Polygenic Scores and Preclinical Cardiovascular Disease in Individuals With HIV: Insights From the REPRIEVE Trial.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non-HIV populations generalize to people with HIV is not well understood. METHODS AND RESULTS: PRSs for CAD (GPSMult) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low-to-moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPSMult was associated with plaque presence with odds ratio (OR) per SD in GPSMult of 1.42 (95% CI, 1.20-1.68; P=3.8×10-5), stenosis >50% (OR, 2.39 [95% CI, 1.48-3.85]; P=3.4×10-4), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23-1.72]; P=9.6×10-6). Effects were consistent in subgroups of age, sex, 10-year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPSMult to established risk factors increased the C-statistic for predicting plaque presence from 0.718 to 0.734 (P=0.02). Furthermore, a PRS for low-density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01-1.44; P=0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01-1.45; P=0.04) per SD. CONCLUSIONS: Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low-to-moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low-density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low-density lipoprotein cholesterol in HIV-associated CAD. REGISTRATION: URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial.

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

Massive underrepresentation of Arabs in genomic studies of common disease.

Arabs represent 5% of the world population and have a high prevalence of common disease, yet remain greatly underrepresented in genome-wide association studies, where only 1 in 600 individuals are Arab. We highlight the persistent and unaddressed underrepresentation of Arabs in genomic databases and discuss its impact on public health genomics and missed opportunities for biological discovery.

A Lifestyle Modification Program for Secondary Prevention of Atrial Fibrillation: A Pilot Study.

Background: Lifestyle modification programs, such as cardiac rehabilitation, may reduce atrial fibrillation (AF) burden and improve quality of life (QOL), but remain unproven. The objective of this pilot study was to assess feasibility, acceptability, and preliminary effectiveness of an exercise and nutrition-based cardiac rehabilitation-like program for AF patients. Methods: We enrolled overweight adults aged ≥ 30 years with symptomatic AF in a 12-week cardiac lifestyle group program, including 6 virtual and 6 in-person visits. All visits included discussion and education about nutrition, exercise, and behavior modification. In-person visits included supervised aerobic exercise and strength training. Outcomes at baseline and 12 weeks included feasibility of participation, acceptability, change in weight and BMI, and changes in survey-based AF burden, symptoms, and QOL. Results: From 84 invitees, 11 (13.1%) were enrolled (mean age 64; baseline BMI 38 kg/m2); 9 (82%) completed the program. Patients attended an average of 9.7 (81%) visits (Range: 6-11). Mean weight loss was 9.1 pounds (Range: 0-16); mean BMI decrease was 1.4 kg/m2 (Range: 0-2.6). Patients found the program helpful overall: all reported making diet and exercise changes during the program. Compared to baseline, patients reported decreased AF burden (12.9 vs. 11.7, p = 0.03) and symptom (10.1 vs. 5.6, p = 0.003) scores at the conclusion of the program. Patients also reported increased QOL overall (68.9 vs. 86.4, p = 0.001). Conclusions: Participation in a cardiac rehab-like program was feasible and acceptable for overweight patients with symptomatic AF. Results suggest preliminary effectiveness of the program for reducing AF burden and symptoms and increasing QOL.

Representation of Race and Ethnicity in the Contemporary US Health Cohort All of Us Research Program.

Importance: To address systemic disparities in biomedical research, the All of Us (AoU) Research Program was created to identify the root causes and consequences of health outcomes in the US. However, the extent of AoU's racial and ethnic diversity is unknown. Objective: To quantify representation of key racial and ethnic groups in the accruing AoU nationwide health cohort and compare with their actual representation in the US. Design, Setting, and Participants: This cohort study compared the AoU program from May 2017 to June 2022 for individuals 18 years and older with the Decennial Survey 2020 (DEC) collected by the US Census Bureau. Exposures: Representation of non-Hispanic Asian, non-Hispanic Black or African American, Hispanic or Latino, non-Hispanic White, and uncategorized or multiple races in AoU. Main Outcomes and Measures: The extent of underrepresentation or overrepresentation of each racial group in the AoU program at both nationwide and state-level relative to DEC. Results: Of the 358 705 US adults in the AoU to date, individuals identified with the following race and ethnicity categories: 12 710 non-Hispanic Asian (3.5%), 73 348 non-Hispanic Black or African American (20.5%), 58 488 Hispanic or Latino (16.3%), 205 457 non-Hispanic White (57.3%), and 8702 uncategorized or reporting multiple categories (2.4%). Of 355 413 participants with available sex at birth and age data, 218 981 (61.6%) were female and had a mean (SD) age of 53.1 (17.0) years, 136 037 (38.28%) were male and had a mean (SD) age of 56.7 (17.0) years, and 395 reported nonbinary sex (0.1%), with a mean (SD) age of 55.4 (15.8) years. Compared with the referent US, non-Hispanic Black or African American individuals were overrepresented in the AoU by 8.73% (AoU, 20.5% [73 348 of 358 705] vs DEC, 11.7% [30 266 080 of 258 343 281]) and by relative scale, 1.94-fold. Non-Hispanic White individuals accounted for the greatest participation in the AoU with generally consistent dominance across all regions yet numerically underrepresented by absolute difference of -3.54% (95% CI, -3.70 to -3.38). Uncategorized or multiracial group in the AoU (2.4% [8702 of 358 705]) was 0.43-fold likely to be represented relative to the DEC (4.6% [11 922 096 of 258 343 281]) with an absolute difference of -2.19% (95% CI, -2.24 to -2.14). Moreover, non-Hispanic Asian individuals were underrepresented by -2.54% (95% CI, -2.60 to -2.48) prominently in most states. Individuals identifying as Hispanic or Latino were nominally underrepresented by -0.46% (95% CI, -0.58 to -0.34) (AoU, 16.3% [58 488 of 358 705] vs DEC, 16.8% [43 322 792 of 258 343 281]). Conclusions and Relevance: Recruitment trends for the ongoing AoU show relatively improved representation of some major race groups with geographic trends. These findings underscore the need to further tailor and augment recruitment and participation initiatives for diverse populations.

Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686). CONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Genetic and clinical factors underlying a self-reported family history of heart disease.

AIMS: To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors. METHODS AND RESULTS: Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33) and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), lipoprotein(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10-1.16), and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined. CONCLUSIONS: A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.

With advances in genetics, it is tempting to assume that the 'family history' of a patient is an imperfect proxy for information we can already glean from genetics and laboratory tests. However, this study shows that much of the information contained in the self-reported family history of heart disease is not captured by currently available genetic and clinical biomarkers and highlights an important knowledge gap. Clinically used biomarkers explained only 21.9% of the likelihood of a patient reporting a family history of heart disease, while genetics explained 22.2%, and a combined model explained 36% of this likelihoodThe majority of the risk of reporting a family history went unexplained, implying that family history still has major relevance in clinical practice.

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Clonal Hematopoiesis Is Associated With Higher Risk of Stroke.

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

Clonal Hematopoiesis of Indeterminate Potential: an Expanding Genetic Cause of Cardiovascular Disease.

PURPOSE OF REVIEW: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease-which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP. RECENT FINDINGS: The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

Association of Diet Quality With Prevalence of Clonal Hematopoiesis and Adverse Cardiovascular Events.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP. Objective: To examine whether there is an association between diet quality and the prevalence of CHIP. Design, Setting, and Participants: This retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline. Exposures: Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA. Main Outcomes and Measures: The primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP. Results: Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%]; P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up. Conclusions and Relevance: This cohort study suggests that an unhealthy diet quality may be associated with a higher prevalence of CHIP and higher rates of adverse cardiovascular events and death independent of CHIP status.

Obesity Is Associated With Pulmonary Hypertension and Modifies Outcomes.

Background Experimental studies support a link between obesity and pulmonary hypertension (PH), yet clinical studies have been limited. This study sought to determine the association of obesity and pulmonary hemodynamic measures and mortality in PH. Methods and Results We examined patients undergoing right-sided heart catherization (2005-2016) in a hospital-based cohort. Multivariable regression models tested associations of body mass index and pulmonary vascular hemodynamics, with PH defined as mean pulmonary artery pressure >20 mm Hg, and further subclassified into precapillary, postcapillary, and mixed PH. Multivariable Cox models were used to examine the effect of PH and obesity on mortality. Among 8940 patients (mean age, 62 years; 40% women), 52% of nonobese and 69% of obese individuals had evidence of PH. Higher body mass index was independently associated with greater odds of overall PH (odds ratio, 1.34; 95% CI, 1.29-1.40; P<0.001 per 5-unit increase in body mass index) as well as each PH subtype (P<0.001 for all). Patients with PH had greater risk of mortality compared with individuals without PH regardless of subgroup (P<0.001 for all). We found that obesity was associated with 23% lower hazard of mortality among patients with PH (hazard ratio, 0.77; 95% CI, 0.69-0.85; P<0.001). The effect of obesity was greatest among those with precapillary PH (hazard ratio, 0.57; 95% CI, 0.46-0.70; P<0.001), where obesity modified the effect of PH on mortality (P for interaction=0.02). Conclusions Obesity is independently associated with PH. PH is associated with greater mortality; this is modified by obesity such that obese patients with precapillary PH have lower mortality compared with nonobese counterparts. Further studies are needed to elucidate mechanisms underlying obesity-related PH.

Prevalence and Impact of Having Multiple Barriers to Medication Adherence in Nonadherent Patients With Poorly Controlled Cardiometabolic Disease.

Adherence to medications remains poor despite numerous efforts to identify and intervene upon nonadherence. One potential explanation is the limited focus of many interventions on one barrier. Little is known about the prevalence and impact of having multiple barriers in contemporary practice. Our objective was to quantify adherence barriers for patients with poorly controlled cardiometabolic condition, identify patient characteristics associated with having multiple barriers, and determine its impact on adherence. We used a linked electronic health records and insurer claims dataset from a large health system from a recent pragmatic trial. Barriers to medication taking before the start of the intervention were elicited by clinical pharmacists using structured interviews. We used multivariable modified Poisson regression models to examine the association between patient factors and multiple barriers and multivariable linear regression to evaluate the relation between multiple barriers and claims-based adherence. Of the 1,069 patients (mean: 61 years of age) in this study, 25.1% had multiple barriers to adherence; the most common co-occurring barriers were forgetfulness and health beliefs (31%, n = 268). Patients with multiple barriers were more likely to be non-white (relative risk [RR] 1.57, 95% confidence interval [CI] 1.21 to 1.74), be single/unpartnered (RR 1.36, 95% CI 1.06 to 1.74), use tobacco (RR 1.54, 95% CI 1.13 to 2.11), and have poor glycemic control (RR 1.77, 95% CI 1.31 to 2.39) versus those with 0 or 1 barrier. Each additional barrier worsened average adherence by 3.1% (95% CI -4.6%, -1.5%). In conclusion, >25% of nonadherent patients present with multiple barriers to optimal use, leading to meaningful differences in adherence. These findings should inform quality improvement interventions aimed at nonadherence.

Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes.

Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.