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Background: Cardiovascular disease (CVD) remains the leading cause of death for African-American (AA) adults. There is a low prevalence of ideal cardiovascular health (CVH) (as defined by the American Heart Association’s Life’s Simple 7 TM (LS7)), especially diet, physical activity and obesity among AAs placing them at a disproportionately high risk for CVD. The identification of psychosocial stress that may influence ideal CVH could assist in the development of more effective behavior change interventions among AAs. Objectives: The aim of this study is to examine the associations of multidimensional stressors (chronic stress, minor stressors, and major life events - MLEs) with the LS7 components (classified as poor, intermediate and ideal) in AAs. We hypothesize that stress is negatively associated with the likelihood of achievement of intermediate/ideal levels of the LS7 components and LS7 composite score after adjusting for traditional socio-demographic factors. Methods: Using the Jackson Heart Study (JHS), a cohort of AAs based in Jackson, Mississippi (n=4383), we conducted a cross-sectional analysis of the association of stress measures with LS7 components (smoking, diet, physical activity, body mass index, blood pressure, total cholesterol and glucose). This association was measured using logistic regression which assessed the odds ratios (OR, 95% confidence interval (CI)) of the achievement of intermediate/ideal levels of CVH with progressive adjustment for demographic, socioeconomic, behavioral and biomedical factors. A composite LS7 score was calculated [range 0-14; categorized as 0 to 6 (poor), 7 to 8 (intermediate) and 9 to 14 (ideal)]. We also constructed a cumulative stress score as a summation of tertiles of each stress measure (range 3-9). Results: Fewer participants achieved intermediate or ideal CVH for the LS7 components including diet (39%), physical activity (51%) and BMI (47%). Higher chronic stress and minor stressors scores were associated a decreased likelihood of achievement of ideal/intermediate levels for smoking [OR 0.80; 95% CI 0.73-0.88 and OR 0.84; 95% CI 0.75-0.94, respectively). Higher MLE scores were associated decreased likelihood of achievement of ideal/intermediate levels for smoking (OR 0.84; 95% CI 0.76-0.92) and glucose (OR 0.90; 95% CI 0.82-0.98). Those with higher minor stressors and MLE scores were less likely to achieve intermediate or ideal LS7 composite score categories (OR 0.89; 95% CI 0.81-0.97 and OR 0.91; 95% CI 0.84-0.98, respectively). There was no statistically significant association between LS7 composite scores and cumulative stress scores. Conclusions: Our results suggest that key stress measures may contribute adversely to CVH among AAs. These findings provide support for future lifestyle interventions which integrate a focus on alleviating stressors in this high risk population to improve CVH.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Introduction: Cardiorenal dysfunction with impaired cyclic guanosine monophosphate (cGMP) response to volume load is a hallmark of heart failure. Phosphodiesterase V (PDEV) is known to be upregulated and may explain the dysfunction of renal response. Hypothesis: We tested the hypothesis that PDEV inhibition in combination with low dose intravenous (IV) B-type natriuretic peptide (BNP) would improve renal function and potentiate urinary sodium and cGMP excretion in patients with acute heart failure. Methods: Randomized open label study in 67 patients admitted to the hospital with acute heart failure. These patients were randomized to standard care, low dose IV BNP (0.005μg/kg/min), or combination low dose BNP/PDEV inhibition with sildenafil (25 mg q12 hrs) for 48 hours. Plasma and urine studies were obtained at baseline, 24 hours, and 48 hours after study drug initiation to assess renal function. The primary endpoint was the percent change in estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) from baseline to 48 hours. Changes from baseline were summarized with median and quartiles and groups were compared using two-sample t-test. [ClinicalTrials.gov Identifier: NCT00972569] Results: Baseline characteristics were similar between groups. Median age was 78 years and median ejection fraction 39%. Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hr (% increase of 25.6 (8.9, 13.1) and 60.8 (32.3, 103.8) for BNP and BNP/PDEV vs % decrease of 13.5 (-29.1, 14.2) for placebo, p=0.001). BNP levels were significantly higher in both groups at 48 hr compared with placebo. However, there was no significant change in eGFR, BUN, or urinary sodium/cGMP excretion between groups. Hypotension was more common in the BNP/PDEV inhibitor group. Conclusions: Low dose IV BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute heart failure but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of low dose IV BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute heart failure.

