The maintenance of intracellular and extracellular adenosine triphosphate (ATP) levels plays a pivotal role in cardiac function. In recent years, burgeoning attention has been directed towards ATP-induced cell death (AICD), revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations, distinguishing it from other forms of cell death such as apoptosis and necrosis. AICD is increasingly acknowledged as a critical mechanism mediating the pathogenesis and progression of various cardiovascular maladies, encompassing myocardial ischemia-reperfusion injury, sepsis-induced cardiomyopathy, hypertrophic cardiomyopathy, arrhythmia, and diabetic cardiomyopathy. Consequently, a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases. This review first elucidates the vital physiological roles of ATP in the cardiovascular system, subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD. Furthermore, it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases, while also delineating the current constraints and future avenues for these innovative therapeutic targets, thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.

Significance: The mitochondrial oxidative phosphorylation (OXPHOS) system, comprising the electron transport chain and ATP synthase, generates membrane potential, drives ATP synthesis, governs energy metabolism, and maintains redox balance. OXPHOS dysfunction is associated with a plethora of diseases ranging from rare inherited disorders to common conditions, including diabetes, cancer, neurodegenerative diseases, as well as aging. There has been great interest in studying regulators of OXPHOS. Among these, ATPase inhibitory factor 1 (IF1) is an endogenous inhibitor of ATP synthase that has long been thought to avoid the consumption of cellular ATP when ATP synthase acts as an ATP hydrolysis enzyme. Recent Advances: Recent data indicate that IF1 inhibits ATP synthesis and is involved in a multitude of mitochondrial-related functions, such as mitochondrial quality control, energy metabolism, redox balance, and cell fate. IF1 also inhibits the ATPase activity of cell-surface ATP synthase, and it is used as a cardiovascular disease biomarker. Critical Issues: Although recent data have led to a paradigm shift regarding IF1 functions, these have been poorly studied in entire organisms and in different organs. The understanding of the cellular biology of IF1 is, therefore, still limited. The aim of this review was to provide an overview of the current understanding of the role of IF1 in mitochondrial functions, health, and diseases. Future Directions: Further investigations of IF1 functions at the cell, organ, and whole-organism levels and in different pathophysiological conditions will help decipher the controversies surrounding its involvement in mitochondrial function and could unveil therapeutic strategies in human pathology. Antioxid. Redox Signal. 37, 370-393.

HDL-Cholesterol (HDL-C) is not an accurate surrogate marker to measure the cardioprotective functions of HDL in coronary artery diseases (CAD) patients. Hence, measurement of other HDL-related parameters may have prognostic superiority over HDL-C. In this work, we examined the predictive value of HDL particles profile for long-term mortality in CAD patients and to compare its informative value to that of HDL-C and apoA-I. HDL particles profiles were measured by nuclear magnetic resonance (NMR) spectroscopy in 214 male participants with stable CAD (45-74 years). Median follow up was 12.5 years with a 36.4% mortality rate. Cardiovascular mortality accounted for 64.5%. Mean concentrations of total HDL particles (HDL-P), small-sized HDL (SHDL-P) and apoA-I were lower in deceased than in surviving patients whereas no difference was observed according to HDL-C and large HDL particles. All NMR-HDL measures were correlated between themselves and with other HDL markers (HDL-C, apoA-I and LpA-I). In a multivariate model adjusted for cardiovascular risk factors and bioclinical variables, HDL-P and SHDL-P displayed the strongest inverse association with all-cause and cardiovascular mortality. Weaker associations were recorded for apoA-I. Based on our results, we conclude that HDL particle profile measured by NMR spectroscopy should be considered to better stratify risk in population at high risk or in the setting of pharmacotherapy.

Stable coronary heart disease (CHD) patients are advised to practice regular physical activity (PA). However, data on very long-term prognosis impact of regular exercise remain scarce. We aimed to evaluate the impact of physical activity level on mortality at long term in stable CHD patients. We analyzed 822 patients with stable CHD. They answered questionnaires on medical history, underwent a standardized clinical examination, and provided a fasting blood sample. PA was evaluated by the MOSPA questionnaire. Three tertiles of patients were individualized according to PA level: 0.0-9 Metabolic Equivalent of Task (METs) hour per week (n = 267); 10-39.9 METs hour per week (n = 279); and ≥40 METs hour per week (n = 276). After a median follow-up of 14.6 years, 324 patients had died. In a multivariate analysis adjusted for age, dyslipidemia, smoking status, diabetes, high blood pressure, waist circumference, left ventricular ejection fraction, Gensini score, heart rate, ankle-brachial index and duration of disease, physical activity was significantly and independently associated with all-cause mortality. Compared to the lowest PA tertile, both the median and the highest PA tertiles, were associated to a reduction of all-cause mortality risk with hazard ratios at 0.79 (95%confidence interval [0.61:1.03], P = 0.08) and 0.71 ([0.53:0.96], P = 0.025) respectively; P for trend = 0.02. Adjusted hazard ratios for an increase of 10 METs hour per week was 0.95 [0.92 to 0.98], (P <0.002). In conclusion, our study demonstrates an independent association between PA and long term vital prognosis with a 5% total mortality decrease for an increase of 10 METs hour per week.