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Background The role of sex hormone-binding globulin (SHBG) levels in clinical risk stratification and intervention for coronary heart disease (CHD) remains uncertain. We aimed to examine whether circulating levels of SHBG are predictive of CHD risk in men and women. Methods We investigated the association between SHBG and the risk of incident CHD in 128 322 men and 135 103 women free of CHD at baseline in the prospective United Kingdom Biobank (UKB) cohort. The unconfounded associations were estimated using Mendelian randomization (MR) analysis. We further conducted a meta-analysis to integrate currently available prospective evidence. CHD events included nonfatal and fatal myocardial infarction and coronary revascularization. Results In the UKB, during a median of 11.7 follow-up years, 10 405 men and 4512 women developed CHD. Serum levels of SHBG were monotonically associated with a decreased risk of CHD in both men (adjusted hazard ratio [HR] per log nmol/L increase in SHBG: 0.88 [0.83–0.94]) and women (HR: 0.89 [0.83–0.96]). MR-based analyses suggested causality and a dose-response relationship of SHBG with CHD risk. A cumulative meta-analysis including 216 417 men and 138 282 women from 11 studies showed that higher levels of SHBG were prospectively associated with decreased CHD risk in men comparing the highest with the lowest quartile: pooled relative risk (RR) 0.81 (0.74–0.89) and women (pooled RR: 0.86 [0.78–0.94]). Conclusions Higher circulating SHBG levels were directly and independently predictive of lower CHD risk in both men and women. The utility of SHBG for CHD risk stratification and prediction warrants further study.

Cardiac rehabilitation (CR) is a guideline-recommended, multidisciplinary program of exercise training, risk factor management, and psychosocial counseling for people with cardiovascular disease (CVD) that is beneficial but underused and with substantial disparities in referral, access, and participation. The emergence of new virtual and remote delivery models has the potential to improve access to and participation in CR and ultimately improve outcomes for people with CVD. Although data suggest that new delivery models for CR have safety and efficacy similar to traditional in-person CR, questions remain regarding which participants are most likely to benefit from these models, how and where such programs should be delivered, and their effect on outcomes in diverse populations. In this review, we describe important gaps in evidence, identify relevant research questions, and propose strategies for addressing them. We highlight 4 research priorities: (1) including diverse populations in all CR research; (2) leveraging implementation methodologies to enhance equitable delivery of CR; (3) clarifying which populations are most likely to benefit from virtual and remote CR; and (4) comparing traditional in-person CR with virtual and remote CR in diverse populations using multicenter studies of important clinical, psychosocial, and cost-effectiveness outcomes that are relevant to patients, caregivers, providers, health systems, and payors. By framing these important questions, we hope to advance toward a goal of delivering high-quality CR to as many people as possible to improve outcomes in those with CVD.

Healthy dietary patterns are rich in micronutrients, but their influence on cardiovascular disease (CVD) risks has not been systematically quantified.The goal of this study was to provide a comprehensive and most up-to-date evidence-based map that systematically quantifies the impact of micronutrients on CVD outcomes.This study comprised a systematic review and meta-analysis of randomized controlled intervention trials of micronutrients on CVD risk factors and clinical events.A total of 884 randomized controlled intervention trials evaluating 27 types of micronutrients among 883,627 participants (4,895,544 person-years) were identified. Supplementation with n-3 fatty acid, n-6 fatty acid, l-arginine, l-citrulline, folic acid, vitamin D, magnesium, zinc, α-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin showed moderate- to high-quality evidence for reducing CVD risk factors. Specifically, n-3 fatty acid supplementation decreased CVD mortality (relative risk [RR]: 0.93; 95% CI: 0.88-0.97), myocardial infarction (RR: 0.85; 95% CI: 0.78-0.92), and coronary heart disease events (RR: 0.86; 95% CI: 0.80-0.93). Folic acid supplementation decreased stroke risk (RR: 0.84; 95% CI: 0.72-0.97), and coenzyme Q10 supplementation decreased all-cause mortality events (RR: 0.68; 95% CI: 0.49-0.94). Vitamin C, vitamin D, vitamin E, and selenium showed no effect on CVD or type 2 diabetes risk. β-carotene supplementation increased all-cause mortality (RR: 1.10; 95% CI: 1.05-1.15), CVD mortality events (RR: 1.12; 95% CI: 1.06-1.18), and stroke risk (RR: 1.09; 95% CI: 1.01-1.17).Supplementation of some but not all micronutrients may benefit cardiometabolic health. This study highlights the importance of micronutrient diversity and the balance of benefits and risks to promote and maintain cardiovascular health in diverse populations. (Antioxidant Supplementation in the Prevention and Treatment of Cardiovascular Diseases; CRD42022315165).

