Cardiac Left Ventricular miRNA-26a Is Downregulated in Ovariectomized Mice, Upregulated upon 17-Beta Estradiol Replacement, and Inversely Correlated with Collagen Type 1 Gene Expression.

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17ß-estradiol (E2) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of IL-1α, IL-6, Mmp9, Mmp12, Col1α1, and Col3α1 was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with Col1α1 and Col3α1 expression 1-week post-surgery (r = -0.79 p < 0.001; r = -0.6 p = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while Col1α1, Col3α1, IL-1α, IL-6, Tnfα, Mmp12, and FasL gene expression was significantly lower in E2- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with Col3α1 in T12/OVX/ E2 (r = -0.56 p = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E2 replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.

Sustained insulin treatment restoring metabolic status, body weight, and cognition in an anorexia nervosa-like animal model in mice.

INTRODUCTION: Anorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. METHODS: AN-like model was established through dietary restriction (DR). On days 1-25, mice were on DR, and on days 26-31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. RESULTS: The delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. CONCLUSION: The PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."

Persistence of vitamin D deficiency among Italian patients with acute myocardial infarction.

BACKGROUND AND AIMS: Vitamin D deficiency is a common cardiovascular risk factor associated with the development of atherosclerosis. We evaluated changes in 25(OH)D concentrations in 1510 patients with acute myocardial infarction (AMI) over a long observation period, including the COVID-19 pandemic. METHODS AND RESULTS: Patients were separated into four groups according to the year of enrolment, group 1 (2009-2010), group 2 (2014-2016), group 3 (2017-2019), and group 4 (2020-2022). The median 25(OH)D concentration in the overall cohort was 17.15 (10.3-24.7) ng/mL. The median plasma concentrations of 25(OH)D for groups 1, 2, 3, and 4 were 14.45 (7.73-22.58) ng/mL, 17.3 ng/mL (10.33-24.2), 18.95 (11.6-26.73) ng/mL and 19.05 (12.5-27.3) ng/mL, respectively. Although 25(OH)D levels increased over the years, the prevalence of vitamin D deficiency remained high in each group (68.4%, 61.4%, 53.8%, and 52% respectively). Hypovitaminosis D was predicted by the season influence (OR:2.03, p < 0.0001), higher body mass index (OR:1.25; p = 0.001), diabetes mellitus (OR:1.54; p = 0.001), smoking (OR:1.47; p = 0.001), older age (OR:1.07; p = 0.008), higher triglycerides levels (OR:1.02; p = 0.01), and female gender (OR:1.3; p = 0.038). After multivariable adjustment, vitamin D ≤ 20 ng/mL was an independent predictor of mortality. CONCLUSION: Vitamin D deficiency is highly prevalent and persistent in patients with AMI despite a trend towards increasing 25(OH)D concentrations over the years. The frequent lockdowns did not reduce the levels of 25(OH)D in the fourth group. Low levels of 25(OH)D are an independent predictor of mortality.

Perceptions of Barriers and Facilitators to Reducing Exposure to Secondhand Smoke in the Home: A Qualitative Study With Palestinian-Arab Women in Israel.

INTRODUCTION: Smoking is a collective and complex problem in the Palestinian-Arab community in Israel, where women and children are particularly vulnerable to exposure to secondhand smoke (SHS), especially in the home. AIMS AND METHODS: We undertook this study to better understand women's experiences with SHS exposure in the home and to identify pathways for intervention. Using the grounded theory approach, seven focus groups were conducted with 66 women in different localities across Israel. Purposive and snowball sampling techniques were applied to recruit women who have currently or previously been exposed to smoking in the home. Focus groups were audio-recorded and transcribed verbatim, and data were then coded and analyzed using the constant comparison analysis method to identify emergent themes and subthemes. RESULTS: Three core themes emerged from the discussions. These include women's perceptions of smoking among men and exposure to SHS in the home, the implications of smoking on spousal and social relationships, and the women's experiences in coping with this situation and their suggestions for interventions. We identified additional sub-themes, including the consequences to women's and children's health, as well as the complex interaction between smoking in the home and women's social position, agency, and home ownership. CONCLUSIONS: Women exposed to SHS in the home experience consequences that affect their health and their spousal and social relationships. They also face several personal and societal challenges in tackling this issue. Culturally tailored interventions targeting both communities and households can raise awareness and impact smoking behaviors in the home. IMPLICATIONS: The findings of this study demonstrate the far-reaching consequences of SHS exposure in the home among women who are exposed. The findings contribute to our understanding of smoking contingencies among men and smoking behaviors in the home. This study lays the groundwork for future community and household-based research and interventions. We suggest several critical junctures that may increase response to smoking cessation interventions and to reduce smoking in the home, such as at the time of marriage when the home policy is set, and the adverse effects of exposure on children and other family members, especially those with illness.

