In this population-based study, we report an independent association between resistin concentrations and risk for incident HF among older persons. This association persisted after controlling for baseline characteristics, predictors for incident HF, markers of inflammation and insulin resistance, adipocytokines, and multiple measures of adiposity. Our data adds to the growing literature on the role of serum resistin in modulating cardiovascular risk.
Beyond the statistical association, the true value of “novel” risk markers is their independent association with outcome. Many markers may provide collinear information affecting common pathophysiologic pathways. In our study, the correlation of resistin with baseline clinical variables and biomarkers, although statistically significant in many instances due to the large sample size, was overall weak. Most importantly, the association between resistin and incident HF risk persisted after extensive adjustment for possible confounders representing various disparate pathways. We also observed that resistin was a stronger predictor of incident HF when directly compared with other biomarkers, with the exception of interleukin-6. Our findings extend the results of the study by the Framingham investigators,20
which demonstrated that serum resistin concentrations were associated with risk for HF after controlling for clinical characteristics, inflammatory markers, and B-type natriuretic peptide levels in a younger population. Taken together, these findings signal to the strength of association between serum resistin and incident HF. Although resistin concentrations have been associated with diabetes mellitus21
the degree of association with incident HF in our study was comparable among prevalent and incident CHD and diabetes mellitus subgroups, a finding that was also present in the Framingham report.20
Finally, this association was consistent across sex and race.
Initially it was felt that resistin was derived primarily from adipocytes. Beyond the originally described “passive” role of storing excess energy, the adipose tissue is an “active” endocrine organ.20–22
Adipocytokines affect the structure and function of various organ systems. Resistin expression and serum concentrations are related to obesity, insulin resistance, and inflammation in humans.23–25
These mechanisms are directly involved in the pathogenesis of CHD10, 26, 27
and the development and progression of both ischemic and non-ischemic cardiomyopathy.28, 29
Beyond the indirect effects, overexpression of resistin in cardiomyocytes has been associated with altered response to ischemia-reperfusion injury,30
All these observations make our association between resistin and HF theoretically plausible. Interestingly, considering the weak correlations that we observed between multiple measures of adiposity and serum resistin concentrations, it raises the question whether resistin is primarily derived from the adipose tissue or elsewhere; and indeed multiple other cell types have now been associated with secretion of resistin e.g. macrophages.2, 3
Multiple reasons for this strong association between serum resistin and risk for incident HF can be hypothesized. A marker associated with multiple pathways of disease causation may be stronger in its association with outcomes than those associated with individual pathways. As discussed above, resistin is associated with inflammation and insulin resistance, and also direct effects of resistin on the myocardium have been demonstrated. Another possibility is a yet undefined direct pathophysiologic role of resistin. Finally, a recent experimental study showed that mechanical stretch enhances expression of resistin in cultured rat cardiomyocytes via TNF-α31
Thus, the possibility that resistin concentrations reflect cardiac load cannot be excluded.
What are the clinical implications of these results? First, considering the novelty of our data, these results will need to be replicated in other populations. If these results are consistent in other studies, then it is conceivable that serum resistin measurements may aid in improved identification of elderly subjects, beyond usual risk factors, at high risk for HF. Similarly, as the pathophysiology of new onset HF in general and the physiologic effects of resistin in specific are better understood, it is possible that serum resistin concentrations may help guide therapy. For example, neutralization of resistin activity by injection of antibodies against resistin decreases blood glucose levels and improves insulin sensitivity in obese, insulin-resistant mice.20
Most data on resistin currently however are derived from mice. Energy metabolism in human differs from mice and therefore it is not known how much of the resistin physiology in mice is applicable to humans. Thus, the role of resistin in modulating HF risk remains speculative at this point.
Our study has several limitations. Diagnosis of HF was based on HF hospitalization. Because some participants may have developed HF without hospitalization, HF rates are likely underestimated. Echocardiography was not performed at baseline. Thus, the association of resistin concentrations with structural characteristics of the heart could not be assessed. Resistin has been shown to modulate release of natriuretic peptides in experimental studies.13,30
However, baseline concentrations of B-type natriuretic peptide (BNP) were not available; thus, we could neither evaluate for possible correlation of resistin with BNP nor adjust for BNP in multivariable models. Ventricular function during hospitalization for HF was not prospectively assessed in Health ABC. The available data on ejection fraction were abstracted from medical records (i.e., the studies were not centrally read), and do not refer to a single modality since ejection fraction values were derived from echocardiography or left ventriclurography reports during hospitalization for HF. Therefore, the differential association of resistin with risk for HF with preserved vs. reduced ejection fraction should be interpreted with caution. Because our cohort included persons of age 70 or older, these findings might not apply in younger populations. Although every effort was taken to control for potential confounders, we cannot exclude the possibility of unmeasured confounding as an alternative explanation of the observed findings. Finally, temporal trends in the use of new classes of drugs or growing use of existing drugs to treat HF risk factors like hypertension or CHD may impact the risk of HF development related to those risk factors. Thus risk estimates for any given risk factors may change over time necessitating periodic reassessment in contemporary cohorts.
In conclusion, in this study we demonstrate that serum resistin concentrations independently predict risk for incident HF among older persons. The practical implications of this finding in terms of diagnostic and therapeutic uses need further study.