Patients experiencing housing insecurity have numerous barriers affecting their utilization of medical care.Determine if housing insecurity is associated with palliative care (PC) encounters and hospice services in patients with heart failure who receive care in United States Veterans Affairs (VA) medical centers.This retrospective study included inpatients in VA hospitals with a primary diagnosis of congestive heart failure from 2010 to 2020. Housing stability was collected from coding and separated into three cohorts: at risk for homelessness, experiencing homelessness, and stably housed. The primary outcome was a PC encounter during admission and the stably housed cohort was used as the analytic reference. Inverse-probability-weighting (IPTW) was calculated to adjust the likelihood of receiving PC during the index admission.Seventy thousand eight hundred fourty nine veterans were identified. Veterans were identified as at risk for homelessness (n=4039, 5.7%), experiencing homelessness (n=1967, 2.8%) and stably housed (n=64,843, 91.5%). PC was delivered to veterans at risk for homelessness (n=484, 12.0%), veterans experiencing homelessness, (n=161, 8.2%) and patients with stable housing (n=6249, 9.6%). Relative to the stably housed and adjusted for IPTW, those at risk for homelessness received PC services similarly (adjusted OR=1.06, 95% CI 0.94,1.19) and those experiencing homelessness were at lower odds of receiving PC services (adjusted OR=0.62, 95% CI 0.52,0.75).Housing stability may be a factor in Veterans receiving PC during hospitalization for heart failure. While the logistical challenges of delivering PC and hospice to people experiencing homelessness are daunting, advocating for these services shows commitment to reducing suffering in life-limiting Illness.

Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).Cross-sectional study.MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.GRS were significantly associated with POAG (Plt; 5 × 10sup-5/sup) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Background Approximately 400,000 people who smoke cigarettes survive Acute Coronary Syndrome (ACS; unstable angina, ST and non-ST elevation myocardial infarction) each year in the US. Continued smoking following ACS is an independent predictor of mortality. Depressed mood post-ACS is also predictive of mortality, and smokers with depressed mood are less likely to abstain from smoking following an ACS. A single, integrated treatment targeting depressed mood and smoking could be effective in reducing post-ACS mortality. Method/design The overall aim of the current study is to conduct a fully powered efficacy trial enrolling 324 smokers with ACS and randomizing them to 12 weeks of an integrated smoking cessation and mood management treatment [Behavioral Activation Treatment for Cardiac Smokers (BAT-CS)] or control (smoking cessation and general health education). Both groups will be offered 8 weeks of the nicotine patch if medically cleared. Counseling in both arms will be provided by tobacco treatment specialists. Follow-up assessments will be conducted at end-of-treatment (12-weeks) and 6, 9, and 12 months after hospital discharge. We will track major adverse cardiac events and all-cause mortality for 36 months post-discharge. Primary outcomes are depressed mood and biochemically validated 7-day point prevalence abstinence from smoking over 12 months. Discussion Results of this study will inform smoking cessation treatments post-ACS and provide unique data on the impact of depressed mood on success of post-ACS health behavior change attempts. Trial registration ClinicalTrials.gov, NCT03413423. Registered 29 January 2018. https://beta.clinicaltrials.gov/study/NCT03413423.

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular pathophysiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program (MVP) and meta-analyzed with the previous largest FECD GWAS, finding twelve significant loci (eight novel). We further confirmed the TCF4 locus in admixed African and Hispanic/Latino ancestries, and found an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and co-localization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

Stress management interventions (SMIs) can alleviate the psychosocial stress often experienced by women with heart failure. The purpose of this meta-analysis was to summarize women's participation rates, and predictors of participation, in SMIs for the management of psychosocial distress in women with chronic HF. Studies were retrieved from bibliographic databases, reference sections of relevant papers, and research registries. Included studies (a) evaluated a SMI approach for the management of chronic HF, (b) sampled chronic HF patients, and (c) used a randomized controlled trial (RCT) design. Independent coders extracted the relevant data. Thirty-five RCTs met inclusion criteria (N = 3,649; mean age = 63.5 ± 7.0 years). All studies sampled both men and women; the mean proportion of women who participated in the trials was 38.8% (95% confidence interval [CI] = 34.5-43.4; I 2 = 82.4, 95% CI = 81.0-83.6). Women's participation rates were higher in studies sampling more HF patients with hypertension (B = 1.01, SE = 0.45, P = .046) but fewer HF patients prescribed beta blockers (B = -1.10, SE = 0.33, P = .006), F (2,12) = 6.27, P = 0.014, adjusted R 2 = 61%. SMIs may offer women a complementary or integrative approach to standard treatment to help manage the psychological distress associated with HF. Future research should explore the potential benefits of offering stress management approaches to women as part of comprehensive HF care.

