Introduction: Redefining the Role of Adiposity in Heart Failure
For decades, the medical community has relied on Body Mass Index (BMI) as the primary tool for assessing obesity and its associated cardiovascular risks. However, in the realm of heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF), BMI has often yielded confusing results, frequently manifesting as the obesity paradox—where higher BMI appears to correlate with better survival. This paradox has long hindered risk stratification and therapeutic targeting for a population where obesity is a central driver of disease.
Recent evidence, culminating in a massive participant-level pooled analysis published in the Journal of the American College of Cardiology, suggests that the problem lies not in the relationship between adiposity and heart failure, but in the tool used to measure it. By examining abdominal-specific metrics such as waist circumference (WC) and waist-to-height ratio (WHtR), researchers have uncovered a more direct, linear relationship between fat distribution and adverse clinical outcomes, effectively challenging the diagnostic dominance of BMI.
The Limitations of Body Mass Index as a Clinical Surrogate
BMI is a simple calculation of weight for height, but it fails to distinguish between lean muscle mass and adipose tissue, nor does it account for where fat is stored. In patients with heart failure, this lack of specificity is particularly problematic. Visceral adiposity—fat stored within the abdominal cavity and around the internal organs—is metabolically active and pro-inflammatory, whereas subcutaneous fat may have different or even protective properties in certain chronic illness contexts.
In HFpEF and HFmrEF, the pathophysiology is deeply intertwined with systemic inflammation, microvascular dysfunction, and increased epicardial fat, all of which are better represented by abdominal measurements than by total body weight. The recent analysis by Ostrominski and colleagues sought to clarify these associations by pooling data from five landmark clinical trials, providing the statistical power necessary to look beyond the BMI paradox.
Study Design: A Comprehensive Pooled Analysis
The study utilized participant-level data from five international randomized clinical trials: DELIVER (Dapagliflozin), PARAGON-HF (Sacubitril/Valsartan), TOPCAT (Spironolactone), I-Preserve (Irbesartan), and CHARM-Preserved (Candesartan). This robust dataset included 21,479 participants with HFpEF or HFmrEF (ejection fraction ≥40%).
The primary objective was to evaluate the association between different adiposity-related anthropometrics—BMI, WC, and WHtR—and clinical outcomes, including heart failure (HF) hospitalization and cardiovascular mortality. The researchers assessed these associations across various subgroups, including age, sex, and race, to determine if the predictive value of these metrics remained consistent across diverse patient populations.
Key Findings: The Prevalence of ‘Normal Weight’ Obesity
One of the most striking findings of the analysis was the sheer prevalence of abdominal adiposity, even among those not categorized as obese by BMI standards. While 46% of the total cohort had a BMI of 30 kg/m2 or higher, a staggering 95% of participants had an elevated waist circumference or waist-to-height ratio.
Most significantly, among participants with a BMI considered lean or normal (less than 30 kg/m2), 89% still exhibited excess abdominal adiposity. This phenomenon was particularly pronounced in older individuals and female participants. These data suggest that a clinical reliance on BMI alone would miss nearly 90% of patients who carry the high-risk phenotype of abdominal obesity, potentially delaying intervention or miscalculating risk in the primary care and cardiology setting.
Linear Risk vs. J-Shaped Curves: Comparing WHtR and BMI
When examining clinical outcomes, the researchers noted a distinct difference in the behavior of BMI versus abdominal metrics. BMI exhibited a complex J-shaped or U-shaped association with mortality and heart failure events. This non-linear relationship is what often gives rise to the obesity paradox, where individuals in the overweight or mildly obese categories appear to have lower risk than those in the lowest BMI categories, who may be experiencing frailty or cardiac cachexia.
In contrast, waist-to-height ratio (WHtR) showed a strong, linear association with increased risk. As WHtR increased, the risk of heart failure hospitalization and cardiovascular death rose consistently. This linear relationship suggests that WHtR is a more reliable and biologically plausible marker of the deleterious effects of fat on the cardiovascular system. Independent of BMI, a higher WHtR remained a potent predictor of adverse outcomes. Conversely, once WHtR was accounted for, the predictive value of BMI was significantly diminished, though it remained associated with heart failure hospitalizations, likely reflecting the overall hemodynamic load of total body mass.
Demographic Modifiers: The Influence of Sex and Race
The study also highlighted important interactions between anthropometrics and demographic factors. Sex and race significantly modified the association between BMI and abdominal fat distribution. Specifically, women were found to have a higher WHtR at higher BMI levels compared to men, suggesting a different pattern of fat accumulation.
