Phenogroups in heart failure with preserved ejection fraction

Phenogroups in heart failure with preserved ejection fraction

Clustering analysis of heart failure with preserved ejection fraction (HFpEF) has been used to define three distinct phenogroups by Shah SJ et al [1]. They used dense phenotypic data for “phenomapping”. They prospectively studied 397 HFpEF patients with clinical, laboratory and echocardiographic data. Several statistical algorithms were used to define and characterize mutually exclusive phenogroups of HFpEF. By phenomapping analysis they arrived at 3 distinct phenogroups with markedly different clinical characteristics, cardiac function, invasive hemodynamic patterns and outcome.

There were different characteristics for the phenogroups:

Phenogroup 1: Younger and lower BNP values

Phenogroup 2: Highest prevalence of obesity, diabetes mellitus, obstructive sleep apnea and highest fasting glucose

Phenogroup 3: Oldest, more likely to have chronic kidney disease with highest serum creatinine and lowest glomerular filtration rate (GFR), highest BNP (B-type natriuretic peptide) and MAGGIC risk score.

Risk level increased sequentially from phenogroup 1 to 3.

MAGGIC risk score was developed by Pocock SJ et al for predicting mortality in heart failure [2]. It was based on 39,372 patients from 30 studies and comprises of 13 clinical parameters. The parameters were age, lower ejection fraction, NYHA (New York Heart Association) class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic blood pressure, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed angiotensin converting inhibitor or angiotensin-receptor blockers, in the order of predictive strength.

Kao DP et al divided 4113 patients with HFpEF into six subgroups – A to F [3]. They used Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) data for derivation. It was validated using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved data. In their study, subgroups C and F had the worst event free survival. Subgroup C had high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency. Subgroup F had female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia.

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) participants were evaluated by Cohen JB et al  to identify HFpEF phenogroups [4]. They used multiple biomarkers from frozen plasma, echocardiography, arterial tonometry, prognosis and response to spironolactone therapy. Patients were classified into phenogroups 1 to 3. Phenogroup 3 had the highest risk of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. All cause mortality was similar in phenogroups 2 and 3. Risk reduction with spironolactone therapy was more in phenogroup 3.

Going through different attempts at phenogrouping HFpEF, different investigators arrived at similar groups, with of course varying parameters. Risk was higher in the numerically higher phenogroups. The parameters used by them were mostly those which are known to carry poor prognostic weightage.


  1. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015 Jan 20;131(3):269-79.
  2. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Køber L, Squire IB, Swedberg K, Dobson J, Poppe KK, Whalley GA, Doughty RN; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J. 2013 May;34(19):1404-13.
  3. Kao DP, Lewsey JD, Anand IS, Massie BM, Zile MR, Carson PE, McKelvie RS, Komajda M, McMurray JJ, Lindenfeld J. Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. Eur J Heart Fail. 2015 Sep;17(9):925-35.
  4. Cohen JB, Schrauben SJ, Zhao L, Basso MD, Cvijic ME, Li Z, Yarde M, Wang Z, Bhattacharya PT, Chirinos DA, Prenner S, Zamani P, Seiffert DA, Car BD, Gordon DA, Margulies K, Cappola T, Chirinos JA. Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone. JACC Heart Fail. 2020 Mar;8(3):172-184.