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. 2023 Apr 1;44(13):1136-1153.
doi: 10.1093/eurheartj/ehad083.

Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox

Jawad H Butt  1   2 , Mark C Petrie  1 , Pardeep S Jhund  1 , Naveed Sattar  1 , Akshay S Desai  3 , Lars Køber  2 , Jean L Rouleau  4 , Karl Swedberg  5 , Michael R Zile  6 , Scott D Solomon  3 , Milton Packer  7 , John J V McMurray  1
Affiliations

Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox

Jawad H Butt et al. Eur Heart J. .

Abstract

Aims: Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful.

Methods and results: The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes were comprehensively adjusted for other prognostic variables, including natriuretic peptides. An 'obesity-survival paradox' related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10 [95% confidence interval (CI) 0.87-1.39]. However, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of the primary outcome and HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (95% CI 1.06-1.81).

Conclusion: In patients with HFrEF, alternative anthropometric measurements showed no evidence for an 'obesity-survival paradox'. Newer indices that do not incorporate weight showed that greater adiposity was clearly associated with a higher risk of HF hospitalization.

Keywords: Angiotensin receptor-neprilysin inhibitor; Body mass index; Clinical trial; Heart failure with reduced ejection fraction; Obesity.

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Conflict of interest statement

Conflict of interest: Dr. Butt reports advisory board honoraria from Bayer. Dr. Petrie has received research grants or consultancy fees from SQ Innovations, AstraZeneca, Roche, Boehringer Ingelheim, Pharmacosmos, Eli Lilly, Napp Pharmaceuticals, Novartis, and Novo Nordisk and has served on clinical events committees for AbbVie, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Resverlogix, and Novo Nordisk. Dr. Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. Dr. Sattar has consulted for or received lecture fees from Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. He has received grant support from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics through his institution, the University of Glasgow. Dr. Desai reported receiving personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Merck, Regeneron, and Relypsa and grants and personal fees from AstraZeneca, Alnylam, and Novartis outside the submitted work. Dr. Kober reports personal fees from speaker honoraria from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim. Dr. Rouleau has received grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. Dr. Swedberg reports honoraria from AstraZeneca, Boehringer 12 Ingelheim, and Novartis. Dr. Zile has received research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr. Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr. Packer has received consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. McMurray reports payments to his employer, Glasgow University, for work on clinical trials, consulting, lecturing and other activities: Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos. Personal lecture fees: Abbott, Hikma, Sun Pharmaceuticals, Servier, Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, Servier. The other authors report no conflicts.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
The upper part of the figure describes the calculation of each of the anthropometric measures. The lower part of the figure shows the risk of outcomes according to continuous body mass index (left panel) and waist-to-height ratio (right panel). The solid line represents the hazard ratio and the shaded area the 95% confidence interval. The blue spline is adjusted for treatment and region. The red spline is adjusted for treatment, age, sex, region, systolic blood pressure, heart rate, estimated glomerular filtration rate, left ventricular ejection fraction, log of n-terminal pro-B-type natriuretic peptide, body mass index (only in the waist-to-height ratio analyses), New York Heart Association functional class, heart failure aetiology, duration of heart failure, prior heart failure hospitalization, a history of diabetes, and atrial fibrillation. BMI, body mass index; BRI, body roundness index; BSA, body surface area; BSI, body shape index; CI, confidence interval; HF, heart failure; HR, hazard ratio; RFM, relative fat mass; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; WWI, weight-adjusted-waist index.
Figure 1
Figure 1
Calculation of anthropometric measures. This figure describes the calculation of each of the anthropometric measures. BMI, body mass index; BRI, body roundness index; BSA, body surface area; BSI, body shape index; RFM, relative fat mass; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; WWI, weight-adjusted-waist index.
Figure 2
Figure 2
Distribution of body mass index and waist-to-height-ratio according to sex. This figure shows the frequency distribution curves of body mass index and waist-to-height ratio, respectively, according to sex. The red line and bars represent women, and the blue line and bars represent men.
Figure 3
Figure 3
Outcomes according to body mass index. This figure shows the risk of heart failure hospitalization or cardiovascular death, its components, and all-cause death, according to continuous body mass index. The solid line represents the hazard ratio and the shaded area the 95% CI. The reference is a body mass index of 25 kg/m2. The blue spline is adjusted for treatment and region. The red spline is adjusted for treatment, age, sex, region, systolic blood pressure, heart rate, estimated glomerular filtration rate, left ventricular ejection fraction, log of n-terminal pro-B-type natriuretic peptide, New York Heart Association functional class, heart failure aetiology, duration of heart failure, prior heart failure hospitalization, a history of diabetes, and atrial fibrillation. CI, confidence interval; HF, heart failure; HR, hazard ratio.
Figure 4
Figure 4
Outcomes according to waist-to-height ratio. This figure shows the risk of heart failure hospitalization or cardiovascular death, its components, and all-cause death, according to continuous waist-to-height ratio. The solid line represents the hazard ratio and the shaded area the 95% CI. The reference is the median waist-to-height ratio (0.58). The blue spline is adjusted for treatment and region. The red spline is adjusted for treatment, age, sex, region, systolic blood pressure, heart rate, estimated glomerular filtration rate, left ventricular ejection fraction, log of n-terminal pro-B-type natriuretic peptide, body mass index, New York Heart Association functional class, heart failure aetiology, duration of heart failure, prior heart failure hospitalization, a history of diabetes, and atrial fibrillation. CI, confidence interval; HF, heart failure; HR, hazard ratio.
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