19. Borlaug, B. A., Kane, G. C., Melenovsky, V. & Olson, T. P. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur. Heart J. 37, 3293–3302 (2016).

    PubMed  Google Scholar 

  20. Gorter, T. M. 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. Eur. J. Heart Fail. 20, 16–37 (2018).

    PubMed  Google Scholar 

  21. Levine, A. R., Simon, M. A. & Gladwin, M. T. Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction. Trends Cardiovasc. Med. 29, 207–217 (2019).

    PubMed  Google Scholar 

  22. Ghio, S. et al. Pulmonary hypertension and right ventricular remodeling in HFpEF and HFrEF. Heart Fail. Rev. 25, 85–91 (2020).

    PubMed  Google Scholar 

  23. Norman, H. S. et al. Decreased cardiac functional reserve in heart failure with preserved systolic function. J. Card. Fail. 17, 301–308 (2011).

    PubMed  Google Scholar 

  24. Borlaug, B. A. et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 56, 845–854 (2010).

    PubMed  PubMed Central  Google Scholar 

  25. Borlaug, B. A. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ. J. 78, 20–32 (2013).

    PubMed  Google Scholar 

  26. Gorter, T. M., Obokata, M., Reddy, Y. N. V., Melenovsky, V. & Borlaug, B. A. Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease. Eur. Heart J. 39, 2825–2835 (2018).

    PubMed  PubMed Central  Google Scholar 

  27. Del Buono, M. G. et al. Exercise intolerance in patients with heart failure: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73, 2209–2225 (2019).

    PubMed  Google Scholar 

  28. Kitzman, D. W. & Shah, S. J. The HFpEF obesity phenotype: the elephant in the room. J. Am. Coll. Cardiol. 68, 200–203 (2016).

    PubMed  Google Scholar 

  29. Paulus, W. J. & Tschope, C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. Coll. Cardiol. 62, 263–271 (2013).

    PubMed  Google Scholar 

  30. Obokata, M., Reddy, Y. N. V., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136, 6–19 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Forman, D. E. & Goodpaster, B. H. Weighty matters in HFpEF and aging. JACC Heart Fail. 6, 650–652 (2018).

    PubMed  Google Scholar 

  32. Westermann, D. et al. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ. Heart Fail. 4, 44–52 (2011).

    PubMed  Google Scholar 

  33. D’Elia, E. et al. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur. J. Heart Fail. 17, 1231–1239 (2015).

    PubMed  Google Scholar 

  34. Abernethy, A. et al. Pro-inflammatory biomarkers in stable versus acutely decompensated heart failure with preserved ejection fraction. J. Am. Heart Assoc. 7, e007385 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. Chirinos, J. A. et al. Multiple plasma biomarkers for risk stratification in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 75, 1281–1295 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. DuBrock, H. M., AbouEzzeddine, O. F. & Redfield, M. M. High-sensitivity C-reactive protein in heart failure with preserved ejection fraction. PLoS ONE 13, e0201836 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Mohammed, S. F. et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131, 550–559 (2015).

    PubMed  Google Scholar 

  38. Lee, J. F. et al. Evidence of microvascular dysfunction in heart failure with preserved ejection fraction. Heart 102, 278–284 (2016).

    CAS  PubMed  Google Scholar 

  39. Franssen, C. et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail. 4, 312–324 (2016).

    PubMed  Google Scholar 

  40. Zeng, H. & Chen, J. X. Microvascular rarefaction and heart failure with preserved ejection fraction. Front. Cardiovasc. Med. 6, 15 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. D’Amario, D. et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front. Physiol. 10, 1347 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. Haykowsky, M. J. et al. Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass. J. Gerontol. A Biol. Sci. Med. Sci. 68, 968–975 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kitzman, D. W. et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am. J. Physiol. Heart Circ. Physiol. 306, H1364–H1370 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Haykowsky, M. J. et al. Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am. J. Cardiol. 113, 1211–1216 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. Dhakal, B. P. et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ. Heart Fail. 8, 286–294 (2015).

    PubMed  Google Scholar 

  46. Hirai, D. M., Musch, T. I. & Poole, D. C. Exercise training in chronic heart failure: improving skeletal muscle O2 transport and utilization. Am. J. Physiol. Heart Circ. Physiol. 309, H1419–H1439 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tromp, J. et al. Heart failure with preserved ejection fraction in Asia. Eur. J. Heart Fail. 21, 23–36 (2019).

    PubMed  Google Scholar 

  48. McHugh, K. et al. Heart failure with preserved ejection fraction and diabetes: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73, 602–611 (2019).

    PubMed  Google Scholar 

  49. Shear, F. E. Novel paradigms in the therapeutic management of heart failure with preserved ejection fraction: clinical perspectives. Am. J. Cardiovasc. Dis. 9, 91–108 (2019).

    PubMed  PubMed Central  Google Scholar 

  50. Wintrich, J. et al. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future. Clin. Res. Cardiol. 109, 1079–1098 (2020).

    PubMed  PubMed Central  Google Scholar 

  51. Paulus, W. J. Unfolding discoveries in heart failure. N. Engl. J. Med. 382, 679–682 (2020).

    PubMed  Google Scholar 

  52. Okayama, H. et al. Alterations in expression of sarcoplasmic reticulum gene in Dahl rats during the transition from compensatory myocardial hypertrophy to heart failure. J. Hypertens. 15, 1767–1774 (1997).

    CAS  PubMed  Google Scholar 

  53. Qu, P. et al. Time-course changes in left ventricular geometry and function during the development of hypertension in Dahl salt-sensitive rats. Hypertens. Res. 23, 613–623 (2000).

    CAS  PubMed  Google Scholar 

  54. Chen-Izu, Y. et al. Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development. Am. J. Physiol. Heart Circ. Physiol. 293, H3301–H3310 (2007).

    PubMed  Google Scholar 

  55. Weber, K. T., Janicki, J. S., Pick, R., Capasso, J. & Anversa, P. Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am. J. Cardiol. 65, 1G–7G (1990).

    CAS  PubMed  Google Scholar 

  56. Fillmore, N. et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol. Med. 24, 3 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. Nagata, K. et al. Early changes in excitation-contraction coupling: transition from compensated hypertrophy to failure in Dahl salt-sensitive rat myocytes. Cardiovasc. Res. 37, 467–477 (1998).

