Chronic reduction of store operated Ca2+ entry is viable therapeutically but is associated with cardiovascular complications.

Loss of function mutations in store-operated Ca2+ entry (SOCE) are associated with severe paediatric disorders in humans, including combined immunodeficiency, anaemia, thrombocytopenia, anhidrosis and muscle hypotonia. Given its central role in immune cell activation, SOCE has been a therapeutic target for autoimmune and inflammatory diseases. Treatment for such chronic diseases would require prolonged SOCE inhibition. It is, however, unclear whether chronic SOCE inhibition is viable therapeutically. Here we address this issue using a novel genetic mouse model (SOCE hypomorph) with deficient SOCE, nuclear factor of activated T cells activation, and T cell cytokine production. SOCE hypomorph mice develop and reproduce normally and do not display muscle weakness or overt anhidrosis. They do, however, develop cardiovascular complications, including hypertension and tachycardia, which we show are due to increased sympathetic autonomic nervous system activity and not cardiac or vascular smooth muscle autonomous defects. These results assert that chronic SOCE inhibition is viable therapeutically if the cardiovascular complications can be managed effectively clinically. They further establish the SOCE hypomorph line as a genetic model to define the therapeutic window of SOCE inhibition and dissect toxicities associated with chronic SOCE inhibition in a tissue-specific fashion. KEY POINTS: A floxed stromal interaction molecule 1 (STIM1) hypomorph mouse model was generated with significant reduction in Ca2+ influx through store-operated Ca2+ entry (SOCE), resulting in defective nuclear translocation of nuclear factor of activated T cells, cytokine production and inflammatory response. The hypomorph mice are viable and fertile, with no overt defects. Decreased SOCE in the hypomorph mice is due to poor translocation of the mutant STIM1 to endoplasmic reticulum-plasma membrane contact sites resulting in fewer STIM1 puncta. Hypomorph mice have similar susceptibility to controls to develop diabetes but exhibit tachycardia and hypertension. The hypertension is not due to increased vascular smooth muscle contractility or vascular remodelling. The tachycardia is not due to heart-specific defects but rather seems to be due to increased circulating catecholamines in the hypomorph. Therefore, long term SOCE inhibition is viable if the cardiovascular defects can be managed clinically.

Controversies in the Use of Omega-3 Fatty Acids to Prevent Atherosclerosis.

PURPOSE OF REVIEW: We discuss current controversies in the clinical use of omega-3 fatty acids (FA), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and examine discrepancies between recent trials. Furthermore, we discuss potential side effects reported in these studies and the role of mixed omega-3 FA dietary supplements and concerns about their use. RECENT FINDINGS: REDUCE-IT showed that addition of icosapent ethyl, a highly purified form of EPA, can reduce risk of cardiovascular events among statin-treated individuals with high triglycerides. Additional supportive evidence for EPA has come from other trials and meta-analyses of omega-3 FA therapy. In contrast, trials of mixed EPA/DHA products have consistently failed to improve cardiovascular outcomes. Discrepancies in results reported in RCTs could be explained by differences in omega-3 FA products, dosing, study populations, and study designs including the placebo control formulation. Evidence obtained from highly purified forms should not be extrapolated to other mixed formulations, including "over-the-counter" omega-3 supplements. Targeting TG-rich lipoproteins represents a new frontier for mitigating ASCVD risk. Clinical and basic research evidence suggests that the use of omega-3 FA, specifically EPA, appears to slow atherosclerosis by reducing triglyceride-rich lipoproteins and/or inflammation, therefore addressing residual risk of clinical ASCVD.

What is the Optimal Low-Density Lipoprotein Cholesterol?

One's total atherosclerotic plaque burden is related to his or her cumulative exposure to low-density lipoprotein cholesterol (LDL-C) and other apoB-containing lipoproteins. Long-term exposure to lower LDL-C levels is associated with a lower risk of cardiovascular events compared with shorter term exposure to lower LDL-C. New lipid-reducing agents have been able to reduce LDL-C to previously unseen levels, showing efficacy in safely decreasing rates of atherosclerotic cardiovascular disease in primary and secondary prevention populations. To date, an LDL-C level less than which there is no clinical benefit has not yet been identified.

Medicine 2032: The future of cardiovascular disease prevention with machine learning and digital health technology.

Machine learning (ML) refers to computational algorithms that iteratively improve their ability to recognize patterns in data. The digitization of our healthcare infrastructure is generating an abundance of data from electronic health records, imaging, wearables, and sensors that can be analyzed by ML algorithms to generate personalized risk assessments and promote guideline-directed medical management. ML's strength in generating insights from complex medical data to guide clinical decisions must be balanced with the potential to adversely affect patient privacy, safety, health equity, and clinical interpretability. This review provides a primer on key advances in ML for cardiovascular disease prevention and how they may impact clinical practice.

Cardiovascular Imaging in Stress Cardiomyopathy (Takotsubo Syndrome).

Stress cardiomyopathy (Takotsubo syndrome) is a reversible syndrome stemming from myocardial injury leading to systolic dysfunction and is usually noted in the setting of a stressful event, be it an emotional or physical trigger. While the exact pathophysiology behind stress cardiomyopathy is yet unknown, there is ample evidence suggesting that neurocardiogenic mechanisms may play an important role. Although historically stress cardiomyopathy was generally thought to be a relatively benign condition, there is growing recognition of the cardiovascular complications associated with it despite its reversibility. Our review aims to shed light onto key cardiovascular imaging modalities used to diagnose stress cardiomyopathy while highlighting the role that imaging plays in assessing disease severity, identifying complications, dictating treatment approaches, and in short-term and long-term prognosis.

The epidemiology of hepatitis C virus in Central Asia: Systematic review, meta-analyses, and meta-regression analyses.

The objective was to delineate hepatitis C virus (HCV) epidemiology in countries of Central Asia (CA), specifically Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan. A systematic review was conducted guided by the Cochrane Collaboration Handbook, and reported using PRISMA guidelines. Meta-analyses were performed using DerSimonian-Laird random-effects models with inverse variance weighting. Random-effects meta-regression analyses were performed on general population studies. The systematic review identified a total of 208 HCV prevalence measures. No incidence or Turkmenistan studies were identified. Meta-analyses estimated HCV prevalence among the general population at 0.7% (95%CI: 0.7-0.8%) in Kazakhstan, 2.0% (95%CI: 1.7-2.4%) in Kyrgyzstan, 2.6% (95%CI: 1.7-3.6%) in Tajikistan, and 9.6 (95%CI: 5.8-14.2%) in Uzbekistan. Across CA, the pooled mean prevalence was 13.5% (95%CI: 10.9-16.4%) among non-specific clinical populations, 31.6% (95%CI: 25.8-37.7%) among populations with liver-related conditions, and 51.3% (95%CI: 46.9-55.6%) among people who inject drugs. Genotypes 1 (52.6%) and 3 (38.0%) were most frequent. Evidence was found for statistically-significant differences in prevalence by country, but not for a temporal decline in prevalence. CA is one of the most affected regions by HCV infection with Uzbekistan enduring one of the highest prevalence levels worldwide. Ongoing HCV transmission seems to be driven by injecting drug use and healthcare exposures.