Background Home Based Cardiac Rehabilitation (HBCR) has been considered a reasonable alternative to Center-based Cardiac Rehabilitation (CBCR) in patients with established cardiovascular disease, especially in the midst of COVID-19 pandemic. However, the long-term cardiovascular outcomes of patients referred to HBCR remains unknown. Objectives To compare outcomes of patients who were referred and attended HBCR vs patients referred but did not attend HBCR (Non-HBCR). Methods We performed a retrospective study of 269 patients referred to HBCR at Providence Veterans Affairs Medical Center (PVAMC). From November 2017 to March 2020, 427 patients were eligible and referred for Cardiac Rehabilitation (CR) at PVAMC. Of total patients, 158 patients were referred to CBCR and 269 patients to HBCR based on patient and/or clinician preference. The analysis of outcomes was focused on HBCR patients. We compared outcomes of patients who were referred and attended HBCR vs patients referred but did not attend HBCR (Non-HBCR) from 3 to 12 months of the referral date. HBCR consisted of face-to-face entry exam with exercise prescription, weekly phone calls for education and exercise monitoring, with adjustments where applicable, for 12-weeks and an exit exam. Primary outcome was composite of all-cause mortality and hospitalizations. Secondary outcomes were all-cause hospitalization, all-cause mortality and cardiovascular hospitalizations, separately. We used cox proportional methods to calculate hazard ratios (HR) and 95% CI. We adjusted for imbalanced characteristics at baseline: smoking, left ventricular ejection fraction and CABG status. Results A total of 269 patients (mean age: 72, 98% Male) were referred to HBCR, however, only 157 (58%) patients attended HBCR. The primary outcome occurred in 30 patients (19.1%) in the HBCR group and 30 patients (30%) in the Non-HBCR group (adjusted HR=0.56, CI 0.33-0.95, P=.03). All-cause mortality occurred in 6.4% of patients in the HBCR group and 13% patients in the Non-HBCR group 3 to 12 months after HBCR referral (adjusted HR=0.43, CI 0.18-1.0, P= .05). There was no difference in cardiovascular hospitalizations (HBCR: 5.7% vs Non-HBCR: 10%, adjusted HR 0.57, CI 0.22-1.4, P= .23) or all cause hospitalizations at 3 to 12 months between the groups (HBCR: 12.7% vs Non-HBCR: 21%, adjusted HR 0.53, CI 0.28-1.01, P= .05). Conclusion Completion of HBCR among referred patients was associated with a lower risk of the combined all-cause mortality and all-cause hospitalizations up to 12 months. Based on the outcomes, HBCR is a reasonable option that can improve access to CR for patients who are not candidates of or cannot attend CBCR. Randomized-controlled studies are needed to confirm these findings.

Background A low right ventricular ejection fraction (RVEF) is a marker of poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Beta-blockers improve outcomes in HFrEF, but whether this effect is modified by RVEF is unknown. Methods and Results Of the 2798 patients in Beta-Blocker Evaluation of Survival Trial (BEST), 2008 had data on baseline RVEF (mean 35%, median 34%). Patients were categorized into an RVEF of less than 35% (n = 1012) and an RVEF of 35% or greater (n = 996). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within each RVEF subgroup and formally tested for interactions between bucindolol and RVEF. The effect of bucindolol on all-cause mortality in 2008 patients with baseline RVEF (HR 0.88, 95% CI 0.75–1.02) is consistent with that in 2798 patients in the main trial (HR 0.90, 95% CI 0.78–1.02). Bucindolol use was associated with a lower risk of all-cause mortality in patients with an RVEF of 35% or greater (HR 0.70, 95% CI 0.55–0.89), but not in those with an RVEF of less than 35% (HR 1.02, 95% CI 0.83–1.24, P for interaction = .022). Similar variations were observed for cardiovascular mortality (P for interaction = .009) and sudden cardiac death (P for interaction = .018), but not for pump failure death (P for interaction = .371) or HF hospitalization (P for interaction = .251). Conclusions The effect of bucindolol on mortality in patients with HFrEF was modified by the baseline RVEF. If these hypothesis-generating findings can be replicated using approved beta-blockers in contemporary patients with HFrEF, then RVEF may help to risk stratify patients with HFrEF for optimization of beta-blocker therapy.

The availability of electronic health record (EHR)-linked biobank data for research presents opportunities to better understand complex ocular diseases. Developing accurate computable phenotypes for ocular diseases for which gold standard diagnosis includes imaging remains inaccessible in most biobank-linked EHRs. The objective of this study was to develop and validate a computable phenotype to identify primary open-angle glaucoma (POAG) through accessing the Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) and Million Veteran Program (MVP) biobank. Accessing CPRS clinical ophthalmology data from VA Medical Center Eye Clinic (VAMCEC) patients, we developed and iteratively refined POAG case and control algorithms based on clinical, prescription, and structured diagnosis data (ICD-CM codes). Refinement was performed via detailed chart review, initially at a single VAMCEC (n = 200) and validated at two additional VAMCECs (n = 100 each). Positive and negative predictive values (PPV, NPV) were computed as the proportion of CPRS patients correctly classified with POAG or without POAG, respectively, by the algorithms, validated by ophthalmologists and optometrists with access to gold-standard clinical diagnosis data. The final algorithms performed better than previously reported approaches in assuring the accuracy and reproducibility of POAG classification (PPV >83% and NPV >97%) with consistent performance in Black or African American and in White Veterans. Applied to the MVP to identify cases and controls, genetic analysis of a known POAG-associated locus further validated the algorithms. We conclude that ours is a viable approach to use combined EHR-genetic data to study patients with complex diseases that require imaging confirmation.

A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

Background: The impact of the COVID-19 pandemic on participation in and availability of cardiac rehabilitation (CR) is unknown. Methods: Among eligible Medicare fee-for-service beneficiaries, we evaluated, by month, the number of CR sessions attended per 100 000 beneficiaries, individuals eligible to initiate CR, and centers offering in-person CR between January 2019 and December 2021. We compared these outcomes between 2 periods: December 1, 2019 through February 28, 2020 (period 1, before declaration of the pandemic-related national emergency) and October 1, 2021 through December 31, 2021 (period 2, the latest period for which data are currently available). Results: In period 1, Medicare beneficiaries participated in (mean±SD) 895±84 CR sessions per 100 000 beneficiaries each month. After the national emergency was declared, CR participation sharply declined to 56 CR sessions per 100 000 beneficiaries in April 2020. CR participation recovered gradually through December 2021 but remained lower than prepandemic levels (period 2: 698±29 CR sessions per month per 100 000 beneficiaries, P =0.02). Declines in CR participation were most marked among dual Medicare and Medicaid enrollees and patients residing in rural areas or socially vulnerable communities. There was no statistically significant change in CR eligibility between the 2 periods. Compared with 2618±5 CR centers in period 1, there were 2464±7 in period 2 ( P Conclusions: The COVID-19 pandemic was associated with a persistent decline in CR participation and the closure of CR centers, which disproportionately affected rural and low-income patients and the most socially vulnerable communities. Innovation in CR financing and delivery is urgently needed to equitably enhance CR participation among Medicare beneficiaries.

