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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.

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.

Introduction: Contemporary guidelines remain to uniformly classify patients with established atherosclerotic cardiovascular disease as high risk despite substantial heterogeneities in risk factors distributions. We examined the independent associations and relative predictabilities of genetic, sociodemographic, lifestyle, and clinical risk factors on coronary artery disease (CAD) recurrence. Methods: From population-based UK Biobank cohort, we identified 7,024 participants aged 40-69 years with established CAD at enrollment. Based on multivariable Cox regression model, we evaluated the hazard ratio (HR) and discrimination index of age at enrollment, age at first CAD diagnosis, sex, smoking, physical activity, diet, sleep, socioeconomic deprivation, body mass index, blood pressure, lipids, glucose, lipoprotein(a), C-reactive protein, estimated glomerular filtration rate, statin prescription, and CAD polygenic risk score (PRS) on first CAD recurrence since enrollment. Results: Over a median [IQR] follow-up of 11.6 [4.0] years, 2,003 (28.5%) recurrent CAD events occurred. Of studied risk factors, the HR [95% CI] for CAD recurrence was the most pronounced with current smoking (1.35 [1.13-1.61]) and per SD increase in age at first CAD (0.74 [0.67-0.82]). Moreover, age at enrollment, Townsend Deprivation Index, sleep quality, cholesterols, glucose, renal function, C-reactive protein, and CAD PRS also significantly associated with recurrence. CAD PRS (C index: 0.58 [0.57-0.59]) largely predicted CAD recurrence, followed by high-density lipoprotein (HDL) cholesterol (0.57 [0.57-0.58]) and age at first CAD (0.57 [0.56-0.57]). In addition to traditional risk factors, a comprehensive model improved the C index from 0.64 [0.63-0.65] to 0.68 [0.67 to 0.69]. Conclusion: Genetic risk, age at first CAD event, and HDL cholesterol contributed the most to CAD recurrence. These features may identify high risk subgroups for treatment intensification or trials for new therapeutic strategies among those with CAD.

SummaryParticipation and inclusion in biomedical research remain disproportionate across sociodemographics limiting discoveries in genomic studies and contributing to systemic disparities in healthcare. To alleviate such inequities, the National Institute of Health initiated theAll of UsResearch Program (AoU), a prospective, population-based cohort to identify the root causes and consequences of health outcomes across diverse demographics. We quantify representation of key racial groups in the accruing AoU cohort of US adults aged ≥18 years and compare to their actual representation in the US. Of the 358,705 AoU participants to date, Hispanic or Latino participants were underrepresented by 0.85-fold, non-Hispanic Asian by 0.58-fold, non-Hispanic White by 0.98-fold, and Other by 0.43-fold. Meanwhile, individuals identifying as non-Hispanic Black or African American were overrepresented by 1.88-fold. While AoU representation better mirrors the US demographics compared to other cohorts, recruitment trends for the ongoing AoU underscore the need to further tailor participation initiatives for diverse populations.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.

Background: While a self-reported family history of cardiovascular disease (CVD) is predictive of incident CVD, the genetic and clinical factors underlying this association remain poorly understood. Methods: We performed a cross-sectional analysis of United Kingdom (UK) Biobank participants without preexisting coronary artery disease (CAD), with genetic, biochemical, and clinical characterization at baseline. Self-reported family history of heart disease (FHHD) was the primary outcome, while clinical (diabetes, hypertension, smoking, apolipoprotein B/A1 ratio, body mass index (BMI), C-reactive protein [CRP], lipoprotein(a) [Lp(a)]) and genetic risk factors for CVD (CAD polygenic risk score [PRS], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex and statin prescription. All features were considered together using multiple logistic regression, and population attributable risks were subsequently estimated. Results: Among 124 203 individuals, 53 318 (42.9%) participants reported FHHD. In a multivariable model, FHHD was significantly enriched for morbid obesity (OR 1.14, CI 1.08-1.21), hypertension (OR 1.21, CI 1.17-1.24), apolipoprotein B/A1 ratio 5th vs 1st quintile (OR 1.24, CI 1.19-1.29), lipoprotein(a) >125 nmol/L (OR 1.20, CI 1.17-1.24), CAD PRS 10th vs 1st decile (OR 1.68, CI 1.59-1.77) and HeFH (OR 1.32, CI 1.09-1.60). PAR analyses indicated that 24.9% (CI 21.9-28.0%) of FHHD is explained by genetic factors alone, 17.2% (CI 15.0 -19.3%) is explained by clinical factors alone, and 34.3% (CI 31.0-37.7%) is explained by both genetic and clinical factors. Conclusions: Both genetic and clinical risk factors, including several modifiable variables, significantly contribute to FHHD. Comprehensive assessment of contributing familial features may facilitate individual FHHD interpretation and risk reduction. Figure 1: Genetic and clinical factors contributing to FHHD