Development and usage of a health recommendation web tool (HeaRT) designed to inform women of personalized preventive health recommendations.

Background: Implementation of guidelines for evidence-based screening and disease prevention remains a core challenge in health care. The lack of access to accurate and personalized health recommendations may contribute to sub-optimal performance of medical screening, and ultimately increased risk for communicable and non-communicable disease. Many women do not monitor their cardiovascular disease (CVD) risk or receive regular medical screenings. A health recommendation tool (HeaRT) that provides women with profiled, individually tailored information about recommended tests and screening was designed to improve women's engagement in preventive health. This study characterized utilization of the tool in a real world setting. Objective: To describe the development and usage patterns of HeaRT, a novel health web-tool that provides personalized health recommendations for women. Methods: Extracted web-tool data including user input (age, BMI, smoking status and family history of CVD) and time spent in the results screen were analysed. Engagement was assessed by time spent in each results category, number of clicks and whether the user emailed/printed the recommendations. Usage patterns were analysed using multivariate analyses, logistic regression and cluster analyses. Results: HeaRT was used 13,749 times in the years between its launch and data extraction three years later. Web-tool analysis found that 68.6 % of users accessed results and approximately 15 % printed or emailed the list of recommendations. Further analysis found that almost all the users entered the nutrition category (78 %), followed by the risk-factor category (69.5 %) and Physical activity category (61.9 %). Three usage patterns were identified by cluster analysis, including a nutrition/physical activity cluster, a risk-factor cluster and an all-categories cluster. Cluster affiliation analysis found BMI and smoking status were not predictors of cluster affiliation, whereas users over the age of 65 were more likely to solely enter the risk-factor tab (P < .001) and users with family history of CVD were more likely to either enter only the risk-factor tab or to enter all tabs (P < .01). Conclusions: HeaRT users looked at health recommendations on a variety of health topics, and 15 % printed or emailed the recommendations. A tailored health recommendation web-tool may empower women to seek preventive-care and health maintenance, and help them interact with health care providers from a position of shared responsibility. This tool and similar programs may enable health care consumers to actively participate in directing their own health maintenance by providing consumers with personalized health recommendations. Additionally, user characteristics may inform future web-tool designers on target population profile and usage patterns.

Is Bicuspid Aortic Valve Morphology Genetically Determined? A Family-Based Study.

Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.

Cardiovascular disease risk factors and health behaviors of ultra-Orthodox Jewish women in Israel: a comparison study.

Objectives: Women from low socio-economic, culturally insular populations are at increased risk for cardiovascular disease (CVD). The ultra-Orthodox Jewish (UOJ) community in Israel is a rapidly growing low socio-economic, insular, cultural-ethnic minority with numerous obstacles to health. The current cross-sectional study investigates CVD-related health behaviors and risk factors in a sample of UOJ females, comparing sample characteristics with the general population. Design: Self-administered questionnaires completed by a cluster randomized sample of 239 UOJ women included demographics, CVD-related health behaviors (consumption of fruit, vegetables, and sweetened beverages; hours of sleep; secondhand smoke exposure; and physical activity engagement) and risk factors (BMI, reported diagnoses of diabetes, high blood pressure, and heart disease). Results: Compared with the general population, UOJ women were less likely to consume 5 fruits and vegetables a day (12.7% vs. 24.3%, p < .001); more likely to consume ≥ 5 cups of sweetened beverages a week (18.6% vs. 12.6%, p = .019), and more likely to sleep <7 hours a night (62.0% vs. 50.6%, p = .002). UOJ women also reported less secondhand smoke exposure (7.2% vs. 51.4%, p < .001) and higher rates of physical activity recommendation adherence (60.1% vs. 25.6%, p < .0001) than the general population. Obesity was higher in UOJ women (24.3% vs. 16.1%, p < .0001). Increased parity and reduced moderate physical activity were associated with increased BMI. Increased parity was also associated with reduced sleep. Grand multiparous women (a 68% prevalence rate), in particular, were more likely to be overweight or obese than women with less than 5 children. Conclusions: This study suggests that health promotion interventions in this population target healthy weight maintenance, nutrition, and physical activity.

Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). OBJECTIVES: The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures. METHODS: Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory. RESULTS: More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m2 vs 41 ± 14 mL/m2; mean change from baseline of -7.5 mL/m2 [95% CI: -9.0 to -6.1 mL/m2] vs -0.09 mL/m2 [95% CI: -1.6 to 1.5 mL/m2]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04). CONCLUSIONS: Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).

Prevalence and impact of concomitant malignancy on outcomes among ambulatory heart failure population.

INTRODUCTION: Heart failure (HF) and cancer are medical conditions with a rising prevalence resulting in increased co-occurrence. We assessed the impact of cancer on clinical outcome in patients with HF and the prognostic impact of specific types of cancers on different HF subpopulations. METHODS: All patients with HF were evaluated for the occurrence of malignant neoplasm at a health maintenance organization and were followed for cardiac-related hospitalizations and death. RESULTS: The study cohort included 7106 HF patients, 1564 of them (22%) had a diagnosis of malignant neoplasm. HF patients with concomitant cancer were older, had more comorbidities and were more likely to have NYHA class III/IV (42% vs. 37%, P < .01), compared with patients with no malignancy. The overall 2-year mortality rate of the entire HF cohort was 23.2%. Survival rate by Kaplan-Meier analysis demonstrated that the presence of a malignancy was directly associated with reduced survival: 67.2 ± 1.2% vs 79.5 ± 0.5%, P < .001. Malignancy was associated with an increase in mortality with a hazard ratio (HR) of 1.36, 95% confidence interval (CI) 1.21-1.54, P < .001. The strongest impact of malignancy on outcomes was related to age; among patients <70 years old, the increase in the risk of mortality was the highest with a HR of 2.07, 95% CI 1.54-2.80, P < .001. CONCLUSIONS: Malignancy is common among patients with HF. Patients with concomitant HF and malignancies have poor outcomes, and the impact of cancer on outcome is stronger among young patients.

Two-Phase Evaluation of a Community-Based Lifestyle Intervention for Palestinian Women in East Jerusalem: A Quasi-Experimental Study Followed by Dissemination.

Palestinian-Arab women are at increased risk of cardiovascular disease due to high prevalence of diabetes and other risk factors. The current study investigates the effectiveness of an intensive group-based intervention on lifestyle habits that can prevent diabetes and cardiovascular disease. To that end, we conducted a group-based intervention based on the diabetes prevention program in two consecutive phases. The first phase consisted of a quasi-experimental study and the second phase included community-wide dissemination, with a 6-month follow-up. Findings from the quasi-experiment indicate increased consumption of fruit, vegetables and whole grains, weight reduction (-2.21 kg, p < 0.01), and a significant increase in the average daily steps in the intervention group (from 4456 to 6404). Findings from the dissemination indicate that average daily vegetables consumption increased from 1.76 to 2.32/day as did physical activity and average daily steps (from 4804 to 5827). There was a significant reduction in blood pressure, total cholesterol and LDL. These gains were sustained over 6 months following the intervention. This community-based, culturally adapted, health-promotion intervention led to improved nutrition and physical activity which were maintained after 6 months. Collaboration with community centers and local community partners created an effective channel for dissemination of the program to pre-clinical individuals.

Acute viral myocarditis: current concepts in diagnosis and treatment.

Acute myocarditis is one of the most challenging diseases to diagnose and treat in cardiology. The true incidence of the disease is unknown. Viral infection is the most common etiology. Modern techniques have improved the ability to diagnose specific viral pathogens in the myocardium. Currently, parvovirus B19 and adenoviruses are most frequently identified in endomyocardial biopsies. Most patients will recover without sequelae, but a subset of patients will progress to chronic inflammatory and dilated cardiomyopathy. The pathogenesis includes direct viral myocardial damage as well as autoimmune reaction against cardiac epitopes. The clinical manifestations of acute myocarditis vary widely--from asymptomatic changes on electrocardiogram to fulminant heart failure, arrhythmias and sudden cardiac death. Magnetic resonance imaging is emerging as an important tool for the diagnosis and follow-up of patients, and for guidance of endomyocardial biopsy. In the setting of acute myocarditis endomyocardial biopsy is required for the evaluation of patients with a clinical scenario suggestive of giant cell myocarditis and of those who deteriorate despite supportive treatment. Treatment of acute myocarditis is still mainly supportive, except for giant cell myocarditis where immunotherapy has been shown to improve survival. Immunotherapy and specific antiviral treatment have yet to demonstrate definitive clinical efficacy in ongoing clinical trials. This review will focus on the clinical manifestations, the diagnostic approach to the patient with clinically suspected acute myocarditis, and an evidence-based treatment strategy for the acute and chronic form of the disease.

Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival.

OBJECTIVE: Uric acid (UA) levels are frequently increased in patients with heart failure (HF), and may be an indicator of a poor prognosis and an innovative target for treatment. We evaluated the effect of UA and allopurinol use on clinical outcome in patients with HF. METHODS AND RESULTS: We evaluated patients with a diagnosis of HF at a Health Maintenance Organization (n = 6204). Patients were followed for cardiac-related hospitalizations and death. Mean UA levels were 6.5 ± 1.9 mg/dL. Median follow-up was 498 days. We divided patients into quartiles of serum UA; 22.6% (n = 1,568) were in the highest UA level quartile (>7.7 mg/dL). Cox regression analysis after adjustment for significant predictors including age, sex, ischemic heart disease, hypertension, atrial fibrillation, body mass index, hemoglobin, sodium, estimated glomerular filtration rate, urea levels, standard HF drug therapies, and allopurinol demonstrated that high UA levels (>7.7 mg/dL) were a predictor of increased mortality (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.17-1.60; P < .0001) and increased cardiac hospitalizations (HR 1.10, 95% CI 1.01-1.22; P < .05). An increase in UA levels during follow-up was also an independent predictor of mortality (HR 1.46, 95% CI 1.25-1.71; P < .00001) and cardiac hospitalizations (HR 1.15, 95% CI 1.06-1.23; P < .00001). Treatment with allopurinol was independently associated with improved survival (HR 0.79, 95% CI 0.64-0.98; P < .05). Echocardiographic data demonstrated a significant correlation between UA levels and E/A ratio, a marker of diastolic dysfunction. CONCLUSIONS: Increased UA levels and an increase in UA during follow-up were independent predictors of increased morbidity and mortality. Treatment with allopurinol was associated with improved survival.

Vitamin D deficiency is a predictor of reduced survival in patients with heart failure; vitamin D supplementation improves outcome.

AIMS: Vitamin D deficiency is a highly prevalent, global phenomenon. The prevalence in heart failure (HF) patients and its effect on outcome are less clear. We evaluated vitamin D levels and vitamin D supplementation in patients with HF and its effect on mortality. METHODS AND RESULTS: 25-Hydroxyvitamin D [25(OH)D] levels were evaluated in HF patients from a health maintenance organization (HMO), and compared them with those of the rest of the members of the HMO. Patients with HF (n = 3009) had a lower median 25(OH)D level compared with the control group (n = 46 825): 36.9 nmol/L (interquartile range 23.2-55.9) vs. 40.7 nmol/L (26.7-56.9), respectively, P < 0.00001. The percentage of patients with vitamin D deficiency [25(OH)D <25 nmol/L] was higher in patients with HF compared with the control group (28% vs. 22%, P < 0.00001). Only 8.8% of the HF patients had optimal 25(OH)D levels (≥75 nmol/L). Median clinical follow-up was 518 days. Cox regression analysis demonstrated that vitamin D deficiency was an independent predictor of increased mortality in patients with HF [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.21-1.92, P < 0.001] and in the control group (HR 1.91, 95% CI 1.48-2.46, P < 0.00001). Vitamin D supplementation was independently associated with reduced mortality in HF patients (HR 0.68, 95% CI 0.54-0.85, P < 0.0001). Parameters associated with vitamin D deficiency in HF patients were decreased previous solar radiation exposure, body mass index, diabetes, female gender, pulse, and decreased calcium and haemoglobin levels. CONCLUSIONS: Vitamin D deficiency is highly prevalent in HF patients and is a significant predictor of reduced survival. Vitamin D supplementation was associated with improved outcome.

Left ventricular intracardiac metastatic germ cell tumor presenting with hemorrhagic cerebrovascular event.

We describe an unusual case of a 26-year-old man admitted with respiratory distress and found to have testicular cancer metastatic to the lung and heart. Twelve days after admission, the patient experienced multiple hemorrhagic strokes. Echocardiography demonstrated testicular cancer metastatic to the septal surface of the left ventricle of the heart with presumed embolization to the cerebrovascular region. The patient received chemotherapy and radiation therapy to the areas of tumor mass with subsequent resolution of tumor burden. This is the first reported case of metastasis from embryonal carcinoma of the testis to the left ventricle of the heart.