The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation.

The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. S6K1-mediated phosphorylation is critical for BMAL1 to both associate with the translational machinery and stimulate protein synthesis. Protein synthesis rates demonstrate circadian oscillations dependent on BMAL1. Thus, in addition to its critical role in circadian transcription, BMAL1 is a translation factor that links circadian timing and the mTOR signaling pathway. More broadly, these results expand the role of the circadian clock to the regulation of protein synthesis.

Projected Change in the Burden of Excess Cardiovascular Deaths Associated With Extreme Heat by Midcentury (2036-2065) in the Contiguous United States.

BACKGROUND: Climate change is causing an increase in extreme heat. Individuals with cardiovascular disease are at high risk of heat-related adverse health effects. How the burden of extreme heat-associated cardiovascular deaths in the United States will change with the projected rise in extreme heat is unknown. METHODS: We obtained data on cardiovascular deaths among adults and the number of extreme heat days (maximum heat index ≥90 °F [32.2 °C]) in each county in the contiguous United States from 2008 to 2019. Based on representative concentration pathway trajectories that model greenhouse gas emissions and shared socioeconomic pathways (SSP) that model future socioeconomic scenarios and demographic projections, we obtained county-level projected numbers of extreme heat days and populations under 2 scenarios for the midcentury period 2036 to 2065: SSP2-4.5 (representing demographic projections from a "middle-of-the-road" socioeconomic scenario and an intermediate increase in emissions) and SSP5-8.5 (demographic projections in an economy based on "fossil-fueled development" and a large increase in emissions). The association of cardiovascular mortality with extreme heat was estimated with a Poisson fixed-effects model. Using estimates from this model, the projected number of excess cardiovascular deaths associated with extreme heat was calculated. RESULTS: Extreme heat was associated with 1651 (95% CI, 921-2381) excess cardiovascular deaths per year from 2008 to 2019. By midcentury, extreme heat is projected to be associated with 4320 (95% CI, 2369-6272) excess deaths annually, which is an increase of 162% (95% CI, 142-182) under SSP2-4.5, and 5491 (95% CI, 3011-7972) annual excess deaths, which is an increase of 233% (95% CI, 206-259) under SSP5-8.5. Elderly adults are projected to have a 3.5 (95% CI, 3.2-3.8) times greater increase in deaths in the SSP2-4.5 scenario compared with nonelderly adults. Non-Hispanic Black adults are projected to have a 4.6 (95% CI, 2.8-6.4) times greater increase compared with non-Hispanic White adults. The projected change in deaths was not statistically significantly different for other race and ethnicity groups or between men and women. CONCLUSIONS: By midcentury, extreme heat is projected to be associated with a significantly greater burden of excess cardiovascular deaths in the contiguous United States.

Association between racial residential segregation and Black-White disparities in cardiovascular disease mortality.

BACKGROUND: Racial residential segregation is associated with racial health inequities, but it is unclear if segregation may exacerbate Black-White disparities in cardiovascular disease (CVD) mortality. This study aimed to assess associations between Black-White residential segregation, CVD mortality rates among non-Hispanic (NH) Black and NH White populations, and Black-White disparities in CVD mortality. METHODS: This cross-sectional study analyzed Black-White residential segregation, as measured by county-level interaction index, of US counties, county-level CVD mortality among NH White and NH black adults aged 25 years and older, and county-level Black-White disparities in CVD mortality in years 2014 to 2017. Age-adjusted, county-level NH Black CVD mortality rates and NH White cardiovascular disease mortality rates, as well as group-level relative risk ratios for Black-White cardiovascular disease mortality, were calculated. Sequential generalized linear models adjusted for county-level socioeconomic and neighborhood factors were used to estimate associations between residential segregation and cardiovascular mortality rates among NH Black and NH White populations. Relative risk ratio tests were used to compare Black-White disparities in the most segregated counties to disparities in the least segregated counties. RESULTS: We included 1,286 counties with ≥5% Black populations in the main analysis. Among adults aged ≥25 years, there were 2,611,560 and 408,429 CVD deaths among NH White and NH Black individuals, respectively. In the unadjusted model, counties in the highest tertile of segregation had 9% higher (95% CI, 1%-20% higher, P = .04) rates of NH Black CVD mortality than counties in the lowest tertile of segregation. In the multivariable adjusted model, the most segregated counties had 15% higher (95% CI, 0.5% to 38% higher, P = .04) rates of NH Black CVD mortality than the least segregated counties. In the most segregated counties, NH Black individuals were 33% more likely to die of CVD than NH White individuals (RR 1.33, 95% CI 1.32 to 1.33, P < .001). CONCLUSIONS: Counties with increased Black-White residential segregation have higher rates of NH Black CVD mortality and larger Black-White disparities in CVD mortality. Identifying the causal mechanisms through which racial residential segregation widens disparities in CVD mortality requires further study.

