Heart failure with preserved ejection fraction: strategies for disease management and emerging therapeutic approaches

Figures & data

Figure 1. Schematic of the integrative pathophysiology of HFpEF and the involvement of different extracardiac mechanisms [16,17]. From top left, counterclockwise: lung involvement including primary lung disease leading to PAH, secondary PVH, impaired lung muscle mechanics, and eventual increased pulsatile RV load; abdominal compartment mechanisms including splanchnic circulation (preload), bowel congestion leading to endotoxin translocation and systemic inflammation; skeletal muscle mechanisms including impaired metabolism and peripheral vasodilation; renal mechanisms including passive congestion leading to renal impairment, changes in neurohormonal axis activation, hypertension, abnormal fluid homeostasis, eventual oliguria/renal insufficiency; ventricular-vascular mechanisms including ventricular stiffening leading to systolic and diastolic impairment, diminished systolic reserve, increased cardiac energetic demands and fluid-pressure shift sensitivity. HTN: hypertension; PAH: pulmonary arterial hypertension; PVH: pulmonary venous hypertension; RV: right ventricular. Figure reproduced from Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circulation Research. 2014;115(1):79–96 [16]. https://www.ahajournals.org/journal/res, with permission from Wolters Kluwer Health

Figure 2. Schematic summary of the role of inflammation on the pathophysiology of HFpEF [14]. Comorbidities, such as obesity, diabetes mellitus, COPD, and hypertension, contribute to a proinflammatory state that results in cardiac hypertrophy and diastolic dysfunction. Similarly, the upregulation of transforming growth factor β ultimately leads to collagen deposition in the interstitial space and diastolic dysfunction. The inflammatory pathway is getting more recognition as one of the pathways contributing to the pathophysiology of HFpEF. cGMP: cyclic guanosine monophosphate; F_passive: resting tension; COPD: chronic obstructive pulmonary disease; IL-6: interleukin 6; NO: nitric oxide; ONOO: peroxynitrite; PKG: protein kinase G; ROS: reactive oxygen species; sGC: soluble guanylate cyclase; TGF-β: transforming growth factor β; TNF-α: tumor necrosis factor α; VCAM: vascular cell adhesion molecule. Reprinted from the Journal of the American College of Cardiology 62(4), Paulus WJ, Tschöpe C, A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation, pg. 263–271, Copyright 2013, with permission from Elsevier

Table 1. Signs and symptoms of HF [4]

Symptoms	Signs
Typical	More specific
Breathlessness Orthopnea Paroxysmal nocturnal dyspnea Reduced exercise tolerance Fatigue, tiredness, increased time to recover after exercise Ankle swelling	Elevated jugular venous pressure Hepatojugular reflux Third heart sound (gallop rhythm) Laterally displaced apical impulse
Less typical	Less specific
Nocturnal cough Wheezing Bloated feeling Loss of appetite Confusion (especially in the elderly) Depression Palpitations Dizziness Syncope Bendopnea	Weight gain (>2 kg/week) Weight loss (in advanced HF) Tissue wasting (cachexia) Cardiac murmur Peripheral edema (ankle, sacral, scrotal) Pulmonary crepitations Reduced air entry and dullness to percussion at lung bases (pleural effusion) Tachycardia Irregular pulse Tachypnea Cheyne–Stokes respiration Hepatomegaly Ascites Cold extremities Oliguria Narrow pulse pressure

HF: heart failure

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines 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. European Journal of Heart Failure, 2016;18(8):891–975, by permission of Oxford University Press and the Heart Failure Association of the European Society of Cardiology.

Table 2. Physiology and clinical utility of natriuretic peptides [4,54–60]