    CAS  PubMed  Google Scholar 

  58. Capasso, J. M., Palackal, T., Olivetti, G. & Anversa, P. Left ventricular failure induced by long-term hypertension in rats. Circ. Res. 66, 1400–1412 (1990).

    CAS  PubMed  Google Scholar 

  59. Lupon, J. et al. Heart failure with preserved ejection fraction infrequently evolves toward a reduced phenotype in long-term survivors. Circ. Heart Fail. 12, e005652 (2019).

    PubMed  Google Scholar 

  60. Nishio, M. et al. Therapeutic effects of angiotensin II type 1 receptor blocker at an advanced stage of hypertensive diastolic heart failure. J. Hypertens. 25, 455–461 (2007).

    CAS  PubMed  Google Scholar 

  61. Yamamoto, K. et al. Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc. Res. 47, 274–283 (2000).

    CAS  PubMed  Google Scholar 

  62. Wake, R. et al. Beneficial effect of candesartan on rat diastolic heart failure. J. Pharmacol. Sci. 98, 372–379 (2005).

    CAS  PubMed  Google Scholar 

  63. Yoshida, J. et al. AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure. Hypertension 43, 686–691 (2004).

    CAS  PubMed  Google Scholar 

  64. Jeong, M. Y. et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci. Transl. Med. 10, eaao0144 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Wallner, M. et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci. Transl. Med. 12, eaay7205 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gallet, R. et al. Cardiosphere-derived cells reverse heart failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation. JACC Basic Transl. Sci. 1, 14–28 (2016).

    PubMed  PubMed Central  Google Scholar 

  67. Fein, F. S. & Sonnenblick, E. H. Diabetic cardiomyopathy. Prog. Cardiovasc. Dis. 27, 255–270 (1985).

    CAS  PubMed  Google Scholar 

  68. Jia, G., Hill, M. A. & Sowers, J. R. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ. Res. 122, 624–638 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Tofovic, S. P., Kusaka, H., Kost, C. K. Jr & Bastacky, S. Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats. Ren. Fail. 22, 387–406 (2000).

    CAS  PubMed  Google Scholar 

  70. Leite, S. et al. Arterial remodeling and dysfunction in the ZSF1 rat model of heart failure with preserved ejection fraction. Circ. Heart Fail. 12, e005596 (2019).

    CAS  PubMed  Google Scholar 

  71. Boustany-Kari, C. M. et al. A soluble guanylate cyclase activator inhibits the progression of diabetic nephropathy in the ZSF1 rat. J. Pharmacol. Exp. Ther. 356, 712–719 (2016).

    CAS  PubMed  Google Scholar 

  72. Lai, Y. C. et al. SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 133, 717–731 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Hopf, A. E. et al. Diabetes-induced cardiomyocyte passive stiffening is caused by impaired insulin-dependent titin modification and can be modulated by neuregulin-1. Circ. Res. 123, 342–355 (2018).

    CAS  PubMed  Google Scholar 

  74. Salah, E. M., Bastacky, S. I., Jackson, E. K. & Tofovic, S. P. Captopril attenuates cardiovascular and renal disease in a rat model of heart failure with preserved ejection fraction. J. Cardiovasc. Pharmacol. 71, 205–214 (2018).

    CAS  PubMed  Google Scholar 

  75. Schiattarella, G. G. et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568, 351–356 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tong, D. et al. Female sex is protective in a preclinical model of heart failure with preserved ejection fraction. Circulation 140, 1769–1771 (2019).

    PubMed  PubMed Central  Google Scholar 

  77. Munagala, V. K., Hart, C. Y., Burnett, J. C. Jr., Meyer, D. M. & Redfield, M. M. Ventricular structure and function in aged dogs with renal hypertension: a model of experimental diastolic heart failure. Circulation 111, 1128–1135 (2005).

    PubMed  PubMed Central  Google Scholar 

  78. Reiter, U. et al. Early-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study. J. Cardiovasc. Magn. Reson. 18, 63 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Sorop, O. et al. Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc. Res. 114, 954–964 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Schwarzl, M. et al. A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction. Am. J. Physiol. Heart Circ. Physiol. 309, H1407–H1418 (2015).

    CAS  PubMed  Google Scholar 

  81. Redfield, M. M. et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309, 1268–1277 (2013).

    CAS  PubMed  Google Scholar 

  82. Reddy, Y. N. V., Carter, R. E., Obokata, M., Redfield, M. M. & Borlaug, B. A. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 138, 861–870 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Zile, M. R. et al. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation 124, 2491–2501 (2011).

    PubMed  Google Scholar 

  84. Lindman, B. R. et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J. Am. Coll. Cardiol. 64, 541–549 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. Armstrong, A. C. et al. Left ventricular mass and hypertrophy by echocardiography and cardiac magnetic resonance: the multi-ethnic study of atherosclerosis. Echocardiography 31, 12–20 (2014).

    PubMed  Google Scholar 

  86. Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).

    CAS  PubMed  Google Scholar 

  87. Wettschureck, N. et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/Gα11 in cardiomyocytes. Nat. Med. 7, 1236–1240 (2001).

    CAS  PubMed  Google Scholar 

  88. Zhang, W. et al. Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. J. Biol. Chem. 281, 5811–5820 (2006).

    CAS  PubMed  Google Scholar 

  89. Takimoto, E. et al. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J. Clin. Invest. 119, 408–420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Bishu, K. et al. Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction. Am. Heart J. 164, 763–770.e3 (2012).

    CAS  PubMed  Google Scholar 

  91. Tschope, C., Van Linthout, S. & Kherad, B. Heart failure with preserved ejection fraction and future pharmacological strategies: a glance in the crystal ball. Curr. Cardiol. Rep. 19, 70 (2017).

    PubMed  Google Scholar 

  92. Sztechman, D., Czarzasta, K., Cudnoch-Jedrzejewska, A., Szczepanska-Sadowska, E. & Zera, T. Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries. J. Physiol. Pharmacol. 69, 829–845 (2018).

    CAS  Google Scholar 

  93. Fraccarollo, D. et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation 123, 400–408 (2011).

    CAS  PubMed  Google Scholar 

  94. Rickard, A. J. et al. Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis. Hypertension 60, 1443–1450 (2012).

    CAS  PubMed  Google Scholar 

  95. Cohen, J. B. et al. Clinical phenogroups in heart failure with preserved ejection fraction: detailed phenotypes, prognosis, and response to spironolactone. JACC Heart Fail. 8, 172–184 (2020).

