Physical capacity, physical activity and skeletal muscle in heart failure : studies of pathophysiology

Abstract

The overall aim of the present thesis was to provide a better understanding of the pathophysiology of heart failure (HF), especially to explore possible mechanistic links between the failing heart and the periphery, as well as to explore variables with possible prognostic utilisation.

In Study I we asked if the degree of variability in physical activity (PA) could hold prognostic value. We examined 60 patients with HF, using echocardiography, blood sampling, VO2 peak and accelerometer. Accelerometer-derived variables were analysed for covariance using a PCA, bi-plotted together with mortality and added to the established clinical score, HFSS, in Cox regression models. Skewness and kurtosis, measurements of asymmetry in intensity level of periods of high PA, were analysed. Conclusion: skewness had additive value to predict all-cause mortality.

In Study II we asked if we could identify links between physical capacity, PA, myocardial function and circulating proteins, comparing patients with HF with controls, and if circulating proteins could hold prognostic information. We examined 66 patients and 28 controls, with echocardiography, blood sampling, VO2 peak and accelerometer. Circulating proteins were quantified via a multiplex immunoassay. Proteins that differed between groups and that were linked with prognosis were identified using OPLS-DA and univariate analyses. Conclusion: 10 circulating proteins covaried with physical capacity, PA and myocardial function, identi-fying possible links in HF pathophysiology, and 8 of these carried prognostic information.

In Study III we asked if circulating proteins could give insights into disease progression and prognosis.16 patients with HF were followed for 2 to 4 years. Depending on changes in LVEF, VO2 peak and NT-proBNP between inclusion and follow-up, the patients were divided into stable or deteriorated. Data was analysed, at baseline (t-test) as were the changes between baseline and follow-up (ANOVA). Conclusion: 10 circulating proteins covaried with disease progression, while 5 different circulating proteins were prognostic.

In Study IV, we asked if skeletal muscle in patients with HF undergoes ryanodine receptor 1 (RyR1) posttranslational remodelling. 8 patients with HF and 7 controls were examined using VO2 peak, echocardiography, NT-proBNP, accelerometer and lateral vastus muscle biopsies. Biopsies were analysed with immunoblots. Conclusion: skeletal muscle RyR1 was post-translationally modified, excessively phosphorylated, S-nitrolysated and oxidized in HF.

In Study V, we asked if EECP in HF patients showed significant up or down-regulation of gene expression in skeletal muscle. 9 patients had 7 weeks of EECP. Before and after, lateral vastus muscle biopsies and 6MWT were obtained. Quality of life (QoL) was assessed by MLHF questionnaire. Skeletal muscle expression was analysed using microarray transcriptional profiling with subsequent differential expression and network analysis. Conclusion: EECP significantly improved 6MWT. QoL remained unchanged. No significantly expressed genes were identified, ruling out skeletal muscle adaptation as the reason behind increase in 6MWT.