Search

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Background Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training (RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS. Methods Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health‐related QOL were assessed pre‐post intervention. Results RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass. Conclusions RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS.

RATIONALE: Pneumonia is the leading cause of death in children worldwide. Identifying and appropriately managing severe pneumonia in a timely manner improves outcomes. Little is known about the readiness of healthcare facilities to manage severe pediatric pneumonia in low-resource settings. OBJECTIVES: As part of the Household Air Pollution Intervention Network (HAPIN) trial, we sought to identify healthcare facilities that were adequately resourced to manage severe pediatric pneumonia in Jalapa, Guatemala (J-GUA); Puno, Peru (P-PER); Kayonza, Rwanda (K-RWA); and Tamil Nadu, India (T-IND). We conducted a facility-based survey of available infrastructure, staff, equipment, and medical consumables. Facilities were georeferenced and a road network analysis was performed. MEASUREMENTS AND MAIN RESULTS: Of the 350 healthcare facilities surveyed, 13% had adequate resources to manage severe pneumonia, 37% had pulse oximeters, and 44% had supplemental oxygen. Mean (±SD) travel time to an adequately-resourced facility was 41±19 minutes in J-GUA, 99±64 minutes in P-PER, 40±19 minutes in K-RWA, and 31±19 minutes in T-IND. Expanding pulse oximetry coverage to all facilities reduced travel time by 44% in J-GUA, 29% in P-PER, 29% in K-RWA, and 11% in T-IND (all p

Ultrasound Core Laboratories (UCL) are used in multicenter trials to assess imaging biomarkers to define robust phenotypes, to reduce imaging variability and to allow blinded independent review with the purpose of optimizing endpoint measurement precision. The Household Air Pollution Intervention Network, a multicountry randomized controlled trial (Guatemala, Peru, India and Rwanda), evaluates the effects of reducing household air pollution on health outcomes. Field studies using portable ultrasound evaluate fetal, lung and vascular imaging endpoints. The objective of this report is to describe administrative methods and training of a centralized clinical research UCL. A comprehensive administrative protocol and training curriculum included standard operating procedures, didactics, practical scanning and written/practical assessments of general ultrasound principles and specific imaging protocols. After initial online training, 18 sonographers (three or four per country and five from the UCL) participated in a 2 wk on-site training program. Written and practical testing evaluated ultrasound topic knowledge and scanning skills, and surveys evaluated the overall course. The UCL developed comprehensive standard operating procedures for image acquisition with a portable ultrasound system, digital image upload to cloud-based storage, off-line analysis and quality control. Pre- and post-training tests showed significant improvements (fetal ultrasound: 71% ± 13% vs. 93% ± 7%, p < 0.0001; vascular lung ultrasound: 60% ± 8% vs. 84% ± 10%, p < 0.0001). Qualitative and quantitative feedback showed high satisfaction with training (mean, 4.9 ± 0.1; scale: 1 = worst, 5 = best). The UCL oversees all stages: training, standardization, performance monitoring, image quality control and consistency of measurements. Sonographers who failed to meet minimum allowable performance were identified for retraining. In conclusion, a UCL was established to ensure accurate and reproducible ultrasound measurements in clinical research. Standardized operating procedures and training are aimed at reducing variability and enhancing measurement precision from study sites, representing a model for use of portable digital ultrasound for multicenter field studies.

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naive, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to "benchmark" results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naive Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to "benchmark" results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.

Background Hypertension remains the major risk factor for cardiovascular diseases (CVDs) worldwide with a prevalence and mortality in low- and middle-income countries (LMICs) among the highest. The early detection of hypertension risk factors is a crucial pillar for CVD prevention. Design and method This cross-sectional study included 4284 subjects, mean age 46 ± 16SD, 56.4% females and mean BMI 26.6 ± 3.7 SD. Data were collected through a screening campaign in rural area of Kirehe District, Eastern of Rwanda, with the objective to characterize and examine the prevalence of elevated blood pressure (BP) and other CVD risk factors. An adapted tool from the World Health Organization STEPwise Approach was used for data collection. Elevated BP was defined as ≥ 140/90 mm/Hg and elevated blood glucose as blood glucose ≥ 100 mg/dL after a 6-h fast. Results Of the sampled population, 21.2% (n = 910) had an elevated BP at screening; BP was elevated among individuals not previously known to have HTN in 18.7% (n = 752). Among individuals with a prior diagnosis of HTN, 62.2% (n = 158 of 254) BP was uncontrolled. Age, weight, smoking, alcohol history and waist circumference were associated with BP in both univariate analyses and multivariate analysis. Conclusion High rates of elevated BP identified through a health screening campaign in this Rwandan district were surprising given the rural characteristics of the district and relatively low population age. These data highlight the need to implement an adequate strategy for the prevention, diagnosis, and control of HTN that includes rural areas of Rwanda as part of a multicomponent strategy for CVD prevention.

The percentage of biomedical, behavioral, and clinical under-represented minority (URM) junior faculty is lower than their respective populations in the United States; whereas racial and ethnic minorities (African Americans, Hispanic Americans/Latinos, American Indians, Alaska Natives, Native

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health [(1)][1]. These guidelines, based on systematic methods to evaluate and classify

