#heart-failure #HFpEF #SGLT2-inhibitors #guideline #acute-heart-failure

Heart Failure

Details of the concept

Heart failure (HF) is a clinical syndrome of symptoms (dyspnoea, ankle swelling, fatigue) ± signs (elevated JVP, pulmonary crackles, peripheral oedema) due to a cardiac structural or functional abnormality causing elevated intracardiac pressures and/or inadequate cardiac output at rest or on effort. Three phenotypes are defined by LVEF: HFrEF (≤40%), HFmrEF (41–49%), and HFpEF (≥50%); a fourth — HFimpEF — describes patients with previously reduced LVEF who recover to >40% on GDMT but retain structural abnormality and relapse risk. The ACC/AHA staging framework (A–D) stratifies from "at risk" (Stage A: risk factors only) through structural disease without symptoms (Stage B: pre-HF) to established symptomatic HF (Stage C) and advanced refractory disease (Stage D), enabling preventive as well as therapeutic intervention. HF affects ~1–2% of adults in developed countries, rising to >10% in those aged >70 years; 5-year mortality is 53–67%, and HF is the leading indication for cardiac transplantation in adults. In HFrEF, the four-pillar GDMT regimen (ARNi/ACEi/ARB, beta-blocker, MRA, SGLT2i) reduces estimated all-cause mortality by ~73%.

Epidemiology

Prevalence ~1–2% of adults in developed countries; rises to >10% in those aged >70 years. (sources/HF-ESC-2021, rating: very high)
ESC registry phenotype distribution: 60% HFrEF, 24% HFmrEF, 16% HFpEF in outpatient settings. (sources/HF-ESC-2021, rating: very high)
1-year mortality ~20%; 5-year mortality ~53–67% in population studies. (sources/HF-ESC-2021, rating: very high)
HF hospitalizations average once per year; 63% of admissions are for non-CV causes. AF, BMI, HbA1c, and eGFR are key hospitalization predictors. (sources/HF-ESC-2021, rating: very high)

Classification

LVEF-Based Phenotypes

HFrEF: LVEF ≤40%. (sources/HF-ESC-2021, rating: very high)
HFmrEF: LVEF 41–49%; may have structural evidence (LA enlargement, LV hypertrophy) supporting the diagnosis. (sources/HF-ESC-2021, rating: very high)
HFpEF: LVEF ≥50% + objective evidence of diastolic dysfunction/raised filling pressures + elevated natriuretic peptides. (sources/HF-ESC-2021, rating: very high)

ACC/AHA Staging Framework (AHA 2022)

Stage A — "At Risk for HF": No symptoms, no structural disease, no biomarkers — includes hypertension, diabetes, obesity, cardiotoxin exposure, family history of cardiomyopathy. (sources/HF-AHA-2022, rating: very high)
Stage B — "Pre-HF": No symptoms/signs + evidence of structural disease, elevated filling pressures, or elevated BNP/troponin. (sources/HF-AHA-2022, rating: very high)
Stage C: Structural heart disease + current or previous HF symptoms. (sources/HF-AHA-2022, rating: very high)
Stage D: Advanced HF with recurrent hospitalizations despite optimized GDMT. (sources/HF-AHA-2022, rating: very high)

HFimpEF

HFimpEF: Previous LVEF ≤40% with follow-up LVEF >40% on GDMT. Distinct from "recovered" EF — structural abnormalities and relapse risk persist. (sources/HF-AHA-2022, rating: very high)
Continue GDMT even if asymptomatic (COR 1, LOE B-R): Withdrawal of GDMT in patients with normalized LVEF (≥50%) → 40% relapsed within 6 months; only 50% withdrew successfully. (sources/HF-AHA-2022, rating: very high)

Pathophysiology

Neurohormonal activation: Reduced cardiac output triggers compensatory RAAS (angiotensin II, aldosterone) and sympathetic nervous system (norepinephrine, epinephrine) activation. Initially adaptive, chronic neurohormonal excess drives maladaptive ventricular remodeling — myocyte hypertrophy, apoptosis, interstitial fibrosis, and progressive chamber dilatation or stiffening. Natriuretic peptides (ANP, BNP/NT-proBNP) are released proportional to wall stress and serve as haemodynamic load markers and therapeutic targets. (sources/HF-ESC-2021, rating: very high)
Haemodynamic consequences: Forward failure (↓CO → fatigue, exertional intolerance) and backward failure (↑filling pressures → pulmonary congestion in LV failure; peripheral oedema/↑JVP in RV or biventricular failure). HFrEF is primarily driven by reduced contractility and ↓CO; HFpEF by impaired relaxation and increased chamber stiffness causing ↑LVEDP at normal or near-normal volumes. (sources/HF-ESC-2021, rating: very high)
Ventricular remodeling: HFrEF → eccentric LV dilatation (volume overload pattern); HFpEF/HFmrEF → concentric hypertrophy (pressure/metabolic load pattern). GDMT reverses eccentric remodeling in HFrEF — the HFimpEF phenotype — but structural risk persists despite LVEF normalisation. (sources/HF-AHA-2022, rating: very high)
Cardiorenal interactions: Venous congestion (↑CVP → ↑renal venous pressure) and ↓renal perfusion pressure both impair kidney function in HF; over two-thirds of advanced HF patients have kidney dysfunction. A creatinine rise during aggressive decongestion does not equal tubular injury — do not reduce diuretics for eGFR decline alone. See concepts/Cardiorenal-Syndrome. (sources/AKI-HF-AHA-2024, rating: very high)
Arrhythmogenic substrate: HF causes comprehensive ventricular electrical remodeling — ↑INaLate (CaMKII-driven), ↑If (HCN4 upregulation), ↑NCX1, ↓IKr/IKs/Ito/IK1 — increasing arrhythmic susceptibility and SCD risk independently of LVEF. This ionic profile explains why HF patients have elevated TdP risk on QT-prolonging drugs and reduced repolarization reserve. See Device Therapy below and concepts/Electrical-Remodeling. (sources/membrane-potential-physrev-2021, rating: very high)

Diagnosis

Natriuretic Peptides and Structural Criteria

HFpEF diagnosis requires LVEF ≥50% + objective evidence of diastolic dysfunction/raised filling pressures + elevated natriuretic peptides. (sources/HF-ESC-2021, rating: very high)
In borderline cases (PAWP 13–15 mmHg + HFpEF features), exercise or fluid challenge testing may be considered (Class IIb) to unmask occult post-capillary PH. (sources/PHT-ESC-2022, rating: very high)

Haemodynamic Assessment (RHC)

See concepts/Right-Heart-Catheterization for full methodology, pitfalls, and haemodynamic variable reference table.

