Physical capacity, physical activity and skeletal muscle in heart failure : studies of pathophysiology
Author: Melin, Michael
Date: 2021-11-05
Location: 4V, Alfred Nobels allé 8, Karolinska University Hospital, Huddinge
Time: 09.00
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
View/ Open:
Thesis (460.7Kb)
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.
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.
List of papers:
I. Melin M, Hagerman I, Gonon A, Gustafsson T, Rullman E. Variability in Physical Activity Assessed with Accelerometer is an Independent Predict of Mortality in CHF Patients. PLOS ONE. 2016 Apr 7;11(4).
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Rullman E, Melin M, Mandić M, Gonon A, Fernandez-Gonzalo R, Gustafsson T. Circulatory Factors Associated with Function and Prognosis in Patients with Severe Heart Failure. Clinical Research in Cardiology. 2020 Jun;109(6):655-672.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Melin M, Hagerman I, Mandić M, Lovric A, Gustafsson T, Jansson E, Rullman E. Circulating Proteins in Progression and Pathophysiology of Heart Failure with Reduced Ejection Fraction. [Manuscript]
IV. Rullman E, Andersson DC, Melin M, Reiken S, Mancini DM, Marks A R, Lund LH, Gustafsson T. Modifications of the Skeletal Muscle Ryanodine Receptor Type 1 and Exercise Intolerance in Heart Failure. J Heart Lung Transplant. 2013 September; 32(9): 925-929.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Melin M, Montelius A, Rydén L, Gonon A, Hagerman I, Rullman E. Effects of enhanced external counterpulsation on skeletal muscle gene expression in patients with severe heart failure. Clin Physiol Funct Imaging. 2016 August; 2018 Jan;38(1):118-12.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Melin M, Hagerman I, Gonon A, Gustafsson T, Rullman E. Variability in Physical Activity Assessed with Accelerometer is an Independent Predict of Mortality in CHF Patients. PLOS ONE. 2016 Apr 7;11(4).
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Rullman E, Melin M, Mandić M, Gonon A, Fernandez-Gonzalo R, Gustafsson T. Circulatory Factors Associated with Function and Prognosis in Patients with Severe Heart Failure. Clinical Research in Cardiology. 2020 Jun;109(6):655-672.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Melin M, Hagerman I, Mandić M, Lovric A, Gustafsson T, Jansson E, Rullman E. Circulating Proteins in Progression and Pathophysiology of Heart Failure with Reduced Ejection Fraction. [Manuscript]
IV. Rullman E, Andersson DC, Melin M, Reiken S, Mancini DM, Marks A R, Lund LH, Gustafsson T. Modifications of the Skeletal Muscle Ryanodine Receptor Type 1 and Exercise Intolerance in Heart Failure. J Heart Lung Transplant. 2013 September; 32(9): 925-929.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Melin M, Montelius A, Rydén L, Gonon A, Hagerman I, Rullman E. Effects of enhanced external counterpulsation on skeletal muscle gene expression in patients with severe heart failure. Clin Physiol Funct Imaging. 2016 August; 2018 Jan;38(1):118-12.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Rullman, Eric
Co-supervisor: Gustafsson, Thomas; Hagerman, Inger
Issue date: 2021-10-15
Rights:
Publication year: 2021
ISBN: 978-91-8016-361-3
Statistics
Total Visits
Views | |
---|---|
Physical ... | 432 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Physical ... | 10 | 4 | 3 | 7 | 5 | 7 | 1 |
File Visits
Views | |
---|---|
Thesis_Michael_Melin.pdf | 236 |
Top country views
Views | |
---|---|
Sweden | 191 |
United States | 56 |
Ireland | 35 |
China | 26 |
Germany | 8 |
South Korea | 7 |
Russia | 6 |
United Kingdom | 5 |
Pakistan | 4 |
Austria | 3 |
Top cities views
Views | |
---|---|
Stockholm | 43 |
Dublin | 34 |
Bromma | 13 |
Djursholm | 13 |
Hangzhou | 13 |
Ashburn | 10 |
Linköping | 5 |
Umeå | 5 |
Beijing | 4 |
Houston | 4 |