Health information technology (HIT) has not been broadly adopted for use in outpatient healthcare settings to effectively address obesity in youth, especially among disadvantaged populations that face greater barriers to good health. A well-designed HIT tool can deliver behavior change recommendations and provide community resources to address this gap, and the Obesity-Related Behavioral Intervention Trials (ORBIT) model can guide its development and refinement. This article reports the application of the ORBIT model to (1) describe the characteristics and design of a novel HIT tool (the PREVENT tool) using behavioral theory, (2) illustrate the use of stakeholder-centered “designing for dissemination and sustainability” principles, and (3) discuss the practical implications and directions for future research. Two types of stakeholder engagement (customer discovery and user testing) were conducted with end users (outpatient healthcare teams). Customer discovery interviews (n = 20) informed PREVENT tool components and intervention targets by identifying (1) what healthcare teams (e.g., physicians, dietitians) identified as their most important “jobs to be done” in helping adolescents who are overweight/obese adopt healthy behaviors, (2) their most critical “pains” and “gains” related to overweight/obesity treatment, and (3) how they define success compared to competing alternatives. Interviews revealed the need for a tool to help healthcare teams efficiently deliver tailored, evidence-based behavior change recommendations, motivate patients, and follow-up with patients within the constraints of clinic schedules and workflows. The PREVENT tool was developed to meet these needs. It facilitates prevention discussions, delivers tailored, evidence-based recommendations for physical activity and food intake, includes an interactive map of community resources to support behavior change, and automates patient follow-up. Based on Self-Determination Theory, the PREVENT tool engages the patient to encourage competence and autonomy to motivate behavior change. The use of this intentional, user-centered design process should increase the likelihood of the intended outcomes (e.g., behavior change, weight stabilization/loss) and ultimately increase uptake, implementation success, and long-term results. After initial tool development, user-testing interviews (n = 13) were conducted using a think-aloud protocol that provided insight into users' (i.e., healthcare teams) cognitive processes, attitudes, and challenges when using the tool. Overall, the PREVENT tool was perceived to be useful, well-organized, and visually appealing.

ImportanceHypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary.ObjectiveTo study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool.DesignA cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training.SettingThree tertiary care hospitals in Rwanda.ParticipantsHealthcare professionals (n=223).Primary outcome(s) and measure(s)The COACH tool consists of 49 items with eight subscales: resources, community engagement, commitment to work, informal payment, leadership, work culture, monitoring services for action (5-point Likert Scale) and sources of knowledge (on a 0–1 scale). Four questions surveyed training on hypertension.ResultsResponders (n=223, 75% women; 56% aged 20–35 years) included nurses (n=142, 64%, midwives (n=42, 19%), primary care physicians (n=28, 13%) and physician specialists (n=11, 5%)). The subscales commitment to work, leadership, work culture and informal payment scored between 4.7 and 4.1 and the community engagement, monitoring services for action and organizational resources scored between 3.1 and 3.5. Sources of knowledge had a mean score of 0.6±0.3. While 73% reported having attended a didactic hypertension seminar in the past year, only 28% had received long-term training and 51% had ConclusionsThere is a need for increased and continuous training in Rwanda. Healthcare responders stated a commitment to work and reported supportive leadership, while acknowledging limited resources and no monitoring systems. The COACH tool provides contextual guidance to develop training strategies prior to the implementation of a sustainable hypertension care programme.

The spread of severe acute respiratory syndrome coronavirus-2 has suspended many non-COVID-19 related research activities. Where restarting research activities is permitted, investigators need to evaluate the risks and benefits of resuming data collection and adapt procedures to minimize risk.In the context of the multicountry Household Air Pollution Intervention (HAPIN) trial conducted in rural, low-resource settings, we developed a framework to assess the risk of each trial activity and to guide protective measures. Our goal is to maximize the integrity of reseach aims while minimizing infection risk based on the latest scientific understanding of the virus.We drew on a combination of expert consultations, risk assessment frameworks, institutional guidance and literature to develop our framework. We then systematically graded clinical, behavioral, laboratory and field environmental health research activities in four countries for both adult and child subjects using this framework. National and local government recommendations provided the minimum safety guidelines for our work.Our framework assesses risk based on staff proximity to the participant, exposure time between staff and participants, and potential viral aerosolization while performing the activity. For each activity, one of four risk levels, from minimal to unacceptable, is assigned and guidance on protective measures is provided. Those activities that can potentially aerosolize the virus are deemed the highest risk.By applying a systematic, procedure-specific approach to risk assessment for each trial activity, we were able to protect our participants and research team and to uphold our ability to deliver on the research commitments we have made to our staff, participants, local communities, and funders. This framework can be tailored to other research studies conducted in similar settings during the current pandemic, as well as potential future outbreaks with similar transmission dynamics. The trial is registered with clinicaltrials.gov NCT02944682 on October 26. 2016 .

IntroductionIncreasing use of cleaner fuels, such as liquefied petroleum gas (LPG), and abandonment of solid fuels is key to reducing household air pollution and realising potential health improvements in low-income countries. However, achieving exclusive LPG use in households unaccustomed to this type of fuel, used in combination with a new stove technology, requires substantial behaviour change. We conducted theory-grounded formative research to identify contextual factors influencing cooking fuel choice to guide the development of behavioural strategies for the Household Air Pollution Intervention Network (HAPIN) trial. The HAPIN trial will assess the impact of exclusive LPG use on air pollution exposure and health of pregnant women, older adult women, and infants under 1 year of age in Guatemala, India, Peru, and Rwanda.MethodsUsing the Capability, Opportunity, Motivation–Behaviour (COM–B) framework and Behaviour Change Wheel (BCW) to guide formative research, we conducted in-depth interviews, focus group discussions, observations, key informant interviews and pilot studies to identify key influencers of cooking behaviours in the four countries. We used these findings to develop behavioural strategies likely to achieve exclusive LPG use in the HAPIN trial.ResultsWe identified nine potential influencers of exclusive LPG use, including perceived disadvantages of solid fuels, family preferences, cookware, traditional foods, non-food-related cooking, heating needs, LPG awareness, safety and cost and availability of fuel. Mapping formative findings onto the theoretical frameworks, behavioural strategies for achieving exclusive LPG use in each research site included free fuel deliveries, locally acceptable stoves and equipment, hands-on training and printed materials and videos emphasising relevant messages. In the HAPIN trial, we will monitor and reinforce exclusive LPG use through temperature data loggers, LPG fuel delivery tracking, in-home observations and behavioural reinforcement visits.ConclusionOur formative research and behavioural strategies can inform the development, implementation, monitoring and evaluation of theory-informed strategies to promote exclusive LPG use in future stove programmes and research studies.Trial registration numberNCT02944682, Pre-results.