Acute HF haemodynamic phenotypes (sources/rhc-hf-ehj-2025, rating: high)

Acute LV failure: PAWP >15 mmHg, usually maintained CI (≥2.5 L/min/m²) and blood pressure
Acute isolated RV failure: PAWP <18 mmHg (normal/high-normal), CI <2.5 L/min/m², RAP >8 mmHg, reduced blood pressure
Acute bi-ventricular failure: PAWP >15 mmHg + RAP >8 mmHg + CI <2.5 L/min/m² + RAP:PAWP >0.5
Diamond-Forrester classification: warm/cold (CI 2.5 cut-off), wet/dry (PAWP 18 cut-off) — still used but superseded by ESC 2021 clinical phenotype framework

Cardiogenic shock (SCAI staging + RHC) (sources/rhc-hf-ehj-2025, rating: high)

SCAI Stages B–E: PAWP >15 mmHg; Stage E: >20 mmHg; CI <2.2 L/min/m² in Stages C–E; RAP >10 mmHg
Isolated RV shock: RAP strongly elevated (>14 mmHg), PAWP <18 mmHg, RAP:PAWP >0.5–0.8, PAPI decreased
Isolated RV infarction: RAP:PAWP ≥0.8
Mixed venous O₂ saturation decreased in Stages C–E; maintained (≥65%) in Stages A+B
Cardiogenic ("cold and wet"): low CI, high PAWP, high SVRI; vasodilatory ("warm and dry"): high CI, normal PAWP, low SVRI
Early RHC (within 2 days): lower AKI (OR 0.69), higher MCS use (OR 1.67), shorter stay (observational, n=46,963)

Advanced HF: LVAD candidacy RHC criteria (sources/rhc-hf-ehj-2025, rating: high)

LVAD candidacy indicator: PAWP ≥20 mmHg + systolic BP ≤90 mmHg, or CI ≤2.0 L/min/m² (among other criteria)
Pre-implantation target: RAP ≤12–15 mmHg; RHC within 1–2 weeks pre-elective surgery
RV failure predictors post-LVAD: RAP >15 mmHg, RAP/PAWP >0.63 (1-year survival 59% vs 78%), PAPI <1.85 (95% sensitivity)
Ramp test post-implantation: target RAP <12 mmHg + PAWP <18 mmHg; detects LVAD malfunction
LVAD explantation (myocardial recovery, Class 2a): CI >2.6 L/min/m² + RAP <10 mmHg + PAWP <13 mmHg on serial speed reduction

Advanced HF: Heart transplantation RHC criteria (sources/rhc-hf-ehj-2025, rating: high)

RHC required prior to listing (ISHLT Class 1); repeated every 3–6 months until transplantation
Prohibitive PH: sPAP ≥50 mmHg + (TPG ≥15 mmHg or PVR ≥3 WU) → vasodilator challenge required
Acceptable vasodilator response: TPG ≤12–15 mmHg + PVR ≤2.5–3 WU + systolic BP >85 mmHg
PVR >2.5 WU independently associated with increased post-HTX mortality (n=26,649)
If PH irreversible after 3–6 months of LVAD unloading → HTX generally precluded

Invasive Exercise Hemodynamics for HFpEF Diagnosis

HFpEF invasive criteria (Table 4 — at least ONE required): (1) resting PAWP ≥15 mmHg; (2) PAWP ≥20 mmHg with fluid bolus or PLR; (3) peak exercise PAWP ≥25 mmHg (supine) or ≥20 mmHg (upright); (4) PAWP/CO slope >2 mmHg·L·min. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
PAWP/CO slope (not absolute PAWP) most consistently differentiates HFpEF from controls across meta-analysis (n=2,180 HFpEF, n=682 controls, 27 studies) and predicted outcomes (n=764 multicenter). (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
Dapagliflozin validated improvement in HFpEF using supine exercise hemodynamics (dynamic pulmonary congestion endpoint); also improved ventilatory abnormalities at submaximal supine exercise. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
See concepts/Right-Heart-Catheterization for full provocative protocols, supine vs upright comparison, and additional exercise phenotypes (chronotropic incompetence, preload insufficiency, PCWL).

Remote PA Pressure Monitoring

Recommended for NYHA Class II–III + recent HF hospitalisation or elevated natriuretic peptides. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
CHAMPION (CardioMEMS): Landmark RCT — PA-guided management → reduced HF hospitalisations and urgent visits. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
GUIDE-HF and MONITOR-HF: Consistent HF hospitalisation reductions across varying ejection fractions. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
PROACTIVE-HF (Cordella PA Sensor, Edwards Lifesciences): Significant HF hospitalisation reductions; confirmed safety of seated PA pressure monitoring. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
Key mechanism: rising PA pressures detected days to weeks before clinical congestion — enables proactive diuretic titration and GDMT optimization without hospitalisation. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)

Iron Deficiency Assessment

Diagnose iron deficiency by: transferrin saturation <20% OR serum ferritin <100 μg/L. (sources/HF-update-ESC-2023, rating: very high)

Cardiac Amyloidosis Work-up (AHA 2022)

Clinical suspicion triggers: LV wall thickness ≥14 mm + dyspnoea/fatigue/oedema, ECG-echo voltage discordance, aortic stenosis, carpal tunnel syndrome, spinal stenosis, polyneuropathy. (sources/HF-AHA-2022, rating: very high)
COR 1: Screen for monoclonal light chains (serum/urine immunofixation electrophoresis + free light chains). (sources/HF-AHA-2022, rating: very high)
COR 1: If no monoclonal proteins, perform bone scintigraphy (99mTc-PYP) to confirm ATTR-CM. (sources/HF-AHA-2022, rating: very high)
COR 1: If ATTR-CM confirmed, TTR gene sequencing to distinguish hereditary (ATTRv) from wild-type (ATTRwt). (sources/HF-AHA-2022, rating: very high)

Pulmonary Hypertension Evaluation in LHD

RHC recommended (Class I): For suspected PH-LHD when results aid management decisions; also before valve repair/intervention in patients with severe tricuspid regurgitation. (sources/PHT-ESC-2022, rating: very high)
Referral to PH centre (Class I): For patients with LHD and suspected severe pre-capillary component (RV dysfunction or PVR >5 WU). (sources/PHT-ESC-2022, rating: very high)
Post-capillary PH (IpcPH or CpcPH) affects ≥50% of HFpEF patients; found in 60–70% of severe mitral valve disease and up to 50% of symptomatic aortic stenosis. (sources/PHT-ESC-2022, rating: very high)

Pharmacological Management

HFrEF

The four foundational drug classes each carry Class I / COR 1A recommendations (ESC 2021 and AHA 2022). Estimated 73% reduction in all-cause mortality with use of all four classes vs. no treatment. (sources/HF-AHA-2022, rating: very high)