Natriuretic peptides	Physiologic function	Upper limits of cutoff to exclude HF^a (pg/mL) [4]		Clinical utility
		Ambulatory setting (without acute symptoms)	Acute setting
BNP	The release of BNP and NT-proBNP, cleaved fragments of proBNP, is enhanced when myocardial wall stress is detected. To compensate for the ventricular volume/pressure overload, these biomarkers are released to promote natriuresis, diuresis, inhibition of RAAS and SNS, ultimately leading to vasodilatory effects [54,55]	<35 HF unlikely ≥35 warrants additional investigation	<100 HF unlikely ≥100 warrants additional investigation	Useful as one of the initial diagnostic tests to stratify patients who may need further workup, especially in the ambulatory setting in which echocardiography is not readily available. Elevated NPs may identify patients who need additional cardiac investigation [4] Useful for exclusion of HF diagnosis: ○ When the level of NP is below the cutoff threshold, it is very likely that the diagnosis of HF can be ruled out [4,54] ● Predicts incident HFpEF in a community-based cohort ○ Over a mean follow-up of 12 years, among 22,756 participants who were prospectively followed, BNP/NT-proBNP was found to be associated with 27% increase of incident HFpEF (HR, 1.27; 95% CI, 1.16, 1.40; P < 0.001) [60] ○ Coupled with clinical, echocardiographic, and biochemical risk factors, NPs may be part of the prediction model for identifying patients at risk for HFpEF [59] ● Prognostic value: ○ For every twofold increase in BNP, the composite risk of all-cause mortality and hospitalization for HF increases by approximately 1.3 times regardless of EF [57] ○ NP at admission or discharge is useful to establish prognosis in patients with ADHF ● Higher BNP levels at admission are associated with increased in-hospital mortality (HFpEF in-hospital mortality rates: 1.6% if BNP <303 pg/mL vs 4.9% if BNP ≥1070 pg/mL) [58] ● Compared with >60% reduction of NT-proBNP at discharge, attaining only 30%–60% reduction or ≤30% reduction is, respectively, associated with ~3 times and ~5 times higher risk of 6-month all-cause mortality in patients with HFpEF [56]
NT-proBNP		<125 HF unlikely ≥125 warrants additional investigation	<300 HF unlikely ≥300 warrants additional investigation

ADHF: acute decompensated heart failure; BNP: B-type natriuretic peptide; EF: ejection fraction; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HR: hazard ratio; NP: natriuretic peptide; NT-proBNP: N-terminal prohormone of B-type natriuretic peptide; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system.

^aLower cutoff values may be used in HFpEF than in HFrEF.

Figure 3. Flowchart of a diagnostic algorithm for diagnosis of HFpEF. ECG: electrocardiogram. [66], by permission of Oxford University Press and the European Society of Cardiology