Oral anticoagulant use in patients with atrial fibrillation and mitral valve repair.

BACKGROUND: Patients with atrial fibrillation (AF) who have undergone mitral valve repair are at risk for thromboembolic strokes. Prior to 2019, only vitamin K antagonists were recommended for patients with AF who had undergone mitral valve repair despite the introduction of direct oral anticoagulants (DOAC) in 2010. OBJECTIVE: To characterize the use of anticoagulants in patients with AF who underwent surgical mitral valve repair (sMVR) or transcatheter mitral valve repair (tMVR). METHODS: We performed a retrospective cohort analysis of patients with AF undergoing sMVR or tMVR between 04/2014 and 12/2018 using Optum's de-identified Clinformatics® Data Mart Database. We identified anticoagulants prescribed within 90 days of discharge from hospitalization. RESULTS: Overall, 1997 patients with AF underwent valve repair: 1560 underwent sMVR, and 437 underwent tMVR. The mean CHA2DS2-VASc score among all patients was 4.1 (SD 1.9). The overall use of anticoagulation was unchanged between 2014 (72.2%) and 2018 (70.0%) (P = .49). Among patients who underwent sMVR or tMVR between April 2014 and December 2018, the use of VKA therapy decreased from 62.9% to 32.1% (P < .01 for trend) and the use of DOACs increased from 12.4% to 37.3% (P < .01 for trend). CONCLUSIONS: Among patients with AF who underwent sMVR or tMVR between 2014 and 2018, roughly 30% of patients were not treated with any anticoagulant within 90 days of discharge, despite an elevated stroke risk in the cohort. The rate of DOAC use increased steadily over the study period but did not significantly increase the rate of overall anticoagulant use in this high-risk cohort.

Association Between County-Level Change in Economic Prosperity and Change in Cardiovascular Mortality Among Middle-aged US Adults.

