Maladaptive lipid partitioning in obesity-related heart failure with preserved ejection fraction: From depot dysfunction to metabolic phenotyping

Table 1 Depot-specific adipose and organ pathways in obesity-related heart failure with preserved ejection fraction

Depot or organ axis	Representative evidence	Proposed mechanism	Clinical measurability	Evidence maturity/key limitation
Subcutaneous adipose tissue	Lower subcutaneous adiposity, together with lower visceral adiposity, was associated with underweight, malnutrition, and poorer outcomes in an East Asian HFpEF cohort[6]; impaired lipid-buffering remains primarily a conceptual framework[8]	Lipid spillover to ectopic depots	Body composition; indirect metabolic markers	Human observational association plus review-level conceptual evidence; direct subcutaneous lipid-buffering capacity has not been established in HFpEF (CT-based East Asian HFpEF cohort, n = 196 + contemporary review)
Visceral adiposity	Visceral or central adiposity is associated with exercise limitation, higher exercise filling pressures, and poorer aerobic capacity[5,22]	Insulin-resistant lipid stress; inflammatory activation	CT/MRI; waist indices; visceral adiposity measures	Human observational and invasive-physiology evidence; causality remains unproven (HFpEF imaging cohort + invasively phenotyped HFpEF cohort)
MASLD/liver	MASLD is associated with incident heart failure, including HFpEF, whereas experimental NASH produces an HFpEF-like phenotype[20,21]	Hepatic-metabolic stress; systemic inflammation	Liver fat/stiffness; liver enzymes; metabolic risk indices	Human longitudinal association plus preclinical mechanistic evidence; human causality remains uncertain (longitudinal human cohort + experimental NASH model)
Skeletal-muscle fat	Intermuscular fat is associated with worse functional limitation, and impaired skeletal muscle mitochondrial respiration is associated with exercise intolerance[22,28]	Impaired peripheral metabolic and oxygen-utilization reserve	CT/MRI muscle composition; grip strength; gait speed	Human imaging/biopsy associations; clinically validated thresholds are lacking (human HFpEF imaging + skeletal biopsy studies)
Epicardial adipose tissue	EAT burden is associated with pericardial constraint and atrial/ventricular dysfunction, whereas lower EAT density is associated with adverse cardiometabolic phenotype and outcomes[23,24,40]	Local mechanical and paracrine amplifier	Echocardiography, CT, CMR; EAT volume/density	Human observational, invasive-physiology, and prospective imaging evidence; EAT density is not a direct measure of inflammation and whether EAT is a mediator or marker remains unresolved (HFpEF observational/invasive-physiology cohorts + prospective imaging cohort, n = 154)
Perivascular adipose tissue	Pericoronary adipose tissue attenuation on CT is associated with HFpEF[41]	Possible vascular-adipose inflammatory and remodeling interface	CT perivascular fat attenuation	Retrospective human imaging association; direct causal and histological validation in HFpEF is lacking (retrospective CCTA/echocardiography cohort, n = 607)

HFpEF: Heart failure with preserved ejection fraction; CT: Computed tomography; MRI: Magnetic resonance imaging; MASLD: Metabolic dysfunction-associated steatotic liver disease; NASH: Non-alcoholic steatohepatitis; EAT: Epicardial adipose tissue; CMR: Cardiovascular magnetic resonance; CCTA: Coronary computed tomographic angiography.

Table 2 Proposed phenotype-enriched research and trial-design framework for obesity-related heart failure with preserved ejection fraction