To encourage person-centered care, the Centers for Medicare and Medicaid require nursing homes to measure resident preferences using the Preferences Assessment Tool (PAT). No known research has examined the implications of respondent type (i.e., resident, proxy, staff) on preference importance; therefore, the purpose of this study was to compare the importance of preferences depending on which respondent completed the PAT. Participants included 16,111 Veterans discharged to community-based skilled nursing facilities after hospitalization for heart failure. A majority (95%) of residents completed the PAT compared to proxy (3%) and staff (2%). Proxy responders were both more and less likely to indicate individual preferences as important compared to residents. Staff members were consistently less likely to indicate all preferences as important compared to residents. Findings from this study emphasize the need for proxy and staff to find methods to better understand residents’ preferences when residents are not able to participate in assessments.

Survivors of coronavirus disease 2019 (COVID-19) may experience persistent symptoms, abnormal diagnostic test findings, incident disease in specific organ systems, or progression of existing disease. Post-acute COVID-19 syndrome (PACS) is defined by persistent, recurrent, or new symptoms, findings, or diagnoses beyond four weeks after the initial infection. PACS has been characterized as a multi-organ syndrome, often with cardiopulmonary symptoms that include fatigue, dyspnea, chest pain, and palpitations. Cardiovascular pathologies in PACS include new-onset arrhythmia, myocarditis, unmasked coronary artery disease, and diastolic dysfunction as well as abnormal findings on electrocardiogram, troponin testing, and cardiac magnetic resonance imaging. In this review, we discuss the cardiovascular symptoms, pathophysiology, clinical investigation, and management strategies for cardiopulmonary symptoms of PACS. We offer a treatment algorithm for primary care clinicians encountering patients with cardiopulmonary PACS and discuss ongoing research on this topic.

Both traditional cardiac rehabilitation (TCR) and intensive cardiac rehabilitation (ICR) have proven benefits for patients with cardiovascular disease. The aim of this study was to compare ICR versus TCR on cardiac rehabilitation (CR) outcomes in patients with cardiovascular disease.In a retrospective cohort study of 970 patients (n = 251, ICR; n = 719, TCR) who were referred for CR between January 2018 and December 2019, 693 (71.4%) patients completed it. The TCR sessions were 90 min (60-min exercise) three times/wk for 12 wk, while ICR sessions were 4 hr (60-min exercise) two times/wk for 9 wk. Primary endpoints were change in cardiorespiratory fitness (CRF) (by difference in exercise prescription metabolic equivalents [METs] between the last session and the average of the second and third sessions), anxiety (Generalized Anxiety Disorder-7) scores, percent depression (Patient Health Questionnaire-9 or Center for Epidemiologic Studies Depression Scale) scores, and health status (36-item Short Form Health Survey physical and mental composite scores). Linear regression adjusted for imbalanced baseline characteristics (age, race, and diagnosis of angina).Of the 693 patients who completed CR (ICR = 204/251 [81%] vs TCR = 489/719 [68%], P.01), mean age was 66 yr and 31% were female. Patients in TCR had a higher improvement in CRF (CR session METs: ICR + 1.5 ± 1.2 vs TCR + 1.9 ± 1.5, P.01) but no difference in health status scores. Conversely, patients in ICR had more reduction in anxiety scores (-2 ± 4 vs -1 ± 3, P.01) and percent reduction in depression scores (-8.3 ± 13.7% vs -5.0 ± 11.7%, P.01) than patients in TCR.Patients in TCR had higher improvement in CRF while patients in ICR had higher improvement in anxiety and depression scores.

Objective: Latent class modeling (LCM) offers a promising approach for examining correlates of heart rate (HR) patterns over multiple exercise sessions. This research examined biological and psychological variables associated with different patterns of HR response to physical activity (PA). Methods: In a three-arm RCT (exercise video games vs. standard exercise vs. non-exercise control), HR was recorded during PA sessions over a 12-week period. LCM identified three patterns of HR during PA across 189 participants in active arms: 1) high HR across sessions with low variability within sessions, 2) linear increase in HR across sessions with low variability within sessions, and 3) high variability in HR across all sessions. Associations with biological (resting heart rate, blood pressure, BMI, age, cholesterol, triglycerides, HbA1c) and psychological (depression, motivations for PA, PA-induced feelings) predictors of latent class membership were iteratively tested. Results: Psychological variables played as important a role in the final model as biological variables for predicting latent class membership. Few differences were found between LC1 and LC2, but LC3 differed from the other two groups in that participants were likelier to report that feel revitalized after PA (vs. LC1 and LC2), to be less motivated for PA (vs. LC1), reported greater depression (vs. LC1 and LC2), and were younger (vs. LC1). Conclusions: These findings demonstrate the potential of LCM to identify biological and psychological factors associated with chronotropic responses to PA, and advance understanding of the role of psychological factors in chronotropic PA outcomes.

