Cardiovascular Effects of Stimulators of Soluble Guanylate Cyclase Administration: A Meta-analysis of Randomized Controlled Trials.

PURPOSE OF REVIEW: Heart failure (HF) is one of the main causes of cardiovascular mortality in the western world. Despite great advances in treatment, recurrence and mortality rates remain high. Soluble guanylate cyclase is an enzyme which, by producing cGMP, is responsible for the effects of vasodilation, reduction of cardiac pre- and after-load and, therefore, the improvement of myocardial performance. Thus, a new therapeutic strategy is represented by the stimulators of soluble guanylate cyclase (sGCs). The aim of this meta-analysis was to analyze the effects deriving from the administration of sGCs, in subjects affected by HF. A systematic literature search of Medline, SCOPUS, and Google Scholar was conducted up to December 2022 to identify RCTs assessing the cardiovascular effects, as NT-pro-BNP values and ejection fraction (EF), and all-cause mortality, of the sGCs. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RECENT FINDINGS: The results obtained documented a statistically significant improvement in NT-proBNP values (SMD: - 0.258; 95% CI: - 0.398, - 0.118; p < 0.001) and EF (WMD: 0.948; 95% CI: 0.485, 1.411; p < 0.001) in subjects treated with sGCs; however, no significant change was found in the all-cause mortality rate (RR 0.96; 95% CI 0.868 to 1.072; I2, p = 0). The sGCs represent a valid therapeutic option in subjects suffering from HF, leading to an improvement in cardiac performance.

Mitochondrial Dysfunction and Cardiovascular Disease: Pathophysiology and Emerging Therapies.

Mitochondria ensure the supply of cellular energy through the production of ATP via oxidative phosphorylation. The alteration of this process, called mitochondrial dysfunction, leads to a reduction in ATP and an increase in the production of reactive oxygen species (ROS). Mitochondrial dysfunction can be caused by mitochondrial/nuclear DNA mutations, or it can be secondary to pathological conditions such as cardiovascular disease, aging, and environmental stress. The use of therapies aimed at the prevention/correction of mitochondrial dysfunction, in the context of the specific treatment of cardiovascular diseases, is a topic of growing interest. In this context, the data are conflicting since preclinical studies are numerous, but there are no large randomized studies.

The role of nutrition in inflammaging.

BACKGROUND: Old age is characterized by a peculiar low-grade, chronic, and "sterile" inflammatory state, which has been termed "inflammaging." This is believed to substantially contribute to the pathogenesis of many age-related diseases and to the progression of the ageing process. An adequate nutritional status is of great importance for maintaining proper immune system functionality and preventing frailty in the elderly. METHODS: The purpose of this narrative review is to synthesize what is known about the interaction between inflammaging and nutrition, focusing on the role of the Mediterranean diet, gut microbiota and calorie restriction (CR) in reducing systemic inflammation and improving clinical outcomes. CONCLUSIONS: Dietary components may affect inflammation directly, counteracting the low grade age-related inflammation. In this regard, healthy diets, including the Mediterranean diet, are associated with lower concentrations of inflammatory mediators, like C-reactive protein (CRP) and Tumor Necrosis Factor-α (TNF-α), that are hallmarks of inflammaging. Among the components of a healthy diet, a higher intake of whole grains, vegetables and fruits, nuts and fish are all associated with lower inflammation. One area of promising research is the microbiome-ageing interaction. Indeed, dysbiosis plays a role in sub-optimal metabolism, immune function and brain function and contributes to the poor health and impaired well-being associated with ageing. Modulation of the gut microbiota has shown promising results in some disorders. Additionally, the discovery of several molecular pathways associated with ageing, and the characterization of the beneficial effects of calorie restriction (CR) in modulating metabolic pathways and preventing inflammation, should encourage research on CR mimetics, drugs able to promote lifespan and extend healthspan.

Current and experimental therapeutics for Fabry disease.

Fabry (or Anderson-Fabry) is a rare pan-ethnic disease affecting males and females. Fabry is an X-linked lysosomal storage disease, affecting glycosphingolipid metabolism, that is caused by mutations of the GLA gene that codes for α-galactosidase A. Fabry disease (FD) can be classified into a severe, classical phenotype, most often seen in men with no residual enzyme activity, that usually appear before 18 years and a usually milder, nonclassical (later-onset) phenotype that usually appear above 18 years. Affected patients show multifactorial complications, including renal failure, cardiovascular problems, and neuropathy. In this review, we briefly report the clinical trials so far performed with the available therapies, and then we focus on the in vitro and the in vivo experimental models of the disease, to highlight the relevance in improving the existing therapeutics and understand the mechanism of this rare disorder. Current available in vivo and in vitro models can assist in better comprehension of the pathogenesis and underlying mechanisms of FD, thus the existing therapeutic approaches can be optimized, and new options can be developed.

Association between sleep disordered breathing, neurocognitive impairment and diastolic function in acute heart failure patients: an insight after the vulnerable phase of the hospitalization.

Sleep disordered breathing (SDB) and neurocognitive impairment (NI) are a typical feature of HF (heart failure), especially with preserved ejection fraction (HFpEF). So far, very few data exist regarding changes in the severity of SDB, the degree of NI, and the diastolic function in acute HF (AHF) patients and during follow up. In a population of 24 AHF patients (12 with reduced ejection fraction-HFrEF- and 12 HFpEF) with SDB a complete echocardiogram, a set of NI tests, and a polysomnography were performed in the acute phase and after 90 days. A control group of 12 non-HF patients hospitalized for other cardiovascular causes was considered. At baseline, SDB were present both in HFpEF and HFrEF, and a consistent reduction of apneic events was observed at follow up. Improvements in diastolic and right ventricular function were documented at three months compared to baseline, both in HFpEF and in HFrEF. Compared to HFrEF patients and controls, HFpEF patients showed lower NI scores at baseline tests, but a more significant improvement at three months follow-up. In AHF patients with SDB the achievement of a better compensation could lead to important beneficial effect not only on echocardiographic variables and nocturnal respiratory profile, but also on NI, especially in HFpEF.

Effects of agalsidase-ß administration on vascular function and blood pressure in familial Anderson-Fabry disease.

Fabry is an X-linked disorder of glycosphingolipid metabolism that is caused by variants of the GLA gene that codes for α-galactosidase A, leading to lysosomal accumulation of globotriaosylceramide in many cell types. As a result, affected patients manifest with an increased risk of developing ischemic stroke, peripheral neuropathy, cardiac dysfunction, and chronic kidney disease. The protective effects of enzyme replacement therapy (ERT), the milestone in Fabry disease treatment, against globotriaosylceramide (GL-3) accumulation and Fabry disease progression are well known. However, the mechanism of action of ERT is not well understood. Since GL-3 also accumulates in the vascular endothelium, we investigated the effects of agalsidase-ß, a recombinant human α-Gal enzyme approved for the treatment of Fabry disease. In this study, vascular function and blood pressure in four adult siblings affected by Fabry disease were evaluated upon agalsidase-ß. In all patients, agalsidase-ß infusion improves flow-mediated dilation and augmentation index. These changes occurred after the first infusion and were then maintained for the whole period of observation, i.e., 1 year, with more pronounced additional increments in flow-mediated dilation after the second agalsidase-ß infusion. Blood pressure was also maintained at optimal levels in all of the patients for the whole period of observation. Our findings show that agalsidase-ß administration can improve vascular function in patients suffering from Fabry disease. Changes in flow-mediated dilation and augmentation index persisted for the whole period of observation (1 year), thus suggesting that early substitutive therapy should be promoted in order to protect the cardiovascular system.

Statin therapy and sex hormones.

Current guidelines recommend statin therapy for all adult patients with coronary artery disease irrespective of sex. Over recent years, some concerns have been raised concerning the effects of statins on endogenous steroid hormones synthesis. The aim of this review was to summarize the effects of statins on endogenous sex hormones in order to clarify their role and safety in different clinical settings. Results suggest that HMG-CoA inhibitors may slightly impair adrenal and/or gonadal steroid hormone production. In men, statins do not cause any clinically-relevant harmful effects on erectile function and spermatogenesis and, in women, statins have beneficial effects in treatment of polycystic ovary syndrome (PCOS). Additional research is needed to provide specific clinical recommendations concerning this topic.

Pathophysiological mechanisms of statin-associated myopathies: possible role of the ubiquitin-proteasome system.

BACKGROUND: Statins are the cornerstone of pharmacotherapy for atherosclerotic cardiovascular disease. While these drugs are generally safe, treatment adherence is not optimal in a considerable proportion of patients because of the adverse effects on skeletal muscles in the forms of myopathy, myalgia, muscular pain, nocturnal muscle cramping, weakness, and rare rhabdomyolysis. METHODS: For the purpose of this narrative review, we searched for the literature suggesting the involvement of the ubiquitin-proteasome system in the development of statin-induced myopathy. RESULTS: Statins have been shown to up-regulate the expression of the muscle-specific ubiquitin-proteasome system as the major non-lysosomal intracellular protein degradation system. It has been postulated that statins may provoke instability in the myocyte cell membrane when subjected to eccentric exercise stress, triggering activation of intracellular proteolytic cascades and changes in protein degradation machinery. This is accompanied by the up-regulation of a series of genes implicated in protein catabolism, in addition to those of the ubiquitin-proteasome system. CONCLUSIONS: Based on the available literature, it seems that the involvement of ubiquitin-proteasome system is potentially implicated in the pathophysiology of statin-induced myopathy.

Gender Differences in Epidemiology, Pathophysiology, and Treatment of Hypertension.