    PubMed  PubMed Central  Google Scholar 

  96. Pitt, B. et al. Spironolactone for heart failure with preserved ejection fraction. N. Engl. J. Med. 370, 1383–1392 (2014).

    CAS  PubMed  Google Scholar 

  97. de Denus, S. et al. Spironolactone metabolites in TOPCAT – new insights into regional variation. N. Engl. J. Med. 376, 1690–1692 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. Bristow, M. R. et al. Detection and management of geographic disparities in the TOPCAT trial: lessons learned and derivative recommendations. JACC Basic Transl. Sci. 1, 180–189 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Ravassa, S. et al. Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. Eur. J. Heart Fail. 20, 1290–1299 (2018).

    CAS  PubMed  Google Scholar 

  100. Maron, M. S. et al. Effect of spironolactone on myocardial fibrosis and other clinical variables in patients with hypertrophic cardiomyopathy. Am. J. Med. 131, 837–841 (2018).

    CAS  PubMed  Google Scholar 

  101. Myhre, P. L. et al. Mechanistic effects of spironolactone on cardiovascular and renal biomarkers in heart failure with preserved ejection fraction: a TOPCAT biorepository study. Circ. Heart Fail. 13, e006638 (2020).

    CAS  PubMed  Google Scholar 

  102. Yamamoto, K., Origasa, H. & Hori, M. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur. J. Heart Fail. 15, 110–118 (2013).

    CAS  PubMed  Google Scholar 

  103. Pal, N. et al. Effect of selective heart rate slowing in heart failure with preserved ejection fraction. Circulation 132, 1719–1725 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Komajda, M. et al. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur. J. Heart Fail. 19, 1495–1503 (2017).

    CAS  PubMed  Google Scholar 

  105. Mesubi, O. O. & Anderson, M. E. Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal. Cardiovasc. Res. 109, 542–557 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Anderson, M. E., Brown, J. H. & Bers, D. M. CaMKII in myocardial hypertrophy and heart failure. J. Mol. Cell. Cardiol. 51, 468–473 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Joiner, M. L. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Suetomi, T., Miyamoto, S. & Brown, J. H. Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling. Am. J. Physiol. Heart Circ. Physiol. 317, H877–H890 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Rusciano, M. R. et al. CaMKII activity in the inflammatory response of cardiac diseases. Int. J. Mol. Sci. 20, 4374 (2019).

    CAS  PubMed Central  Google Scholar 

  110. Hegyi, B., Bers, D. M. & Bossuyt, J. CaMKII signaling in heart diseases: emerging role in diabetic cardiomyopathy. J. Mol. Cell. Cardiol. 127, 246–259 (2019).

    CAS  PubMed  Google Scholar 

  111. Shi, J. et al. Molecular determinants for cardiovascular TRPC6 channel regulation by Ca2+/calmodulin-dependent kinase II. J. Physiol. 591, 2851–2866 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Lin, B. L. et al. In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease. Proc. Natl Acad. Sci. USA 116, 10156–10161 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Davis, J., Burr, A. R., Davis, G. F., Birnbaumer, L. & Molkentin, J. D. A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev. Cell 23, 705–715 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kong, Y. et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113, 2579–2588 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ago, T. et al. A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133, 978–993 (2008).

    CAS  PubMed  Google Scholar 

  118. Doi, R. et al. Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J. Hypertens. 18, 111–120 (2000).

    CAS  PubMed  Google Scholar 

  119. Yamamoto, K. et al. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc. Res. 55, 76–82 (2002).

    CAS  PubMed  Google Scholar 

  120. van Heerebeek, L. et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 117, 43–51 (2008).

    PubMed  Google Scholar 

  121. Fukui, S. et al. Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin-angiotensin system in hypertensive rats. Hypertens. Res. 32, 472–480 (2009).

    CAS  PubMed  Google Scholar 

  122. Liu, F. et al. Upregulation of MG53 induces diabetic cardiomyopathy through transcriptional activation of peroxisome proliferation-activated receptor α. Circulation 131, 795–804 (2015).

    CAS  PubMed  Google Scholar 

  123. Cavalera, M., Wang, J. & Frangogiannis, N. G. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl. Res. 164, 323–335 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Alex, L., Russo, I., Holoborodko, V. & Frangogiannis, N. G. Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction. Am. J. Physiol. Heart Circ. Physiol. 315, H934–H949 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Panchal, S. K. et al. High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J. Cardiovasc. Pharmacol. 57, 611–624 (2011).

    PubMed  Google Scholar 

  126. Hahn, V. S. et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 8, 712–724 (2020).

    PubMed  Google Scholar 

  127. Fu, X. et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J. Clin. Invest. 128, 2127–2143 (2018).

    PubMed  PubMed Central  Google Scholar 

  128. Xiao, Y. et al. Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis. Genes Dev. 33, 1491–1505 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. DeLeon-Pennell, K. Y., Meschiari, C. A., Jung, M. & Lindsey, M. L. Matrix metalloproteinases in myocardial infarction and heart failure. Prog. Mol. Biol. Transl. Sci. 147, 75–100 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Gonzalez, A. et al. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension 55, 1418–1424 (2010).

    CAS  PubMed  Google Scholar 

  131. Kasner, M. et al. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J. Am. Coll. Cardiol. 57, 977–985 (2011).

    CAS  PubMed  Google Scholar 

  132. Lopez, B., Querejeta, R., Gonzalez, A., Larman, M. & Diez, J. Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase. Hypertension 60, 677–683 (2012).

    CAS  PubMed  Google Scholar 

  133. Kanagala, P. et al. Relationship between focal and diffuse fibrosis assessed by CMR and clinical outcomes in heart failure with preserved ejection fraction. JACC Cardiovasc Imaging 12, 2291–2301 (2019).

    PubMed  Google Scholar 

  134. Zile, M. R. et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131, 1247–1259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Lopez, B. et al. Is plasma cardiotrophin-1 a marker of hypertensive heart disease? J. Hypertens. 23, 625–632 (2005).

    CAS  PubMed  Google Scholar 

  136. de Boer, R. A. et al. Galectin-3 in heart failure with preserved ejection fraction. Eur. J. Heart Fail. 15, 1095–1101 (2013).

    PubMed  Google Scholar 

  137. Polat, V., Bozcali, E., Uygun, T., Opan, S. & Karakaya, O. Diagnostic significance of serum galectin-3 levels in heart failure with preserved ejection fraction. Acta Cardiol. 71, 191–197 (2016).