Importance: After a decline in cardiovascular mortality for nonelderly US adults, recent stagnation has occurred alongside rising income inequality. Whether this is associated with underlying economic trends is unclear. Objective: To assess the association between changes in economic prosperity and trends in cardiovascular mortality in middle-aged US adults. Design, Setting, and Participants: Retrospective analysis of the association between change in 7 markers of economic prosperity in 3123 US counties and county-level cardiovascular mortality among 40- to 64-year-old adults (102 660 852 individuals in 2010). Exposures: Mean rank for change in 7 markers of economic prosperity between 2 time periods (baseline: 2007-2011 and follow-up: 2012-2016). A higher mean rank indicates a greater relative increase or lower relative decrease in prosperity (range, 5 to 92; mean [SD], 50 [14]). Main Outcomes and Measures: Mean annual percentage change (APC) in age-adjusted cardiovascular mortality rates. Generalized linear mixed-effects models were used to estimate the additional APC associated with a change in prosperity. Results: Among 102 660 852 residents aged 40 to 64 years living in these counties in 2010 (51% women), 979 228 cardiovascular deaths occurred between 2010 and 2017. Age-adjusted cardiovascular mortality rates did not change significantly between 2010 and 2017 in counties in the lowest tertile for change in economic prosperity (mean [SD], 114.1 [47.9] to 116.1 [52.7] deaths per 100 000 individuals; APC, 0.2% [95% CI, -0.3% to 0.7%]). Mortality decreased significantly in the intermediate tertile (mean [SD], 104.7 [38.8] to 101.9 [41.5] deaths per 100 000 individuals; APC, -0.4% [95% CI, -0.8% to -0.1%]) and highest tertile for change in prosperity (100.0 [37.9] to 95.1 [39.1] deaths per 100 000 individuals; APC, -0.5% [95% CI, -0.9% to -0.1%]). After accounting for baseline prosperity and demographic and health care-related variables, a 10-point higher mean rank for change in economic prosperity was associated with 0.4% (95% CI, 0.2% to 0.6%) additional decrease in mortality per year. Conclusions and Relevance: In this retrospective study of US county-level mortality data from 2010 to 2017, a relative increase in county-level economic prosperity was significantly associated with a small relative decrease in cardiovascular mortality among middle-aged adults. Individual-level inferences are limited by the ecological nature of the study.

Mortality trends around the one-year survival mark after heart, liver, and lung transplantation in the United States.

INTRODUCTION: One-year post-transplant survival is a significant quality measure for solid organ transplant programs in the United States. It is not known whether the use of this metric is associated with changes in life-sustaining clinical practices that would delay mortality for solid organ recipients until just beyond the one-year time point. METHODS: We compared trends in mortality in the time period immediately preceding the one-year post-transplant mark compared to the period immediately after using second-order Cox proportional hazard regression models. RESULTS: Among recipients of heart, liver, and lung transplantation, mortality did not decrease significantly in the period immediately before day 365 or increase in the 14 days thereafter. There was an increased adjusted hazard of mortality in the 30 days following day 365 among lung transplant recipients (HR 1.33, 95% CI 1.03-1.72, P = .03) with a 0.76% absolute mortality rate (94 deaths) in month 12 following lung transplantation and a 1.14% absolute mortality rate in month 13 (113 deaths). CONCLUSION: Although we did not find evidence that life-sustaining treatment is routinely continued until just beyond the one-year mark in heart and liver transplantation recipients, there was an unexpected increased risk of mortality in the 30 days following day 365 among lung transplant recipients.

Outcomes of catheter-directed versus systemic thrombolysis for the treatment of pulmonary embolism: A real-world analysis of national administrative claims.

Catheter-directed thrombolysis (CDT) and systemic thrombolysis (ST) are used to treat intermediate/high-risk pulmonary embolism (PE) in the absence of comparative safety and effectiveness data. We utilized a large administrative database to perform a comparative safety and effectiveness analysis of catheter-directed versus systemic thrombolysis. From the Optum® Clinformatics® Data Mart private-payer insurance claims database, we identified 100,744 patients hospitalized with PE between 2004 and 2014. We extracted demographic characteristics, high-risk PE features, components of the Elixhauser Comorbidity Index, and outcomes including intracranial hemorrhage (ICH), all-cause bleeding, and mortality among all patients receiving CDT and ST. We used propensity score methods to compare outcomes between matched cohorts adjusted for observed confounders. A total of 1915 patients (1.9%) received either CDT (n = 632) or ST (n = 1283). Patients in the CDT group had fewer high-risk features including less shock (5.4 vs 11.1%; p < 0.001) and cardiac arrest (6.8 vs 11.0%; p = 0.004). In 1:1 propensity-matched groups, ICH rates were 1.9% in both the CDT and ST groups (p = 1.0). All-cause bleeding was higher in the CDT group (15.9 vs 8.7%; p < 0.001), while in-hospital mortality was lower (6.5 vs 10.0%; p = 0.02). Among a nationally representative cohort of patients with PE at higher risk for mortality, CDT was associated with similar ICH rates, increased all-cause bleeding, and lower short and intermediate-term mortality when compared with ST. The competing risks and benefits of CDT in real-world practice suggest the need for large-scale randomized clinical trials with appropriate comparator arms.

