This study comprises the largest amount of prospective data to date on the relationship between major cardiovascular risk factors with HF mortality in populations from the Asia-Pacific region. The key findings from this individual participant data meta-analysis indicate positive and independent relationships between elevated blood pressure, obesity, diabetes and cigarette smoking with death from HF in Asians and non-Asians, but no evidence of an association with TC. With the possible exception for blood pressure, the relationships were consistent in those with and without a history of CVD at study baseline. Overall, these current findings are broadly consistent with those reported from Western population-based studies, including Framingham [24, 25] and NHANES . Both of these US studies reported hypertension to be a major, if not the leading, modifiable cause of incident HF in addition to diabetes, smoking and obesity [24, 25]. Comparative population-based data from Asia are sparse, but those derived from hospital-based studies have also indicated the frequently high co-occurrence of hypertension and diabetes among individuals hospitalized for HF .
That diabetes may also be an independent risk factor for incident HF was first shown by the Framingham study where a clinical history of diabetes was associated with a two-fold increased risk in men and a five-fold increased risk for women . Since then, numerous studies have reported higher incidence rates of HF among those with diabetes compared with those without the condition, as well as a relatively higher relative risk of HF in populations of women and young people [27, 28]. Data from the current study, confirmed an independent association between diabetes and mortality from HF for non-Asians and (to a lesser extent) Asians. That diabetes may have a slightly weaker association with mortality from HF in Asians than in non-Asians is an intriguing finding that warrants further investigation.
In the current study, a U-shaped association between BMI and mortality from HF was observed such that individuals who were either underweight or obese were at similarly greater risk of dying from HF compared with those of normal weight. This remained unaffected by adjustment for smoking, which may have operated as a confounder of the association given that smokers tend to be relatively leaner than their non-smoking counterparts. Efforts to reduce the impact of reverse causality by excluding the first two years of follow-up also had little impact on the relationship. Our observation that underweight is a risk factor for mortality from HF is tangentially supported by previous hospital-based studies that have shown patients with chronic HF who are underweight have a lower survival than those of normal weight or who are overweight or obese . The increased risk of HF death for underweight individuals may be due to cardiac cachexia, a wasting syndrome observed in patients with advanced HF that has no accepted definition but is characterized by significant weight loss in the absence of peripheral edema [30, 31]. Studies have demonstrated that many patients with advanced HF are malnourished, with a calorie and protein intake that is inadequate to meet their energy requirements [32, 33]. But, this is unlikely to account for all of the increased risk as even in the absence of cachexia studies have shown that the increased risk of HF for the underweight individual remains . The relationship between low BMI with increased risk of mortality from heart failure may also reflect pre-existing heart failure at study baseline. We did not have information on prevalent HF so could not examine this further but in the sensitivity analysis comparing those with and without a history of CVD at study baseline, the relationship between BMI with mortality from HF was the same. Perhaps of more relevance to Western countries, is the increased risk of mortality from HF for obese compared with relatively lean individuals that we, and other authors, have shown. In Framingham, for example, there was a continuous association between BMI and risk of new onset HF and each unit increase in BMI was associated with a 5% increase in the risk of HF for men and 7% for women .
The epidemiological literature describing the relationship between TC and mortality from HF is inconsistent; some studies have reported a positive  or inverse relation  between TC and mortality from HF, but others including NHANES have shown no association . In the current study there was no good evidence of an association between TC with mortality from HF –either positive or inverse- as shown by the confidence intervals around the point estimate spanning unity in both the unadjusted and adjusted models. This is consistent with randomized data from two clinical trials –CORONA  and GISSI-HF –which demonstrated that in patients with HF the incidence of cardiovascular events, which are greatly driven by non-atherosclerotic events, was not importantly affected with statin therapy. Moreover, the Cholesterol Treatment Trialist’s showed that LDL-cholesterol lowering with statin therapy has no benefit on cardiac deaths due to non-occlusive mechanisms, such as HF .
There are some important limitations of this analysis. The lack of a universal definition of HF, and between study differences in its diagnosis and reporting, may have introduced bias. For example, misdiagnosis of HF as stroke, myocardial infarction or IHD in the early 1990’s has been suggested to account for the observed increase in IHD mortality between 1990–1995 in Japan . In the current analysis, over half of the data from Asia were derived from Japanese cohorts, many of which were initiated in the early 1990’s. Therefore, it is conceivable that there was some under-reporting of mortality from HF in these cohorts; such misclassification is likely to draw estimates of association towards the null. We also did not have information on incident heart failure which precludes examination of the possible effects of reverse causality on the results (i.e. whether the association between a particular risk factor with mortality from heart failure is impacted by the development on heart failure at some point during follow-up). Another limitation of our data was the lack of information on rheumatic heart disease, coronary artery disease and Chagas’ disease, which are major causes of HF in South Asia and China  and which have been reported to be independent predictors of HF risk . Finally, we were unable to examine the relationships between emerging cardiovascular risk factors with HF. In a recent report from the Strong Heart Study, inflammatory markers were shown to be associated with incident HF, although the relationships were substantially attenuated after adjusting for more traditional coronary risk factors .