Furthermore, Asian and Black participants exhibited higher WHtR at lower BMI levels than their White counterparts. This finding is of critical importance for global health, as it suggests that standard BMI cutoffs for obesity are particularly inadequate for non-White populations, who may develop metabolic and cardiovascular complications at lower total body weights due to a predisposition for visceral fat storage.
Expert Commentary: Mechanistic Insights into Abdominal Fat
The superiority of WHtR and WC over BMI in predicting HFpEF outcomes can be explained by the unique biological activity of visceral adipose tissue. Unlike subcutaneous fat, visceral fat is a source of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha. In HFpEF, this systemic inflammation leads to coronary microvascular endothelial dysfunction, which in turn promotes myocardial fibrosis and stiffening.
Additionally, abdominal obesity increases intra-abdominal pressure, which can impair venous return and exacerbate the hemodynamic stresses on the heart. The presence of epicardial fat—which correlates more closely with abdominal fat than total body fat—can also exert direct local inflammatory and mechanical effects on the myocardium. By measuring the waist, clinicians are essentially getting a proxy for this metabolic and mechanical burden that BMI simply cannot capture.
Conclusion: A Call for Anthropometric Precision
The findings from this pooled analysis of over 21,000 patients provide a compelling argument for the routine measurement of waist circumference and the calculation of waist-to-height ratio in heart failure management. The high prevalence of abdominal obesity in patients with ‘normal’ BMI highlights a significant diagnostic gap in current practice.
For clinicians, the takeaway is clear: do not be reassured by a normal BMI in a patient with HFpEF or HFmrEF. A simple tape measure may be one of the most cost-effective tools for risk stratification available. As we move toward more personalized and precision-based heart failure care—incorporating new therapies like SGLT2 inhibitors and GLP-1 receptor agonists—understanding the true adiposity-related risk of our patients is more important than ever.
Funding and Clinical Trial Registration
This analysis was supported by various grants and the data originated from the following trials: DELIVER (NCT03619213), PARAGON-HF (NCT01920711), TOPCAT (NCT00094302), I-Preserve (NCT00095238), and CHARM-Preserved (NCT00634712). Individual trial sponsors included AstraZeneca, Novartis, and the National Heart, Lung, and Blood Institute (NHLBI).
Reference：
Ostrominski JW, Højbjerg Lassen MC, Butt JH, Claggett BL, Anand IS, Desai AS, Jhund PS, Lam CSP, Pfeffer MA, Pitt B, Zannad F, Zile MR, Packer M, McMurray JJV, Solomon SD, Vaduganathan M. Adiposity-Related Anthropometrics and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Participant-Level Pooled Analysis of Randomized Clinical Trials. J Am Coll Cardiol. 2025 Nov 18;86(20):1760-1777. doi: 10.1016/j.jacc.2025.08.012 IF: 22.3 Q1 . Epub 2025 Aug 27. PMID: 40864017 IF: 22.3 Q1 .
Lassen MCH, Ostrominski JW, Claggett BL, Neuen BL, Beldhuis IE, Butt JH, Biering-Sørensen T, Desai AS, Lewis EF, Jhund PS, Mc Causland F, Anand IS, Pfeffer MA, Pitt B, Zannad F, Zile MR, McMurray JJV, Solomon SD, Vaduganathan M. Obesity and Risk of Kidney Outcomes in Heart Failure With Preserved Ejection Fraction: A Participant-Level Pooled Analysis of 4 Contemporary Trials. JACC Heart Fail. 2025 Aug;13(8):102498. doi: 10.1016/j.jchf.2025.03.042 IF: 11.8 Q1 . Epub 2025 Jun 9. PMID: 40494011 IF: 11.8 Q1 .
Inciardi RM, Lu H, Claggett BL, Desai AS, Jhund PS, Lam CSP, Kosiborod MN, Inzucchi SE, Martinez FA, de Boer RA, Hernandez AF, Shah SJ, Køber L, Ponikowski P, Sabatine MS, Petersson M, Langkilde AM, McMurray JJV, Vaduganathan M, Solomon SD. Severe Heart Failure and Treatment With Dapagliflozin Across the Ejection Fraction Spectrum: DAPA-HF and DELIVER. JACC Heart Fail. 2025 Apr;13(4):618-627. doi: 10.1016/j.jchf.2024.11.023. Epub 2025 Mar 5. PMID: 40047763.
Huang X, Liu X, Jiang Y, Cao Z, Wu M, Chen Z, Sun R, Yu P, Ma J, Zhu W, Chen Y, Wu G, Zhang Y, Wang J. Association of Body Mass Index and Abdominal Obesity with Incidence of Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction. Curr Med Chem. 2025;32(16):3283-3294. doi: 10.2174/0929867330666230606100903. PMID: 37282653.