    PubMed  Google Scholar 

  138. Corden, B., Adami, E., Sweeney, M., Schafer, S. & Cook, S. A. IL-11 in cardiac and renal fibrosis: late to the party but a central player. Br. J. Pharmacol. 177, 1695–1708 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, W. Y., Hong, J., Gannon, J., Kakkar, R. & Lee, R. T. Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33. Proc. Natl Acad. Sci. USA 112, 7249–7254 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Hedman, A. K. et al. Identification of novel pheno-groups in heart failure with preserved ejection fraction using machine learning. Heart 106, 342–349 (2020).

    PubMed  Google Scholar 

  141. Du, W. et al. Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production. Theranostics 8, 4155–4169 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Luo, M. & Anderson, M. E. Mechanisms of altered Ca2+ handling in heart failure. Circ. Res. 113, 690–708 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Nagayama, T. et al. Control of in vivo left ventricular contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation 116, 2399–2408 (2007).

    CAS  PubMed  Google Scholar 

  144. Kapur, S. et al. Early development of intracellular calcium cycling defects in intact hearts of spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 299, H1843–H1853 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Primessnig, U. et al. Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction. Eur. J. Heart Fail. 18, 987–997 (2016).

    CAS  PubMed  Google Scholar 

  146. Borbely, A. et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation 111, 774–781 (2005).

    PubMed  Google Scholar 

  147. van Heerebeek, L. et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113, 1966–1973 (2006).

    PubMed  Google Scholar 

  148. van Heerebeek, L. et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126, 830–839 (2012).

    PubMed  Google Scholar 

  149. Kruger, M. et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ. Res. 104, 87–94 (2009).

    PubMed  Google Scholar 

  150. Asram, M. I. et al. Reduced right ventricular sarcomere contractility in HFpEF with severe obesity. Circulation https://doi.org/10.1161/CIRCULATIONAHA.120.052414 (2020).

    Article  Google Scholar 

  151. Hamdani, N. et al. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ. Heart Fail. 6, 1239–1249 (2013).

    CAS  PubMed  Google Scholar 

  152. Perreault, C. L., Bing, O. H., Brooks, W. W., Ransil, B. J. & Morgan, J. P. Differential effects of cardiac hypertrophy and failure on right versus left ventricular calcium activation. Circ. Res. 67, 707–712 (1990).

    CAS  PubMed  Google Scholar 

  153. Akella, A. B., Ding, X. L., Cheng, R. & Gulati, J. Diminished Ca2+ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat. Circ. Res. 76, 600–606 (1995).

    CAS  PubMed  Google Scholar 

  154. Papadaki, M. et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function. JCI Insight 3, e121264 (2018).

    PubMed Central  Google Scholar 

  155. Lin, Y. H. et al. Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity. J. Mol. Cell. Cardiol. 139, 135–147 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Foster, D. B. et al. The cardiac acetyl-lysine proteome. PLoS ONE 8, e67513 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Samant, S. A. et al. HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. J. Biol. Chem. 286, 5567–5577 (2011).

    CAS  PubMed  Google Scholar 

  158. Francis, S. H., Busch, J. L., Corbin, J. D. & Sibley, D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol. Rev. 62, 525–563 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Surks, H. K. et al. Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Iα. Science 286, 1583–1587 (1999).

    CAS  PubMed  Google Scholar 

  160. Sawada, N. et al. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem. Biophys. Res. Commun. 280, 798–805 (2001).

    CAS  PubMed  Google Scholar 

  161. Sawada, N. et al. Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels. Mol.Cell. Biol. 29, 6018–6032 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Farah, C., Michel, L. Y. M. & Balligand, J. L. Nitric oxide signalling in cardiovascular health and disease. Nat. Rev. Cardiol. 15, 292–316 (2018).

    CAS  PubMed  Google Scholar 

  163. Lau, K. S. et al. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol. Genomics 2, 21–27 (2000).

    CAS  PubMed  Google Scholar 

  164. Stamler, J. S. & Meissner, G. Physiology of nitric oxide in skeletal muscle. Physiol. Rev. 81, 209–237 (2001).

    CAS  PubMed  Google Scholar 

  165. Holtwick, R. et al. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J. Clin. Invest. 111, 1399–1407 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat. Med. 11, 214–222 (2005).

    CAS  PubMed  Google Scholar 

  167. Lee, D. I. et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519, 472–476 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Koitabashi, N. et al. Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation: novel mechanism of cardiac stress modulation by PDE5 inhibition. J. Mol. Cell. Cardiol. 48, 713–724 (2010).

    CAS  PubMed  Google Scholar 

  169. Kinoshita, H. et al. Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ. Res. 106, 1849–1860 (2010).

    CAS  PubMed  Google Scholar 

  170. Tokudome, T. et al. Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Circulation 117, 2329–2339 (2008).

    CAS  PubMed  Google Scholar 

  171. Ranek, M. J. et al. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature 566, 264–269 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Ranek, M. J., Terpstra, E. J., Li, J., Kass, D. A. & Wang, X. Protein kinase G positively regulates proteasome-mediated degradation of misfolded proteins. Circulation 128, 365–376 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Wang, W. Z., Jones, A. W., Wang, M., Durante, W. & Korthuis, R. J. Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice. Am. J. Physiol. Heart Circ. Physiol. 305, H521–H532 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Inserte, J. & Garcia-Dorado, D. The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism. Br. J. Pharmacol. 172, 1996–2009 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Kokkonen-Simon, K. M. et al. Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease. JCI Insight 3, e121739 (2018).

    PubMed Central  Google Scholar 

  176. Collins, S. A heart–adipose tissue connection in the regulation of energy metabolism. Nat. Rev. Endocrinol. 10, 157–163 (2014).

    CAS  PubMed  Google Scholar 

  177. Mitschke, M. M. et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27, 1621–1630 (2013).

    CAS  PubMed  Google Scholar 

  178. Layland, J., Li, J. M. & Shah, A. M. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J. Physiol. 540, 457–467 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Dunkerly-Eyring, B. & Kass, D. A. Myocardial phosphodiesterases and their role in cGMP regulation. J. Cardiovasc. Pharmacol. 75, 483–493 (2019).

    Google Scholar 

  180. Sasaki, H. et al. PDE5 inhibitor efficacy is estrogen dependent in female heart disease. J. Clin. Invest. 124, 2464–2471 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Fukuma, N. et al. Estrogen receptor-α non-nuclear signaling confers cardioprotection and is essential to cGMP-PDE5 inhibition efficacy. JACC Basic. Transl. Sci. 5, 282–295 (2020).

