Modifiable cardiovascular risk factors and lifestyle behaviours in relation to cardiometabolic health: Opportunities for prevention

The research described in this thesis addresses the association of several traditional and novel cardiovascular risk factors and lifestyle behaviours with cardiometabolic diseases. This was further specified into two research objectives: I. What are potential mechanisms of the relationship between the modifiable lifestyle factor alcohol consumption and cardiometabolic diseases? II. What is the causal role of modifiable cardiovascular and lifestyle-related risk factors in the development of cardiometabolic diseases? Potential mechanisms of the relation between alcohol consumption and cardiometabolic diseases In Chapters 2 and 3, cardiac function and structure, insulin sensitivity and adiposity were investigated as potential underlying mechanisms in the relation of alcohol consumption with cardiometabolic diseases. Chapter 2 showed that higher levels of alcohol consumption were linearly associated with a decrease in left ventricular ejection fraction, a measure of systolic function, in a prospective study of 404 participants. No association was observed between alcohol consumption and left atrial volume index, which is a measure of diastolic function, or left ventricular mass index, a measure of cardiac structure. These findings suggest that alcohol consumption might play a role in the pathophysiology of heart failure with reduced ejection fraction. Chapter 3 showed that heavy drinking was associated with higher liver fat in a cross-sectional study on 787 men with prediabetes, and central adiposity seemed to explain part of this association. Moderate amounts of alcohol consumption appeared to be associated with a decrease in liver fat in the prospective analysis, but the definitive shape of this association warrants investigation in larger and more long-term follow-up studies. Altogether, heavy alcohol consumption is harmful for preclinical aspects of cardiometabolic health, but whether there is a safe drinking threshold for moderate amounts of alcohol consumption remains a point of discussion. The causal role of modifiable cardiovascular and lifestyle-related risk factors in the development of cardiometabolic diseases In Chapter 4, a systematic review of the current evidence from Mendelian randomization (MR) studies on the association between alcohol consumption and cardiometabolic diseases, mortality and cardiovascular risk factors was conducted. There was large heterogeneity in the methodological quality of the MR studies on this topic so far. It was not possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. Recent developments in MR reporting guidelines and methodology including instrument selection and non-linearity are expected to improve evidence from future MR studies. In Chapters 5, 6 and 7, the two-sample MR method was used to investigate the potential causal association of several cardiovascular risk factors and lifestyle behaviours with risk of hypertension, heart failure and longevity, respectively. These MR studies confirmed the causal role of several traditional risk factors in the development of cardiometabolic diseases, with for example genetically predicted smoking initiation being detrimentally associated with hypertension, heart failure and longevity, and genetically predicted higher body mass index being harmful for hypertension and longevity. A genetically predicted higher educational level was associated with a reduced risk of hypertension and increased life expectancy. The MR studies implied that sleep might be an important novel risk factor for cardiometabolic health, with a genetically predicted longer sleep duration being associated with a lower heart failure risk en a potentially lower hypertension risk, and genetically predicted insomnia increasing the risk of hypertension and possibly reducing life expectancy. For lifestyle factors including physical activity, sedentary behaviour and coffee consumption, the precision was low in the majority of the MR analyses, making it not possible to draw causal conclusions for these factors.