Adiponectin and Cardiovascular Mortality: Evidence for “Reverse Epidemiology”

Rathmann W, Herder C. Adiponectin: Reverse Epidemiology . Horm Metab Res 2007; 39: 1 – 2 The terms “ reverse epidemiology ” or “ risk factor reversal ” refer to alterations in the relations between risk factors and clinical outcomes [1] . This phenomenon occurs in certain populations and can result in the opposite of the association between a risk factor and an outcome that is found in the general population, and has been observed in advanced chronic kidney failure, congestive heart failure, cancer, among elderly hospitalized patients, and residents in nursing homes. As an example, in these conditions low body mass index (BMI) is related to a poor outcome. Reverse epidemiology has also been reported for blood pressure, total and LDL cholesterol, homocysteine, and parathyroid hormone concentrations. Low nutrient intake or increased nutrient loss have been suggested as underlying reasons for these risk factor switches to the opposite [1] . Here, we provide evidence for the existence of reverse epidemiology in the association between adiponectin and cardiovascular mortality. Adiponectin has been postulated to be the most relevant (and the only protective) adipocytokine linking obesity, the metabolic syndrome, and type 2 diabetes to their cardiovascular consequences [2, 3] . In the general population, adiponectin is inversely related to obesity, insulin resistance, type 2 diabetes and several other cardiovascular risk factors [2] . However, recent prospective studies suggest that once a chronic condition is established, the reverse to this traditional epidemiology occurs: high adiponectin concentrations were associated with increased total and cardiovascular mortality in patients with congestive heart failure [4, 5] , coronary heart disease or myocardial infarction [6, 7] , and chronic kidney disease [8] . Increased adiponectin concentrations were also independently associated with incident microalbuminuria in type 1 diabetes [9] . In addition, cross-sectional studies demonstrated elevated adiponectin levels in liver cirrhosis [10] , rheumatoid arthritis [11] , infl ammatory bowel disease (IBD) [12] , systemic lupus erythematosus (SLE) [13] and old age [2 – 7] . Which factors determine adiponectin levels in the circulation, and what are the causes for these reversed epidemiological associations? Adiponcetin levels are decreased in obesity, and expression and secretion can be increased by weight loss [2] . End-stage renal disease and congestive heart failure are often associated with wasting and malnutrition and higher adiponectin was indeed associated with lower BMI in the aforementioned studies. However, adiponectin levels predicted mortality independently of BMI [4, 6 – 8] . As BMI may not be the most appropriate index to assess obesity, it is premature to exclude that disease-related weight loss causes this unexpected fi nding, but further studies including more precise measurements of fat and lean body mass could resolve this question. In addition to higher expression and secretion, it is conceivable that alterations of the adiponectin protein such as post-translational modifi cation affecting multimerization or receptor binding affi nity as well as adiponectin cleavage or dysregulation of adiponectin receptors may attenuate adiponectin activity and lead to a state of ‘ ‘ adiponectin resistance ’ ’ . All previously discussed studies only measured total adiponectin concentrations including high-molecular-weight (HMW), middle-molecular-weight and low-molecularweight isoforms, so that it is not clear which isoform was upregulated in these conditions. Impaired multimerization could be important because HMW adiponectin has been suggested to be more closely related with insulin sensitivity and reduced abdominal obesity than total adiponectin or the smaller isoforms, and may thus be the most biologically active Adiponectin and Cardiovascular Mortality: Evidence for ‘ ‘ Reverse Epidemiology ’ ’