ARNi (sacubitril-valsartan): AHA COR 1A — preferred over ACEi for NYHA II–III; 20% RRR in CV death or HF hospitalization (PARADIGM-HF). ESC Class I. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
ACEi: AHA COR 1A — if ARNi not feasible. ESC Class I. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
ARB: AHA COR 1A — if intolerant to ACEi (cough/angioedema) and ARNi not feasible. (sources/HF-AHA-2022, rating: very high)
Beta-blocker (bisoprolol, carvedilol, or metoprolol succinate): AHA COR 1A, ESC Class I — reduces mortality and HF hospitalizations. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
MRA (spironolactone or eplerenone): AHA COR 1A, ESC Class I — reduces mortality and HF hospitalization. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
SGLT2i (dapagliflozin or empagliflozin): AHA COR 1A (17% RRR all-cause mortality), ESC Class I — reduces CV death and worsening HF regardless of diabetes status. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
Loop diuretics: ESC Class I — for fluid retention (symptom relief). (sources/HF-ESC-2021, rating: very high)
H-ISDN (hydralazine + isosorbide dinitrate): AHA COR 1A for self-identified Black patients with NYHA III–IV already on optimized GDMT (A-HeFT); AHA COR 2a / ESC Class IIa if intolerant to all RAAS therapies. (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
Ivabradine: AHA COR 2a (B-R), ESC Class IIa — stable symptomatic HFrEF (LVEF ≤35%) + sinus rhythm + resting HR ≥70 bpm on maximally tolerated beta-blocker; reduces HF hospitalization (SHIFT). (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
Vericiguat (soluble guanylate cyclase stimulator): AHA COR 2b (B-R), ESC Class IIb — NYHA II–IV HFrEF with recent worsening HF event despite GDMT; reduces composite of CV death or HF hospitalization (VICTORIA; HR 0.90, 95% CI 0.82–0.98). (sources/HF-AHA-2022, sources/HF-ESC-2021, rating: very high)
Digoxin: AHA COR 2b (B-R) — may reduce HF hospitalization; no mortality benefit. (sources/HF-AHA-2022, rating: very high)

Drugs to AVOID in HFrEF (AHA COR 3 Harm): non-dihydropyridine CCBs, Class IC antiarrhythmics + dronedarone, thiazolidinediones, saxagliptin/alogliptin, NSAIDs. (sources/HF-AHA-2022, rating: very high)

Hypertension management in HFrEF (2025 AHA HT Guideline): (sources/HT-AHA-2025, rating: very high)

Uptitrate GDMT (ARNi/ACEi/ARB + BB + MRA + SGLT2i) to maximally tolerated doses as first-line strategy for BP control — serves dual purpose of HF benefit and BP reduction
Add dihydropyridine CCB (e.g., amlodipine) only if BP remains elevated despite optimised GDMT
Non-dihydropyridine CCBs are contraindicated in HFrEF — negative inotropic effects (Class III Harm, consistent across HT and HF guidelines)
Goal SBP <130 mmHg; SPRINT demonstrated HF incidence reduced by 38% (HR 0.62) with SBP <120 mmHg target
Antiarrhythmic drugs in HFrEF: Amiodarone is the only antiarrhythmic considered safe (not harmful) in HFrEF, but SCD-HeFT (n=2521) demonstrated no mortality benefit for amiodarone vs placebo in symptomatic patients with LVEF <35% — confirming amiodarone does not substitute for ICD in primary prevention. Class IC agents (flecainide, propafenone) and dronedarone are actively harmful in HFrEF. (sources/amiodarone-cvdrug-2020, rating: high; sources/HF-AHA-2022, rating: very high)
See entities/Amiodarone for full amiodarone pharmacology, dosing, toxicity monitoring, and drug interactions.

HFmrEF

SGLT2i (dapagliflozin or empagliflozin): ESC 2023 Class I, Level A — reduces HF hospitalization or CV death (upgraded from Class IIb in 2021 following DELIVER trial). AHA 2022: COR 2a (B-R). (sources/HF-update-ESC-2023, sources/HF-AHA-2022, rating: very high)
ACEi/ARNi/ARB, beta-blocker, MRA: ESC Class IIb (based on HFrEF trial subgroup analyses); AHA COR 2b — may be considered especially at lower LVEF. (sources/HF-ESC-2021, sources/HF-AHA-2022, rating: very high)
Diuretics for fluid retention: Class I. (sources/HF-ESC-2021, rating: very high)

HFpEF

SGLT2i (dapagliflozin or empagliflozin): ESC 2023 Class I, Level A (new; no pharmacotherapy recommendation existed in ESC 2021). AHA 2022: COR 2a (B-R). Benefit driven primarily by reduction in HF hospitalizations; no significant reduction in CV death. See concepts/HFpEF for full SGLT2i evidence. (sources/HF-update-ESC-2023, sources/HF-AHA-2022, rating: very high)
BP control: AHA COR 1 (C-LD). (sources/HF-AHA-2022, rating: very high)
Sodium restriction and potassium intake: Sodium reduction lowers BP and blunts age-related BP rise; combined ↓sodium + ↑potassium (from fruits and vegetables or potassium-enriched salt substitutes) is the most effective dietary strategy for BP management in HFpEF. Caution with potassium-enriched salt substitutes in those with impaired urinary potassium excretion. sources/diet-aha-2026 (very high)
AF management: AHA COR 2a. (sources/HF-AHA-2022, rating: very high)
MRA: AHA COR 2b. ARB: AHA COR 2b. ARNi: AHA COR 2b. (sources/HF-AHA-2022, rating: very high)

Hypertension management in HFpEF (2025 AHA HT Guideline): (sources/HT-AHA-2025, rating: very high)

RAASi preferred (ARNi > ARB > ACEi); MRA added for BP and HFpEF benefit
Beta-blockers: NOT recommended for BP control in HFpEF — negative chronotropic effects impair diastolic filling; restrict to specific comorbid conditions (arrhythmia, ACS)
SGLT2i lower BP modestly; adjust other antihypertensives if symptomatic hypotension develops
Diuretics essential for volume management to enable BP-lowering agents to work effectively
Goal SBP <130 mmHg; hypertension is the leading modifiable cause of HFpEF development
Nitrates and PDE5 inhibitors: AHA COR 3 No Benefit — routine use ineffective. NEAT-HFpEF (isosorbide mononitrate) and RELAX (sildenafil) both showed no benefit. ESC PHT guideline similarly assigns PDE5i Class III in isolated post-capillary PH. (sources/HF-AHA-2022, sources/PHT-ESC-2022, rating: very high)
Diuretics for fluid retention: Class I. (sources/HF-ESC-2021, rating: very high)
Treatment of aetiology, CV and non-CV comorbidities: Class I. (sources/HF-ESC-2021, rating: very high)

Acute HF

Early empagliflozin in hospitalized acute HF (EMPULSE): Clinical benefit (death, HF events, KCCQ score) superior with empagliflozin vs. placebo (win ratio 1.36, 95% CI 1.09–1.68; P=0.0054). Benefit independent of LVEF and diabetes status. (sources/HF-update-ESC-2023, rating: very high)
STRONG-HF — rapid up-titration strategy (Class I, Level B): Intensive oral HF therapy initiation pre-discharge + close follow-up in first 6 weeks → HF readmission or all-cause death at 180 days: 15.2% vs. 23.3% (aRR 0.66; P=0.0021). Readmissions reduced (aRR 0.56); all-cause death alone not significantly reduced. (sources/HF-update-ESC-2023, rating: very high)
Close follow-up visits should monitor: congestion signs, BP, HR, NT-proBNP, potassium, eGFR. (sources/HF-update-ESC-2023, rating: very high)