The Household Air Pollution Intervention Network trial is a multi-country study on the effects of a liquefied petroleum gas (LPG) stove and fuel distribution intervention on women's and children's health. There is limited data on exposure reductions achieved by switching from solid to clean cooking fuels in rural settings across multiple countries. As formative research in 2017, we recruited pregnant women and characterized the impact of the intervention on personal exposures and kitchen levels of fine particulate matter (PM2.5) in Guatemala, India, and Rwanda. Forty pregnant women were enrolled in each site. We measured cooking area concentrations of and personal exposures to PM2.5 for 24 or 48 h using gravimetric-based PM2.5 samplers at baseline and two follow-ups over two months after delivery of an LPG cookstove and free fuel supply. Mixed models were used to estimate PM2.5 reductions. Median kitchen PM2.5 concentrations were 296 μg/m3 at baseline (interquartile range, IQR: 158–507), 24 μg/m3 at first follow-up (IQR: 18–37), and 23 μg/m3 at second follow-up (IQR: 14–37). Median personal exposures to PM2.5 were 134 μg/m3 at baseline (IQR: 71–224), 35 μg/m3 at first follow-up (IQR: 23–51), and 32 μg/m3 at second follow-up (IQR: 23–47). Overall, the LPG intervention was associated with a 92% (95% confidence interval (CI): 90–94%) reduction in kitchen PM2.5 concentrations and a 74% (95% CI: 70–79%) reduction in personal PM2.5 exposures. Results were similar for each site. Conclusions The intervention was associated with substantial reductions in kitchen and personal PM2.5 overall and in all sites. Results suggest LPG interventions in these rural settings may lower exposures to the WHO annual interim target-1 of 35 μg/m3. The range of exposure contrasts falls on steep sections of estimated exposure-response curves for birthweight, blood pressure, and acute lower respiratory infections, implying potentially important health benefits when transitioning from solid fuels to LPG., Highlights • There was high uptake of an LPG stove and fuel intervention in 3 rural settings. • The LPG intervention was associated with a 92% reduction in kitchen PM2.5 levels. • The intervention was associated with a 74% reduction in personal exposure to PM2.5 • Maternal PM2.5 exposure was reduced to the WHO annual interim target-1 of 35 μg/m3. • Results from 3 countries indicate switching to clean fuel could improve health., Capsule summary: LPG stove and fuel intervention can reduce kitchen area and personal PM2.5 exposure levels in a pilot study of clean cookstove intervention trial. This strongly suggests switching to clean cook can improve health.

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to “benchmark” results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly liberal. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p-values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to “benchmark” results. In conclusion, we generally recommend the Safe Approach to handle heterogeneity in the LRS based genome-wide interaction meta-analyses.

Background Hypertension (HTN) affects nearly 1 billion people globally and is a major cause of morbidity and mortality. In low- and middle-income countries (LMICs), HTN represents an unmet health care gap that can be addressed by strengthening national health care systems. The National Heart, Lung, and Blood Institute recently funded the T4 Translation Research Capacity Building Initiative in Low Income Countries (TREIN) program to build capacity in dissemination and implementation (D&I) research in HTN in LMICs. The Special Programme for Research and Training in Tropical Diseases (TDR) at the World Health Organization (WHO) recently developed a massive open online course (MOOC) to train in D&I. Herein, we report on the use of the TDR WHO MOOC in D&I for the TREIN program in Rwanda, assessing feasibility of the MOOC and D&I competencies after MOOC training. Methods Participants in one-group MOOC training completed pre- and post-training questionnaires to assess dissemination and implementation (D&I) competency outcomes and feasibility. D&I competencies were measured by use of a scale developed for a US-based training program, with the change in competency scores assessed by paired t test. Feasibility was measured by completion of homework and final project assignment and analyzed using descriptive statistics. Results Of the 92 trainees enrolled, 35 (38%) completed all MOOC components. D&I competency scores showed strong evidence of improvements from pre- to post-test. The full-scale average score improved by an average of 1.09 points, representing an effect size of 1.25 (CI 0.48-2.00); all four subscales also showed strong evidence of improvements. Trainees reported challenges to MOOC course completion that included technological issues (i.e., limited internet access) and competing demands (i.e., work, family). Conclusions In the context of LMIC training, the MOOC course was feasible and course completion showed improvement in D&I competency scores. While the program was designed with a focus on training for tropical diseases, there is potential for scalability to a wider audience of health care researchers, workers, administrators, and policymakers in LMIC interested in D&I research in non-communicable diseases.

Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene-multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome-wide gene-environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome-wide significant (P-value < 5 × 10(−8)) and 11 suggestive (P-value < 1 × 10(−6)) loci. Gene-environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1, and DAPK2. Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene-environment interaction analysis can identify additional loci missed by single lifestyle approaches.

Readmission or death after heart failure (HF) hospitalization is a consequential and closely scrutinized outcome, but risk factors may vary by population. We characterized the risk factors for post-discharge readmission/death in subjects treated for acute heart failure (AHF).A post hoc analysis was performed on data from 744 subjects enrolled in 3 AHF trials conducted within the Heart Failure Network (HFN): Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF), Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF). All-cause readmission/death occurred in 26% and 38% of subjects within 30 and 60 days of discharge, respectively. Non-HF cardiovascular causes of readmission were more common in the ≤30-day timeframe than in the 31-60-day timeframe (23% vs 10%, P = .016). In a Cox proportional hazards model adjusting a priori for left ventricular ejection fraction50% and trial, the risk factors for all-cause readmission/death included: elevated baseline blood urea nitrogen, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) non-use, lower baseline sodium, non-white race, elevated baseline bicarbonate, lower systolic blood pressure at discharge or day 7, depression, increased length of stay, and male sex.In an AHF population with prominent congestion and prevalent renal dysfunction, early readmissions were more likely to be due to non-HF cardiovascular causes compared with later readmissions. The association between use of ACEI/ARB and lower all-cause readmission/death in Cox proportional hazards model suggests a role for these drugs to improve post-discharge outcomes in AHF.

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The “omics”—genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics— of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.