The Lotus Valve System: an In-depth Review of the Technology.

PURPOSE OF REVIEW: Innovation for transcatheter aortic valve replacement (TAVR) has transformed a medically complex treatment into a standardized procedure. While Edwards SAPIEN and Medtronic CoreValve occupy the market for TAVR in the United States (US), additional valve systems are being developed. The Boston Scientific Lotus Valve system was recently FDA-approved and will represent the third valve in the US market. This evidence-based review will summarize advantages, disadvantages, and projected impact of this new TAVR system. RECENT FINDINGS: The Lotus Valve system demonstrates superiority in terms of rates of paravalvular leak, with similar rates of mortality and disabling stroke. This benefit is at the expense of increased pacemaker implantation rates, though preliminary data from subsequent iterations of the Lotus Valve suggest decreasing rates over time. There is much anticipation from ongoing trials utilizing the Lotus Edge system, which may perform best for those with pre-existing pacemakers or anatomy that increases likelihood of paravalvular leak.

Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study.

BACKGROUND: Continued dual antiplatelet therapy and optimal medical therapy (OMT) improve outcomes in selected patient populations with established coronary heart disease, but whether OMT modifies the treatment effect of dual antiplatelet therapy is unknown. METHODS: The DAPT (Dual Antiplatelet Therapy) Study, a double-blind trial, randomly assigned 11 648 patients who had undergone coronary stenting and completed 1 year of dual antiplatelet therapy without major bleeding or ischemic events to an additional 18 months of continued thienopyridine or placebo. OMT was defined as a combination of statin, ß-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in patients with an American College of Cardiology/American Heart Association class I indication for each medication. Per protocol, all patients were treated with 75 to 325 mg aspirin daily. End points included myocardial infarction, major adverse cardiovascular and cerebrovascular events, and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries moderate or severe bleeding events. RESULTS: Of 11 643 randomly assigned patients with complete medication data, 63% were on OMT. Between 12 and 30 months, continued thienopyridine reduced myocardial infarction in comparison with placebo in both groups (on OMT 2.1% versus 3.3%, hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.48-0.86; P=0.003; off OMT 2.2% versus 5.2%, HR, 0.41; CI, 0.29-0.58; P<0.001; interaction P=0.103). Comparing continued thienopyridine versus placebo, rates of major adverse cardiovascular and cerebrovascular events were 4.2% versus 5.0% among patients on OMT (HR, 0.82; CI, 0.66-1.02; P=0.077) and 4.5% versus 7.0% among those off OMT (HR, 0.63; CI, 0.49-0.82; P<0.001; interaction P=0.250); rates of bleeding for thienopyridine versus placebo in patients on OMT were 2.2% versus 1.0% (HR, 2.13; CI, 1.43-3.17; P<0.001), and in patients off OMT were 2.8% versus 2.2% (HR, 1.30; CI, 0.88-1.92; P=0.189; interaction P=0.073). Overall, patients on OMT had lower rates of myocardial infarction (2.7% versus 3.7%, P=0.003), major adverse cardiovascular and cerebrovascular events (4.6% versus 5.7%, P=0.007), and bleeding (1.6% versus 2.5%, P<0.001) in comparison with patients off OMT. Rates of stent thrombosis (0.8% versus 1.0%, P=0.171) and death (1.6% versus 1.9%, P=0.155) did not differ. CONCLUSIONS: Continued thienopyridine therapy reduced the rate of myocardial infarction regardless of OMT status and had consistent effects on reduction in major adverse cardiovascular and cerebrovascular events and increased bleeding. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00977938.

Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation.

