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Heart Failure - Cardiac Rehabilitation

Heart Failure - Cardiac Rehabilitation

Peripheral determinants of exercise capacity in Chronic Heart Failure

Background

Exercise intolerance is one of the hallmarks of chronic heart failure (CHF). Besides central cardiac and hemodynamic abnormalities, peripheral endothelial dysfunction and skeletal muscle maladaptive responses are largely responsible for impaired exercise capacity. Regular physical exercise training is by far the most efficacious way to improve physical performance in this patient population.

Research facilities

The Cardiac Rehabilitation Centre of the Department of Cardiology UZA has a long-standing tradition as a referral centre for CHF patients, combining both clinical activities and translational research. Currently, two large multicentre studies are running. SMARTEX-HF study (Controlled study of myocardial recovery after interval training in heart failure) is simultaneously run in close collaboration with an international network (Norwegian University of Science and Technology, Trondheim; Leipzig University, Herzzentrum, Germany; Bispebjerg University Hospital, Copenhagen, Denmark; Technische Universität, Klinikum rechts der Isar, Munich, Germany). The SAINTEX-CAD study (Study of Aerobic INTerval EXercise in Coronary Artery Disease), a randomized multicentre trial) is supported by IWT (Agentschap voor Innovatie door Wetenschap en Technologie) and runs at the UZA and UZ Leuven. Besides the clinical evaluation of the feasibility and effects of high intensity interval training in terms of aerobic capacity, the translational aspect involves the comparison of in vivo assessment of peripheral endothelial function, as well as the ex vivo assessment of bone marrow related endothelial repair mechanisms. The latter takes place at the Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, UZA and mainly involves the assessment of endothelial progenitor cells, as well as endothelial microparticles.

1. Endothelial dysfunction

Endothelial dysfunction is associated with a number of cardiovascular diseases (CVD). The capacity of peripheral vessels to respond adequately to shear stress and to dilate during exercise is one of the main determinants of exercise capacity in CHF patients.

Maintenance of a normal endothelial function depends on the balance between damage on the one hand, and endothelial repair on the other hand. We, as well as others, have previously shown that physical exercise has a significant impact on these reparative mechanisms in CHF patients.

It appears, however, that the endothelial reparative capacity of CHF patients is hampered by intrinsic bone marrow dysfunction. One of the our main focuses for future research involves the description of the extent of bone marrow dysfunction in patients with ischemic CHF and the exploration of underlying mechanisms.

Besides in vitro assessment of markers of endothelial dysfunction, several in vivo methods have been implemented in parallel; these include flow-mediated dilation, peripheral arterial tonometry and assessment of vascular stiffness (pulse wave velocity).

2. Skeletal muscle abnormalities – the role of adiponectin

Disturbed skeletal muscle function and wasting significantly contribute to exercise intolerance of CHF patients. Alterations in skeletal muscle energy metabolism and insulin resistance have been put forward as contributing factors.

Adiponectin displays its insulin-sensitizing properties by stimulating glucose uptake and both the uptake and oxidation of fatty acids. In strong contrast with patients at risk for cardiovascular disease, CHF patients demonstrate high circulating adiponectin concentrations. In skeletal muscle biopsies taken from CHF patients, we recently suggested that functional adiponectin resistance might trigger elevated, compensatory circulating adiponectin levels. The exact signaling pathways for adiponectin resistance needs to be further explored. Preparations for further in vitro assessment have resulted in the development of myoblast cultures, which will allow us to mimic the CHF “milieu” in vitro, but will also permit to selectively inhibit or upregulate relevant pathways.

Endothelial dysfunction as a relevant pathophysiological process in several related acute and chronic diseases

1. Obesity in adolescents

The epidemic of obesity is alarming and unfortunately has now also reached young individuals. Childhood obesity is associated with early endothelial dysfunction and increased arterial wall stiffness and is considered an early step in the development of atherosclerotic disease.

Effective intervention at a young age is therefore mandatory. Therefore, in the EDOC project (Endothelial Dysfunction in Obese Children), the effects of a hypocaloric diet plus exercise intervention will be assessed for its effect on modifying vascular risk in obese children, as well as endothelial function and endothelial progenitor cells. This project is run together with the Department of Pediatrics, UZA (Prof. J Ramet).

2. Chronic kidney disease

Compared to a healthy matched population, life expectancy for chronic kidney disease (CKD) patients is significantly shortened, due to early and rapidly progressive cardiovascular disease. Endothelium-dependent vasodilation is also impaired in CKD and a negative impact on prognosis has been attributed to this phenomenon.  Recent reports suggest that regular physical training is a valuable intervention to partially reverse endothelial dysfunction in patients with CKD. The aims of the present study are to assess the gradual decrease in peripheral endothelial-dependent vasodilation, according to the severity of CKD, and to relate these changes to circulating numbers of EPC and EMP. In addition, the effect of exercise training in CKD patients will be studied.

The ENDURE project (ENdothelial DysfUnction in Renal disease and Exercise training) is run together with the Department of Nephrology, UZA (Prof. G Verpooten).

3. Sepsis

Sepsis remains the most important cause of death (mortality 40%) and morbidity on the intensive care unit, mainly due to organ failure caused by a general microvascular/endothelial dysfunction. While there is growing evidence in the literature concerning endothelial progenitor cells in cardiovascular diseases, little is known about these cells – in relation to endothelial dysfunction - in critically ill patients with sepsis.

In addition, endothelial microparticles (EMP), which are increasingly recognized as markers of endothelial damage, may serve as markers of endothelial dysfunction in this population.

The aims of the MEDICI study (Markers of Endothelial Dysfunction In Critical Ill) are to evaluate whether numbers of EPC/EMP as markers of endothelial (dys)function are correlated with in vivo assessment of endothelial dysfunction, as well as outcome of patients with sepsis. This project is run together with the Department of Intensive Care, UZA (Prof. P Jorens).

V. Conraads