2. Literature Review and Rationale for Specific Aims
2.5 Rationale for investigating the association between a weight-height index (as a proxy for total
2.5.6 Obesity and post-HF survival
Whilst the biologic evidence for the nefarious effects of excess body weight on the structure and functioning of the myocardium and the epidemiologic evidence linking obesity to increased HF incidence are both compelling, several studies (table 6) have suggested that overweight and obese persons with heart failure have a demonstrably higher survival compared to leaner subjects – a phenomenon coined as the obesity paradox.
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Table 6: Previous studies investigating the association between measures of Obesity and post-HF mortality.
Authors Study Description Covariates Findings Limitations
Horwich et al [109].
1203 patients (23.4%
female, mean age = 52 years) with advanced HF (mean LVEF = 22%) referred for care.
Age, sex, medications, hypertension, diabetes, LVEF, peak VO2, serum sodium, serum lipids, serum
creatinine, mitral and tricuspid regurgitation.
- 537 deaths
- HR for 1Kg/m2 increase in BMI: 0.952 (0.915- 0.991).
- Higher Cumulative survival at 2 years in
overweight (BMI= 27.8-31Kg/m2) and obese (BMI
>31Kg/m2) groups compared to normal weight.
1. Small sample size 2. Categorization: loss of precision and
misrepresentation of the nature of the dose-response relationship.
3. Potential differential effects by race wasn’t investigated.
Lavie et al [110]. 209 ambulatory HF patients (mean age = 53.9yrs) with chronic systolic HF referred for care at UCLA
cardiomyopathy center.
Age, sex, ischemic vs non-ischemic cardiomyopathy, NYHA class, LVEF and peak VO2.
28 major events (urgent transplant or CV death).
1. Percent body fat:
For every 1% increase in percent body fat there was a 13% reduction in major CV events.
2. Categorical BMI
Kaplan-Meier plot showed higher survival for 5th BMI quintile compared to 1st quintile.
1. Small sample size 2. Categorization: loss of precision and potential misrepresentation of the dose-response relationship.
Clark et al [111]. 3187 patients (25.2%
female, mean age = 53.0 years, mean LVEF = 22.9%) referred for HF management or transplant evaluation at UCLA.
Age, diabetes, LVEF, peak VO2, NYHA class, HF cause (ischemic vs non- ischemic)
988 Major events (deaths, heart transplants, ventricular assist device placements) 1. Body Mass Index
HR (95%CI) for normal vs High BMI (≥25 Kg/m2):
- Men: 1.34 (1.13-1.58); Women:1.38 (1.02-1.89) 2. Waist circumference (WC)
- Men
HR (95%CI) for normal vs High WC (≥102cm): 2.02 (1.18-3.45)
- Women
HR (95%CI) for normal vs High WC (≥88cm): 2.99 (0.90-4.8).
1. Categorization: loss of precision and
misrepresentation of the nature of the dose-response relationship.
2. Potential differential effects by race wasn’t investigated.
Oreopoulos et al [112].
Meta-Analysis of 9 observational HF studies (n= 28,209) with average follow-up ≈ 2.7 years.
BMI categories
- HR (95% CI) for Overweight vs Normal CV death: 0.81 (0.72 – 0.92)
All-cause Mortality: 0.84 (0.79 – 0.90) - HR (95% CI) Obese vs. Normal CV death: 0.60 (0.53 – 0.69)
All-cause Mortality: 0.67 (0.62 – 0.73)
Categorization: loss of precision and
misrepresentation of the nature of the dose-response relationship
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Some authors have suggested a few underlying biological reasons to explain this phenomenon.
- Higher metabolic reserve among obese persons in addition to leaner HF patients having a higher likelihood of being cachectic and thus at a higher risk of death [113].
- The specificities of the neuro-humoral profile and hemodynamics of obese persons with heart failure such as the secretion of soluble TNF alpha receptors which have beneficial neutralizing effects; higher circulating lipoproteins which may bind and detoxify lipopolysaccharides that play a role in stimulating the release of inflammatory cytokines and elevated blood pressure which raises the tolerance of obese individuals to higher doses of cardio-protective agents including beta blockers, aldosterone antagonists and RAAS inhibitors [114, 115].
Other investigators have advanced epidemiologic reasons related to:
1) Study participants who experienced unintended weight loss before study enrollment and who may have had higher mortality risk [114].
2) The fact that compared to normal weight persons, overweight and obese persons were found to have lower atrial natriuretic peptide levels which was correlated with having higher muscle mass and muscle strength [116]. The latter have been associated with improved survival in other patient populations and this may be analogous to patients with advanced HF as well [117].
2.5.6.2 Rationale for investigating the association between anthropometric surrogates and all-cause mortality among HF patients in SCCS.
There is a wealth of data suggesting that in persons with HF, intentional weight loss mitigates some of the hemodynamic abnormalities and reduces LV mass and chamber size [90, 92, 93, 100, 114, 118]. However, in light of the epidemiologic evidence suggesting an obesity paradox, some
cardiovascular societies – whilst still advocating weight loss – have been conservative, recommending intentional weight reduction only at higher cut-points for BMI. For example, the AHA recommends intentional weight loss in HF only for persons with BMI >40 kg/m2, the Heart Failure Society of America
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for individuals with BMI >35 kg/m2, both the European Society of Cardiology and the Canadian
Cardiovascular Society recommend weight loss above a BMI cut-point of 30 kg/m2 and none of the major societies recommend weight loss for overweight patients with HF.
These recommendations seem to make the assumption that there exists a discontinuous
relationship between the survival probability of persons with heart failure and body mass index; and the discontinuities (or sharp inflexion points) are found at the recommended cut points. If the dose-response relationship between body mass index and survival probability in heart failure is in fact a smooth function, making recommendations about specific cut-points may be counter-intuitive.
We plan to use data from SCCS to investigate the dose-response relationship between W/Hn and mortality risk in persons with incident heart failure while accommodating potential nonlinearity of effects and effect modification by race.
[However, many experts acknowledge that in patients with heart failure more data on the effects of intentional weight loss on morbidity (hospitalizations) and long-term prognosis including hard endpoints like cardiovascular and all-cause mortality would provide better insights.]
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