Peak oxygen consumption (pVO2) measured by cardiopulmonary exercise test (CPET) predicts mortality in adults with a Fontan circulation. The purpose of this study was to assess the additive prognostic value of change in pVO2 over time. METHODS: We analyzed a cohort of adults (≥18 years old) with a Fontan circulation who underwent at least 2 maximal CPETs separated by 6-30 months at Boston Children's Hospital between 2000 and 2015. Survival analysis was performed to determine whether changes in CPET variables, including pVO2 between consecutive tests, were associated with subsequent clinical events. The primary outcome was transplant-free survival. RESULTS: The study included 130 patients with 287 CPET test pairs. Average age was 26.6±9.5 years. Baseline pVO2 averaged 22.0±5.7 mL/kg/min or 60.9%±13.7% predicted. In the cohort overall, there was no change in mean pVO2 between sequential CPETs. Eleven patients died and 2 underwent transplant. On average, pVO2 declined for patients who subsequently died or underwent transplant but remained stable among those who did not (-9.8%±14.6% vs 0.0±13.0%, P<.01). Those with a decline in pVO2 between CPETs were at greater risk of death or transplantation (per 10% decrease in pVO2: HR=2.0, 95% CI 1.2-3.1, P=.004). Change in pVO2 remained a significant predictor of death or transplant after adjusting for pVO2 at first CPET (per 10% decline in pVO2: HR=2.5, 95% CI 1.5-4.2, P<.001). CONCLUSIONS: A decline in pVO2 between consecutive CPETs predicts increased risk for death or transplant in adults with a Fontan circulation independent of baseline pVO2. These results support the additive clinical value of serial CPET in this population.

Antiplatelet Therapy for Secondary Prevention of Vascular Disease Complications.

PURPOSE OF REVIEW: Platelets are activated upon interaction with injured vascular endothelium to form a primary hemostatic plug. Pathogenic thrombosis driven by platelet aggregation can occur in the setting of vascular disease leading to ischemic events. The use of antiplatelet agents has become a mainstay for prevention of the secondary complications of vascular disease. This review summarizes seminal and recent literature related to this area. RECENT FINDINGS: Aspirin is a cornerstone of antiplatelet therapy for coronary artery disease and cerebrovascular disease for prevention of myocardial infarction, stroke, and vascular death. Alternative antiplatelet agents have shown promise for use in patients with peripheral artery disease though further validation is necessary. Dual antiplatelet therapy (DAPT) with clopidogrel, prasugrel, or ticagrelor, and aspirin demonstrates benefit in patients with higher thrombotic risk. However, use of DAPT predictably increases bleeding risk, thus limiting mortality benefit. Individualization of DAPT to patient-specific features is an area of active research with the development the DAPT score and pharmacogenomic approaches. Application of pharmacogenetic data could allow for a precision medicine approach to tailoring antiplatelet therapy. Recommendations for management of cardiovascular, cerebrovascular, and peripheral artery disease are largely based on large-scale randomized control trials and meta-analyses. Seminal trials have largely focused on prevention of vascular events including non-fatal MI, stroke, and vascular death in subsets of patients with cardiovascular disease. Data from these trials along with smaller studies have driven recommendations for secondary prevention management in patients with cerebrovascular and peripheral artery disease.

Bioresorbable Scaffolds for Coronary Artery Disease.

PURPOSE OF REVIEW: The purpose of this review is to present an overview of the recent evidence regarding the use of bioresorbable scaffolds in percutaneous coronary intervention. RECENT FINDINGS: Bioresorbable scaffolds represent a potentially unique engineering solution to the problems associated with metallic stents. The Absorb everolimus-eluting bioresorbable scaffold has been the most extensively tested of this class and is currently Food and Drug Administration-approved for use in the USA. While early studies suggested that it has comparable overall efficacy as compared to drug-eluting metallic stents, they also demonstrated a significantly increased risk of stent thrombosis. Bioresorbable scaffolds may be comparable to drug-eluting stents, though associated with an increased risk of stent thrombosis. They are a nascent technology with several competitive product designs in development and continued iterative technological improvements are expected over the next several years.

