New York, NY - Contrary to what may have been expected, raised blood levels of adiponectin, the major protein secreted by fat cells, appear to indicate a higher risk of coronary heart disease (CHD) in older adults, a new study suggests [1].

The study, published in the September 2008 issue of the Journal of Clinical Endocrinology & Metabolism (available online now), was conducted by a team led by Dr Jorge Kizer (Weill Medical College of Cornell University, New York, NY).

Kizer explained to heartwire that adiponectin has long been thought to be protective against both diabetes and CHD. It is known to be an insulin sensitizer, and clinical studies have confirmed animal and laboratory findings that it protects against the development of diabetes. But its role in CHD is more uncertain, and although raised levels of adiponectin are associated with leanness, better cholesterol fractions, and lower levels of blood glucose and inflammatory markers, studies of its relation to actual CHD events have produced contradictory results, he elaborated.

While a study published in the Journal of the American Medical Association in 2004 suggested a protective effect of adiponectin against CHD in initially healthy middle-aged men [2], this has not been easily replicated, with subsequent studies in patients with established heart disease suggesting an opposite association, he added.

Kizer commented: "When we first planned this study we thought high levels of adiponectin would be protective, but we actually found the opposite—that people with the highest levels had a higher risk of heart disease than those with lower levels. And then two other studies have also recently been reported showing an association between higher levels of adiponectin and all-cause mortality and cardiovascular mortality. Our findings are in line with these studies and suggest that higher adiponectin levels do not necessarily signal a healthier population, as we initially thought."

The current nested case-control study focused on 3857 participants free of cardiovascular disease at the 1992-1993 examination in the Cardiovascular Health Study, a population-based longitudinal survey of community-dwelling adults aged 65 to 100. Cases consisted of 604 men and women who experienced a CHD event through June 2001. Of these events, 255 were nonfatal MI, 115 were fatal CHD, and the remainder nonfatal CHD. Controls were participants free of incident CHD who were matched to cases in terms of age, sex, race/ethnicity, subclinical disease status, and center.

Results showed that serum adiponectin concentration did not differ significantly among participants with and without baseline subclinical cardiovascular disease. As has been shown before, adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. However, after researchers controlled for matching factors, adjustment for waist/hip ratio, hypertension, smoking, alcohol, LDL cholesterol, creatinine, and leptin, individuals in the highest adiponectin quintile had a modestly increased risk of incident CHD than those in the lower four quintiles. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD.

The findings were not influenced by additional adjustment for weight change, health status, or cystatin C or by adjustment for potential mediators such as diabetes, cholesterol, and inflammatory markers.

The authors write: "Our findings, which are based on the largest number of first incident CHD events in an elderly cohort to date, are at odds with prior reports of a protective association with CHD, whether overall or limited to nonfatal events. They also contrast with previous null results regarding fatal and nonfatal CHD, while failing to confirm a previously noted interaction by race."

Kizer told heartwire that these results confirm that the adiponectin story is more complicated than first thought. "This peptide does not seem to be associated with a straightforward protective effect, as we first thought it would be. There has been much enthusiasm about this hormone, resulting in many published studies, but each study just seems to complicate the picture more. While it does seem to have a beneficial effect in diabetes, its associations in CHD are all over the place. The best summary is perhaps that, in middle-aged individuals free of heart disease, adiponectin may be modestly protective against developing CHD, while in people already affected with heart disease and in older persons, it appears to be a marker of harm."

Kizer suggested that adiponectin may have both beneficial and detrimental actions, some of which have not been elucidated yet. Discussing this in the paper, the authors say: "This leaves the possibility that, in addition to its salutary actions, adiponectin has direct harmful effects, which could be more operative in the elderly. Indeed, adiponectin has been shown to increase energy expenditure through direct actions in the central nervous system in mice, an effect that, if present in humans, could be particularly deleterious in older adults by potentially accelerating sarcopenia."

Kizer commented: "We had initially hoped that high levels of adiponectin would be protective against both diabetes and CHD. Then one could set about looking for drugs to increase it. But now we are realizing that we have to know more about the full range of actions of this hormone before we can think about manipulating it with drugs." He added that future research will focus on individual multimers of adiponectin as well as more investigation into the effect of altered body composition, particularly in the elderly.