    PubMed  PubMed Central  Google Scholar 

  182. Chirinos, J. A. & Zamani, P. The nitrate-nitrite-NO pathway and its implications for heart failure and preserved ejection fraction. Curr. Heart Fail. Rep. 13, 47–59 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Scott, N. J. A., Rademaker, M. T., Charles, C. J., Espiner, E. A. & Richards, A. M. Hemodynamic, hormonal, and renal actions of phosphodiesterase-9 inhibition in experimental heart failure. J. Am. Coll. Cardiol. 74, 889–901 (2019).

    CAS  PubMed  Google Scholar 

  184. Santos, C. X., Raza, S. & Shah, A. M. Redox signaling in the cardiomyocyte: from physiology to failure. Int. J. Biochem. Cell Biol. 74, 145–151 (2016).

    CAS  PubMed  Google Scholar 

  185. Faria, A. & Persaud, S. J. Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential. Pharmacol. Ther. 172, 50–62 (2017).

    CAS  PubMed  Google Scholar 

  186. Takimoto, E. & Kass, D. A. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49, 241–248 (2007).

    CAS  PubMed  Google Scholar 

  187. Kaludercic, N. et al. Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload. Circ. Res. 106, 193–202 (2010).

    CAS  PubMed  Google Scholar 

  188. Takimoto, E. et al. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J. Clin. Invest. 115, 1221–1231 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Noordali, H., Loudon, B. L., Frenneaux, M. P. & Madhani, M. Cardiac metabolism – a promising therapeutic target for heart failure. Pharmacol. Ther. 182, 95–114 (2018).

    CAS  PubMed  Google Scholar 

  190. Karwi, Q. G., Uddin, G. M., Ho, K. L. & Lopaschuk, G. D. Loss of metabolic flexibility in the failing heart. Front. Cardiovasc. Med. 5, 68 (2018).

    PubMed  PubMed Central  Google Scholar 

  191. Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010).

    CAS  PubMed  Google Scholar 

  192. Beer, M. et al. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with 31P-SLOOP magnetic resonance spectroscopy. J. Am. Coll. Cardiol. 40, 1267–1274 (2002).

    CAS  PubMed  Google Scholar 

  193. Conway, M. A. et al. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet 338, 973–976 (1991).

    CAS  PubMed  Google Scholar 

  194. Kato, T. et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ. Heart Fail. 3, 420–430 (2010).

    PubMed  Google Scholar 

  195. Nascimben, L. et al. Enalapril treatment increases cardiac performance and energy reserve via the creatine kinase reaction in myocardium of Syrian myopathic hamsters with advanced heart failure. Circulation 91, 1824–1833 (1995).

    CAS  PubMed  Google Scholar 

  196. Neubauer, S. et al. Downregulation of the Na+-creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation 100, 1847–1850 (1999).

    CAS  PubMed  Google Scholar 

  197. Fillmore, N. & Lopaschuk, G. D. Targeting mitochondrial oxidative metabolism as an approach to treat heart failure. Biochim. Biophys. Acta 1833, 857–865 (2013).

    CAS  PubMed  Google Scholar 

  198. Phan, T. T. et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J. Am. Coll. Cardiol. 54, 402–409 (2009).

    PubMed  Google Scholar 

  199. Neubauer, S. et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86, 1810–1818 (1992).

    CAS  PubMed  Google Scholar 

  200. Arany, Z. et al. Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle. Cell Metab. 1, 259–271 (2005).

    CAS  PubMed  Google Scholar 

  201. Berthiaume, J. M., Kurdys, J. G., Muntean, D. M. & Rosca, M. G. Mitochondrial NAD+/NADH redox state and diabetic cardiomyopathy. Antioxid. Redox Signal. 30, 375–398 (2019).

    CAS  PubMed  Google Scholar 

  202. Pillai, V. B. et al. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J. Biol. Chem. 285, 3133–3144 (2010).

    CAS  PubMed  Google Scholar 

  203. Horton, J. L. et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2, e84897 (2016).

    PubMed  Google Scholar 

  204. Lee, C. F. et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Diguet, N. et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation 137, 2256–2273 (2018).

    CAS  PubMed  Google Scholar 

  206. Karamanlidis, G. et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239–250 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Diakos, N. A. et al. Evidence of glycolysis up-regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart: implications for cardiac reloading and conditioning. JACC Basic. Transl. Sci. 1, 432–444 (2016).

    PubMed  PubMed Central  Google Scholar 

  208. Doenst, T., Nguyen, T. D. & Abel, E. D. Cardiac metabolism in heart failure: implications beyond ATP production. Circ. Res. 113, 709–724 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Lei, B. et al. Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J. Mol. Cell. Cardiol. 36, 567–576 (2004).

    CAS  PubMed  Google Scholar 

  210. Tumova, J., Andel, M. & Trnka, J. Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle. Physiol. Res. 65, 193–207 (2015).

    PubMed  Google Scholar 

  211. Lauzier, B. et al. Metabolic effects of glutamine on the heart: anaplerosis versus the hexosamine biosynthetic pathway. J. Mol. Cell. Cardiol. 55, 92–100 (2013).

    CAS  PubMed  Google Scholar 

  212. Sowton, A. P., Griffin, J. L. & Murray, A. J. Metabolic profiling of the diabetic heart: toward a richer picture. Front. Physiol. 10, 639 (2019).

    PubMed  PubMed Central  Google Scholar 

  213. Davila-Roman, V. G. et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 40, 271–277 (2002).

    CAS  PubMed  Google Scholar 

  214. Mahmod, M. et al. The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study. J. Cardiovasc. Magn. Res. 20, 88 (2018).

    Google Scholar 

  215. Wei, J. et al. Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women. Am. J. Physiol. Heart Circ. Physiol. 310, H14–H19 (2016).

    PubMed  Google Scholar 

  216. Djousse, L. et al. Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study. Circ. Heart Fail. 6, 964–969 (2013).

    CAS  PubMed  Google Scholar 

  217. Hunter, W. G. et al. Metabolomic profiling identifies novel circulating biomarkers of mitochondrial dysfunction differentially elevated in heart failure with preserved versus reduced ejection fraction: evidence for shared metabolic impairments in clinical heart failure. J. Am. Heart Assoc. 5, e003190 (2016).

