In a cohort of patients with stable IHD, we found that higher adiponectin concentrations were associated with lower BMI, lower non-HDL cholesterol, higher HDL cholesterol, and less diabetes. Despite this favorable metabolic profile, higher adiponectin concentrations were also associated with worse cardiovascular outcomes, particularly heart failure and death. Remarkably, nearly half of participants with adiponectin levels in the highest quartile died during the 7 years of follow-up. After adjustment for worse baseline cardiac disease severity, the association between higher adiponectin levels and adverse cardiovascular events was no longer statistically significant. These findings provide further evidence for an “adiponectin paradox” in which higher levels of adiponectin may be secreted as a protective or compensatory response to worse cardiovascular disease.
Previous studies in patients with existing cardiovascular disease also found that despite having a more favorable traditional cardiovascular risk profile, patients with higher adiponectin had worse cardiovascular outcomes [17
]. In a population study including both individuals with and without cardiovascular disease, higher adiponectin was protective in those without cardiovascular disease and predictive of worse outcomes in those with existing disease [17
]. Similarly, studies of patients with coronary disease found that higher concentrations of adiponectin were associated with a higher risk of future cardiovascular events [12
]. Our study extends these findings to a population of outpatients with stable IHD. In addition, our study provides insight into the potential mechanisms for this association by demonstrating worse baseline cardiovascular disease severity in patients with higher adiponectin concentrations. We found not only that higher adiponectin was associated with worse baseline cardiac dysfunction, but also that the association between adiponectin and heart failure, myocardial infarction, or death was attenuated by adjusting for markers of baseline cardiac dysfunction. This suggests that the association between adiponectin and worse cardiovascular outcomes may be related to worse baseline cardiovascular function in those with higher adiponectin.
Of note, we found that the association between adiponectin and adverse cardiovascular events was limited to heart failure and death and did not extend to myocardial infarction. This is in contrast to a study of subjects with coronary disease by Cavusoglu et al in which adiponectin was associated with greater risk of myocardial infarction [18
]. A potential explanation for these findings may be differences in the populations studied. Whereas our study includes only subjects with stable IHD, Cavusoglu et al studied a heterogenous population of subjects referred for cardiac catheterization, with a majority of participants referred for acute coronary syndrome, which may have different effects on adiponectin concentrations than stable IHD. More similar to our population of patients, Maiolino et al studied subjects undergoing cardiac catheterization for chest pain or suspected coronary artery disease with a majority of subjects having stable IHD, and found that adiponectin was not associated with greater risk of myocardial infarction, but was associated with greater risk of cardiovascular mortality [19
]. While adiponectin may have a neutral association with future myocardial infarction in patients with stable IHD, its primary relationship with worse cardiovascular outcomes appears to be in the realm of myocardial dysfunction. In past studies of patients with heart failure, higher adiponectin was associated with heart failure and death [10
The apparent paradox of adiponectin, a protein known to have insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties [1
], being associated with worse cardiovascular outcomes has been referred to as “reverse epidemiology” [21
] or index event bias [22
]. Reverse epidemiology, where the risk factors for a disease identified in a healthy population are unexpectedly inversely associated with outcomes in a population with the disease, has been described in several other diseases, including heart failure [23
]. It remains unknown whether the reversal of associations is related to alterations in causal pathways, timing differences amongst multiple risk factors, survival bias, or unknown mechanisms. In recurrence risk research, participants selected on the basis of having had an event will likely have a different distribution and interrelatedness of risk factors than the general population, and the effects of this index event bias can unpredictably influence findings [22
The mechanisms behind the phenomenon of reverse epidemiology for adiponectin and heart disease are not known. One hypothesis is that while adiponectin protects against the development of disease, once disease is established, adiponectin concentrations are elevated as a counter-regulatory response to try to protect against further inflammation and atherosclerosis [18
]. In addition to its vascular effects, adiponectin has been noted to have several direct effects on the heart. On a cellular level, adiponectin has been noted to block apoptosis of cardiac myocytes in in vitro
models, including models of hypoxia and reoxygenation injury [1
]. On an anatomic level, higher levels of adiponectin have been associated with greater formation of coronary collaterals in patients with at least one occluded coronary artery [24
]. Recent evidence suggests that adiponectin may even be released from the heart in patients with heart failure [25
One potential mechanism for increasing adiponectin levels in patients with greater severity of cardiac disease may be stimulation of adiponectin production by natriuretic peptides [26
]. Natriuretic peptides and adiponectin are correlated in patients with heart failure [20
]. In vitro
, natriuretic peptides enhance the expression and secretion of adiponectin from adipocytes in a dose-dependent fashion [26
]. In addition, it has been demonstrated that infusion of atrial natriuretic peptide in patients with heart failure results in increased adiponectin levels compared with a saline infusion control group [26
]. Despite the ability of adiponectin to favorably influence traditional cardiac risk factors and directly impact the heart, its compensatory effects may not be sufficient to overcome the burden of existing disease. Indeed, our results support the theory that worse baseline cardiac disease explains part of the association between adiponectin and heart failure. Those with greater disease severity may have greater secretion of adiponectin to attempt to compensate for the effects of IHD, implicating adiponectin as a marker of disease severity.
Another potential explanation for the association of elevated adiponectin with worse outcomes is adiponectin resistance [27
]. Animal models support the phenomenon of adiponectin resistance at the level of adiponectin receptor gene expression [28
]. In human studies of heart failure patients, compared to normal controls, the heart failure patients exhibit functional adiponectin resistance, with increased adiponectin expression and decreased expression of the predominant adiponectin receptor in skeletal muscle [29
]. Van Berendoncks et al [29
] found that the relative overexpression of adiponectin and underexpression of the adiponectin receptor in heart failure patients could be reversed with exercise training, which suggests a future area of study for treating adiponectin-associated adverse cardiovascular outcomes.
Several limitations should be considered in the interpretation of these results. Our study population was predominantly male, and sex-specific differences in adiponectin limit generalizability to females [6
]. Most participants had IHD documented by history of prior myocardial infarction or revascularization, but 23% of participants were included based on angiogram or positive stress test. Due to the imperfect specificity of stress testing, our study may have included some individuals without significant obstructive coronary artery disease. The adiponectin immunoassay used in this study measured total adiponectin, rather than high-molecular weight adiponectin. In some studies, high-molecular weight adiponectin was shown to be a more predictive marker for cardiovascular events [30
]. Additionally, due to the observational nature of the study, we cannot exclude the effects of confounding from variables not represented in our models.
In summary, we found that higher adiponectin concentrations are associated with death and heart failure in a cohort of patients with stable IHD, and that this association is related to greater baseline cardiac disease severity. This contributes to the weight of evidence demonstrating that adiponectin, considered to be protective against incident IHD, is paradoxically associated with worse outcomes in those with existing cardiovascular disease. With the observation that the association between adiponectin and outcomes is related to worse baseline cardiac disease, we provide additional insight into the possibility that adiponectin is elevated as a compensatory response to IHD. Still, the mechanisms by which cardiovascular disease and adiponectin influence each other remain incompletely understood and merit further study.