Transcatheter aortic valve replacement achieves similar predicted effective orifice area to surgical aortic valve replacement in bicuspid aortic stenosis.

BACKGROUND: Studies comparing transcatheter and surgical aortic valve replacement (TAVR and SAVR) for patients with trileaflet aortic stenosis (AS) have found similar or larger effective orifice area (EOA) for TAVR prostheses. To our knowledge, no studies have compared EOA in patients undergoing TAVR versus SAVR for bicuspid AS. METHODS: We retrospectively compared prosthetic valvular sizing and predicted EOA for patients with bicuspid AS undergoing TAVR or SAVR at our institution between January 1, 2016, and December 31, 2021. We excluded patients undergoing procedures for indications other than AS and those without a pre-procedural gated Chest CT. Comparisons included demographics, comorbidities, annular size, prosthetic valve size, predicted EOA and prosthesis-patient mismatch (PPM) for TAVR (N = 78) and SAVR (N = 74) cohorts. RESULTS: TAVR patients had smaller pre-procedural annular area (501.7 mm2 vs. 571.8 mm2, p < 0.05) and annular perimeter (80.6 mm vs. 86.5 mm, p < 0.05), but larger mean implanted prosthetic valve size (26.4 mm vs 24.2 mm, p < 0.001) compared to SAVR patients. No differences were observed in predicted EOA, predicted EOA indexed to patient body surface area (EOAi), or predicted PPM grade between TAVR and SAVR groups, including in cohorts sorted by pre-procedural annular size. CONCLUSIONS: For bicuspid AS patients undergoing aortic valve replacement, TAVR achieves similar predicted EOA to SAVR. These data support the use of TAVR in selected patients with bicuspid AS and can inform heart team discussions.

Association Between Diagnosis-to-Limb Revascularization Time and Clinical Outcomes in Outpatients With Chronic Limb-Threatening Ischemia: Insights From the CLIPPER Cohort.

BACKGROUND: The extent and consequences of ischemia in patients with chronic limb-threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may worsen outcomes. We sought to describe the association between time from diagnosis to endovascular lower extremity revascularization (diagnosis-to-limb revascularization [D2L] time) and clinical outcomes in outpatients with CLTI. METHODS AND RESULTS: In the CLIPPER cohort, comprising patients between 66 and 86 years old diagnosed with CLTI betweeen 2010 and 2019, we used Medicare claims data to identify patients who underwent outpatient endovascular revascularization within 180 days of diagnosis. We described the risk-adjusted association between D2L time and clinical outcomes. Among 1 130 065 patients aged between 66 and 86 years with CLTI, 99 221 (8.8%) underwent outpatient endovascular lower extremity revascularization within 180 days of their CLTI diagnosis. Among patients with D2L time <30 days, there was no association between D2L time and all-cause death or major lower extremity amputation. However, among patients with D2L time >30 days, each additional 10-day increase in D2L time was associated with a 2.5% greater risk of major amputation (hazard ratio, 1.025 [95% CI, 1.014-1.036]). There was no association between D2L time and all-cause death. CONCLUSIONS: A delay of >30 days from CLTI diagnosis to lower extremity endovascular revascularization was associated with an increased risk of major lower extremity amputation among patients undergoing outpatient endovascular revascularization. Improving systems of care to reduce D2L time could reduce amputations.

Medicaid Expansion And Outpatient Cardiovascular Care Use Among Low-Income Nonelderly Adults, 2012-15.