Background Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting. Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular function are unknown. We sought to characterize myocardial glucose, fatty acid and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and left ventricular function. METHODS/RESULTS: Young adults with BTHS (n=14) and unaffected controls (n=11, Control, total n=25) underwent bolus injections of (15)O-water and 1-(11)C-glucose, palmitate and leucine and concurrent positron emission tomography (PET) imaging. Left ventricular function and cardiac high-energy phosphate metabolism were examined via echocardiograpy and (31)P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14 vs. 10 ± 8 %, P =0.03) and glucose utilization (828.0 ± 470.0 vs. 393.2 ± 361.0 μmol•g(−1)•min(−1), P =0.02) were significantly higher in BTHS vs. Control. Myocardial fatty acid extraction fraction (31 ± 7 vs. 41 ± 6 %, P

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and in low- and middle-income countries, and hypertension (HTN) is a major risk factor for CVD. Although effective evidence-based interventions for control of HTN in high-income countries exist, implementation of these in low- and middle-income countries has been challenging due to limited capacity and infrastructure for latephase translational research. In Rwanda, the 2015 STEPS NCD (STEPwise Approach to Surveillance of Noncommunicable Diseases) risk survey reported an overall prevalence of HTN of 15% (95% confidence interval [CI]: 13.8 to 16.3) for those ages 15 to 64 years; prevalence increased with increasing age to 39% (95% CI: 35.7 to 43.1) for those ages 55 to 64 years; CVD was the third most common cause of mortality (7%). Suboptimal infrastructure and capacity in Rwanda hinders research and community knowledge for HTN control.Objectives: To address the issue of suboptimal capacity to implement evidence-based interventions in HTN, this project was designed with the following objectives: 1) to develop a regional needs assessment of infrastructure for dissemination and implementation (D & I) strategies for HTN-CVD control; 2) to develop HTNCVD research capacity through creation of countrywide resources such as core research facilities and training in the fields of HTN-CVD, D & I, and biostatistics; and 3) to engage and train multiple stakeholders in D & I and HTN-CVD evidence-based interventions.Methods: A weeklong training program in HTN-CVD, biostatistics, and D & I was conducted in Rwanda in August 2018, and pre- and post-D & I training competency questionnaires were administered.Results: Questionnaire results show a statistically significant increase in D & I knowledge and skills as a result of training (full scale pre- to post-test scores: 2.12 ± 0.78 vs. 3.94 ± 0.42; p < 0.0001).Conclusions: Using principles of community engagement and train-the-trainer methods, we will continue to adapt guidelines and treatments for HTN-CVD developed in high-income countries to the context of Rwanda with the goal of establishing a sustainable platform to address the burden of disease from HTN-CVD.HighlightsImplementation research in LMIC has been challenging due to limited capacity.A training program was developed to support implementation research strategies in Rwanda.Implementation research training resulted in significant increases in knowledge and skills.

Introduction: ICR has been used for the treatment of patients recovering from a myocardial infarction, cardiac surgery, percutaneous intervention, and/or stable angina. Pritikin ICR is a comprehensive program whereby patients follow a structured diet and exercise program. The first outpatient Pritikin ICR program was implemented at Barnes-Jewish Hospital/Washington University School of Medicine. While patients domiciled at the Pritikin Longevity Center show marked improvements in several cardiovascular disease (CVD) risk factors, the effects of the outpatient Pritikin ICR program are unknown. Hypothesis: Patients who complete 24 sessions of the outpatient Pritikin ICR program will have improvements in several clinically important CVD risk factors, including body mass index (BMI, primary endpoint), adiposity, lipid profiles, and cardiorespiratory fitness. Methods: This observational study of the outpatient Pritikin ICR program was conducted as part of routine clinical care. Patients referred for ICR since 1/1/2017 were invited to participate in assessments at baseline and after completing 24 sessions. ICR was comprised of monitored exercise sessions plus Pritikin education sessions focusing on dietary changes (low-fat, low-sodium, high-fiber foods) and stress management through a series of videos, cooking classes, and workshops. Body composition was assessed using bioelectrical impedance. Fitness was estimated with the 6-minute walk test. Hand grip strength was assessed by dynamometry. Results: 140 ICR patients (28% women; age 68 ± 9 y, mean ± SD) completed baseline and visit 24 assessments over an average of 9.9 weeks. Significant improvements ( P 2 ), weight (mean ± SD, -1.6 ± 3.0 kg), whole-body fat % (-1.2 ± 2.5), trunk fat % (-1.7 ± 3.3), 6-min walk distance (+37.6 ± 53.6 m), and hand grip strength (+1.22 ± 3.42 kg). Improvements also were observed for waist circumference, total cholesterol, and LDL cholesterol ( P Conclusion: An outpatient Pritikin ICR program results in significant cardiovascular benefits by reducing adiposity, improving lipid profiles, and enhancing exercise capacity. These favorable results should lead to fewer cardiovascular events.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U-13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% V ˙ O 2 peak ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.

BACKGROUND Left ventricular mass offers prognostic information for assessing cardiovascular disease risk. M-mode and two-dimensional (2D) echocardiographically-derived left ventricular mass values have shown high accuracy and reproducibility; however, no studies to date have compared left ventricular mass genetic association findings on the basis of both the methods. The aim of this study was to compare associations of single-nucleotide polymorphisms (SNPs) from genome-wide association study analyses of left ventricular mass using both methods in the same cohort. METHODS AND RESULTS Left ventricular mass was determined using 2D and M-mode echocardiography in 711 patients (390 women); SNP genotype data were obtained using the Genome-wide Human SNP Array 6.0. Genome-wide association study analyses were performed to obtain panels of SNPs associated with left ventricular mass and left ventricular mass index. The unindexed left ventricular mass showed excellent agreement [M-mode: 170 ± 47 vs. 2D: 178 ± 56 g; intraclass correlation coefficient 0.929 (95% confidence interval 0.932, 0.909)]. The presence of left ventricular hypertrophy based on M-mode and 2D-derived left ventricular mass index values showed moderate agreement (kappa = 0.49). Eleven SNPs showed suggestive association with at least two of the four left ventricular mass traits, with one SNP in CDH13 common to all four derived traits. CONCLUSION M-mode and 2D echocardiography left ventricular mass measurements in the same cohort identified suggestive genetic associations, both shared and unshared, suggesting common left ventricular mass biology underlying the two measures of left ventricular mass. The combined use of M-mode and 2D echo is a novel approach that may increase the yield of genetic association with left ventricular mass.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during acute heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the NHLBI Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72h fluid output per total equivalent loop diuretic dose; subjects were stratified to high and low DE groups by the median value. We then utilized data from the DOSE-AHF to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72h, the high DE group had median fluid output of 9071 ml (25(th) %, 75(th)%: 7240, 11775) with median furosemide dose of 320 mg (220, 480) compared to 8030 ml (6300, 9915) and 840 mg (600, 1215) for the low DE group. Weight change at 72h was −4.3 kg (25(th) %, 75(th)%: −6.5, −1.9) vs. −2.9 kg (−4.9, −1.3) in the high and low DE groups (p < 0.001). Cystatin C was independently associated with DE [OR 0.36 per 1mg/L increase; 95% CI: 0.24, 0.56 (P < 0.001)]. Independent of baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with eGFR below the median, those randomized to a high-dose strategy had improved symptoms compared to those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response independently identifies a high-risk population with increased mortality.

