Boosting autophagy in the diabetic heart: a translational perspective

Diabetes, obesity, and dyslipidemia are main risk factors that promote the development of cardiovascular diseases. These metabolic abnormalities are frequently found to be associated together in a highly morbid clinical condition called metabolic syndrome. Metabolic derangements promote endothelial dysfunction, atherosclerotic plaque formation and rupture, cardiac remodeling and dysfunction. This evidence strongly encourages the elucidation of the mechanisms through which obesity, diabetes, and metabolic syndrome induce cellular abnormalities and dysfunction in order to discover new therapeutic targets and strategies for their prevention and treatment. Numerous studies employing both dietary and genetic animal models of obesity and diabetes have demonstrated that autophagy, an intracellular system for protein degradation, is impaired in the heart under these conditions. This suggests that autophagy reactivation may represent a future potential therapeutic intervention to reduce cardiac maladaptive alterations in patients with metabolic derangements. In fact, autophagy is a critical mechanism to preserve cellular homeostasis and survival. In addition, the physiological activation of autophagy protects the heart during stress, such as acute ischemia, starvation, chronic myocardial infarction, pressure overload, and proteotoxic stress. All these aspects will be discussed in our review article together with the potential ways to reactivate autophagy in the context of obesity, metabolic syndrome, and diabetes

New Insights into the role of GSK-3 in the regulation of human cardiac electrophysiology

Cardiac arrhythmias still represent a serious health issue, leading to adverse outcomes, such as heart failure and sudden death. Several drugs used to treat noncardiac diseases, including antibiotics or antipsychotics, can also be responsible for arrhythmia development. Therefore, a major challenge is a deeper comprehension of the molecular mechanisms regulating cardiac electro- physiology, together with the development of predic- tive tools aimed at understanding how a specific condition or drug can favor arrhythmic events

The T2238C human atrial natriuretic peptide molecular variant and the risk of cardiovascular diseases

Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts the most substantial effects. The T to C transition at the 2238 position of the gene (13-23% allele frequency in the general population) leads to the production of a 30-, instead of 28-, amino-acid-long α-carboxy-terminal peptide. In vitro, CC2238/αANP increases the levels of reactive oxygen species and causes endothelial damage, vascular smooth muscle cells contraction, and increased platelet aggregation. These effects are achieved through the deregulated activation of type C natriuretic peptide receptor, the consequent inhibition of adenylate cyclase activity, and the activation of Giα proteins. In vivo, endothelial dysfunction and increased platelet aggregation are present in human subjects carrying the C2238/αANP allele variant. Several studies documented an increased risk of stroke and of myocardial infarction in C2238/αANP carriers. Recently, an incomplete response to antiplatelet therapy in ischemic heart disease patients carrying the C2238/αANP variant and undergoing percutaneous coronary revascularization has been reported. In summary, the overall evidence supports the concept that T2238C/ANP is a cardiovascular genetic risk factor that needs to be taken into account in daily clinical practice

Surgical embolectomy for acute massive pulmonary embolism: state of the art

Massive pulmonary embolism (PE) is a severe condition that can potentially lead to death caused by right ventricular (RV) failure and the consequent cardiogenic shock. Despite the fact thrombolysis is often administrated to critical patients to increase pulmonary perfusion and to reduce RV afterload, surgical treatment represents another valid option in case of failure or contraindications to thrombolytic therapy. Correct risk stratification and multidisciplinary proactive teams are critical factors to dramatically decrease the mortality of this global health burden. In fact, the worldwide incidence of PE is 60–70 per 100,000, with a mortality ranging from 1% for small PE to 65% for massive PE. This review provides an overview of the diagnosis and management of this highly lethal pathology, with a focus on the surgical approaches at the state of the art

Cerebrovascular complications and infective endocarditis. impact of available evidence on clinical outcome

Infective endocarditis (IE) is a life-threatening disease. Its epidemiological profile has substantially changed in recent years although 1-year mortality is still high. Despite advances in medical therapy and surgical technique, there is still uncertainty on the best management and on the timing of surgical intervention. The objective of this review is to produce further insight intothe short- and long-term outcomes of patients with IE, with a focus on those presenting cerebrovascular complications

Angiotensin II receptor blockers and myocardial infarction: an updated analysis of randomized clinical trials

OBJECTIVE: To evaluate the effects of treatments based on angiotensin II receptor blockers (ARBs) on the risk of myocardial infarction (MI), cardiovascular and all-cause death, as compared with conventional treatment or placebo. METHODS: We performed a meta-analysis of all available major international, randomized clinical trials (20 trials, n = 108 909 patients, mean age 66.5 +/- 4.1 years), published by 31 August 2008, comparing ARBs with other drugs or conventional therapies (placebo) and reporting MI incidence. RESULTS: During a mean follow-up of 3.3 +/- 1.1 years, a total of 2374/53 208 and 2354/53 153 cases of MI were recorded in ARB-based groups and in comparator arms, respectively [odds ratio (OR) 95% confidence interval (CI) 1.008 (0.950-1.069)]. Risks of MI were not different when tested in different clinical conditions, including hypertension, high cardiovascular risk, stroke, coronary disease, renal disease and heart failure. No significant differences in the risk of MI between treatment with ARBs versus placebo [OR 95% CI 0.944 (0.841-1.060)], beta-blockers and diuretics [OR 95% CI 0.970 (0.804-1.170)], calcium channel blockers [OR 95% CI 1.112 (0.971-1.272)], or angiotensin-converting enzyme (ACE) inhibitors [OR 95% CI 1.008 (0.926-1.099)] were observed. Analysis of trials comparing combination therapy based on ARBs plus ACE inhibitors versus active treatments or placebo showed equivalent MI risk [OR 95% CI 0.996 (0.896-1.107)]. CONCLUSION: The present meta-analysis indicates that the risk of MI is comparable with use of ARBs and other antihypertensive drugs in a wide range of clinical conditions

Chronic Thromboembolic Pulmonary Hypertension: the therapeutic assessment

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a severe and complex condition that evolves from unresolved pulmonary embolism, leading to fibrotic obstruction of pulmonary arteries, pulmonary hypertension, and potential right heart failure. The cornerstone of CTEPH management lies in a multifaceted therapeutic approach tailored to individual patient profiles, reflecting the disease's heterogeneity. This review delves into the current therapeutic strategies for CTEPH, including surgical pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and targeted pharmacological treatments such as PDE5 inhibitors, endothelin receptor antagonists, sGC stimulators, and prostanoids. Lifelong anticoagulation is also highlighted as a preventive strategy against recurrent thromboembolism. Special emphasis is placed on the interdisciplinary nature of CTEPH care, necessitating collaboration among PEA surgeons, BPA interventionists, PH specialists, and thoracic radiologists to ensure comprehensive treatment planning and execution. The review underscores the importance of selecting an appropriate treatment modality based on the patient's specific disease characteristics and the evolving landscape of CTEPH treatment, aiming to improve patient outcomes through integrated care strategies

The light and shadow of senescence and inflammation in cardiovascular pathology and regenerative medicine

Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation