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.

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.

Lung ultrasonography for early management of patients with respiratory symptoms during COVID-19 pandemic.

COVID-19 pandemic is representing a serious challenge to worldwide public health. Lung Ultrasonography (LUS) has been signaled as a potential useful tool in this pandemic contest either to intercept viral pneumonia or to foster alternative paths. LUS could be useful in determining early lung involvement suggestive or not of COVID-19 pneumonia and potentially plays a role in managing decisions for hospitalization in isolation or admission in general ward. In order to face pandemic, in a period in which a large number of emergency room accesses with suspicious symptoms are expected, physicians need a standardized ultrasonographic approach, fast educational processes in order to be able to recognize both suggestive and not suggestive echographic signs and shared algorithms for LUS role in early management of patients.

Goal-oriented requirements engineering: an extended systematic mapping study.

Over the last two decades, much attention has been paid to the area of goal-oriented requirements engineering (GORE), where goals are used as a useful conceptualization to elicit, model, and analyze requirements, capturing alternatives and conflicts. Goal modeling has been adapted and applied to many sub-topics within requirements engineering (RE) and beyond, such as agent orientation, aspect orientation, business intelligence, model-driven development, and security. Despite extensive efforts in this field, the RE community lacks a recent, general systematic literature review of the area. In this work, we present a systematic mapping study, covering the 246 top-cited GORE-related conference and journal papers, according to Scopus. Our literature map addresses several research questions: we classify the types of papers (e.g., proposals, formalizations, meta-studies), look at the presence of evaluation, the topics covered (e.g., security, agents, scenarios), frameworks used, venues, citations, author networks, and overall publication numbers. For most questions, we evaluate trends over time. Our findings show a proliferation of papers with new ideas and few citations, with a small number of authors and papers dominating citations; however, there is a slight rise in papers which build upon past work (implementations, integrations, and extensions). We see a rise in papers concerning adaptation/variability/evolution and a slight rise in case studies. Overall, interest in GORE has increased. We use our analysis results to make recommendations concerning future GORE research and make our data publicly available.

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.

Gender differences in cardiovascular prophylaxis: Focus on antiplatelet treatment.

Cardiovascular disease (CVD) represents the leading cause of death worldwide, and equally affects both sexes although women develop disease at an older age than men. A number of clinical evidence has identified the female sex as an independent factor for poor prognosis, with the rate of mortality and disability following an acute cardiovascular (CV) event being higher in women than men. It has been argued that the different level of platelet reactivity between sexes may account for a different responsiveness to anti-platelet therapy, with consequent important implications on clinical outcomes. However, conclusive evidence supporting the concept of a gender-dependent effectiveness of platelet inhibitors are lacking. On the contrary, sex-related dissimilarities have been evidenced in cardiovascular patients in terms of age of presentation, comorbidities such as obesity, diabetes and renal disease, and a different pharmacological approach to and effectiveness in controlling classical cardiovascular risk factors such as hypertension, glucose profile and lipid dysmetabolism. All these factors could place women at an increased level of cardiovascular risk compared to men, and may concur to an enhanced pro-thrombogenic profile. The purpose of this manuscript is to provide an overview of gender-related differences in cardiovascular treatment, in order to highlight the need to improve the pharmacological prophylaxis adopted in women through a more accurate evaluation of the overall cardiovascular risk profile with consequent establishment of a more effective and targeted anti-thrombotic strategy which is not limited to the use of anti-platelet agents.

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.

Effects of pomegranate juice on blood pressure: A systematic review and meta-analysis of randomized controlled trials.