The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability has not been attributed to specific variants. Interactions between genes and BP-associated factors may explain some “missing heritability.” Cigarette smoking increases BP after short-term exposure and decreases BP with longer exposure. Gene-smoking interactions have discovered novel BP loci, but the contribution of smoking status and intensity to gene discovery is unknown. Methods We analyzed gene-smoking intensity interactions for association with systolic BP (SBP) in three subgroups from the Framingham Heart Study: current smokers only (N = 1,057), current and former smokers (“ever smokers,” N = 3,374), and all subjects (N = 6,710). We used three smoking intensity variables defined at cutoffs of 10, 15, and 20 cigarettes per day (CPD). We evaluated the 1 degree-of-freedom (df) interaction and 2df joint test using generalized estimating equations. Results Analysis of current smokers using a CPD cutoff of 10 produced two loci associated with SBP. The rs9399633 minor allele was associated with increased SBP (5 mmHg) in heavy smokers (CPD > 10) but decreased SBP (7 mmHg) in light smokers (CPD ≤ 10). The rs11717948 minor allele was associated with decreased SBP (8 mmHg) in light smokers but decreased SBP (2 mmHg) in heavy smokers. Across all nine analyses, 19 additional loci reached P < 1 × 10−6. Discussion Analysis of current smokers may have the highest power to detect gene-smoking interactions, despite the reduced sample size. Associations of loci near SASH1 and KLHL6/KLHL24 with SBP may be modulated by tobacco smoking.

Cardioskeletal myopathy is thought to contribute to exercise intolerance, and reduced quality of life (QOL) in Barth syndrome (BTHS). The objectives of this study were to examine: (1) skeletal muscle strength/performance in adolescents and young adults with BTHS and (2) the safety, feasibility, and initial efficacy of 12 weeks of progressive resistance exercise training (RET) on muscle strength, mass, and performance, bone mineral density, exercise tolerance, cardiac function, and QOL in individuals with BTHS.Individuals with BTHS (n = 9, 23 ± 6 years), and age-, sex-, and activity level-matched unaffected Controls (n = 7, 26 ± 5 years) underwent baseline testing to assess muscle performance, exercise capacity, cardiac structure and function, body composition, and health-related QOL. Subsequently, n = 3 participants with BTHS performed 12 weeks of supervised RET (60 min per session, 3 sessions/week). All testing was repeated post-RET.BTHS had lower strength and lean muscle mass compared to Controls (all p 0.05). BTHS also had diminished lower extremity, upper extremity, thoracic spine, lumbar spine, and pelvic bone mineral density (all p 0.05) and reduced exercise capacity (p 0.001) compared to Controls. RET was well-tolerated and attended, was not associated with any adverse events, and significantly increased muscle strength (p 0.05).Individuals with BTHS demonstrate reduced muscle strength and mass, bone mineral density, and exercise capacity. RET appears safe and well-tolerated in BTHS and promotes increased muscle strength. Larger studies are needed to confirm these improvements and to fully determine the effects of RET in individuals with BTHS.

Cardiovascular diseases are among the most significant health problems in the United States. Genome-wide association studies (GWASs) have identified hundreds of common genetic variants associated with many common, complex disease traits (http://www.genome.gov). However, most identified variants confer relatively small increments in risk and explain only a small fraction of the heritability.1 For example, the 29 common variants identified through 3 recent GWASs consortia2–4 have shown to collectively explain 8 million deaths annually by 2030, according to World Health Organization estimates. Smoking is a major risk factor for cancer, heart disease, stroke, and lung diseases. In the acute setting, cigarette smoking produces a rise in BP. Some epidemiologic studies have associated chronic smoking with lower BP, even after adjustment for other cardiovascular risk traits.12 Therefore, genome-wide studies incorporating interactions between genetic variants and smoking may enhance BP gene discovery efforts and provide novel insights into the biological mechanisms and pathways underlying BP regulation.7 We examined the contribution of interactions between genetic variants and 3moking measures on BP traits: (i) cigarettes per day, measuring a smoking rate (per day); (ii) pack-years of smoking, measuring a volume of smoking exposure during a person’s entire lifetime; and (iii) smoking status, a binary (yes/no) indicator of a current smoking status. We performed a genome-wide analysis of single nucleotide polymorphism (SNP)–smoking interactions on systolic BP (SBP) and diastolic BP (DBP) using 6,889 participants from the Framingham Heart Study (FHS). Our aim was to identify novel BP loci; discovery of such loci may facilitate smoking intervention strategies and achievement of BP goals in genetically susceptible individuals, thereby reducing the public health burden of hypertension.

