Bilancia, Rossella (2021) Heart failure with preserved ejection fraction and its comorbidities: role of adenosine pathway. [Tesi di dottorato]

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Heart failure (HF) is a systemic, multifactorial disease that affects most of the world's population. It causes a large increase in hospitalizations so affecting the health economics. About 50% of patients with HF symptoms have a normal left ventricular ejection fraction (HFpEF) and its prevalence continues to increase compared to heart failure with a reduced ejection fraction (HFrEF). Current research suggests that HFpEF is characterized by cardiac fibrosis and remodeling, and occurs when chronic medical conditions (e.g. obesity, hypertension, diabetes mellitus, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, thrombosis) damage the heart and other organ systems. These diseases are thought to gradually change the structure and function of the heart over time. There is evidence that an imbalance of extracellular purine levels may be associated with increased cardiovascular risk. Adenosine is an endogenous nucleoside with autocrine/paracrine functions, acting as signal molecule to preserve host defense and tissue integrity during inflammation and trauma. Adenosine is produced primarily from sequential dephosphorylation of extracellular adenosine triphosphate (ATP) to AMP by activity of CD39 (ectonucleoside triphosphate diphosphohydrolase), followed by ecto-5'-nucleotidase CD73. There is much evidence for a role of adenosine in cardiac fibrosis associated with the progression of heart failure. Endogenous adenosine appears to play a significant role in reshaping the microenvironment during inflammatory processes through the interaction with four subtypes of cell surface G-protein-coupled adenosine receptors. These receptors are widely expressed on cardiac cells including fibroblast, endothelial cells, smooth muscle cells and leukocytes, all with a cardioprotective role. Scientific evidence has shown that the expression of CD39 and CD73 are involved in the extracellular adenosine accumulation, were upregulated in human circulating leukocytes of heart failure patients, suggesting that HF could benefit from adenosine-based drug therapy. It is well recognized that patients with HF have an increased risk of venous thromboembolism, stroke, and sudden death. The increased cardiovascular risk may be associated with an imbalance of extracellular purine levels. Platelets are an important source of purine nucleotides and nucleosides. In case of stress, adenosine is released in large quantities by the CD39 enzyme. It is expressed on the endothelium, circulating blood cells, and smooth muscle cells. Changes in CD39 expression and activity affect the thrombogenic potential of a tissue. Gender difference in the cardiovascular risk has been extensively observed; however, while the age-dependent difference in the prevalence of cardiovascular events between men and women has been attributed to the loss of the protective effect of estrogens in the postmenopausal period, the physiological mechanism behind gender disparity is still unclear. In the light of these considerations, the aims of this study were: 1) to investigate comparatively platelet functionality in male and female rats and the possible link to CD39 enzyme 2) to evaluate the changes in the adenosine pathway in Dahl salt-sensitive hypertensive rat, a model of heart failure with preserved ejection fraction. We found a reduced in vitro response to ADP of female compared to male platelets, associated to increased platelet CD39 expression and activity. Platelet response to ADP was strongly increased by incubation (10 min) with the CD39 inhibitor, ARL67156, while male platelet response was unaffected. Rat treatment with clopidogrel (30 mg/kg, per os) inhibited ex vivo platelet aggregation. Bleeding time was prolonged in female compared to male. Dahl rats, feeding with a 8% NaCl diet, progressively developed hypertension, compared to LS animals that remained normotensive. While systolic parameters were not altered, diastolic parameters were changed in high salt animals. Indeed, hemodynamic analysis showed a decreased dP/dt min, increased end-diastolic pressure, longer time constant Tau and steeper slope of the end-diastolic pressure-volume relationship. In addition, our data showed an increase of LV systolic and diastolic posterior wall thickness in the HS group of animals at both 5 and 13 weeks, respectively. In our animal model of HFpEF we observed, in the myocardium of 13 HS animals, an increase in perivascular fibrosis due to collagen accumulation and an increase in reactive oxygen species and nitrogen. Western blot analysis showed a reduced production of adenosine in rats with HFpEF, an increased production of inosine, which has pro�inflammatory action, and a greater expression of the A2B receptors which, with their pro�fibrotic, cause cardiac rigidity in the hearts of Dahl rats at 13 weeks and thus worsening the inflammatory state in the latter group. Our results suggest that the sex variability in platelet ATPase and ADPase activity should be taken into account for understanding more in depth the molecular mechanisms behind gender difference in cardiovascular risk. These preliminary results suggest, also, that adenosine pathway may represent an attractive target to test potential therapeutic strategies to prevent and/or delay the progression of HFpEF syndrome.

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