PURPOSE OF REVIEW: This review aims to examine gender differences in both the epidemiology and pathophysiology of hypertension and to explore gender peculiarities on the effects of antihypertensive agents in decreasing BP and CV events. RECENT FINDINGS: Men and women differ in prevalence, awareness, and control rate of hypertension in an age-dependent manner. Studies suggest that sex hormones changes play a pivotal role in the pathophysiology of hypertension in postmenopausal women. Estrogens influence the vascular system inducing vasodilatation, inhibiting vascular remodeling processes, and modulating the renin-angiotensin aldosterone system and the sympathetic system. This leads to a protective effect on arterial stiffness during reproductive age that is dramatically reversed after menopause. Data on the efficacy of antihypertensive therapy between genders are conflicting, and the underrepresentation of aged women in large clinical trials could influence the results. Therefore, further clinical research is needed to uncover potential gender differences in hypertension to promote the development of a gender-oriented approach to antihypertensive treatment.

Climate Changes and Human Health: A Review of the Effect of Environmental Stressors on Cardiovascular Diseases Across Epidemiology and Biological Mechanisms.

BACKGROUND: Climate change is rapidly affecting all the regions of our planet. The most relevant example is global warming, which impacts on the earth's ecosystems, threatening human health. Other effects include extreme variations in temperature and increases in air pollution. These events may negatively impact mortality and morbidity for cardiovascular diseases. METHODS: In this review, we discuss the main effects of climate changes on cardiovascular diseases, reporting the epidemiological evidences and the biological mechanisms linking climate change consequences to hypertension, diabetes, ischemic heart diseases, heart failure and stroke. RESULTS: Up to now, findings suggest that humans acclimate under different weather conditions, even though extreme temperatures and higher levels of air pollution can influence health-related outcomes. In these cases, climate change adversely affects cardiovascular system and the high-risk subjects for cardiovascular diseases are those more exposed. CONCLUSION: Finally, we examine climate change implications on publich health and suggest adaptation strategies to monitor the high-risk population, and reduce the amount of hospital admissions associated to these events. Such interventions may minimize the costs of public health and reduce the mortality for cardiovascular diseases.

Comparison of Clinical Outcomes Between Genders Following Antihypertensive Therapy: A Meta-Analysis.

BACKGROUND: Numerous studies have reported sex and gender differences in the prevalence and treatment of cardiovascular diseases. However, sex differences in the therapy of hypertension have not been completely examined. OBJECTIVE: To estimate the gender-specific dissimilarity in outcomes among patients following antihypertensive treatment, using a meta-analysis of available studies. METHODS: A systematic literature search in Medline and SCOPUS databases was performed from January 1990 to January 2015 to find studies assessing clinical outcomes in male and female subjects after hypertension treatment, separately. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RESULTS: the analysis included 10 studies with 16 treatment arms. Outcomes were found to be significantly more frequent in men then in women (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.17, 1.33, p < 0.001; I2:40.17%), and this result was robust and independent. Random-effects meta-regression showed no association of outcomes with treatment duration and baseline levels. CONCLUSION: The present meta-analysis demonstrates that clinical outcomes are more frequent in men compared with women after the same treatment of hypertension. Numerous reasons, including disparities in compliance, age, and intrinsic higher risk in male, contribute to justify these findings.

Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms.

AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an emerging class of low-density lipoprotein cholesterol (LDL-C)-lowering agents. In spite of their known effects on lipids, the impact of these drugs on systemic inflammation is less known. We aimed to investigate the effect of PCSK9 inhibitors on high-sensitivity C-reactive protein (hs-CRP) levels through a meta-analysis of randomized controlled trials (RCTs). METHODS: A systematic literature search of Medline, SCOPUS and Google Scholar was conducted up to December 2015 to identify RCTs assessing changes in hs-CRP concentrations during treatment with PCSK9 inhibitors. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RESULTS: Sixteen treatment arms, with a total of 2546 participants, were included. Random-effects meta-analysis did not show any significant effect of PCSK9 inhibitors on hs-CRP levels (WMD: 0.002 mg l(-1) , CI: -0.017, 0.021; P = 0.807; I(2) = 37.26%). This effect size was robust, not sensitive to any single study, and not affected by the type of PCSK9 inhibitor (evolocumab: WMD: 0.002 mg l(-1) , CI: -0.02, 0.02; P = 0.855; alirocumab WMD: 0.15 mg l(-1) , CI: -0.11, 0.40; P = 0.259; I(2) = 0%), or dosing frequency (biweekly: WMD: 0.13 mg l(-1) , CI: -0.20, 0.46; P = 0.433; I(2) = 55.19%; monthly: WMD: 0.003 mg l(-1) , CI: -0.01, 0.01; P = 0.59; I(2) = 0%). Random-effects meta-regression did not suggest any association of changes in hs-CRP levels with changes in plasma LDL-C concentrations (P = 0.697) or cumulative dosage of the drug (P = 0.980). CONCLUSIONS: This meta-analysis of RCTs did not suggest an effect of PCSK9 inhibitors on hs-CRP concentrations.