Background The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants. Objectives The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms. Methods The RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months. Results Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p Conclusions HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867 )

Metabolic syndrome (MetS) is a widely recognized concept generally defined as a clustering of risk factors including hypertension, insulin resistance, and obesity. This clustering of risk factors then leads to an increased risk for diabetes and cardiovascular disease (CVD; Ford, Li, & Zhao, 2010). It is estimated that in the United States, MetS affects more than 34% of the population and contributes to a threefold increase in cardiovascular-related deaths (Ford et al., 2010). Still, diagnostic criteria of MetS differ among experts and organizations (American Association of Clinical Endocrinologists [AACE]; National Cholesterol Education Program Adult Treatment Panel III [ATPIII]; World Health Organization [WHO]), and this difference leads to a lack of consensus in the clinical utility of the diagnosis (Simmons et al., 2010). In 2009, an effort was made by many expert organizations to standardize the diagnosis of this complex disorder by using a harmonizing definition (Table 1; Alberti et al., 2009). Diagnosis of MetS using the harmonizing definition is contingent on meeting a threshold value in at least three of the following five factors: waist circumference, triglycerides, high-density lipoprotein-cholesterol, blood pressure, and glucose (Alberti et al., 2009). Table 1 Harmonizing Definition of Metabolic Syndrome (MetS) Even with a harmonizing definition, the global prevalence of MetS can be difficult to estimate because it can affect patients by gender groupings differently. For example, in India, the prevalence of MetS for men is approximately 8%, whereas for women it is estimated at 46% (Cameron, Shaw, & Zimmet, 2004). In Iran, 30% of men and 55% of women met the diagnostic criteria for MetS (Azimi-Nezhad et al., 2012). Some of these differences are clearly due to gender, but racial and ethnic differences may also play a role. When the U.S. population is divided by both gender and ethnicity, adult African American women have a 38.8% prevalence of MetS, and African American men have 25.3% prevalence, whereas their Caucasian counterparts have a prevalence of 31.5% and 37.2%, respectively (Roger et al., 2011). Risk factors associated with the development of MetS are similar to those associated with hypertension, diabetes, renal disease, and obesity, with variables such as lifestyle, gender, ethnicity, and genomic precursors playing important roles in the development of MetS. Because MetS is the combination of the effects of more than one risk factor, pinpointing a causative genotype has been difficult. Genomic and molecular methodologies including linkage analysis, genome-wide association (GWA) studies, epigenetics, and proteomics have all been used to attempt to unravel this genetic puzzle (Table 2). The results of these studies have shown that MetS is a polygenetic (under the control of more than one gene) condition with varying influence from multiple environmental factors. Therefore the inheritance of a single specific risk allele may be less important than the additive effects of many alleles, some of which may be “high risk,” some which may be “moderate risk,” and others of which may be “low risk.” However, the current understanding of the disease shows that certain risk alleles that have relevance for the individual components of the disease may also have an overlapping value in the overall risk for the development of MetS. This review will examine the possible contributions of cardiovascular, obesity, and diabetes genomic risk factors to the development of MetS as reported in the literature. Table 2 Definitions of Common Methodologies Used in the Study of Metabolic Syndrome

Background/Aims: Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of CKD-MBD. Methods: We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months. Results: There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23, Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2- to 3-fold at baseline, but were not affected by LaCO3. Conclusion: Twelve months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of CKD-MBD.

Background Multiple studies have reported echocardiographically determined normal reference values for left ventricular (LV) mass (LVM) derived using fundamental imaging (FI). Modern ultrasound systems now use harmonic imaging (HI) because of the improved LV endomyocardial definition. However, the 2005 American Society of Echocardiography (ASE) recommendations noted that the applicability of the reference values to HI-derived measurements has not been established. Methods LVM and LV end-diastolic volume, diameter, and wall thickness were determined using HI in healthy subjects ( n = 251), including normal-weight (NW) (body mass index 2 , n = 149, 68% women) and otherwise healthy, overweight (OW) (body mass index ≥ 25 and 2 , n = 102, 41% women) groups. Measurements were compared with ASE-endorsed reference values. The agreement between FI and HI was determined in a prospective cohort of 51 subjects. Results Two-dimensional (2D) derived LV volumes were similar between NW and OW subjects, although M-mode (MM)–derived LV diameters were slightly greater in OW subjects. 2D and MM-derived LVM was greater in OW compared with NW subjects, including after adjustment by height or height 2.7 ; however, indexing to body surface area eliminated these differences. The partition values for abnormal 2D and MM-derived LVM were generally greater in NW and OW subjects of both sexes compared with the ASE-endorsed values (except MM-derived LVM in NW men). However, there were no significant differences in LVM determined by HI compared with FI in a prospectively studied cohort. Conclusions Reference values for LVM derived from NW and OW cohorts are generally higher than the ASE-endorsed referenced values. The difference between NW and ASE-endorsed values is unlikely to result from the use of HI rather than FI, because there is excellent agreement between these two imaging modalities. This study emphasizes the need to update normal reference values to reflect modern imaging methods.

ObjectivesThe objective of this prospective, single-site, 2-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function.BackgroundObesity is associated with adverse cardiac and vascular structural and functional alterations.MethodsSixty obese subjects (age 46 ± 10 years, body mass index 37 ± 3 kg/m2) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention.ResultsForty-seven subjects (78%) completed the entire 2-year follow-up. Average weight loss was 7.3 ± 4.0%, 9.2 ± 5.6%, 7.8 ± 6.6%, and 3.8 ± 7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex-adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p < 0.0001), left ventricular (LV) mass (p = 0.001), and carotid intima-media thickness (p < 0.0001); there was also significant improvement in LV diastolic (p ≤ 0.0001) and systolic (p = 0.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at 2 years still showed a net benefit compared with baseline.ConclusionsDiet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects. (The Safety and Effectiveness of Low and High Carbohydrate Diets; NCT00079547)

Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis.

Prolonged interatrial conduction time (IACT) can be associated with abnormal left atrial (LA) function but has not been characterized in patients with left ventricular (LV) systolic dysfunction (LVSD) and QRS intervals130 ms.Two-dimensional Doppler echocardiography and Doppler tissue imaging (DTI) were performed in 41 patients with LVSD (mean LV ejection fraction, 26 +/- 5%) and 41 similarly aged normal controls. Two-dimensional measurements included LV volume and ejection fraction and LA volume for the determination of LA emptying fraction and LA ejection fraction. IACT was defined as the time from the onset of the P wave to the onset of the DTI-derived late diastolic (A') velocity at the lateral mitral annulus. Two-dimensional Doppler measurements were reassessed in patients with LVSD 4 +/- 2 months after cardiac resynchronization therapy (CRT).IACT was longer in patients with compared to controls (105 +/- 25 vs 74 +/- 12 ms, P.001); none of the controls had an IACT100 ms. In patients with LVSD, IACT was correlated modestly with measurements of LA volume (r = .41-.48, all P values.009) but not with measurements of LA function. Patients with LVSD with IACTs100 ms (n = 20) prior to CRT had larger LA volumes and lower indices of LA function after CRT compared to those with IACTsor = 100 ms. Significant reductions in LV end-systolic volumes and increases in LV ejection fractions occurred in both groups after CRT.DTI-derived IACT can be prolonged in patients with severe LVSD and wide QRS intervals. An IACT100 ms can affect LA remodeling and function at early follow-up after CRT but does not influence the response in LV end-systolic volume or ejection fraction.