Adults with lower socioeconomic status have a disproportionately higher burden of cardiovascular disease. Medicaid expansion under the Affordable Care Act, which went into effect January 1, 2014, in adopting states, led to an expansion of health insurance coverage for low-income adults. To understand whether Medicaid expansion was associated with increased access to outpatient cardiovascular care in expansion states, we examined Medicaid Analytic eXtract administrative claims data for nonelderly adult beneficiaries from the period 2012-15 for two states that expanded Medicaid eligibility (New Jersey and Minnesota) and two states that did not (Georgia and Tennessee) and calculated population-level rates of cardiovascular care use. There was a 38.1 percent greater increase in expansion states in the rate of beneficiaries with outpatient visits for cardiovascular disease management associated with Medicaid expansion relative to nonexpansion states. This was accompanied by a 42.9 percent greater increase in the prescription rate for cardiovascular disease management agents. These results suggest that expansion of Medicaid eligibility was associated with an increase in cardiovascular care use among low-income nonelderly adults in expansion states.

Enrollment of Older Patients, Women, and Racial and Ethnic Minority Individuals in Valvular Heart Disease Clinical Trials: A Systematic Review.

Importance: Inadequate representation of older patients, women, and racial minority individuals in cardiovascular clinical trials limits both the generalizability of trial findings and inclusivity in access to novel therapies and therapeutic strategies. Objective: To report on temporal trends in the representation of older patients, women, and racial and ethnic minority individuals in clinical trials studying treatments for valvular heart disease. Evidence Review: All published clinical trials enrolling more than 100 adults with any valvular heart disease published between 2005 and 2020 were included after searches with PubMed and ClinicalTrials.gov. Data on age, sex, race, and ethnicity reported in the included studies were collected. Trials were assigned to 4 time periods based on the publication date, and temporal trends were analyzed in the representation of older patients, women, and racial and ethnic minority individuals. Findings: A total of 139 clinical trials with 51 527 participants were identified. Of these trials, 103 (74%) investigated aortic valve disease and the remainder mitral valve disease. Overall, 63 trials (45.3%) enrolled patients only in Europe, 24 (17.3%) only in North America, and 19 (13.7%) in multiple geographical regions. The weighted mean (SD) age of enrolled patients was 68.4 (11.4) years, increasing nonsignificantly from 61.9 (5.9) years in 2005-2008 to 72.8 (9.6) years in 2017-2020 (P = .09 for trend). The overall proportion of women enrolled in valvular heart disease trials was 41.1%, with no significant changes over time. Data on race and ethnicity of trial participants were reported in 13 trials (9.4%), in which trial-level representation of American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander patients ranged from 0.27% to 43.9%. There were no significant temporal trends noted in the enrollment of racial and ethnic minority populations. The representation of women in clinical trials was positively associated with enrollment rates of older patients and underrepresented racial and ethnic groups. Conclusions and Relevance: This review found that over the past 2 decades, women and racial and ethnic minority individuals have remained underrepresented in North American valvular heart disease clinical trials. Further work is needed to improve the reporting of race and ethnicity data and address barriers to trial enrollment for older patients, women, and racial and ethnic minority individuals.

Racial, Ethnic, and Socioeconomic Inequities in Access to Left Atrial Appendage Occlusion.