Table 3. Characteristics of studies investigating treatments for HFpEF

Study	Purpose	Study design/ methodology	Treatment arms	Key outcomes measured	Key results
PARAMOUNT Jhund PS, et al. 2014 Voors AA, et al. 2015 Solomon SD, et al. 2012 [84,85,90]	Prospective comparison of the efficacy and safety of LCZ696 (sacubitril/ valsartan) to valsartan in management of HFpEF	Phase 2, randomized, double-blind, parallel-group, active-controlled trial Eligibility: Patients aged ≥40 years with LVEF ≥45% and documented history of HF with associated signs or symptoms Trial duration: 36 weeks – 12 weeks main study period and 24-week extension period	301 HFpEF patients randomly assigned to sacubitril/ valsartan or valsartan Treatment stratified by previous use of ACEI or ARB and region 274 patients (sacubitril/valsartan, n = 137; valsartan, n = 137) had valid SBP reading at baseline and at 12 weeks	Primary: Change from baseline in NT-proBNP at 12 weeks Secondary: Changes in echocardiographic measures, BP, and NYHA class Other: Renal function (assessed by serum creatinine, eGFR, cystatin C, UACR, and WRF)	Primary: At 12 weeks, NT-proBNP was significantly reduced in the sacubitril/valsartan group compared with the valsartan group (ratio of change, 0.77; 95% CI, 0.64, 0.92; P = 0.005) Secondary: Mean reduction in SBP in the sacubitril/valsartan group at 12 weeks, was −9 mm Hg and in the valsartan group was −3 mm Hg; P = 0.002 Greater improvements in left atrial diameter and volume index at 36 weeks with sacubitril/valsartan vs valsartan Greater proportion of patients showed improvement in NYHA class at 36 weeks with sacubitril/valsartan Renal function: Less decline in eGFR with sacubitril/valsartan vs valsartan (–1.5 ± 13.1 vs –5.2 ± 11.4 mL/min per 1.73 m^2; P = 0.008) Fewer patients had WRF in the sacubitril/valsartan (12%) vs valsartan (18%) groups; adjusted P = 0.28 UACR increased with sacubitril/valsartan (2.4–2.9 mg/mmol) and remained stable with valsartan (2.1–2.0 mg/mmol; P for difference = 0.016). Effects of sacubitril/valsartan on left atrial size, NT-proBNP, NYHA class, and eGFR were independent of change in blood pressure
PARAGON-HF Solomon SD, et al. 2017 and 2019 [87,88]	To compare the long-term efficacy and safety of sacubitril/valsartan to valsartan in patients with chronic symptomatic HFpEF	Phase 3, randomized, double-blind, parallel-group, active-controlled, 2-arm, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic symptomatic HFpEF. Patients aged ≥50 years, have LVEF ≥45%, evidence of structural heart disease, including either LV hypertrophy or left atrial enlargement	Valsartan 160 mg bid or sacubitril/valsartan 97/103 mg bid (LCZ696 200 mg bid)	Primary: Composite of CV death and total (first and recurrent) HHF Secondary: Change in KCCQ and NYHA class at 8 months, time to first occurrence of either ≥50% eGFR decrease from baseline, ESRD, or death due to renal failure; time to all-cause death	Primary: The primary composite outcome was reduced by sacubitril/valsartan, but failed to reach statistical significance (rate ratio, 0.87; 95% CI, 0.75, 1.01; P = 0.06) Secondary: More patients in the sacubitril/valsartan group had an improvement in NYHA class than those in the valsartan group (odds ratio for improvement, 1.45; 95% CI, 1.13, 1.86) Worsening renal function occurred more commonly in the valsartan group than the sacubitril/valsartan group (2.7% vs 1.4%; HR, 0.50; 95% CI, 0.33, 0.77) At 8 months, the sacubitril/valsartan group experienced less reduction in KCCQ clinical summary score compared with the valsartan group (mean decrease in score was 1.6 points and 2.6 points, respectively [95% CI, 0.0, 2.1]) All-cause death did not differ between groups (HR, 0.97; 95% CI, 0.84, 1.13)
DECLARE-TIMI 58 Wiviott SD, et al. 2019 [89]	To determine the effect of dapagliflozin on renal and cardiovascular outcomes in patients with established type 2 DM and risk factors for or with established ASCVD	Phase 3, randomized, double-blind, placebo-controlled, international study Patients aged ≥40 years, had type 2 DM and established or with multiple risk factors (aged ≥55 years for men; ≥60 years for women) for ASCVD, which is defined as ischemic heart disease, ischemic cerebrovascular disease, or peripheral artery disease	Dapagliflozin 10 mg daily or matching placebo	Primary safety outcome: MACE (defined as CV death, MI, or ischemic stroke) Primary efficacy outcomes: MACE and the composite of CV death or HHF Secondary renal composite outcome: eGFR declined by 40% or more to <60 mL/min/1.73 m^2, new diagnosis of ESRD, or CV or renal death Other secondary outcome: All-cause death	Primary safety outcome: Dapagliflozin was noninferior to placebo in the reduction of MACE (P < 0.001 for noninferiority) Primary efficacy outcomes: Compared with placebo, patients in the dapagliflozin group had a lower rate of CV death or HHF (4.9% dapagliflozin vs 5.8% placebo; HR, 0.83; P = 0.005), and this was mainly because of a lower rate of HHF in the dapagliflozin group (HR, 0.73; 95% CI, 0.61, 0.88) Secondary renal composite outcome: 4.3% of patients in the dapagliflozin group experienced the secondary renal composite outcome, compared with 5.6% in the placebo group (HR, 0.76; 95% CI, 0.67, 0.87) All-cause death did not differ significantly between groups (6.2% dapagliflozin vs 6.6% placebo; HR, 0.93; 95% CI, 0.82, 1.04)
EMPEROR-Preserved (NCT03057951) [91]	To evaluate the effects of empagliflozin versus placebo on morbidity and mortality (on top of guideline-directed medical therapy for HF) in patients with HFpEF	Phase 3, randomized, double-blind, parallel-group, placebo-controlled study Patients aged ≥18 years, with a LVEF >40%, chronic HF (NYHA class II–IV) for ≥3 months, elevated NT-proBNP, and evidence of structural heart disease	Empagliflozin 10 mg daily or placebo	Primary: Composite of time to first event of CV death or HHF Secondary: Occurrence of HHF; change from baseline in eGFR; CV death; time to DM onset; all-cause death	Study initiated 2 March 2017 Results expected second half of 2020
DELIVER (NCT03619213)	To determine whether dapagliflozin is superior to placebo, when added to standard of care, in reducing the composite of CV death and HF events	Phase 3, international, multicenter, parallel-group, event-driven, randomized, placebo-controlled, double-blind study Adult patients aged ≥40 years with HFpEF (LVEF >40% and evidence of structural heart disease) and NYHA class II–IV	Dapagliflozin 10 mg daily versus placebo	Primary: Time to the first occurrence of any of the components of this composite: (1) CV death; (2) HHF; (3) urgent HF visit Secondary: Total number of HHF and CV deaths; change from baseline in total symptom KCCQ; proportion of patients with worsened NYHA class from baseline; time to occurrence of death from any cause	Study start date: 27 August 2018 Results expected second half of 2021

