Physiological and lifestyle-related cardiovascular risk factors for vessels, ventricle, and valve

Abstract

Cardiovascular diseases are the most common cause of mortality globally, claiming twice as many lives as cancer and more than all nutritional disorders, infectious diseases, and maternal/neonatal conditions combined. The field of cardiovascular epidemiology has been highly influenced by the pioneering Framingham heart study, which has increased the focus on the prevention of CVD in susceptible populations. As a consequence, accurate risk stratification scores combining age, cholesterol, blood pressure, diabetes, and smoking have been developed. Nevertheless, CVD mortality remains high, and additional research is urgently needed to improve these prediction efforts. It also underscores the critical importance of managing other modifiable risk factors to mitigate the CVD burden.

The thesis intended to elucidate the associations between physical activity, cardiovascular risk factors, and aortic valve stenosis in a variety of patient cohorts with a diverse set of methodologies. It focused on determining the significance of physical activity in relation to cardiovascular function in patients with rheumatoid arthritis (Article I), the potential protective role of physical activity regarding AVS risk (Article II), sex-specific transcriptomic driving factors for calcification of the aortic valve (Article III), and establishing the association between blood pressure and AVS incidence, as well as the impact of blood pressure-lowering therapies on AVS risk (Article IV).

The first study in the thesis (Article I) aimed to determine the effects of guided physical activity on vascular and cardiac function in rheumatoid arthritis patients without known cardiovascular disease. The investigation involved a prospective substudy of the Physical Activity in RA trial 2010 and included 29 participants. The subjects were evaluated at three different points in time, namely, at baseline, after one year, and after two years, with pulse wave velocity, arterial augmentation index, and echocardiographic measures. The findings indicated that, in RA patients with normal blood pressure, there was an increase in vascular stiffness relative to normal reference values. Additionally, there was an association between decreased aerobic capacity and left ventricular diastolic dysfunction and a link between higher vascular stiffness and lower muscular strength. After completing a guided physical activity program, ventricular-arterial coupling significantly improved. The findings indicated that improved diastolic function and vascular stiffness are related, and ventricular-arterial coupling optimization may be a part of the positive benefits of exercise in RA patients.

The project presented in Article II aimed to determine whether physical activity reduces the risk of aortic valve stenosis in a cohort of 69,288 Swedish adults aged 45– 83 years. Physical activity was assessed using a validated questionnaire, and AVS diagnosis was based on data from national registers. A total of 1,238 cases of AVS were identified during the 15.3-year follow-up. No significant associations were detected between AVS incidence and the levels of physical activity, reflected by walking or cycling or leisure-time exercise, after adjustment for possible confounders and mediators, including BMI and comorbidities. The results suggest that physical activity, both less strenuous (walking/bicycling) and more strenuous (exercise), does not decrease the risk of AVS overall or of AVS requiring aortic valve replacement. This evidence implies that PA may not serve as a preventative measure for AVS, illustrating the necessity for further research to identify modifiable lifestyle factors.

The study presented in Article III aimed to establish sex-specific gene expression patterns in aortic stenosis patients through artificial intelligence-based analysis of transcriptome-wide array data from stenotic aortic valves. Thirty-six patients received surgical aortic valve replacement, and their valves were divided into three categories - non-diseased, thickened, and calcified based on macroscopic examination. Gene expression analysis showed that there are sex-specific differences differentiating calcified and non-diseased valve tissues. In particular, fibrotic pathways enriched in female patients were found, with collagen and elastic fibers pathways being highly represented. The obtained sex-specific gene expression data were used to predict aortic valve calcification using artificial intelligence models. Machine learning and deep learning algorithms showed high accuracy in this prediction task, outperforming logistic regression. Notably, several genes identified by the AI models have potential mechanistic roles in valvular calcification, such as tissue factor pathway inhibitor 2 and X-inactive-specific transcript. Thus, the results indicated that by using gene expression data, AI models can accurately predict the degree of valvular calcification and potentially pave the way for the discovery of novel medical interventions.

The final study (Article IV) determined the association between blood pressure (BP) over time and the incidence of aortic valve stenosis. Subjects were enrolled from the Swedish Primary Care Cardiovascular Database (SPCCD), consisting of 72,756 hypertensive patients within the temporal interval of 2001-2008. The predictors of AVS included baseline, mean, and last measurements of systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. Cox proportional hazards regression models were used as the main multivariable model. The results showed that all measurements of systolic BP and pulse pressure were positively associated with AVS incidence, with mean pulse pressure having the strongest association. Mean diastolic BP was inversely associated with AVS. Age, ischemic heart disease, heart failure, and peripheral arterial disease were significant covariates associated with AVS risk. The association between BP and AVS was attenuated in patients with ischemic heart disease, and the use of antihypertensive medications did not significantly alter the risk of AVS. Ultimately, BP over time is an important risk factor for AVS incidence in hypertensive individuals, with pulse pressure being a particularly strong predictor.

In conclusion, this thesis established the complex interplay between physical activity, cardiovascular risk factors, and aortic valve stenosis across diverse patient cohorts. While no significant association between physical activity and the risk of aortic valve stenosis was found in a large Swedish population, guided physical activity was shown to improve ventricular-arterial coupling in patients with rheumatoid arthritis. Furthermore, the sex-specific gene expression pattern and artificial intelligence classification proved to be effective in predicting valvular gene expression and may pave the way for the development of new therapeutic targets. The strong association between BP and AVS risk underscored the importance of effective hypertension management.