Background Inequitable access to high-technology therapeutics may perpetuate inequities in care. We examined the characteristics of US hospitals that did and did not establish left atrial appendage occlusion (LAAO) programs, the patient populations those hospitals served, and the associations between zip code-level racial, ethnic, and socioeconomic composition and rates of LAAO among Medicare beneficiaries living within large metropolitan areas with LAAO programs. Methods and Results We conducted cross-sectional analyses of Medicare fee-for-service claims for beneficiaries aged 66 years or older between 2016 and 2019. We identified hospitals establishing LAAO programs during the study period. We used generalized linear mixed models to measure the association between zip code-level racial, ethnic, and socioeconomic composition and age-adjusted rates of LAAO in the most populous 25 metropolitan areas with LAAO sites. During the study period, 507 candidate hospitals started LAAO programs, and 745 candidate hospitals did not. Most new LAAO programs opened in metropolitan areas (97.4%). Compared with non-LAAO centers, LAAO centers treated patients with higher median household incomes (difference of $913 [95% CI, $197-$1629], P=0.01). Zip code-level rates of LAAO procedures per 100 000 Medicare beneficiaries in large metropolitan areas were 0.34% (95% CI, 0.33%-0.35%) lower for each $1000 zip code-level decrease in median household income. After adjustment for socioeconomic markers, age, and clinical comorbidities, LAAO rates were lower in zip codes with higher proportions of Black or Hispanic patients. Conclusions Growth in LAAO programs in the United States had been concentrated in metropolitan areas. LAAO centers treated wealthier patient populations in hospitals without LAAO programs. Within major metropolitan areas with LAAO programs, zip codes with higher proportions of Black and Hispanic patients and more patients experiencing socioeconomic disadvantage had lower age-adjusted rates of LAAO. Thus, geographic proximity alone may not ensure equitable access to LAAO. Unequal access to LAAO may reflect disparities in referral patterns, rates of diagnosis, and preferences for using novel therapies experienced by racial and ethnic minority groups and patients experiencing socioeconomic disadvantage.

Cardiovascular Disease Burden and Outcomes Among American Indian and Alaska Native Medicare Beneficiaries.

Importance: American Indian and Alaska Native persons face significant health disparities; however, data regarding the burden of cardiovascular disease in the current era is limited. Objective: To determine the incidence and prevalence of cardiovascular disease, the burden of comorbid conditions, including cardiovascular disease risk factors, and associated mortality among American Indian and Alaska Native patients with Medicare insurance. Design, Setting, and Participants: This was a population-based cohort study conducted from January 2015 to December 2019 using Medicare administrative data. Participants included American Indian and Alaska Native Medicare beneficiaries 65 years and older enrolled in both Medicare part A and B fee-for-service Medicare. Statistical analyses were performed from November 2022 to April 2023. Main Outcomes and Measures: The annual incidence, prevalence, and mortality associated with coronary artery disease (CAD), heart failure (HF), atrial fibrillation/flutter (AF), and cerebrovascular disease (stroke or transient ischemic attack [TIA]). Results: Among 220 598 American Indian and Alaska Native Medicare beneficiaries, the median (IQR) age was 72.5 (68.5-79.0) years, 127 402 were female (57.8%), 78 438 (38.8%) came from communities in the most economically distressed quintile in the Distressed Communities Index. In the cohort, 44.8% of patients (98 833) were diagnosed with diabetes, 61.3% (135 124) were diagnosed with hyperlipidemia, and 72.2% (159 365) were diagnosed with hypertension during the study period. The prevalence of CAD was 38.6% (61 125 patients) in 2015 and 36.7% (68 130 patients) in 2019 (P < .001). The incidence of acute myocardial infarction increased from 6.9 per 1000 person-years in 2015 to 7.7 per 1000 patient-years in 2019 (percentage change, 4.79%; P < .001). The prevalence of HF was 22.9% (36 288 patients) in 2015 and 21.4% (39 857 patients) in 2019 (P < .001). The incidence of HF increased from 26.1 per 1000 person-years in 2015 to 27.0 per 1000 person-years in 2019 (percentage change, 4.08%; P < .001). AF had a stable prevalence of 9% during the study period (2015: 9.4% [14 899 patients] vs 2019: 9.3% [25 175 patients]). The incidence of stroke or TIA decreased slightly throughout the study period (12.7 per 1000 person-years in 2015 and 12.1 per 1000 person-years in 2019; percentage change, 5.08; P = .004). Fifty percent of patients (110 244) had at least 1 severe cardiovascular condition (CAD, HF, AF, or cerebrovascular disease), and the overall mortality rate for the cohort was 19.8% (43 589 patients). Conclusions and Relevance: In this large cohort study of American Indian and Alaska Native patients with Medicare insurance in the US, results suggest a significant burden of cardiovascular disease and cardiometabolic risk factors. These results highlight the critical need for future efforts to prioritize the cardiovascular health of this population.