    PubMed  PubMed Central  Google Scholar 

  218. Hage, C. et al. Inflammatory biomarkers predict heart failure severity and prognosis in patients with heart failure with preserved ejection fraction: a holistic proteomic approach. Circ. Cardiovasc. Genet. 10, e001633 (2017).

    CAS  PubMed  Google Scholar 

  219. Zordoky, B. N. et al. Metabolomic fingerprint of heart failure with preserved ejection fraction. PLoS ONE 10, e0124844 (2015).

    PubMed  PubMed Central  Google Scholar 

  220. Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Mizuno, Y. et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 77, 65–72 (2017).

    CAS  PubMed  Google Scholar 

  222. Ho, K. L. et al. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovasc. Res. 115, 1606–1616 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).

    CAS  PubMed  Google Scholar 

  224. Ferrannini, E., Mark, M. & Mayoux, E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 39, 1108–1114 (2016).

    PubMed  Google Scholar 

  225. Xia, Y. et al. Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload. Histochem. Cell Biol. 131, 471–481 (2009).

    CAS  PubMed  Google Scholar 

  226. Suetomi, T. et al. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase IIδ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation 138, 2530–2544 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Patel, B. et al. CCR2+ monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload. JACC Basic. Transl. Sci. 3, 230–244 (2018).

    PubMed  PubMed Central  Google Scholar 

  228. Laroumanie, F. et al. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation 129, 2111–2124 (2014).

    CAS  PubMed  Google Scholar 

  229. Kallikourdis, M. et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat. Commun. 8, 14680 (2017).

    PubMed  PubMed Central  Google Scholar 

  230. Sanders-van Wijk, S. et al. Proteomic evaluation of the comorbidity–inflammation paradigm in heart failure with preserved ejection fraction: results from the PROMIS-HFpEF study. Circulation 142, 2029–2044 (2020).

    CAS  PubMed  Google Scholar 

  231. Tartiere-Kesri, L., Tartiere, J. M., Logeart, D., Beauvais, F. & Cohen Solal, A. Increased proximal arterial stiffness and cardiac response with moderate exercise in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 59, 455–461 (2012).

    PubMed  Google Scholar 

  232. Borlaug, B. A. et al. Impact of arterial load and loading sequence on left ventricular tissue velocities in humans. J. Am. Coll. Cardiol. 50, 1570–1577 (2007).

    PubMed  Google Scholar 

  233. Mohammed, S. F. et al. Resting ventricular-vascular function and exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ. Heart Fail. 7, 580–589 (2014).

    PubMed  PubMed Central  Google Scholar 

  234. Kass, D. A. & Kelly, R. P. Ventriculo-arterial coupling: concepts, assumptions, and applications. Ann. Biomed. Eng. 20, 41–62 (1992).

    CAS  PubMed  Google Scholar 

  235. Kelly, R. P., Tunin, R. & Kass, D. A. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ. Res. 71, 490–502 (1992).

    CAS  PubMed  Google Scholar 

  236. Chirinos, J. A. et al. Impact of diabetes mellitus on ventricular structure, arterial stiffness, and pulsatile hemodynamics in heart failure with preserved ejection fraction. J. Am. Heart Assoc. 8, e011457 (2019).

    PubMed  PubMed Central  Google Scholar 

  237. Bache, R. J., Arentzen, C. E., Simon, A. B. & Vrobel, T. R. Abnormalities in myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy: metabolic evidence for myocardial ischemia. Circulation 69, 409–417 (1984).

    CAS  PubMed  Google Scholar 

  238. Bache, R. J., Dai, X. Z., Alyono, D., Vrobel, T. R. & Homans, D. C. Myocardial blood flow during exercise in dogs with left ventricular hypertrophy produced by aortic banding and perinephritic hypertension. Circulation 76, 835–842 (1987).

    CAS  PubMed  Google Scholar 

  239. Toyota, E. et al. Dynamics of flow velocities in endocardial and epicardial coronary arterioles. Am. J. Physiol. Heart Circ. Physiol. 288, H1598–H1603 (2005).

    CAS  PubMed  Google Scholar 

  240. Wei, T. et al. Sirtuin 3 deficiency accelerates hypertensive cardiac remodeling by impairing angiogenesis. J. Am. Heart Assoc. 6, e006114 (2017).

    PubMed  PubMed Central  Google Scholar 

  241. Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. He, X. et al. Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. J. Mol. Cell. Cardiol. 112, 104–113 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Marechaux, S. et al. Vascular and microvascular endothelial function in heart failure with preserved ejection fraction. J. Card. Fail. 22, 3–11 (2016).

    PubMed  Google Scholar 

  244. Yang, J. H. et al. Endothelium-dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. Eur. J. Heart Fail. 22, 432–441 (2020).

    CAS  PubMed  Google Scholar 

  245. Taqueti, V. R. et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur. Heart J. 39, 840–849 (2018).

    CAS  PubMed  Google Scholar 

  246. AbouEzzeddine, O. F. et al. Myocardial energetics in heart failure with preserved ejection fraction. Circ. Heart Fail. 12, e006240 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Haykowsky, M. J., Tomczak, C. R., Scott, J. M., Paterson, D. I. & Kitzman, D. W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J. Appl. Physiol. 119, 739–744 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Wong, L. L. et al. Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur. J. Heart Fail. 17, 393–404 (2015).

    CAS  PubMed  Google Scholar 

  249. Yan, H. et al. miRNAs as biomarkers for diagnosis of heart failure: a systematic review and meta-analysis. Medicine 96, e6825 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Wong, L. L. et al. Combining circulating microRNA and NT-proBNP to detect and categorize heart failure subtypes. J. Am. Coll. Cardiol. 73, 1300–1313 (2019).

    CAS  PubMed  Google Scholar 

  251. Chen, Y. T., Wong, L. L., Liew, O. W. & Richards, A. M. Heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF): the diagnostic value of circulating microRNAs. Cells 8, 1651 (2019).

    PubMed Central  Google Scholar 

  252. Hahn, V. S. et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation https://doi.org/10.1161/CIRCULATIONAHA.120.050498 (2020).

    Article  PubMed  Google Scholar 

  253. Obokata, M., Reddy, Y. N. V., Melenovsky, V., Pislaru, S. & Borlaug, B. A. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur. Heart J. 40, 689–697 (2019).