Mechanical Circulatory Support in ACS-Related Cardiogenic Shock (sources/ACS-AHA-2025, rating: very high)

Emergency culprit vessel revascularization (PCI or CABG) is the foundational therapy for ACS with cardiogenic shock, regardless of time from onset — Class I/B-R
Microaxial flow pump (Impella): Class IIa/B-R for selected STEMI + severe/refractory cardiogenic shock — DanGer-SHOCK trial (n=360, 14 European specialised centres): 26% reduction in all-cause mortality at 180 days (HR 0.74; 95% CI 0.55–0.99; absolute risk reduction 12.7%; NNT=8). Selection: SCAI Stage C/D/E, noncomatose (GCS ≥8), LVEF <45%, lactate ≥2.5 mmol/L, adequate peripheral vasculature for large-bore access. Increased limb ischemia, bleeding, and renal replacement therapy vs standard care.
IABP: Routine use NOT recommended — Class III: No Benefit/B-R. IABP-SHOCK II (n=600): no difference in 30-day or long-term all-cause death. IABP may still be used as bridge for mechanical complications (VSR, acute MR).
VA-ECMO: Routine use NOT recommended — Class III: No Benefit/B-R. ECLS-SHOCK: no difference in 30-day mortality; higher moderate/severe bleeding and peripheral vascular complications. ECMO-CS: no benefit in primary endpoint; higher adverse events.
Contradiction with earlier practice: Prior observational data and small trials suggested MCS benefit broadly; three 2023–2024 RCTs consistently show no benefit for IABP and VA-ECMO. The microaxial flow pump is the only device with RCT mortality benefit in this setting, but only in the specific DanGer-SHOCK population.

Ischaemic Cardiomyopathy

Revascularisation Strategy (sources/CCS-AHA-2023, rating: very high)

CABG for LVEF ≤35% (COR 1/B-R): STICH trial (n=1,212, LVEF ≤35%, CAD amenable to CABG): CABG + optimal medical therapy vs medical therapy alone — CV death lower (28% vs 33%; P=0.05); all-cause death lower at 10-year follow-up. Patient selection: multi-vessel disease with viable myocardium, acceptable surgical risk.
PCI for LVEF ≤35% — no survival benefit: REVIVED-BCIS2 (n=700, LVEF ≤35%, extensive CAD with viable myocardium): PCI + GDMT vs GDMT alone — no difference in all-cause death or HF hospitalisation at median 3.4 years (38.0% vs 37.2%). ICA can still diagnose cause of HF and direct lipid/medical therapy.
Viability imaging: Multiple modalities (LGE-CMR, PET-FDG, SPECT, dobutamine echo) predict segmental contractile recovery after revascularization, but no trial has demonstrated that viability-guided revascularization improves survival vs GDMT alone. STICH viability substudy (SPECT/dobutamine echo, n=618): patients with viable myocardium had lower 5-year mortality but viability status did NOT discriminate who benefited from CABG. See concepts/Myocardial-Viability for full imaging performance data and clinical algorithms. (sources/imaging-viability-aha-2020, rating: very high)
SGLT2 inhibitors for HFrEF (LVEF ≤40%) — COR 1/A regardless of diabetes status: Reduces CV death and HF hospitalisation; improves QOL (DAPA-HF, EMPEROR-Reduced). Effect independent of aetiology (ischaemic ~50% of trials). See entities/Chronic-Coronary-Disease for CCD + HF overlap.
SGLT2 inhibitors for HFpEF (LVEF >40%) — COR 2a/B-R regardless of diabetes status: Reduces HF hospitalisation and improves QOL (EMPEROR-PRESERVED, DELIVER, PRESERVED-HF). CV mortality reduction not statistically significant; economic value uncertain at current US prices.
Contradiction with prior revascularisation evidence: REVIVED-BCIS2 conflicts with prior observational data suggesting PCI improves outcomes in ischaemic cardiomyopathy. The 2023 CCD guideline reflects the shift: CABG retains survival benefit for LVEF ≤35%; PCI does not.

Iron Deficiency in HF

Applies to HFrEF and HFmrEF (most evidence from LVEF ≤45%); IV iron not currently recommended in HFpEF.

To improve symptoms and QoL: IV iron (ferric carboxymaltose or ferric derisomaltose) Class I, Level A (upgraded from Class IIa in 2021). (sources/HF-update-ESC-2023, rating: very high)
To reduce HF hospitalization risk: Ferric carboxymaltose or ferric derisomaltose Class IIa, Level A. (sources/HF-update-ESC-2023, rating: very high)

HF Prevention in CKD + T2DM

SGLT2 inhibitors: Class I, Level A — reduces HF hospitalization or CV death. Based on DAPA-CKD, EMPA-KIDNEY, CREDENCE, SCORED. (sources/HF-update-ESC-2023, rating: very high)
Finerenone (selective non-steroidal MRA): Class I, Level A — reduces HF hospitalization (HR 0.78; FIDELIO-DKD + FIGARO-DKD pooled). Caution: hyperkalaemia risk. (sources/HF-update-ESC-2023, rating: very high)

Device Therapy

Ventricular Electrical Remodeling in HF

HF causes comprehensive ventricular electrical remodeling that increases arrhythmic susceptibility independently of LVEF. (sources/membrane-potential-physrev-2021, rating: very high)
↑INaLate (central mechanism, CaMKII-driven): CaMKII is hyperactivated in HF via neurohormonal signalling (norepinephrine, angiotensin II), oxidative stress, and mechanical stretch. CaMKII phosphorylates Nav1.5 → shift from peak to late Na⁺ current → APD prolongation + Na⁺ overload → Ca²⁺ overload via NCX reverse mode → further CaMKII activation (feed-forward loop). This underpins the arrhythmogenic substrate in HF. (sources/membrane-potential-physrev-2021)
↑If in ventricles (HCN4 upregulation): Pacemaker channels, normally restricted to the SAN, are upregulated in HF ventricular myocytes → spontaneous phase 4 depolarizations → abnormal automaticity and triggered activity. (sources/membrane-potential-physrev-2021)
↑NCX (Na⁺/Ca²⁺ exchanger NCX1): Upregulated NCX1 drives forward mode (Ca²⁺ extrusion = 3Na⁺ in) during diastolic Ca²⁺ elevation → net inward depolarizing current → DADs. (sources/membrane-potential-physrev-2021)
↓IKr (KCNH2) and ↓IKs (KCNQ1): Reduced rapid and slow delayed rectifier currents deplete repolarization reserve → APD prolongation → EAD generation; increases susceptibility to drug-induced TdP (reduced reserve makes HF patients more sensitive to QT-prolonging drugs). (sources/membrane-potential-physrev-2021)
↓Ito and ↓IK1: Loss of transient outward K⁺ and inward rectifier K⁺ → blunted Phase 1, increased automaticity, and further APD prolongation. (sources/membrane-potential-physrev-2021)
Clinical implication: This electrical remodeling profile explains why HF patients have elevated TdP risk on QT-prolonging drugs, why CaMKII inhibition is a target of interest, and why amiodarone (the only antiarrhythmic with no evidence of harm in HFrEF per SCD-HeFT) does not worsen these ionic changes. See concepts/Electrical-Remodeling for full disease-by-disease summary. (sources/membrane-potential-physrev-2021)