BackgroundCausal interpretation of findings from existing epidemiological studies on long-term clinical outcomes of coronavirus disease 2019 (COVID-19) may be limited by the choice of comparator (control) group.ObjectiveWe compare two approaches to control group selection (based on requirement for negative SARS-CoV-2 test for eligibility) in long-term clinical outcomes after COVID-19 in patients with history of heart failure (HF).DesignRetrospective cohort study using data from February 1, 2020 to July 31, 2021. Setting: Veteran Health Administration (VHA).ParticipantsWe studied two cohorts of Veterans with COVID-19 and history of HF which selected comparison group using two different approaches. In Cohort I, Veterans with HF who tested for positive for SARS-CoV-2 were age, sex, and race matched to Veterans with no evidence of COVID-19 in 1:5 ratio. In Cohort II Veterans with HF who tested positive for SARS-CoV-2 were age, sex, and race matched with Veterans with HF who tested negative for SARS-CoV-2 within +/-15 days of the positive test date within the same VHA facility.ExposureCOVID-19 as determined by a positive SARS-CoV-2 test.Main Outcomes and Measures1-year all-cause mortality and hospital admissions beyond the first 30 days after COVID-19 diagnosis. Adjusted hazard ratios (HRs) accounting for comorbidity and 95% confidence intervals were calculated.ResultsCohort I comprised 13,722 Veterans with HF with COVID-19 (mean [SD] age 72.0 [10.2] years, 2.4% female, 71.1% White) and 60,956 matched controls not known to have COVID-19. Cohort II comprised 6,725 Veterans with HF with COVID-19 (mean [SD] age 72.5 [7.5] years, 0.1% female, 80.8% White) and 6,726 matched controls with negative SARS-CoV-2 test. The adjusted HRs for 1-year mortality and hospital admission beyond the first 30 days after diagnosis of COVID-19 were 1.40 (1.32-1.49) and 1.34 (1.28-1.41), respectively, in analysis of Cohort-I (where the comparator group was not required to test negative for SARS-CoV-2). However, in Cohort-II (using the second comparator group specifying negative SARS-CoV-2 test for eligibility), the associations were markedly attenuated; adjusted HRs 1.05 (0.95-1.17) and 1.07 (0.96-1.19), respectively.ConclusionsWe found significant attenuation of associations between COVID-19 and long-term risk of mortality and hospital admissions beyond the first 30 days among patient with existing HF, when comparing with a control group selected based on a negative SARS-CoV-2 test versus control group not known to have COVID-19. The findings have implications for the design of studies of long-term CVD (and non-CVD) outcome of COVID-19.

Background/aims Direct‐acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)‐infected patients. The real‐world treatment outcome in Taiwanese patients on a nationwide basis is elusive. Methods The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end‐of‐treatment). Results A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype‐1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment‐naïve noncirrhotic, treatment‐naïve cirrhotic, treatment‐experienced noncirrhotic and treatment‐experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment‐experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment‐naïve noncirrhotic patients (94.8%) and treatment‐experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence

Objective To examine whether diabetes shared medical appointments (SMAs) implemented as part of usual clinical practice in diverse health systems are more effective than usual care in improving and sustaining A1c improvements. Research Design and Methods A multi-site cluster randomized pragmatic trial examining implementation in clinical practice of diabetes SMAs in five Veterans Affairs (VA) health systems was conducted from 2016 to 2020 among 1537 adults with type 2 diabetes and elevated A1cs. Eligible patients were randomly assigned to either: (1) invitation to participate in a series of SMAs totaling 8–9 h; or (2) continuation of usual care. Relative change in A1c (primary outcome) and in systolic blood pressure, insulin starts, statin starts, and anti-hypertensive medication classes (secondary outcomes) were measured as part of usual clinical care at baseline, at 6 months and at 12 months (~7 months after conclusion of the final SMA in four of five sites). We examined outcomes in three samples of SMA participants: all those scheduled for a SMA, those attending at least one SMA, and those attending at least half of SMAs. Results Baseline mean A1c was 9.0%. Participants scheduled for an SMA achieved A1c reductions 0.35% points greater than the control group between baseline and 6-months follow up (p = .001). Those who attended at least one SMA achieved reductions 0.42 % points greater (p p < .001) than the control group. At 12-month follow-up, the three SMA analysis samples achieved reductions from baseline ranging from 0.16 % points (p = 0.12) to 0.29 % points (p = .06) greater than the control group. Conclusions Diabetes SMAs as implemented in real-life diverse clinical practices improve glycemic control more than usual care immediately after the SMAs, but relative gains are not maintained. Our findings suggest the need for further study of whether a longer term SMA model or other follow-up strategies would sustain relative clinical improvements associated with this intervention. Trial Registration ClinicalTrials.gov ID NCT02132676