    PubMed  Google Scholar 

  254. Mohammed, S. F. et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 130, 2310–2320 (2014).

    PubMed  PubMed Central  Google Scholar 

  255. Melenovsky, V., Hwang, S. J., Lin, G., Redfield, M. M. & Borlaug, B. A. Right heart dysfunction in heart failure with preserved ejection fraction. Eur. Heart J. 35, 3452–3462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Zakeri, R. & Mohammed, S. F. Epidemiology of right ventricular dysfunction in heart failure with preserved ejection fraction. Curr. Heart Fail. Rep. 12, 295–301 (2015).

    PubMed  Google Scholar 

  257. Kanjanahattakij, N. et al. High right ventricular stroke work index is associated with worse kidney function in patients with heart failure with preserved ejection fraction. Cardiorenal Med. 8, 123–129 (2018).

    PubMed  PubMed Central  Google Scholar 

  258. Patel, R. B. et al. Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension. ESC. Heart Fail. 7, 253–263 (2020).

    PubMed  PubMed Central  Google Scholar 

  259. Williams, J. L. et al. Defining the molecular signatures of human right heart failure. Life Sci. 196, 118–126 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Mancini, D. M., Davis, L., Wexler, J. P., Chadwick, B. & LeJemtel, T. H. Dependence of enhanced maximal exercise performance on increased peak skeletal muscle perfusion during long-term captopril therapy in heart failure. J. Am. Coll. Cardiol. 10, 845–850 (1987).

    CAS  PubMed  Google Scholar 

  261. Sullivan, M. J., Knight, J. D., Higginbotham, M. B. & Cobb, F. R. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation 80, 769–781 (1989).

    CAS  PubMed  Google Scholar 

  262. LeJemtel, T. H., Maskin, C. S., Lucido, D. & Chadwick, B. J. Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 74, 245–251 (1986).

    CAS  PubMed  Google Scholar 

  263. Adams, V., Linke, A. & Winzer, E. Skeletal muscle alterations in HFrEF vs. HFpEF. Curr. Heart Fail. Rep. 14, 489–497 (2017).

    PubMed  Google Scholar 

  264. Tucker, W. J., Haykowsky, M. J., Seo, Y., Stehling, E. & Forman, D. E. Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function. Curr. Heart Fail. Rep. 15, 323–331 (2018).

    PubMed  PubMed Central  Google Scholar 

  265. Weiss, K. et al. Fatigability, exercise intolerance, and abnormal skeletal muscle energetics in heart failure. Circ. Heart Fail. 10, e004129 (2017).

    PubMed  PubMed Central  Google Scholar 

  266. Molina, A. J. 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. JACC Heart Fail. 4, 636–645 (2016).

    PubMed  PubMed Central  Google Scholar 

  267. Tucker, W. J. et al. Impact of exercise training on peak oxygen uptake and its determinants in heart failure with preserved ejection fraction. Card. Fail. Rev. 2, 95–101 (2016).

    PubMed  PubMed Central  Google Scholar 

  268. Wu, H. & Ballantyne, C. M. Skeletal muscle inflammation and insulin resistance in obesity. J. Clin. Invest. 127, 43–54 (2017).

    PubMed  PubMed Central  Google Scholar 

  269. Zamani, P. et al. Peripheral determinants of oxygen utilization in heart failure with preserved ejection fraction: central role of adiposity. JACC Basic. Transl. Sci. 5, 211–225 (2020).

    PubMed  PubMed Central  Google Scholar 

  270. Bowen, T. S. et al. Effects of endurance training on detrimental structural, cellular, and functional alterations in skeletal muscles of heart failure with preserved ejection fraction. J. Card. Fail. 24, 603–613 (2018).

    PubMed  Google Scholar 

  271. Olson, T. P., Johnson, B. D. & Borlaug, B. A. Impaired pulmonary diffusion in heart failure with preserved ejection fraction. JACC Heart Fail. 4, 490–498 (2016).

    PubMed  PubMed Central  Google Scholar 

  272. Hoeper, M. M. et al. Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction. JACC Heart Fail. 4, 441–449 (2016).

    PubMed  Google Scholar 

  273. Fayyaz, A. U. et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 137, 1796–1810 (2018).

    PubMed  Google Scholar 

  274. Wang, L. et al. Treatment with treprostinil and metformin normalizes hyperglycemia and improves cardiac function in pulmonary hypertension associated with heart failure with preserved ejection fraction. Arterioscler. Thromb. Vasc. Biol. 40, 1543–1558 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Agrawal, V. et al. Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension. Pulm. Circ. 9, 2045894019878599 (2019).

    PubMed  PubMed Central  Google Scholar 

  276. Shah, K. S. & Fang, J. C. Is heart failure with preserved ejection fraction a kidney disorder? Curr. Hypertens. Rep. 21, 86 (2019).

    PubMed  Google Scholar 

  277. van de Wouw, J. et al. Chronic kidney disease as a risk factor for heart failure with preserved ejection fraction: a focus on microcirculatory factors and therapeutic targets. Front. Physiol. 10, 1108 (2019).

    PubMed  PubMed Central  Google Scholar 

  278. Agrawal, A., Naranjo, M., Kanjanahattakij, N., Rangaswami, J. & Gupta, S. Cardiorenal syndrome in heart failure with preserved ejection fraction–an under-recognized clinical entity. Heart Fail. Rev. 24, 421–437 (2019).

    PubMed  Google Scholar 

  279. Upadhya, B., Amjad, A. & Stacey, R. B. Optimizing the management of obese HFpEF phenotype: can we mind both the heart and the kidney? J. Card. Fail. 26, 108–111 (2020).

    PubMed  Google Scholar 

  280. Robinson, T. W. & Freedman, B. I. The impact of APOL1 on chronic kidney disease and hypertension. Adv. Chronic Kidney Dis. 26, 131–136 (2019).

    PubMed  PubMed Central  Google Scholar 

  281. Franceschini, N. et al. Association of APOL1 with heart failure with preserved ejection fraction in postmenopausal African American women. JAMA Cardiol. 3, 712–720 (2018).

    PubMed  PubMed Central  Google Scholar 

  282. Jhund, P. S. et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation https://doi.org/10.1161/circulationaha.120.050391 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  283. Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Eng.l J. Med. 383, 1413–1424 (2020).

    CAS  Google Scholar 

  284. Ferreira, J. P. et al. Covariate adjusted reanalysis of the I-Preserve trial. Clin. Res. Cardiol. 109, 1358–1365 (2020).