Punica granatum L. (Pomegranate) has been claimed to provide several health benefits. Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. Several studies suggested that pomegranate juice can exert antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects. Nevertheless, the potential cardioprotective benefits of pomegranate juice deserve further clinical investigation. To systematically review and meta-analyze available evidence from randomized placebo-controlled trials (RCTs) investigating the effects of pomegranate juice consumption and blood pressure (BP). A comprehensive literature search in Medline and Scopus was carried out to identify eligible RCTs. A meta-analysis of eligible studies was performed using a random-effects model. Quality assessment, sensitivity analysisand publication bias evaluations were conducted using standard methods. Quantitative data synthesis from 8 RCTs showed significant reductions in both systolic [weighed mean difference (WMD): -4.96mmHg, 95% CI: -7.67 to -2.25, p<0.001) and diastolic BP (WMD: -2.01mmHg, 95% CI: -3.71 to -0.31, p=0.021) after pomegranate juice consumption. Effects on SBP remained stable to sensitivity analyses. Pomegranate juice reduced SBP regardless of the duration (>12 wks: WMD=-4.36mmHg, 95% CI: -7.89 to -0.82, p=0.016) and <12 wks: WMD=-5.83 mmHg, 95% CI: -10.05 to -1.61, p=0.007) and dose consumed (>240cc: WMD=-3.62mmHg, 95% CI: -6.62 to -0.63, p=0.018) and <240cc: WMD=-11.01mmHg, 95% CI: -17.38 to -4.65, p=0.001, pomegranate juice per day) whereas doses >240cc provided a borderline significant effect in reducing DBP. The present meta-analysis suggests consistent benefits of pomegranate juice consumption on BP. This evidence suggests it may be prudent to include this fruit juice in a heart-healthy diet.

Impact of statin therapy on plasma resistin and visfatin concentrations: A systematic review and meta-analysis of controlled clinical trials.

The beneficial effects of statin therapy in reducing cardiovascular morbidity and mortality is not merely explained by the lipid-modulating effects. Although adipokines levels have been associated with cardiometabolic disorders, a few studies have explored the effect of statin on resistin and visfatin. We aimed to evaluate the impact of statin therapy on levels of resistin and visfatin through a meta-analysis of published studies. A systematic literature search in Medline and SCOPUS databases was conducted up to January 2015 to identify controlled trials assessing changes in plasma concentrations of visfatin and resistin during treatment with statins. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. 12 eligible studies with 14 treatment arms were included. Overall, 844 participants were studied. No significant change in plasma resistin concentrations was observed following statin therapy (WMD: -0.11ng/mL, CI: -1.94,1.73, p=0.909). This effect was robust and not affected by statin type, treatment duration and LDL-cholesterol concentrations. With respect to visfatin concentrations, there was a marginally significant reduction following statin therapy (WMD: -2.40ng/mL, CI: -4.79,-0.002, p=0.050). However, this effect size was weak and sensitive to three of the trials included in the analysis. This meta-analysis did not suggest any effect of statin therapy on plasma resistin levels, while a slight reduction in visfatin levels was found. The effect of statins on visfatin levels may represent a novel pleiotropic characteristic of these drugs.

Lipid profile changes after pomegranate consumption: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Transport of oxidized low-density lipoprotein across the endothelium into the artery wall is considered a fundamental priming step for the atherosclerotic process. Recent studies reported potential therapeutic effects of micronutrients found in natural products, indicating positive applications for controlling the pathogenesis of chronic cardiovascular disease driven by cardiovascular risk factors and oxidative stress. A particular attention has been recently addressed to pomegranate; however findings of clinical studies have been contrasting. PURPOSE: To evaluate the effects of pomegranate consumption on plasma lipid concentrations through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: The study was designed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. Scopus and Medline databases were searched to identify randomized placebo-controlled trials investigating the impact of pomegranate on plasma lipid concentrations. A fixed-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the one-study remove approach. Random-effects meta-regression was performed to assess the impact of potential confounders on the estimated effect sizes. RESULTS: A total of 545 individuals were recruited from the 12 RCTs. Fixed-effect meta-analysis of data from 12 RCTs (13 treatment arms) did not show any significant effect of pomegranate consumption on plasma lipid concentrations. The results of meta-regression did not suggest any significant association between duration of supplementation and impact of pomegranate on total cholesterol and HDL-C, while an inverse association was found with changes in triglycerides levels (slope: -1.07; 95% CI: -2.03 to -0.11; p = 0.029). There was no association between the amount of pomegranate juice consumed per day and respective changes in plasma total cholesterol, LDL-C, HDL-C and triglycerides. CONCLUSION: The present meta-analysis of RCTs did not suggest any effect of pomegranate consumption on lipid profile in human.

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.