ICD

Primary prevention, ischaemic DCM: Class I — LVEF ≤35% after ≥3 months OMT. (sources/HF-ESC-2021, rating: very high)
Primary prevention, non-ischaemic DCM: Class IIa — LVEF ≤35% after ≥3 months OMT. (sources/HF-ESC-2021, rating: very high)
ICD consideration even with LVEF >35% for LMNA/C, desmosomal proteins, phospholamban, FLNC — due to arrhythmia risk disproportionate to EF. (sources/HF-AHA-2022, rating: very high)
ICD in CKD: Meta-analysis (MADIT I/II, SCD-HeFT): ICD survival benefit in GFR >60 (HR 0.49) but NOT in GFR <60 (HR 0.80); Cleveland Clinic CKD Registry shows benefit in eGFR 30–59 but not eGFR <30. DANISH: no ICD benefit in non-ischaemic HFrEF including CKD. Higher complication rates in CKD (infections, bleeding, venous stenosis). S-ICD is a reasonable alternative — comparable efficacy, no lead complications; CKD is an independent predictor of appropriate therapy for polymorphic VT/VF (HR 2.10). (sources/cardiorenal-aha-2019, rating: very high)

CRT

Class I: QRS ≥150 ms with LBBB + LVEF ≤35%. (sources/HF-ESC-2021, rating: very high)
Class IIa: QRS 130–149 ms with LBBB. (sources/HF-ESC-2021, rating: very high)
CRT in CKD: MIRACLE post hoc: improvements in NYHA class, EF, and MR across eGFR 30–59; eGFR improvement noted in the CKD3 subgroup. Meta-analysis (Bazoukis, 13/16 studies): higher all-cause mortality with baseline CKD post-CRT (HR 1.66 for eGFR <60 vs ≥60). Benefits for HF hospitalisation reduction and QoL should be weighed against higher mortality in advanced CKD — multidisciplinary cardionephrology approach recommended. (sources/cardiorenal-aha-2019, rating: very high)

TEER (Transcatheter Edge-to-Edge Repair) for Secondary MR

Class IIb: May be considered in carefully selected patients with significant functional MR + LVEF >20% + maximally optimised GDMT who remain symptomatic and have suitable anatomy. (sources/HF-ESC-2021, rating: very high)
Benefit driven by COAPT (disproportionate MR); MITRA-FR (proportionate MR) showed no benefit — patient selection is critical. (sources/HF-ESC-2021, rating: very high)
[2025 ESC VHD Upgrade] Class I A (ESC 2025 VHD guidelines): TEER is now recommended (upgraded from IIb) for haemodynamically stable symptomatic patients with LVEF <50%, persistent severe ventricular SMR despite optimised GDMT + CRT, fulfilling specific criteria (NYHA ≥II, LVEF 20–50%, LVESD ≤70 mm, ≥1 HF hospitalisation/year or elevated BNP, SPAP ≤70 mmHg, no severe RV dysfunction, no advanced HF, no revascularisation-requiring CAD). Based on COAPT, RESHAPE-HF2, and meta-analysis. (sources/vhd-esc-2025, rating: very high)
Cardiogenic shock + ventricular SMR post-MI: M-TEER supported by propensity-matched data showing lower mortality vs surgery or medical therapy — may facilitate weaning from mechanical circulatory support. (sources/vhd-esc-2025, rating: very high)

Cardiac Rehabilitation

Qualifying HF indication for CR: Stable chronic HF with LVEF ≤35% + NYHA Class II–IV symptoms despite optimal HF therapy for ≥6 weeks is a Medicare-qualifying diagnosis for CR. (sources/cardiac-rehab-aha-2024, rating: very high)
CR reduces mortality and improves quality of life in patients with CVD including HF; it is a high-value but greatly underutilised intervention (~20% national enrollment; target 70%). (sources/cardiac-rehab-aha-2024, rating: very high)
CR for HF includes aerobic exercise (3–5 days/week, 40–89% HRR), strength training (2–3 days/week, 40–60% 1-RM), nutritional counseling, psychosocial management, and risk factor optimization with BP and lipid targets identical to secondary prevention guidelines. (sources/cardiac-rehab-aha-2024, rating: very high)
Virtual and hybrid CR delivery models are equivalent to in-person CR for low–moderate risk HF patients — important for HF patients with limited mobility or transportation barriers. (sources/cardiac-rehab-aha-2024, rating: very high)
Aerobic exercise in HCM/cardiac-oncology settings: CR demonstrates 14% reduction in CVD mortality per 1 MET increase in cardiorespiratory fitness in cancer survivors (also noted in sources/Cardio-Oncology-ESC-2022). See concepts/Cardiac-Rehabilitation for full prescription framework.

Advanced HF

Definition: ≥2 episodes of congestion/low output in 12 months requiring IV therapy, NYHA III–IV, severe cardiac dysfunction (LVEF ≤30%, pVO2 <12 mL/kg/min), or ≥1 recent hospitalization. (sources/HF-ESC-2021, rating: very high)
Heart transplantation: Class I for advanced HF refractory to medical/device therapy. (sources/HF-ESC-2021, rating: very high)
Long-term LVAD (destination therapy): Viable alternative when transplant is not an option. (sources/HF-ESC-2021, rating: very high)

Kidney Dysfunction in Advanced HF

Over two-thirds of patients with advanced HF have kidney dysfunction. See concepts/Cardiorenal-Syndrome for the full pathophysiology and assessment framework. Key clinical points: (sources/AKI-HF-AHA-2024, rating: very high)

Assessment

Serum creatinine (not eGFR) preferred for day-to-day tracking during hospitalisation; cystatin C useful when sarcopenia suspected
Multi-domain reversibility assessment: alleviate congestion/hypoperfusion → quantify kidney response; transkidney perfusion pressure (MAP − CVP) goal >60 mmHg
Heart-Kidney Profiles: A = no dysfunction; B = transient/reversible; C = persistent, requires KRT
A creatinine rise during aggressive decongestion does not equal tubular injury; do NOT reduce diuretics solely for eGFR decline

GDMT and Kidney Function

Pharmacological eGFR decline with RAAS inhibitors or SGLT2i is paradoxically renoprotective; do NOT discontinue GDMT for eGFR decline alone
Hyponatremia and hypochloremia are independent mortality predictors in advanced HF with kidney involvement