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; bid: twice a day; ASCVD: atherosclerotic cardiovascular disease; BP: blood pressure; CV: cardiovascular; DM: diabetes mellitus; EF: ejection fraction; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HHF: hospitalization due to heart failure; HR: hazard ratio; KCCQ: Kansas City Cardiomyopathy Questionnaire; LV: left ventricular; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NT-proBNP: N-terminal prohormone of B-type natriuretic peptide; NYHA: New York Heart Association; SBP: systolic blood pressure; UACR: urinary albumin to creatinine ratio; WRF: worsening renal function (determined as serum creatinine increase of >0.3 mg/dL and/or >25% between 2 time points).

Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014;115(1):79–96.

 PubMed Web of Science ®Google Scholar

 Huis In 't Veld, de Man FS, van Rossum AC, et al. How to diagnose heart failure with preserved ejection fraction: the value of invasive stress testing. Neth Heart J. 2016;24(4):244–251.

 PubMed Web of Science ®Google Scholar

Paulus WJ, Tschöpe 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(4):263–271.

 PubMed Web of Science ®Google Scholar

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines 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. Eur J Heart Fail. 2016;18(8):891–975.

 PubMed Web of Science ®Google Scholar

Weber M, Hamm C. Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart. 2006;92(6):843–849.

 PubMed Web of Science ®Google Scholar

Nathisuwan S, Talbert RL. A review of vasopeptidase inhibitors: a new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy. 2002;22(1):27–42.

 PubMed Web of Science ®Google Scholar

de Boer RA, Nayor M, deFilippi CR, et al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol. 2018;3(3):215–224.

 PubMed Web of Science ®Google Scholar

Meijers WC, van der Velde AR, de Boer RA. Biomarkers in heart failure with preserved ejection fraction. Neth Heart J. 2016;24(4):252–258.

 PubMed Web of Science ®Google Scholar

van Veldhuisen DJ, Linssen GCM, Jaarsma T, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol. 2013;61(14):1498–1506.

 PubMed Web of Science ®Google Scholar

Fonarow GC, Peacock WF, Phillips CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol. 2007;49(19):1943–1950.

 PubMed Web of Science ®Google Scholar

Salah K, Stienen S, Pinto YM, et al. Prognosis and NT-proBNP in heart failure patients with preserved versus reduced ejection fraction. Heart. 2019;105(15):1182–1189.

 PubMed Web of Science ®Google Scholar

Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA–PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology. European Heart Journal, 2019;40(40):3297–3317

 PubMed Web of Science ®Google Scholar

Jhund PS, Claggett B, Packer M, et al. Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur J Heart Fail. 2014;16(6):671–677.

 PubMed Web of Science ®Google Scholar

Voors AA, Gori M, Liu LC, et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail. 2015;17(5):510–517.

 PubMed Web of Science ®Google Scholar

Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–1395.

 PubMed Web of Science ®Google Scholar

Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial. JACC Heart Fail. 2017;5(7):471–482.

 PubMed Web of Science ®Google Scholar

Solomon SD, JJV M, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609–1620.

 PubMed Web of Science ®Google Scholar

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–357.

 PubMed Web of Science ®Google Scholar

Anker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail. 2019;21(10):1279–1287.

 PubMed Web of Science ®Google Scholar