Background Osteopontin (OPN)-transgenic mice exhibit increased carotid artery intima-media thickness (CIMT), smooth muscle cell proliferation, and atheroma formation. Methods An association of the human T-66G promoter variant with CIMT was examined in Caucasian adults grouped according to metabolic syndrome criteria: present (+MetS; n=70) or absent (−MetS; n=70). Results The G-allele frequency was 22%. For the entire cohort, the G group (TG and GG) was associated with significantly lower age-adjusted and gender-adjusted CIMT compared with the TT group ( P = .008); similar analysis by metabolic syndrome group found a significant difference only in the −MetS group ( P = .018). Stepwise multivariate regression showed that after age and waist circumference, the T-66G variant was the next most predictive of CIMT ( P = .007). These data suggest that in a normoglycemic environment, human vascular OPN gene expression contributes to arterial structure, an effect diminished in dysmetabolic states. Conclusion Humans with the OPN -66 TT genotype, particularly those without metabolic syndrome, exhibit thicker CIMT.

Pediatric obesity is common, particularly in children treated with antipsychotic medications. Antipsychotic exposure can increase cardiometabolic risk by increasing adiposity, and possibly via other adiposity-independent pathways.The objectives were to characterize relationships of adiposity with intrahepatic triglyceride (IHTG) content and carotid intima media thickness (CIMT) in children with and without antipsychotic drug treatment, and to explore whether vitamin D alters any effects in these relationships.This was a cross-sectional case-control study.The setting was an academic medical center.Participants were 44 children (ages, 6-19 y): 25 cases treated with antipsychotic and other psychotropic drug therapies and 19 untreated controls, frequency-matched on age, gender, and body mass index.Main outcome measures were dual-energy x-ray absorptiometry percentage body fat (DEXA %fat), IHTG measured by magnetic resonance spectroscopy, and CIMT measured by ultrasonography. Fasting blood glucose, insulin, lipids, C-reactive protein, and liver enzymes were also evaluated.There were no significant differences between cases and controls on measures of IHTG, CIMT, or DEXA %fat. In combined crude and adjusted analyses, DEXA %fat predicted IHTG (R(2) = 0.30) but not CIMT. Low levels of vitamin D were associated with larger effects of DEXA %fat on IHTG.In treated and untreated children alike, adiposity is a significant predictor of liver fat content. This relationship was altered by low vitamin D level. These results suggest a modifiable pathway to hepatic steatosis. Further research is needed to test the hypothesis that children with high adiposity and low vitamin D have particularly increased risks for the development of fatty liver.

The prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) is increasing.1 In patients with HFpEF, the burden of symptoms, functional decline, and mortality is high,2 and health-related quality of life is poor.3 Physicians caring for these patients currently have limited therapeutic options beyond diuresis and management of comorbid conditions. Hence there remains an immediate and critical need for therapies to alleviate symptoms and meaningfully improve quality of life for patients with HFpEF. Long-acting nitrates are used as the cornerstone of antianginal therapy and have demonstrated beneficial effects for treatment of patients with HF and reduced EF (HFrEF). In randomized studies, sustained increases in treadmill exercise time4,5 and peak oxygen consumption6 have been observed at 3 months after initiation of nitrate therapy in patients with HFrEF, including those already treated with angiotensin converting enzyme inhibitors.5 Attenuation of pathological left ventricular (LV) remodeling and improved LV systolic function have also been reported.5 Although no study has directly examined the effects of nitrate monotherapy on survival in HF, symptom relief is a key management goal in patients with HFpEF, whose primary chronic symptom is often exercise limitation.7 Practice guidelines for the management of chronic HF from the American College of Cardiology/American Heart Association8 and Heart Failure Society of America9 advocate a potential role for nitrates in diminishing symptoms in HFpEF but acknowledge the lack of supportive data and the risk of excessive nitrate–induced hypotension in elderly patients with HFpEF. Therefore, it is desirable that a randomized, controlled evaluation of the efficacy and tolerance of nitrate therapy in HFpEF is performed to support its therapeutic applications. To address this lack of data and current clinical equipoise for nitrate therapy in HFpEF, the Nitrate’s Effect on Activity Tolerance in Heart Failure …

To investigate the correlations of plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) levels with echocardiographic measurements of left ventricular (LV) systolic and/or diastolic function.Plasma levels of NT-proBNP are increased in heart failure. The extent to which NT-proBNP levels increase in LV diastolic dysfunction has not been well characterized.Plasma NT-proBNP levels were measured in 191 consecutive, clinically stable, ambulatory patients. Echocardiography was used to determine LV systolic (LV ejection fraction [LVEF]) and diastolic function by mitral E wave to Doppler tissue early diastolic lateral annulus velocity ratio (E/Em). Patients with a history, physical findings, and/or echocardiographic evidence of cardiovascular disease (n = 148) were grouped as: (1) normal LV systolic function (LVEFor = 55%, n = 81); and (2) LV systolic dysfunction (LVEF55%, n = 67). They were compared to a group of healthy control subjects (n = 43). Multivariate regression analyses were used to determine significant correlations with plasma NT-proBNP levels.NT-proBNP levels correlated negatively with LVEF (P.001) and positively with E/Em (P = .001). Multivariate regression analysis demonstrated a significant correlation of NT-proBNP levels with LVEF (P.001) and E/Em (P = .03).In this clinically stable, ambulatory cohort of patients with cardiovascular disease and healthy control subjects, plasma NT-proBNP levels were significantly higher in those with LV systolic dysfunction and/or elevated filling pressures, independent of the effects of LV mass, renal function, and age. These results suggest that NT-proBNP levels may be a useful adjunct in the characterization of patients presenting with history and/or symptoms compatible with LV systolic and/or diastolic dysfunction.