ImportanceExtant data on the performance of cardiovascular disease (CVD) risk score models in people living with HIV have not been synthesized.ObjectiveTo synthesize available data on the performance of the various CVD risk scores in people living with HIV.Data SourcesPubMed and Embase were searched from inception through January 31, 2021.Study SelectionSelected studies (1) were chosen based on cohort design, (2) included adults with a diagnosis of HIV, (3) assessed CVD outcomes, and (4) had available data on a minimum of 1 CVD risk score.Data Extraction and SynthesisRelevant data related to study characteristics, CVD outcome, and risk prediction models were extracted in duplicate. Measures of calibration and discrimination are presented in tables and qualitatively summarized. Additionally, where possible, estimates of discrimination and calibration measures were combined and stratified by type of risk model.Main Outcomes and MeasuresMeasures of calibration and discrimination.ResultsNine unique observational studies involving 75 304 people (weighted average age, 42 years; 59 490 male individuals [79%]) living with HIV were included. In the studies reporting these data, 86% were receiving antiretroviral therapy and had a weighted average CD4+ count of 449 cells/μL. Included in the study were current smokers (50%), patients with diabetes (5%), and patients with hypertension (25%). Ten risk prediction scores (6 in the general population and 4 in the HIV-specific population) were analyzed. Most risk scores had a moderate performance in discrimination (C statistic: 0.7-0.8), without a significant difference in performance between the risk scores of the general and HIV-specific populations. One of the HIV-specific risk models (Data Collection on Adverse Effects of Anti-HIV Drugs Cohort 2016) and 2 of the general population risk models (Framingham Risk Score [FRS] and Pooled Cohort Equation [PCE] 10 year) had the highest performance in discrimination. In general, models tended to underpredict CVD risk, except for FRS and PCE 10-year scores, which were better calibrated. There was substantial heterogeneity across the studies, with only a few studies contributing data for each risk score.Conclusions and RelevanceResults of this systematic review and meta-analysis suggest that general population and HIV-specific CVD risk models had comparable, moderate discrimination ability in people living with HIV, with a general tendency to underpredict risk. These results reinforce the current recommendations provided by the American College of Cardiology/American Heart Association guidelines to consider HIV as a risk-enhancing factor when estimating CVD risk.

Prenatal exposure to famine has been linked to increased diabetes risk in adulthood. However, one fundamental issue to be addressed is that the reported famine-diabetes relation may be confounded by the age differences between the exposed and non-exposed groups. We aimed to determine the association between prenatal exposure to the Chinese famine of 1959-1962 and risk of diabetes by applying age well-controlled strategies.Among 20,535 individuals born in 1955-1966 who participated in the China Health and Nutrition Survey from 1997 to 2015, we constructed age-matched exposed vs. non-exposed groups to investigate the role of prenatal exposure to the Chinese famine of 1959-1962 in relation to diabetes. We also built a hierarchical age-period-cohort (HAPC) model to specifically examine the relation of famine to diabetes risk independent of age.Compared to the age-balanced men in the non-exposed group, the exposed men born in 1961 had a 154% increased risk of diabetes [odds ratio (OR) 2.54 (95% CI 1.07-6.03), P = 0.04). In the HAPC analysis, the predicted probabilities of diabetes peaked in the 1961-birth cohort of men [3.4% (95% CI 2.4%-5.0%)], as compared to the average probability of diabetes (reference) of 1.8% for men overall. Neither analytical strategy revealed any strong relation between famine exposure and diabetes risk in women.Among the pre-defined Chinese famine period of 1959-1962, early-life exposure to famine was associated with increased diabetes risk in men but not in women, and these relations were independent of age.

1.1. BACKGROUND: It was reported that Hemoglobin A1c (HbA1c) values of African-Americans (AAs) were on average higher than whites whereas AAs with Sickle-Cell-Trait (SCT) had lower HbA1c values compared to AAs without SCT despite controlling for average glycaemia. We evaluated the HbA1c-glucose relationship between AAs with and without SCT, and whites using data from two cohort studies. 1.2. METHODS: We pooled data from Coronary-Artery-Risk-Development-Study-in-Young-Adults (CARDIA, n= 5,115, 2005–2011) and the Jackson-Heart-Study (JHS, n=5,301, 2000–2013). Whole exome sequencing in JHS and TaqMan-SNP-Genotyping Assays in CARDIA determined the SCT status in AAs. HbA1c was measured by two NGSP-certified assays without reportedly clinically significant interference from hemoglobin S. Participants without data on SCT or with hemoglobin SS, CC or AC were excluded, resulting in 6,623 participants (n=3,575 from CARDIA and n=3,048 from JHS). Generalized-estimating-equations estimated the cross-sectional association between fasting glucose and HbA1c(outcome) amongst whites, AAs with SCT, and AAs without SCT controlling for clinical-demographic factors. 1.3. RESULTS: Our analyses included 2,003 whites, 4,253 AAs without SCT and 367 AAs with SCT. AAs with and without SCT had similar clinical-demographic characteristics, whereas whites have lower fasting- and 2-hour-glucose values than AAs. Despite higher fasting-glucose values in AAs with SCT versus whites, their HbA1c values were similar (p=0.39). In the subset with 2-hour-glucose values, HbA1c values in AAs with SCT were lower than whites (p=0.007) despite higher 2-hour-glucose values. 1.4. CONCLUSIONS: AAs with SCT have at least similar, if not lower, levels of mean HbA1c values than whites despite higher levels of glycaemia. Future research is warranted to assess whether these findings translate to clinical outcomes.