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.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a newly recognized aging-related condition due to clonal expansion of mutated hematopoietic stem cells (HSC) that results in increased risk for coronary artery disease (CAD). The extent to which CHIP is associated with stroke risk is not well understood. Methods: CHIP genotypes were obtained from 6 cohort studies [the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), the Women’s Health Initiative (WHI)] and two electronic health record-based biobanks [UK Biobank (UKBB) and Massachusetts General Brigham Biobank (MGBB)]. Incident stroke was ascertained by physician adjudicators in the cohort studies, and by ICD codes in the biobanks. Cox proportional hazards models were fitted with adjustment for age, sex, diabetes mellitus, smoking status (never, past, current) and race. Fixed-effects meta-analysis was used to estimate pooled effect sizes. Results: A total of 74,306 participants from 8 studies were included. In the fixed-effects meta-analysis, CHIP mutations were associated with an increased risk of total stroke (HR= 1.17, 95% CI 1.05-1.28) ( Figure 1 ). In analysis of stroke subgroups, the risk was greater for hemorrhagic (HR= 1.37, 95% CI 1.15-1.59) than ischemic stroke (HR= 1.13, 95% CI 1.00-1.26). Individuals with particularly expanded CHIP mutations (i.e. variant allele fraction >10%), showed similar effect estimates of association for total stroke, ischemic stroke, or hemorrhagic stroke were observed (HR any stroke = 1.21, 95% CI 1.09-1.34; HR ischemic stroke = 1.15, 95% CI 1.01-1.30; HR hemorrhagic stroke = 1.43, 95% CI 1.20-1.67) . Conclusions: CHIP is associated with incident ischemic and hemorrhagic stroke.

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.

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 Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Introduction: The COVID-19 pandemic has catalyzed widespread usage of telemedicine due to the unprecedented need for remote patient care. Scaling virtual visits from occasional occurrences to standard of care is not without hurdles. Here we describe operationalizing virtual cardiovascular clinic in one large academic teaching hospital. Methods: To avoid implicit bias in perceived comfort with technology, virtual video (VV) visits were offered to all patients whose in-person office visit was cancelled. Those who declined were subsequently offered phone appointments. Patients who agreed to VV were called prior to their appointment time by staff to guide them through setup. Providers were given written, illustrated instructions on setup augmented with short how-to video demonstrations. They each completed a practice session with a staff member acting as a “test patient” to demonstrate basic functions within Zoom including use of chat, virtual waiting room, screen share and inviting additional participants (such as family, staff or interpreters). Providers were trained on workflows to allow seamless transitions across multidisciplinary team members involved in patient care. Results: Prior to the pandemic, there were mean (SD) 12.6 (2.8) VV appointments per month. Telemedicine adoption rose rapidly across provider types after travel restrictions were enacted, with the majority of visits initially occurring telephonically (Figure 1A and 1B). VV visits were also noted to increase swiftly with 3,164 VV visits in April 2020 and 5,452 in May 2020. After training sessions, providers felt comfortable using integrated virtual care tools (Figure 1C). Conclusions: Virtual clinic can be rapidly implemented and scaled within a healthcare system. Training materials and support for both patients and providers are key to increasing adoption of new technology. Hybrid systems will be needed to harmonize synchronous in-person and asynchronous virtual care in the longer term.

Cardiovascular Disease (CVD) causes about 17 million deaths annually, and is the leading cause of death in the U.S. and worldwide, accounting for over 30% of all deaths globally. Diagnosis and delineation of effective non-pharmacological and pharmacological interventions are key to the prevention of cardiovascular diseases (‘primary prevention’) and of the risk factors themselves (‘primordial prevention’). To that end, we focus on four entities in the following chapter: Lifestyle Recommendations, Hypertension, Diabetes, and Lipoprotein Disorders [1].

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 P P P P 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.

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 (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.

The purpose of this paper is to describe recent advances in liquid toner technology and their applications, both present and potential. As a preface, it is important to keep in mind that liquid toners represent only a segment of an overall imaging system that also incorporates hardware, media and quite possibly, pertinent software. Recent advances in toner design has occurred as a direct outcome of simultaneous advances in the design of the overall imaging system.