Introduction: Atrial natriuretic peptide (ANP) plays an important role in blood pressure (BP) regulation via the second messenger cGMP. ANP also induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA). MANP is a new Mayo Clinic designed ANP analog consisting of the native ANP with a novel 12-amino-acid C-terminus extension. In experimental models, MANP is more potent than ANP in reducing BP and inducing natriuresis. These actions are mediated by the activation of the pGC-A receptor and generation of cGMP. To date, the BP pressure lowering, cGMP generating and lipolytic actions of MANP remain unexplored along with its safety and tolerability in subjects with hypertension (HTN) associated with metabolic disease. Hypothesis: In subjects with HTN, obesity and metabolic syndrome (MS), MANP administration is safe, well tolerated, activates cGMP and exerts BP lowering and lipolytic properties. Methods: Double-blind, placebo-control clinical trial in 22 subjects (17 receiving MANP) with HTN, obesity and MS involving a single subcutaneous (SQ) injection of MANP (2.5 μg/Kg) or placebo. Subjects were monitored and cardiovascular, cGMP and metabolic parameters were collected during 24 hours after the injection. Results: In all subjects, MANP was safe and well-tolerated with no serious adverse side effects. MANP increased mean cGMP plasma levels after 30 minutes (delta: 4.8 ± 2.0 pmol/mL, p=0.02) and 1 hour (delta: 2.9 ±1.3 pmol/mL, p=0.03) when compared to baseline. Six hours after MANP injection systolic BP decreased by 5.7 ± 2.9 mmHg (p=0.06) whereas subjects receiving placebo had no decrease in blood pressure values compared to baseline. During fasting period, one hour after the administration of MANP, NEFA plasma levels increased by 108.2 ± 37.4 μM (p=0.01). Conclusions: In subjects with HTN, obesity and MS, SQ MANP is safe, well tolerated and activates the pGC-A receptor as measured by a significant increase in the second messenger cGMP. Subjects receiving MANP showed a borderline significant decrease in systolic BP and a significant increase in NEFA circulating levels supporting anti-hypertensive and lipolytic properties. Our findings support MANP as a potential novel therapy for HTN associated with metabolic disease.

Background: Papillary fibroelastoma (PFE) is the most common benign cardiac tumor. Because PFEs have the potential to embolize, they typically are surgically excised. Prior studies have suggested that postoperative recurrence of PFE is rare or does not occur. Objectives: To determine the rate at which PFEs recurred after surgical removal and to identify any risk factors associated with recurrence. Methods: Patients with pathologically proven PFE were retrospectively identified from a single center. Patients were included in the study if they had an echocardiographic examination at least 1 year after surgery. Echocardiographic images obtained intraoperatively (after excision) and at dismissal were compared with those of the most recent examination to assess the possibility of PFE recurrence. Results: Ninety eight patients were identified. The mean (SD) duration of follow-up was 5.4 (3.7) years (range, 1-17 years). Twelve patients (12.2%) had echocardiographically proven PFE recurrence. Three patients had the recurrent lesion surgically re-excised, and pathologic analysis showed that 2 were recurrent PFEs and 1 was a Lambl excrescence. Clinical presentation of stroke or TIA was more common for the recurrence patients (for the first PFE) than for the nonrecurrence patients (83% vs 26%; P <.001). Conclusions: Contrary to published data, PFEs do recur after surgical excision. This emphasizes the importance of postoperative follow-up with transesophageal echocardiography for identifying recurrent masses. Table. Characteristics of Patients With Recurrent PFE Abbreviations: AV, aortic valve; LA, left atrium; LE, Lambl excrescence; LVOT, left ventricular outflow tract; MV, mitral valve; PV, pulmonary valve; RA, right atrium; RC, right cusp; TV, tricuspid valve. a Corresponds to the same location. b Corresponds to a different location .

Background: The aims of this study are to evaluate the rate of progression of preclinical (Stage A and B) heart failure, identify associated characteristics, and evaluate long-term outcomes. Methods: Retrospective review of the Olmsted County Heart Function Study. Individuals categorized as Stage A or B heart failure at initial visit that returned for a second visit 4 years later were included. Logistic regression analyses evaluated group differences with adjustment for age and sex. Results: At visit 1, 413 (32%) individuals were classified as Stage A and 413 (32%) as Stage B. By visit 2, 146 (35%) individuals from Stage A progressed with the vast majority (n=142) progressing to Stage B. In comparison, a total of 23 (6%) individuals progressed from Stage B. A greater rate of progression was seen for Stage A compared with Stage B (8.7 per 100 person-years [95% CI, 7.4–10.2] versus 1.4 per 100 person-years [95% CI, 0.9–2.1]; P <0.001). NT-proBNP correlated with progression for Stage B ( P =0.01), but not for Stage A ( P =0.39). A multivariate model found female sex (odds ratio, 1.65 [95% CI, 1.05–2.58]; P =0.03), increased E/e’ (odds ratio, 1.13 [95% CI, 1.02–1.26], P =0.02), and beta blocker use (odds ratio, 2.19 [95% CI, 1.25–3.82], P =0.006) were associated with progression for Stage A. There was a signal that cardiovascular mortality was higher in individuals who progressed, although not statistically significant ( P =0.06 for Stage A and P =0.05 for Stage B). Conclusions: There is significant progression of preclinical heart failure in a community population, with progression rates higher for Stage A. NT-proBNP correlated with progression for Stage B, but not for Stage A. No statistically significant differences in long-term outcomes were seen. Study results have clinical implications important to help guide future heart failure screening and prevention strategies.