Background: Real-world implementation of supervised exercise therapy (SET) referral for symptomatic intermittent claudication has been limited by poor provider awareness around reimbursement and low patient adherence owing to factors including limited center availability and long travel distances to sites. Methods: In this study, 76 of 77 consecutive male veteran patients with intermittent claudication managed at a single-center vascular specialty clinic were referred to SET prior to revascularization. Pre- and post-SET submaximal exercise treadmill testing was performed for assessment of exercise capacity in metabolic equivalents (METs). Results: In the 48.7% of subjects who completed 36 sessions of SET ( n = 37), the average improvement in METs was 60.3%, reflecting improvement from baseline average of 3.4 METs to 5.5 METs after SET. Another 14 patients pursued self-guided exercise therapy and 25 patients declined any participation in exercise therapy. Reasons for declining participation in SET included inadequate transportation, cost of copayment, and interference with full-time work schedules. There was a nonsignificant numeric trend toward improved change in ankle–brachial index in the combined SET and self-guided exercise groups compared to those that declined exercise therapy (0.011 ± 0.124 vs –0.040 ± 0.105, p = 0.156). Conclusion: High acceptance of referral to SET is possible, despite the limitations to implementation. Incorporation of novel pre- and post-SET submaximal exercise treadmill testing allows for assessment of change in exercise capacity and aids in risk stratification and management of intermittent claudication symptoms.

The causes of death in COVID-19 patients with cardiac injury are uncertain.We conducted a case-control study and reviewed the electronic medical record of 109 deceased COVID-19 patients with cardiac injury on admission and 32 deceased COVID-19 patients without cardiac injury at two hospitals in Rhode Island.Among the 109 deceased COVID-19 patients who had cardiac injury on admission, 79 patients (72.5%) died of hypoxic respiratory failure, 21 patients (19.2%) of multi-organ failure and septic shock, 6 patients (5.5%) of cardiac arrhythmia, 3 patients (2.8%) of severe kidney failure as the immediate causes of death. We observed a similar pattern of distribution when compared to deceased patients without cardiac injury on admission (n=32).The main causes of death of COVID-19 patients with cardiac injury were non-cardiac, mostly hypoxic respiratory failure. Cardiac-related arrhythmia only accounted for a small proportion of cases.

OBJECTIVE: To determine predictors of adverse outcomes in peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: We conducted a multi-center cohort study across four centers to identify subjects with PPCM with the following criteria: LVEF

Objectives This study sought to evaluate a decision algorithm for the estimation of left ventricular filling pressure (LVFP) in patients with mitral annular calcification (MAC). Background In a single center study, Abudiab et al evaluated echocardiographic parameters to estimate LVFP in patients with MAC against invasive hemodynamic measurements and developed a decision algorithm which demonstrated high predictive accuracy. Methods Retrospectively, 55 patients (mean age 68.5 ± 11.5) with MAC and a left heart catheterization within 24 hours of an echocardiogram were identified. The decision algorithm was applied using echo data to classify patients as having normal or elevated LVFP which was then compared with the invasively obtained LVFP. Results The algorithm performed poorly at predicting pre-A LVFP as normal or high (P = .182). Accuracy for the algorithm was 0.59 [0.46, 0.72] (mean [95% CI]), sensitivity was 0.45 [0.28, 0.62], specificity was 0.73 [0.54, 0.86], false positive rate was 0.27 [0.14, 0.46], and false negative rate was 0.55 [0.38, 0.72]. E/A ratio, IVRT, and E/e'ratio showed no significant relationship to actual patient LVFP. Conclusions The Abudiab et al algorithm failed to demonstrate comparable sensitivity, specificity, and accuracy in our sample. Additional study is necessary to refine this tool prior to more widespread use in clinical practice.

Background Adiponectin is a polypeptide hormone related to obesity, and a known modulator of pulmonary vascular remodeling. Association between plasma adiponectin levels and pulmonary hypertension (PH) has not been studied in African Americans (AAs) who are disproportionately affected by obesity. The relationship between adiponectin and heart failure (HF) and mortality, outcomes associated with PH, is unclear. Methods We performed cross-sectional and longitudinal analysis to examine if there is an association between plasma adiponectin and PH and associated clinical outcomes, in participants of Jackson Heart Study (JHS). JHS is a prospective observational cohort study of heart disease in AAs from Jackson, Mississippi. Results Of the 3161 participants included in the study, mean age (SD) was 56.38 (12.61) years, 1028 were men (32.5%), and mean (SD) BMI was 31.42 (7.05) kg/m 2 . Median (IQR) adiponectin was 4516.82 (2799.32–7065.85) ng/mL. After adjusting for potential confounders including BMI, higher adiponectin levels were associated with increased odds of PH (adjusted odds ratio per log increment in adiponectin, (1.81; 95% CI, 1.41–2.32). High adiponectin levels were also associated with associated HF admissions (adjusted hazard ratio [HR] per log increment in adiponectin, 1.63, 95% CI, 1.24–2.14) and mortality (adjusted HR per log increment in adiponectin, 1.20; 95% CI 1.02–1.41). Conclusions Elevated plasma adiponectin levels are associated with PH, HF admissions and mortality risk in AAs. High adiponectin levels may help identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies

Background Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. Methods In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. Results Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. Conclusion Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