LVAD Candidacy

Preoperative kidney dysfunction (especially chronic KRT: median survival ~3 weeks post-LVAD) predicts poor outcomes
Temporary MCS/inotropes to test kidney reversibility reasonable before LVAD when function is questionable
Post-LVAD AKI in 37%; early eGFR improvement in 85% but sustained improvement in only 3.3%
Peritoneal dialysis preferred over hemodialysis in LVAD patients (smaller hemodynamic shifts, no vascular access, no heparin)

Heart Transplantation

Evaluate all HTx candidates with eGFR <45 mL/min/1.73m² for simultaneous heart-kidney transplantation (sHKTx); UNOS criterion ≤30 mL/min/1.73m²
Post-HTx kidney failure requiring dialysis: 13.4% within 90 days; CNI-delaying induction protocols and nephrotoxin avoidance are key strategies
Safety net policy: priority deceased donor kidney access for HTx recipients meeting KTx criteria at 60–365 days post-HTx

HF in Kidney Transplant Recipients

(sources/cardiorenal-aha-2019, rating: very high)

HF prevalence in ESKD dialysis patients 12–36× the general population; 83% 3-year mortality after HF hospitalisation in ESKD
70% of HFrEF patients (LVEF <40% pre-transplant) had LVEF >50% by 1 year post-KT; longer pre-KT dialysis duration independently predicted failure to improve LVEF
De novo HF after KT: 10.2% at 12 months, 18.3% at 36 months; predicts death (HR 2.6) and graft failure (HR 2.7)
De novo HF after KT is as common as de novo ischaemic heart disease (1.26 vs 1.22 events/100 patient-years) and carries similar prognosis
Preexisting LVEF <45%: independent predictor of cardiac death (HR 4.8), overall mortality, and cardiac hospitalisation post-KT; associated with delayed graft function and longer renal recovery time
RAAS inhibition in KT: Conflicting evidence; Paoletti et al. (lisinopril, n=70): significant CV benefit; Knoll et al. (ramipril, n=213): no benefit; meta-analysis (n=8 trials): no survival benefit, higher hyperkalemia (RR 2.44)
Pre-KT pulmonary hypertension (sPAP >50 mmHg): nearly 4× post-KT mortality; lower graft survival at 5 years (54.6% vs 76.0%); multidisciplinary PH work-up required before listing
See concepts/Cardiorenal-Syndrome for full CRS classification and management framework

Special Populations

Clonal Hematopoiesis and Heart Failure

Meta-analysis of 56,597 individuals without baseline HF → 25% higher HF risk in CH carriers, independent of traditional risk factors and CAD. (sources/ch-aha-2026, rating: very high)
CH not significantly associated with overall HFrEF/HFpEF phenotype, but gene-specific: TET2 variants 2.4-fold enriched in HFpEF; ASXL1 CH associated with modestly reduced EF in HF cohort studies. (sources/ch-aha-2026)
CH in patients with established HF → higher all-cause mortality and higher HF-related hospitalisations. (sources/ch-aha-2026)
CH worsens outcomes after MI and after cardiogenic shock (independent of HF phenotype). (sources/ch-aha-2026)
Mechanism (TET2): LOF → NLRP3 inflammasome overactivation → increased IL-1β secretion; elevated circulating IL-1β is unique to TET2-CH. CANTOS post-hoc data: canakinumab (anti-IL-1β) reduced ischemic events far more in TET2-CH carriers — mechanistic implication for HF-inflammatory phenotype. (sources/ch-aha-2026)
Mechanism (DNMT3A): LOF → impaired efferocytosis; increased secretion of HB-EGF (heparin-binding EGF-like growth factor) → cardiac fibrosis. (sources/ch-aha-2026)
Mechanism (PPM1D, therapy-related CH): PPM1D-CH → increased IL-1β + myocardial fibrosis after angiotensin II infusion in mice; effects reversed by NLRP3 inhibitor — possible relevance for HF in cancer survivors. (sources/ch-aha-2026)
No CH-targeted HF therapy proven in a prospective trial. See concepts/Clonal-Hematopoiesis for full gene-specific mechanisms and emerging strategies (vitamin C, metformin, colchicine, canakinumab).

CTRCD definition: Graded by severity of LVEF decline, GLS change, and cardiac biomarker rise. Asymptomatic mild = LVEF ≥50% + new GLS decline >15% and/or new biomarker rise. Moderate = LVEF 40–49% with ≥10 pp decline. Severe = LVEF <40%. (sources/Cardio-Oncology-ESC-2022, rating: very high)
Standard HF therapies serve dual roles: ACEi/ARNi + beta-blockers + MRA + SGLT2i are used both to treat CTRCD and as cardioprotective strategies to prevent CTRCD in high-risk patients. (sources/Cardio-Oncology-ESC-2022, rating: very high)
Anthracycline CTRCD — severity-stratified management:
- Symptomatic severe → discontinue anthracycline + full HF therapy (Class I).
- Symptomatic moderate → interrupt + HF therapy; MDT restart after recovery (Class I).
- Asymptomatic severe/moderate → interrupt + HF therapy (ACEi/ARNi + BB + SGLT2i + MRA; Class I).
- Asymptomatic mild (LVEF ≥50% + GLS decline >15%/biomarker rise) → continue anthracycline + ACEi/ARB ± BB (Class IIa/B).
- Rechallenge: dose minimization, liposomal anthracycline switch (IIb/C), dexrazoxane pre-treatment (IIb/C); monitor every 1–2 cycles. (sources/Cardio-Oncology-ESC-2022, rating: very high)
HER2-targeted therapy CTRCD — more permissive continuation:
- Moderate asymptomatic (LVEF 40–49%) → continue HER2 therapy + ACEi/ARB + BB + frequent monitoring (Class IIa/B). Major departure from prior guidance.
- Restart after interruption when LVEF ≥40% and asymptomatic; echo + biomarkers every 2 cycles × 4 cycles. (sources/Cardio-Oncology-ESC-2022, rating: very high)
End-of-treatment assessment (within 1 year of completing cardiotoxic therapy): Class I for all. Long-term surveillance TTE at years 1, 3, 5, then every 5 years for high/VH risk. (sources/Cardio-Oncology-ESC-2022, rating: very high)
CTRCD medication weaning: Full recovery (LVEF >50% + normal GLS + normal biomarkers) in low-risk patients → consider weaning after MDT (Class IIa). Continue long-term in severe/very severe CTRCD or incomplete recovery (Class I). (sources/Cardio-Oncology-ESC-2022, rating: very high)
Aerobic exercise/cardiac rehab: 14% decrease in CVD mortality per 1 MET increase in CRF. Targeted cardiac rehab in high CV risk cancer survivors (Class IIa/B). HIIT is safe and improves CRF, fatigue, and QoL. (sources/Cardio-Oncology-ESC-2022, rating: very high)

HF During Haematopoietic Stem Cell Transplantation (HSCT)