    CAS  PubMed  Google Scholar 

  285. Borlaug, B. A. et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA 320, 1764–1773 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. Pieske, B. et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur. Heart J. 38, 1119–1127 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Udelson, J. E. et al. Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF). Am. Heart J. 222, 183–190 (2020).

    CAS  PubMed  Google Scholar 

  288. Hahn, V. S. et al. Myocardial transcriptomics reveal distinct gene expression in human heart failure with preserved ejection fraction. Circulation 140 (Suppl. 1), abstr. A16227 (2019).

  289. Khush, K. K. et al. Obese patients have lower B-type and atrial natriuretic peptide levels compared with nonobese. Cong. Heart Fail. 12, 85–90 (2006).

    CAS  Google Scholar 

  290. Solomon, S. D. et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med. 381, 1609–1620 (2019).

    CAS  PubMed  Google Scholar 

  291. McMurray, J. J. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 371, 993–1004 (2014).

    PubMed  Google Scholar 

  292. Vaduganathan, M. et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J. Am. Coll. Cardiol. 75, 245–254 (2019).

    PubMed  PubMed Central  Google Scholar 

  293. Sharma, K. et al. Randomized evaluation of heart failure with preserved ejection fraction patients with acute heart failure and dopamine: the ROPA-DOP trial. JACC Heart Fail. 6, 859–870 (2018).

    PubMed  Google Scholar 

  294. Van Tassell, B. W. et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ. Heart Fail. 11, e005036 (2018).

    PubMed  PubMed Central  Google Scholar 

  295. Reddy, Y. N. V. et al. The β-adrenergic agonist albuterol improves pulmonary vascular reserve in heart failure with preserved ejection fraction. Circ. Res. 124, 306–314 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  296. Singh, S. et al. Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome. Fut. Cardiol. 10, 693–698 (2014).

    CAS  Google Scholar 

  297. Abraham, W. T. et al. Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure. Eur. J. Heart Fail. 21, 932–942 (2019).

    CAS  PubMed  Google Scholar 

  298. Physicians’ Academy for Cardiovascular Education. No Improvement in Exercise Ability with SGLT2i in Two HF Trials, One in HFrEF and One in HFpEF Patients https://pace-cme.org/2020/01/06/no-improvement-in-exercise-ability-with-sglt2i-in-two-hf-trials-one-in-hfref-and-one-in-hfpef-patients/ (2020).

  299. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03448406 (2020).

  300. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02941705 (2020).

  301. Kaye, D. M., Nanayakkara, S., Vizi, D., Byrne, M. & Mariani, J. A. Effects of milrinone on rest and exercise hemodynamics in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 67, 2554–2556 (2016).

    PubMed  Google Scholar 

  302. Nanayakkara, S. et al. Extended-release oral milrinone for the treatment of heart failure with preserved ejection fraction. J. Am. Heart Assoc. 9, e015026 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03541603 (2020).

  304. Swain, E. Mixed results for levosimendan in HFpEF, pulmonary hypertension. Healio.com https://www.healio.com/news/cardiology/20201004/mixed-results-for-levosimendan-in-hfpef-pulmonary-hypertension (2020).

  305. Patel, H. C. et al. Effects of renal denervation on vascular remodelling in patients with heart failure and preserved ejection fraction: a randomised control trial. JRSM Cardiovasc. Dis. 6, 2048004017690988 (2017).

    PubMed  PubMed Central  Google Scholar 

  306. Feldman, T. et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): a phase 2, randomized, sham-controlled trial. Circulation 137, 364–375 (2018).

    PubMed  Google Scholar 

  307. Serova, M. et al. A new algorithm for optimization of rate-adaptive pacing improves exercise tolerance in patients with HFpEF. Pacing Clin. Electrophysiol. 43, 223–233 (2020).

    PubMed  Google Scholar 

  308. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02145351 (2020).

  309. Borlaug, B. A. et al. Percutaneous pericardial resection: a novel potential treatment for heart failure with preserved ejection fraction. Circ. Heart Fail. 10, e003612 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  310. Tucker, W. J. et al. Mechanisms of the improvement in peak VO2 with exercise training in heart failure with reduced or preserved ejection fraction. Heart Lung Circ. 27, 9–21 (2018).

    PubMed  Google Scholar 

  311. Pandey, A. et al. Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ. Heart Fail. 8, 33–40 (2015).

    PubMed  Google Scholar 

  312. Rodriguez Flores, M., Aguilar Salinas, C., Piche, M. E., Auclair, A. & Poirier, P. Effect of bariatric surgery on heart failure. Expert Rev. Cardiovasc. Ther. 15, 567–579 (2017).

    CAS  PubMed  Google Scholar 

  313. Mikhalkova, D. et al. Bariatric surgery-induced cardiac and lipidomic changes in obesity-related heart failure with preserved ejection fraction. Obesity 26, 284–290 (2018).

    CAS  PubMed  Google Scholar 

  314. de Boer, R. A. et al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol. 3, 215–224 (2018).

    PubMed  PubMed Central  Google Scholar 

  315. Chan, M. M. et al. Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. Eur. J. Heart Fail. 18, 81–88 (2016).

    CAS  PubMed  Google Scholar 

  316. Putko, B. N. et al. Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. PLoS ONE 9, e99495 (2014).

    PubMed  PubMed Central  Google Scholar 

  317. Gohar, A. et al. The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction. Eur. J. Heart Fail. 19, 1638–1647 (2017).

    CAS  PubMed  Google Scholar 

  318. Sanders-van Wijk, S. et al. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur. J. Heart Fail. 17, 1006–1014 (2015).

    CAS  PubMed  Google Scholar 

  319. Salah, K. et al. Prognosis and NT-proBNP in heart failure patients with preserved versus reduced ejection fraction. Heart 105, 1182–1189 (2019).

    CAS  PubMed  Google Scholar 

  320. Pandey, A. et al. Factors associated with and prognostic implications of cardiac troponin elevation in decompensated heart failure with preserved ejection fraction: findings from the American Heart Association Get With The Guidelines-Heart Failure program. JAMA Cardiol. 2, 136–145 (2017).

    PubMed  Google Scholar 

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  1. Department of Medicine, Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Sumita Mishra & David A. Kass

  2. Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David A. Kass

  3. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David A. Kass

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Mishra, S., Kass, D.A. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 18, 400–423 (2021). https://doi.org/10.1038/s41569-020-00480-6

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