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A Changing Phenotype in Heart Failure: What Should be the Therapeutic Focus Now?

July 29, 2019

mungerHeart failure is a life-threatening disease, affecting approximately 26 million persons worldwide, and is considered to be a major health priority.1 As such, changes in the phenotypic presentation of heart failure must be studied, identified, and addressed. 

Over the past three decades, preserved ejection fraction (HFpEF, >50%) has become more prevalent than reduced ejection fraction (HFrEF, < 40%).2-3 HFpEF increased from 41.0% to 56.2%, while HFrEF reduced from 44.1% to 31.1% (p=0.002).3  There is a third categorization of heart failure called heart failure midrange left ventricular ejection fraction (HFmrEF; LVEF: 40-50%).4-5 The proportion of HFmrEF has also remained stable over the same time period (14.5% versus 12.8%, p=0.66). 

HFrEF cardiovascular mortality has improved over the last three decades (HR: 0.61, 95% CI: 0.39-0.97).3 In comparison, HFpEF was unchanged over the same period.  These statistics show that evidenced-based HFrEF treatment has improved cardiovascular outcomes but there remains a great need for showing benefit in HFpEF clinical trials.  Interestingly, coronary artery disease (CAD) prevalence declined in HRrEF.  However, CAD increasing by 75% may be the explanation for the increase in HFpEF.3 Other patient characteristics that appear to be causing an increase in HFpEF are type 2 diabetes and obesity.6-7

New therapeutic targets are needed based on the changing heart failure phenotype.  Research focus will be on the pathophysiology phenotyping of HFpEF, such as sodium retention and systemic inflammation, so as to inform clinical trial targets.1, 9-11 Clinical targets may include symptoms, functional capacity, and identification of early deterioration markers to improve clinical outcomes and safety.  You will note that long-term outcomes are not the focus of this new line of research, at least not at this point, because of the large morbidity burden of HFpEF. 


  1. Heart Failure: Preventing Death 2017;and Disease Worldwide.   [Accessed Mar 16 2019].
  2. Benjamin EJ, Alalha MJ, Chiuve SE, et al. Heart disease and stroke statistics---2017 update: a report from the American Heart Association. Circulation 2017;135:e146-603.
  3. Vasan RS, Xanthakis V, Lyass A, et al. Epidemiology of left ventricular systolic dysfunction and heart failure in the Framingham Study. An echocardiographic study over 3 decades. JACC Cardiovascular Imaging 2018;11(1):1-11.
  4. Lam CS, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40-50%). Eur J Heart Fail 2014;16:1049-55.
  5. Lund LH. Herat failure with “mid-range” ejection fraction—new opportunities. J Card Fail 2016;22:769-71.
  6. Altara R, Giordano M, Norděn ES, et al. Targeting obesity and diabetes to treat heart failure with preserved ejection fraction. Front Endocrinol (Lausanne) 2017;8:160.
  7. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017;136:6-19.
  8. Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype=specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 2016;134:73-90.
  9. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfiedl MM. Coronary microvascular rarefarction and myocardial fibrosis is heart failure with preserved ejection fraction. Circulation 2015:131:500-9.
  10. Franssen C, Chen S, Unger A, et al. Myocardial microvascular inflammation endothelial activation in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;4:312-24.
  11. Paulus WJ, Tschŏpe 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 2013;62:263-71.
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