par Hubesch, Geraldine
Président du jury Lybaert, Pascale
Promoteur Dewachter, Laurence
Co-Promoteur Entee, Kathleen Mc
Publication Non publié, 2023-08-31
Thèse de doctorat
Résumé : Heart failure with preserved ejection fraction (HFpEF) has become as a major public health problem worldwide, with increasing prevalence due to the aging of the population and the epidemic in obesity, hypertension and diabetes mellitus. HFpEF is a syndrome defined by the presence of clinical signs and/or symptoms of left heart failure, diastolic dysfunction leading to increased left ventricular (LV) filling pressure, LV hypertrophy and elevated blood levels of natriuretic peptides, associated with a preserved LV ejection fraction (>50%). HFpEF accounts for about half of heart failure cases and frequently leads to pulmonary hypertension (PH) and right ventricular (RV) failure, both known to increase morbidity-mortality in these patients. The presence of renal dysfunction is also frequently described in these patients and associated with a poor prognosis. Despite recent findings showing beneficial effects of gliflozins inhibitors of the sodium/glucose co-transporter (SGLT-2) in patients with HFpEF, no curative therapeutic strategy has shown beneficial effects on mortality in these patients, making this issue an urgent need in cardiology. The lack of preclinical experimental models recapitulating the complex pathophysiology of HFpEF as observed in patients represents a real obstacle to therapeutic innovation. Moreover, the mechanisms underlying the pathogenesis of HFpEF, as well as PH, RV dysfunction and renal failure associated with HFpEF, remain largely unknown. In this context, the aim of the present work was to develop a model of HFpEF associated with multiple comorbidities, by subjecting a strain of rats prone to develop obesity (obesity-prone rats or OP rats) to a high-fat diet and to characterize the development of HFpEF over time (after 4 and 12 months on specific dieting) (1) to study the pathogenesis of PH and RV-pulmonary artery (un)coupling (2), as well as renal function (3) in these rats, by comparing them to control rats (obesity-resistant rats on standard chow diet). After 4 and 12 months of high-fat diet, OP rats developed a metabolic syndrome characterized by increased total body weight and abdominal fat weight, glucose intolerance, and dyslipidemia (characterized by hypercholesterolemia and hypertriglyceridemia), as well as arterial hypertension (characterized by an increase in LV systolic pressure measured by catheterization, which was only present after 12 months of diet). After 12 months of diet, these rats with metabolic syndrome developed a HFpEF characterized by the presence of diastolic dysfunction (confirmed by an increase in LV end-diastolic pressure measured by catheterization) associated with concentric LV hypertrophy (assessed by echocardiography and histology showing cardiomyocyte hypertrophy) and a preserved LV ejection fraction. Circulating plasma levels of soluble ST2 were increased in these HFpEF rats, while plasma NT-proBNP levels were decreased. In these HFpEF rats, myocardial RNA sequencing showed clusters of upregulated genes involved in lipid metabolism and calcium-dependent contraction. These rats with HFpEF developed PH (assessed by increased RV systolic pressure and pulmonary vascular resistance), associated with pulmonary artery (PA) dilatation (evaluated by echocardiography). In the pulmonary arteries, no differences were observed in terms of pulmonary vascular remodeling and density, or PA reactivity assessed ex vivo in response to acetylcholine and endothelin-1. These lungs did not show inflammatory foci or fibrosis. However, the balance between vasodilator and vasoconstrictor production was altered in HFpEF rats, with increased PA nitric oxide release and decreased endothelin-1 precursor expression. In HFpEF rats, RV cavity dilatation and RV systolic dysfunction characterized by a decrease in RV fractional area change (FAC) were present, as well as impaired RV-pulmonary artery coupling assessed by the ratio of tricuspid annular plane systolic excursion (TAPSE) and systolic PA pressure (sPAP); TAPSE/sPAP. Cardiomyocyte hypertrophy and activation of apoptotic processes were shown in both the LV and RV. An inverse correlation between the TAPSE-to-sPAP ratio and the rate of apoptosis in the RV was demonstrated. In addition, increased circulating plasma levels of various pro-inflammatory cytokines were found for interleukin (IL)-1, -6 and -17a. Circulating levels of monocyte chemoattractant protein (MCP)-1 and IL-18 were unchanged.HFpEF rats also developed renal dysfunction, characterized by elevated circulating levels of cystatin C, associated with diffuse structural damages to the kidney characterized by the presence of glomerular damage (with global glomerular sclerosis), tubular lesions (with extensive necrosis), interstitial lesions (with inflammation), vascular and medullary involvement (medullary tubular necrosis), as well as interstitial fibrosis and tubular atrophy. Renal expression of inflammatory markers IL-1b, tumor necrosis factor (TNF)-a, intercellular adhesion molecule (ICAM)1, vascular adhesion molecule (VCAM)1 and macrophage-specific marker CD68 were increased in HFpEF rats, with an increase in ICAM1 and VCAM1 already present after 4 months of diet. SGLT-2 expression was increased in HFpEF rats after 4 and 12 months of diet. RNA sequencing of renal tissue also showed a clear clustering of genes involved in inflammatory signaling pathways.In conclusion, OP rats fed with a high-fat diet for 12 months developed HFpEF associated with a metabolic syndrome. This experimental model mimics the natural evolution of the disease as observed in patients. It allowed us to demonstrate the presence of VD-pulmonary artery uncoupling disproportionate to the rise in PA pressure, before the development of PA remodeling, suggesting cardiac global myocardial damage in these rats. In addition, diffuse and pronounced renal damage was demonstrated in this early model of HFpEF.

Documents en relation

DI-fusion