CV complications during HSCT (HF, arterial events, tamponade, arrhythmias) are uncommon but clinically relevant. (sources/Cardio-Oncology-ESC-2022, rating: very high)
Each CV complication should be managed per the relevant ESC guideline — no HSCT-specific protocol deviates from standard ESC guidance. (sources/Cardio-Oncology-ESC-2022, rating: very high)
ACEi + beta-blockers may be effective for CTRCD in the HSCT setting, though HSCT-specific trial confirmation is lacking. (sources/Cardio-Oncology-ESC-2022, rating: very high)
Post-HSCT exercise programmes improve exercise capacity and QoL. Pre-HSCT prehabilitation is under investigation; not yet standard of care. (sources/Cardio-Oncology-ESC-2022, rating: very high)

PH Associated with Left Heart Disease (Group 2 PH-LHD)

Post-capillary PH affects ≥50% of HFpEF patients; found in 60–70% of severe mitral valve disease and up to 50% of symptomatic aortic stenosis. (sources/PHT-ESC-2022, rating: very high)
PDE5i in HFpEF + isolated post-capillary PH: Class III — not recommended. Consistent with AHA 2022 COR 3 No Benefit. (sources/PHT-ESC-2022, rating: very high)
CpcPH with severe pre-capillary component (PVR >5 WU): Individualized approach (Class I); PAH drugs may be considered with close monitoring. (sources/PHT-ESC-2022, rating: very high)
See entities/Pulmonary-Hypertension for full PH classification and management.

Genetic Testing

COR 1, LOE B-NR: Genetic screening and counseling for first-degree relatives of confirmed genetic/inherited cardiomyopathy. (sources/HF-AHA-2022, rating: very high)
COR 2a, LOE B-NR: Genetic counseling and testing in select patients with nonischemic cardiomyopathy. (sources/HF-AHA-2022, rating: very high)
ICD consideration even with LVEF >35% for high-risk pathogenic variants (LMNA/C, desmosomal proteins, phospholamban, FLNC). (sources/HF-AHA-2022, rating: very high)

Precision Medicine / Multi-Omics in HF

An AHA 2019 Scientific Statement (Cresci et al.) summarises six omics domains relevant to HF precision medicine: (sources/HF-Precision-Medicine-AHA-2019, rating: high)

Genomics: Pathogenic variant detection yields vary by cardiomyopathy type (HCM 60–70%, DCM 30–40%, ARVC 50–60%). Key genes with precision management implications: LMNA (high arrhythmia risk, early ICD consideration) and TTN (metabolic stress vulnerability; triggers include pregnancy and alcohol).
Pharmacogenomics: ADRB1, GRK5, and GNB3 variants influence beta-blocker and H-ISDN response; GRK5 Leu41 allele frequency is 10-fold higher in Black patients, partly explaining observed racial differences in beta-blocker efficacy. CYP2D6 poor metabolisers of metoprolol have 4-fold higher bradycardia risk. See concepts/Pharmacogenomics-in-HF.
Epigenomics: DNA methylation, histone modifications, and non-coding RNAs (miRNAs, lncRNAs) are implicated in HF pathophysiology and as potential biomarkers (miR-423-5p, lncRNA LIPCAR).
Proteomics: NT-proBNP-guided therapy tested in GUIDE-IT (multicenter RCT) was stopped early for futility; sST2 tracks therapy response and is unaffected by age/renal function/BMI.
Metabolomics: Advanced HF shifts from fatty acid oxidation to glucose utilisation; acylcarnitine and ketone body profiles distinguish HFrEF from HFpEF and predict outcomes.
Microbiomics: Gut dysbiosis in HF → TMAO elevation (independent 5-year mortality predictor); Mediterranean diet reduces incident HF by 21%. See concepts/Gut-Microbiome-in-HF.

Perioperative Management of HF

Active decompensated HF is one of the four "active cardiac conditions" requiring evaluation and treatment before any noncardiac surgery (NCS), except emergency procedures. (sources/periop-aha-2024, rating: very high)
Perioperative mortality: Patients with HF have 3× increased 30-day mortality vs those with CAD alone undergoing NCS. (sources/periop-aha-2024, rating: very high)
GDMT continuation (COR 2a): Continue evidence-based HF therapies (ACEi/ARB/ARNI, beta-blockers, MRA) throughout the perioperative period in most patients. (sources/periop-aha-2024, rating: very high)
RAASi holding (COR 2b): ACEi/ARB may be held 24 h before elevated-risk NCS in patients taking them purely for hypertension; however, COR 2a: continue if prescribed for HFrEF — the HF indication takes precedence. (sources/periop-aha-2024, rating: very high)
SGLT2i (COR 1): Stop 3–4 days before any surgery regardless of indication — euglycaemic diabetic ketoacidosis risk with anaesthesia, fasting, and fluid shifts. Note: this temporarily interrupts a Class I HFrEF and HFpEF therapy. (sources/periop-aha-2024, rating: very high)
BNP/NT-proBNP (COR 2a): Preoperative natriuretic peptide measurement recommended in patients with HF or HF symptoms undergoing elevated-risk NCS. Abnormal: BNP >92 ng/L; NT-proBNP ≥300 ng/L — markedly elevated values should prompt HF optimisation before elective surgery. (sources/periop-aha-2024, rating: very high)
Postoperative surveillance: cTn at 24 h and 48 h post-NCS (COR 2b) in known CVD or symptomatic patients undergoing elevated-risk surgery — elevated postop cTn without ischaemic features still confers 3× 30-day mortality hazard. (sources/periop-aha-2024, rating: very high)

Obesity and Heart Failure

HF incidence increases 5% (men) and 7% (women) per 1-unit BMI increase after adjustment for other risk factors (Framingham Heart Study, n=5,881). (sources/obesity-cv-aha-2021, rating: very high)
HFpEF is more strongly associated with obesity than HFrEF: Overweight → 38% higher HFpEF risk; class 1 obesity → 56% higher HFpEF risk, independently of other CVD risk factors (Pandey et al., pooled analysis of 3 longitudinal studies). (sources/obesity-cv-aha-2021, rating: very high)
Obesity-HFpEF phenotype: Compared with non-obese HFpEF, obesity + HFpEF is characterized by greater concentric LV remodeling, RV dilatation and dysfunction, pericardial restraint, ventricular interdependence (driven by greater epicardial fat thickness/volume), and significantly lower exercise capacity — a distinct pathophysiological phenotype. (sources/obesity-cv-aha-2021, rating: very high)
Obesity paradox in HF: Patients with overweight or class 1 obesity and HF have better clinical outcomes than normal-weight HF patients; documented in HFrEF, HFpEF, and acutely decompensated HF. See concepts/Obesity-Paradox. (sources/obesity-cv-aha-2021, rating: very high)
BNP lower in obesity including in HF: Normal BNP does not exclude HFpEF in obese patients. Weight loss after bariatric surgery increases NT-proBNP concomitantly with improved LVDD. (sources/obesity-cv-aha-2021, rating: very high)
Low fitness explains ~50% of HF risk attributable to BMI: Physical activity and improved cardiorespiratory fitness are highly encouraged in obese patients with HF. (sources/obesity-cv-aha-2021, rating: very high)
Treatment in obesity: SGLT2 inhibitors (dapagliflozin) reduce risk of worsening HF or CV death in overweight/obese HFrEF regardless of diabetes. GLP-1 agonists show promise for combined obesity–HF management. Weight loss improves candidacy for LVAD and heart transplantation. Class 3 obesity is a relative contraindication for heart transplantation (higher acute rejection and 5-year mortality). (sources/obesity-cv-aha-2021, rating: very high)
See entities/Obesity, concepts/Visceral-Adiposity, concepts/HFpEF, and concepts/Obesity-Paradox.