Abstract Background We have demonstrated that a neural network is able to predict a person’s age from the electrocardiogram (ECG) [artificial intelligence (AI) ECG age]. However, some discrepancies were observed between ECG-derived and chronological ages. We assessed whether the difference between AI ECG and chronological age (Age-Gap) represents biological ageing and predicts long-term outcomes. Methods and results We previously developed a convolutional neural network to predict chronological age from ECGs. In this study, we used the network to analyse standard digital 12-lead ECGs in a cohort of 25 144 subjects ≥30 years who had primary care outpatient visits from 1997 to 2003. Subjects with coronary artery disease, stroke, and atrial fibrillation were excluded. We tested whether Age-Gap was correlated with total and cardiovascular mortality. Of 25 144 subjects tested (54% females, 95% Caucasian) followed for 12.4 ± 5.3 years, the mean chronological age was 53.7 ± 11.6 years and ECG-derived age was 54.6 ± 11 years (R2 = 0.79, P &lt; 0.0001). The mean Age-Gap was small at 0.88 ± 7.4 years. Compared to those whose ECG-derived age was within 1 standard deviation (SD) of their chronological age, patients with Age-Gap ≥1 SD had higher all-cause and cardiovascular disease (CVD) mortality. Conversely, subjects whose Age-Gap was ≤1 SD had lower all-cause and CVD mortality. Results were unchanged after adjusting for CVD risk factors and other survival influencing factors. Conclusion The difference between AI ECG and chronological age is an independent predictor of all-cause and cardiovascular mortality. Discrepancies between these possibly reflect disease independent biological ageing.

Objective: To identify an efficacious intervention on treating adolescents with overweight and obesity, this might result in health benefits. Methods: Adolescents with overweight or obesity aged 10–17 years with BMI percentile ≥85th were included in this historical observational analysis. Subjects used an entirely remote weight loss program combining mobile applications, frequent self-weighing, and calorie restriction with meal replacement. Body weight changes were evaluated at 42, 60, 90, and 120 days using different metrics including absolute body weight, BMI, and BMI z-score. Chi-square or Fisher exact tests (categorical variables) and Student's t -test (continuous variables) were used to compare subjects. Results: In total, 2,825 participants, mean age 14.4 ± 2.2 years, (54.8% girls), were included from October 27, 2016, to December 31, 2017, in mainland China; 1355 (48.0%) had a baseline BMI percentile ≥97th. Mean BMI and BMI z-score were 29.20 ± 4.44 kg/m 2 and 1.89 ± 0.42, respectively. At day 120, mean reduction in body weight, BMI, and BMI z-score was 8.6 ± 0.63 kg, 3.13 ± 0.21 kg/m 2 , and 0.42 ± 0.03; 71.4% had lost ≥5% body weight, 69.4% of boys and 73.2% of girls, respectively. Compared with boys, girls achieved greater reduction on BMI z-score at all intervals ( p < 0.004 for all comparisons). Higher BMI percentile at baseline and increased frequency of use of the mobile application were directly associated with more significant weight loss. Conclusions: An entirely remote digital weight loss program is effective in facilitating weight loss in adolescents with overweight or obesity in the short term and mid term.

Objective: Cardiovascular disease remains a leading cause of mortality worldwide. Ceramide scores have been associated with adverse outcomes in patients with established coronary artery disease. The prognostic value of ceramide score has not been assessed in the general population. We tested the hypothesis that ceramide scores are associated with major adverse cardiac events (MACE) in a community-based cohort with average coronary artery disease burden at enrollment. Approach and results: In a prospective community-based cohort, we performed passive follow-up using a record linkage system to ascertain the composite outcome of MACE, defined as acute myocardial infarction, coronary revascularization (bypass grafting or percutaneous intervention), stroke, or death. Ceramides were analyzed as log-transformed continuous variables, ratios or scores, and quartiles with adjustment for confounders. We analyzed 1131 subjects, 52% females, mean age±(SD) 64±9 years. After a median follow-up of 13.3 years (Q1, 12.7; Q3, 14.4), 486 patients experienced a MACE: myocardial infarction (80), coronary artery bypass surgery (34), percutaneous coronary intervention (62), stroke (94), and all-cause death (362). Ceramide ratios were significantly associated with MACE independently of LDL-c (low-density lipoprotein cholesterol) and conventional coronary artery disease risk factors. Those in the highest quartile of ceramide score had nearly 1.5-fold risk of MACE, hazard ratio, 1.47 (95% CI, 1.12–1.92). There was a dose-response association across quartiles of ceramide ratios and MACE. Conclusions: Elevated ceramide score is a robust predictor of cardiovascular disease and MACE in the community. The risk conferred by the ceramide score has a dose-response behavior and is independent of conventional risk factors.