Background: Cardiac resynchronization therapy (CRT) improves functional outcomes in patients with severe systolic heart failure. Whether the effects of CRT on left ventricular (LV) diastolic function and clinical outcomes are influenced by the cause as either ischemic or nonischemic cardiomyopathy (CM) has not been well established. Methods: A total of 57 patients (age 60 11 years; 25% women; LV ejection fraction 25 5%) were studied before and 4 2 months after CRT by echocardiography. Heart failure cause was ischemic CM in 19 and nonischemic CM in 38. Measurements of LV systolic and diastolic function were determined by 2-dimensional and Doppler echocardiography with Doppler tissue imaging of regional myocardial velocities. Clinical outcome events were assessed at long-term follow-up and included hospitalization for heart failure exacerbation, heart transplantation, or cardiac-related death. Results: There were significant increases in LV ejection fraction, reductions in end-systolic volumes, and improved LV systolic dyssynchrony in both groups. However, significant improvements in LV diastolic function were observed only in the patients with nonischemic CM. Clinical events occurred in 53% of the ischemic group versus 26% of the nonischemic group (P < .05) after 20 11 months of CRT. Univariate and multivariate analysis revealed that Doppler-estimated LV filling pressures were predictors of clinical outcome events. Conclusions: After CRT patients with ischemic CM exhibit lack of improvement in LV diastolic function despite favorable effects on LV systolic performance. The Doppler-derived LV filling indices may be an important predictor of long-term clinical outcomes after CRT. (J Am Soc Echocardiogr 2006;19:307-313.)

Background Invasive studies have shown that cardiac resynchronization therapy (CRT) acutely improves left ventricular (LV) systolic performance and lowers filling pressures in a majority of patients with medically-refractory severe heart failure. Measurements included LV volume, ejection fraction, PWD early (E-wave) and atrial (A-wave) velocities, diastolic filling time (DFT), and DTI early diastolic mitral annular velocity (Em) at the lateral and septal annulus; PWD mitral E-wave/Em and E/FP were calculated to estimate LV filling pressures. Results Immediately after CRT, LV volumes decreased and LVEF increased significantly. PWD mitral E-wave velocity decreased and E-wave duration and DFT increased significantly; mitral E/FP ratio also decreased significantly, consistent with a decrease in LV filling pressure. Patients with a pre-CRT mitral E/A ratio >1 (n = 20), demonstrated improvements in LV diastolic filling and lower filling pressures whereas those with an E/A ratio ≤1 (n = 21) did not show significant changes in diastolic indices. Conclusions The acute effects of CRT include echocardiographic evidence of reduced LV volumes and increased LVEF with improved diastolic filling and lower filling pressures; LV relaxation is not significantly altered. The benefits in diastolic function are dependent on the PWD-determined LV filling characteristics prior to CRT.

Left ventricular (LV) hypertrophy is very common, particularly among hypertensives. The presence of LV hypertrophy profoundly affects morbidity and mortality from cardiovascular diseases and stroke, and is now recognized as the most important predictor of chronic heart failure. Hypertension, obesity, and diabetes are important determinants of LV hypertrophy, but they fail to identify many individuals with the condition, suggesting that other factors, likely genetic in origin, play a role. Although much research has been undertaken to understand the causes of hypertrophy and the medical treatments that can lead to its regression, much remains unknown about its genetic basis. LV hypertrophy is considered a complex genetic disease, likely representing an interaction of several genes with the environment. The heritability of LV mass, measured as a quantitative trait, falls between 0.3 and 0.7 in different populations, suggesting it has a familial component. Genes encoding proteins involved in LV structure, as well as genes encoding cell signal transduction, hormones, growth factors, calcium homeostasis, substrate metabolism, and blood pressure are likely candidates for the development of common forms of LV hypertrophy. An overview of the pathophysiology of LV hypertrophy and dysfunction is provided, in addition to evidence of the genetic basis for LV hypertrophy in humans and animal models.

Previous work shows that patients with heart failure patients who have peak oxygen consumption (VO2 peak)14 ml/kg/min do not derive a survival benefit from cardiac transplantation. However, this was shown before beta-blocker therapy for patients with systolic heart failure became common, and beta-blockers improve survival in patients with heart failure without changing VO(2) peak. Our purpose was to re-evaluate the utility of VO(2) peak14 ml/kg/min as an indicator of the need for cardiac transplantation in patients with heart failure who are taking beta-blockers.Actuarial, hemodynamic, and exercise ventilatory data were collected from 540 patients with heart failure, 256 of whom were taking beta-blockers. We tracked death and cardiac transplantation. We stratified the percentage of patients event-free 1 and 3 years after VO(2) peak study by their VO(2) peak and beta-blocker status, and compared 1- and 3-year post-transplant survival (United Network of Organ Sharing [UNOS] data). We also compared total mortality for the patients with heart failure as stratified by beta-blocker stats and VO(2) peak (excluding the 42 who underwent transplantation) with UNOS post-transplant survival.Patients with heart failure who were receiving beta-blockers and whose VO(2) peak wasor =12 ml/kg/min had greater 1- and 3-year event-free survival rates (95% confidence intervals, 92.6%-96.6% and 85.8%-96.0%) than did post-transplant patients (83.9%-86.3% and 75.4%-76.6%). However, in patients with heart failure not taking beta-blockers, VO(2) peak14 ml/kg/min was associated with worse 3-year survival (38.9 - 62.1%) than that for post-transplant patients. Excluding the 42 patients with heart failure in our study who underwent transplantation and then evaluating survival of the remaining patients with heart failure (not event-free survival) did not substantially change these results.Patients with heart failure who are receiving beta-blockers do not derive a survival advantage at 1 and 3 years after cardiac transplantation if VO(2) peak isor =12 ml/kg/min. Patients not taking beta-blockers whose VO(2) peak is14 ml/kg/min have superior survival with cardiac transplantation.