Candidate phenotype axis	Phenotype-enrichment variables	Candidate intervention domain for prospective testing	Key trial monitoring variables	Evidence maturity; key limitation (study design/population/model)
Circulatory overload	Congestion; elevated filling pressure; plasma-volume expansion; exercise PCWP elevation	Decongestion strategies; SGLT2 inhibitors; MRA/finerenone according to established clinical indications	Renal function; blood pressure; potassium; volume depletion	Tier I: EMPEROR-Preserved[55]; DELIVER[56]; FINEARTS-HF[59]. Tier II: CAMEO-DAPA[25]. Randomized outcome trials in heart failure with mildly reduced or preserved ejection fraction; randomized placebo-controlled HFpEF hemodynamic study
EAT/pericardial restraint	High EAT burden and/or low computed tomography-derived EAT density; right-sided congestion; pericardial restraint; atrial enlargement	Decongestion; obesity-directed strategies for prospective testing; serial EAT imaging as a research measure	Imaging availability; overdiuresis risk; symptom-volume mismatch	Tier II: SUMMIT CMR substudy[62]. Tier III: Crum et al[23]; Jin et al[24]; Liu et al[40]. HFpEF-obesity randomized-trial CMR substudy; invasive-physiology HFpEF cohort; observational HFpEF imaging cohort; prospective HFpEF imaging cohort, n = 154
Inflammatory-metabolic phenotype	Elevated CRP/IL-6; leptin/resistin imbalance; TyG/HOMA-IR; diabetes/metabolic syndrome	Incretin-based obesity therapy; exercise; SGLT2 inhibitors according to established indications; nutritional intervention	GI intolerance; renal-volume status; lean-mass preservation	Tier I: STEP-HFpEF[10]; SUMMIT[11]. Tier III: Ramirez et al[26]; Lau et al[27]. Obesity-HFpEF randomized outcome trials; invasive-CPET biomarker cohort, n = 509; lipidomic cohort, n = 510
MASLD-dominant phenotype	Liver fat/stiffness; elevated metabolic risk; visceral adiposity	Weight loss strategies; incretin-based therapy; SGLT2 inhibitors according to established indications; hepatometabolic risk control	Liver markers; nutrition; sarcopenia risk	Tier III: Chang et al[20]. Tier IV: Kucsera et al[21]. Longitudinal human cohort; experimental NASH model
Frailty/sarcopenic obesity	Low muscle mass; poor grip strength or gait speed; low exercise reserve	Resistance training; protein/nutrition support; cautious weight-loss strategies	Lean-mass loss; falls; undernutrition	Tier II: Edelmann et al[53]; SURMOUNT-1 DXA substudy[63]. Tier III: Upadhya et al[54]. HFpEF randomized exercise trial with secondary functional outcomes; randomized DXA substudy in adults with obesity or overweight, not an HFpEF-specific population and therefore indirect body-composition evidence; small long-term HFpEF follow-up
Atrial-myopathy dominant phenotype	Low LA strain; AF; EAT proximity; LA enlargement; right-sided congestion	AF/rhythm management; decongestion according to established indications; obesity-directed weight loss strategies; EAT-aware assessment as a research measure	Atrial reserve; anticoagulation eligibility; renal function	Tier II: STEP-HFpEF atrial-fibrillation analysis[65]. Tier III: Weerts et al[48]; Wang et al[49]. Pooled randomized-trial secondary analysis; HFpEF observational atrial-function/imaging cohorts

This table shows a proposed, hypothesis-generating framework for phenotype-enriched research and trial design. It has not been prospectively validated for clinical treatment selection and should not be interpreted as guidance for assigning therapy to individual patients. Candidate intervention domains are included for prospective testing only. Evidence tiers apply to the individually cited studies rather than to the proposed phenotype-enriched research framework, which remains unvalidated in all rows. Tier I: Primary randomized clinical outcome evidence. Tier II: Randomized evidence from secondary, subgroup, substudy, mechanistic, or hemodynamic analyses or studies. Tier III: Nonrandomized human observational, prospective, longitudinal, imaging, biomarker, or other associative evidence. Tier IV: Preclinical or experimental mechanistic evidence. PCWP: Pulmonary capillary wedge pressure; SGLT2: Sodium-glucose cotransporter 2; EMPEROR-Preserved: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; FINEARTS-HF: Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; CAMEO-DAPA: Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure with Preserved Ejection Fraction; EAT: Epicardial adipose tissue; CMR: Cardiovascular magnetic resonance; CRP: C-reactive protein; IL-6: Interleukin-6; TyG: Triglyceride-glucose index; HOMA-IR: Homeostatic model assessment of insulin resistance; GI: Gastrointestinal; SUMMIT: A study of tirzepatide (LY3298176) in Participants with Heart Failure with Preserved Ejection Fraction and Obesity; STEP-HFpEF: Semaglutide treatment effect in people with obesity and heart failure with preserved ejection fraction; MASLD: Metabolic dysfunction-associated steatotic liver disease; NASH: Non-alcoholic steatohepatitis; SURMOUNT-1: A study of tirzepatide (LY3298176) in Participants With Obesity or Overweight; DXA: Dual-energy X-ray absorptiometry; LA: Left atrial; AF: Atrial fibrillation.