Contradictions / Open Questions

AHA 2022 (COR 2a) vs. ESC 2023 (Class I) for SGLT2i in HFpEF/HFmrEF: AHA 2022 assigned COR 2a because only EMPEROR-Preserved data were available at the time. The 2023 ESC update incorporated the DELIVER trial (dapagliflozin, n=6263) and upgraded to Class I, Level A. The underlying trial data are the same; the different recommendation strength reflects only the timing of publication — not a clinical disagreement. (sources/HF-AHA-2022, sources/HF-update-ESC-2023, rating: very high)
SGLT2i reduces HF hospitalizations but not CV death in HFpEF/HFmrEF: Both EMPEROR-Preserved and DELIVER showed no significant individual reduction in CV death; pooled meta-analysis also non-significant for CV death (HR 0.88, P=0.052). The Class I, Level A recommendations are based on composite primary endpoints driven by hospitalization reduction. (sources/HF-update-ESC-2023, rating: very high)
STRONG-HF limitations: Enrolled only patients not already on full doses of evidence-based HF therapy; SGLT2 inhibitors not included in protocol; may not reflect current optimally-treated contemporary HF populations. (sources/HF-update-ESC-2023, rating: very high)
IV iron IRONMAN primary endpoint not met: Recommendation upgrade to Class I is based on meta-analysis data, including a COVID-adjusted sensitivity analysis of IRONMAN, not a single pivotal trial. (sources/HF-update-ESC-2023, rating: very high)

Complementary and Alternative Medicine (CAM) in HF

See concepts/CAM-in-Heart-Failure for full evidence synthesis.

Key Evidence-Based Points

Omega-3 PUFA (AHA 2022 Class 2b, LOE B-R): Only CAM agent with a guideline recommendation in HF — adjunctive therapy for NYHA II–IV to reduce mortality and CV hospitalizations; avoid doses ≥4 g/day due to AF risk (sources/alt-medicine-hf-aha-2023, rating: very high)
Yoga and Tai Chi: Safe, well-tolerated adjunctive therapies; demonstrated improvements in VO2, quality of life, 6MWD, and inflammatory markers in HF RCTs; suitable for HFrEF and HFpEF (sources/alt-medicine-hf-aha-2023, rating: very high)
CoQ10: Q-SYMBIO trial (n=420) showed 50% MACE reduction (HR 0.50) and NYHA class improvement, but no change in 6MWD or NT-proBNP; larger RCTs needed before recommendation (sources/alt-medicine-hf-aha-2023, rating: very high)
Thiamine: Supplement only if deficient (loop diuretics deplete thiamine); no benefit in ambulatory HFrEF without deficiency (sources/alt-medicine-hf-aha-2023, rating: very high)

CAM to Avoid in HF

Licorice: Mineralocorticoid excess → hypokalemia, cardiac arrest; potentiated by MRA co-prescription (sources/alt-medicine-hf-aha-2023, rating: very high)
Vitamin E ≥400 IU/day: 13% increased HF incidence and 21% increased HF hospitalisation (HOPE trial) (sources/alt-medicine-hf-aha-2023, rating: very high)
Grapefruit juice: CYP3A4 inhibition increases bioavailability of amiodarone, carvedilol; reduces efficacy of losartan, clopidogrel; additive QT prolongation with dofetilide/sotalol (sources/alt-medicine-hf-aha-2023, rating: very high)
Hawthorn in LVEF ≤35%: Subanalysis data suggest potential HF progression; large trial (SPICE) failed primary endpoint (sources/alt-medicine-hf-aha-2023, rating: very high)
L-Arginine after acute MI: Associated with increased mortality in older patients in RCT data — avoid post-MI (sources/alt-medicine-hf-aha-2023, rating: very high)
High-dose alcohol (>10 drinks/week): New-onset AF risk; cardiomyopathy at 6–7 drinks/day. See concepts/Alcoholic-Cardiomyopathy (sources/alt-medicine-hf-aha-2023, rating: very high)

Connections

Related to entities/Amiodarone
Related to entities/Hypertension — antecedent in 71% HF; BP management critical in HFrEF and HFpEF
Related to entities/DCM
Related to entities/Atrial-Fibrillation
Related to entities/LMNA
Related to entities/TTN
Related to entities/ATTR-Amyloidosis
Related to entities/Pulmonary-Hypertension
Related to entities/Obesity — obesity as major HF risk factor and HFpEF driver
Related to concepts/HFpEF
Related to concepts/Secondary-Mitral-Regurgitation
Related to concepts/Valvular-Heart-Disease
Related to concepts/Cardio-Oncology
Related to concepts/Cancer-Therapy-Related-CV-Toxicity
Related to concepts/Right-Heart-Catheterization
Related to concepts/Perioperative-Cardiovascular-Assessment
Related to concepts/Heart-Healthy-Dietary-Patterns — sodium/potassium dietary management in HFpEF
Related to concepts/Cardiac-Rehabilitation — stable HF (LVEF ≤35%, NYHA II–IV) is a qualifying CR indication; CR reduces mortality and improves QoL
Related to concepts/Cardiorenal-Syndrome — kidney dysfunction in >2/3 of advanced HF; Heart-Kidney Profiles guide LVAD/HTx candidacy
Related to concepts/Visceral-Adiposity — epicardial fat and obesity-HFpEF phenotype
Related to concepts/Obesity-Paradox — paradox documented across HFrEF, HFpEF, and acute HF
Related to concepts/Myocardial-Viability
Related to concepts/CAM-in-Heart-Failure — omega-3 PUFA, yoga/tai chi, CoQ10, drug-interaction catalog
Related to concepts/Electrical-Remodeling — HF ventricular electrical remodeling: ↑INaLate, ↑If, ↑NCX, ↓IKr/IKs/Ito/IK1; CaMKII as central arrhythmogenic hub
Related to concepts/Clonal-Hematopoiesis — 25% higher HF risk; TET2 2.4× enriched in HFpEF; ASXL1 → reduced EF; CH worsens HF mortality and hospitalisations; PPM1D-CH drives myocardial fibrosis via NLRP3/IL-1β
Related to sources/ch-aha-2026