BACKGROUND AND AIMS: Calcific aortic valve disease is highly prevalent in patients with significant smoking history and is a marker of atherosclerosis. The aim of this study was to define the prognostic value of aortic valve calcification (AVC) derived from low dose, lung cancer screening computed tomography (LCSCT) for all-cause mortality in this higher risk population. METHODS: This is a single site, retrospective analysis of 1529 moderate-to-high atherosclerotic cardiovascular risk U.S. veterans (65 years [IQI: 61, 68] years; 96% male), who underwent clinically indicated LCSCT. CTs were scored for aortic valve calcification (AVC) and coronary artery calcification (CAC). The primary endpoint was all-cause mortality and secondary endpoints were nonfatal myocardial infarction (MI) and nonfatal cerebrovascular accident (CVA). RESULTS: Over 4-year follow-up, 227 patients (15%) died, 112 patients (7%) had nonfatal MI, and 52 patients (3%) had nonfatal CVA. AVC was predictive of all-cause mortality (HR per 100: 1.041 [1.030–1.052], p < 0.001), and this association remained significant after multivariate adjustment for traditional atherosclerotic risk factors, including CAC (1.021 [1.007–1.036], p = 0.003). After excluding patients with severe aortic stenosis (AS) or severe AVC (≥1274 AU in women and ≥2065 AU in men), in a subset of 765 patients who had echocardiograms, this association remained significant after multivariate analysis (HR per 100: 1.052 [1.010–1.095], p = 0.014). Despite controlling for CAC in the models, AVC was still associated with MI (HR per 100: 1.021 [1.004–1.039], p = 0.017) and with CVA (HR per 100: 1.027 [1.002–1.051], p = 0.032). CONCLUSIONS: Scoring AVC derived from LCSCT is predictive of mortality, nonfatal MI, and nonfatal CVA in patients at known risk for cardiovascular disease, independent of coronary calcification or severe aortic valve stenosis.

Background Smoking cessation is recommended for adults with heart failure (HF). The prevalence of e-cigarette use among adults with HF is unknown. Objective To determine prevalence of and reasons for e-cigarette use among adults with HF. Methods Data from the Population Assessment of Tobacco and Health Study (Wave 1) were examined. Results Of 484 respondents with HF, 1% (weighted) reported current e-cigarette use, and 5% (weighted) reported dual cigarette/e-cigarette use. Adults with HF had higher odds of dual use (OR = 1.76, 95% CI: 1.22–2.54) compared to those without HF, controlling for age, sex, race, and income. Dual users with HF reported using e-cigarettes because they may be less harmful to nearby people and to themselves than cigarettes. Conclusions E-cigarette use should be assessed and monitored to understand the safety and potential efficacy of e-cigarettes as a harm reduction approach for HF patients.

BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC). AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis. METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival. RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues. CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

Objective To study the relationship between county-level COVID-19 outcomes (incidence and mortality) and county-level median household income and status of Medicaid expansion of US counties. Methods Retrospective analysis of 3142 US counties was conducted to study the relationship between County-level median-household-income and COVID-19 incidence and mortality per 100,000 people in US counties, January-20th-2021 through December-6th-2021. County median-household-income was log-transformed and stratified by quartiles. Multilevel-mixed-effects-generalized-linear-modeling adjusted for county socio-demographic and comorbidities and tested for Medicaid-expansion-times-income-quartile interaction on COVID-19 outcomes. Results There was no significant difference in COVID-19 incidence-rate across counties by income quartiles or by Medicaid expansion status. Conversely, for non-Medicaid-expansion states, counties in the lowest income quartile had a 41% increase in COVID-19 mortality-rate compared to counties in the highest income quartile. Mortality-rate was not related to income in counties from Medicaid-expansion states. Conclusions Median-household-income was not related to COVID-19 incidence-rate but negatively related to COVID-19 mortality-rate in US counties of states without Medicaid-expansion.

Background: Early-life exposures play key roles in the development of metabolic diseases. Whether such effects exist beyond one generation remains unclear. This study aimed to determine the transgenerational association of early-life exposure to the Chinese famine of 1959 to 1962 with the trajectories of body mass index (BMI), waist circumference (WC), and blood pressure (BP) in 2 consecutive generations. Methods: We included 21 106 F1 observations born between 1954 and 1967 (median age: 45 years) and 1926 F2 observations (median age: 23 years) from the longitudinal household-based China Health and Nutrition Survey from 1993 to 2015. Trajectories of BMI, WC, systolic BP, and diastolic BP were fitted and compared between groups using linear mixed effect models. Results: Early-life exposure to famine was associated with increased BMI, WC, and BP in 2 consecutive generations with sex and age disparities. In F1, famine was associated with increased BMI, WC, systolic BP, and diastolic BP, especially in men or those aged older than 50 years ( P ranged from 2 ([95% CI, 0.10–1.08], P =0.02) increase in BMI. In F2 aged ≥25 years but not those younger ones, the parental exposure to famine was associated with increased BMI (0.83 kg/m 2 [0.14–1.51], P =0.03), systolic BP (2.04 mm Hg [0.20–3.88], P =0.03), and diastolic BP (1.73 mm Hg [0.28–3.18], P =0.02). Conclusions: The effects of an adverse developmental environment through famine in early life on BMI and BP later in life may persist beyond one generation.