Background

Catheter‐based slow‐pathway modification (SPM) is the treatment of choice for symptomatic atrioventricular nodal reentrant tachycardia (AVNRT). We sought to investigate the interactions between patient age and procedural outcomes in pediatric patients undergoing catheter‐based SPM for AVNRT.

Methods and Results

A retrospective cohort study was performed, including consecutive patients undergoing acutely successful SPM for AVNRT from 2008 to 2017. Those with congenital heart disease, cardiomyopathy, and accessory pathways were excluded. Patients were stratified by age quartile at time of SPM. The primary outcome was AVNRT recurrence. A total of 512 patients underwent successful SPM for AVNRT. Age quartile 1 had 129 patients with a median age and weight of 8.9 years and 30.6 kg, respectively. Radiofrequency energy was used in 98% of cases. Follow‐up was available in 447 (87%) patients with a median duration of 0.8 years (interquartile range, 0.2–2.5 years). AVNRT recurred in 22 patients. Multivariable Cox proportional hazard modeling identified atypical AVNRT (hazard ratio [HR], 5.83; 95% CI, 2.01–16.96; P=0.001), dual atrioventricular nodal only (HR, 4.09; 95% CI, 1.39–12.02; P=0.011), total radiofrequency lesions (HR, 1.06 per lesion; 95% CI, 1.01–1.12; P=0.032), and the use of a long sheath (HR, 3.52; 95% CI, 1.23–10.03; P=0.010) as predictors of AVNRT recurrence; quartile 1 patients were not at higher risk of recurrence (HR, 0.45; 95% CI, 0.10–1.97; P=0.29). Complete heart block requiring permanent pacing occurred in one quartile 2 patient at 14.9 years of age.

Conclusions

Pediatric AVNRT can be treated with radiofrequency‐SPM with high procedural efficacy and minimal risk of complications, including heart block. Atypical AVNRT and dual atrioventricular nodal physiology without inducible tachycardia remain challenging substrates.

Background

Improved prediction of atrial fibrillation (AF) may allow for earlier interventions for stroke prevention, as well as mortality and morbidity from other AF‐related complications. We developed a clinically feasible and accurate AF prediction model using electronic health records and computerized ECG interpretation.

Methods and Results

A total of 671 318 patients were screened from 3 tertiary hospitals. After careful exclusion of cases with missing values and a prior AF diagnosis, AF prediction models were developed from the derivation cohort of 25 584 patients without AF at baseline. In the internal/external validation cohort of 117 523 patients, the model using 6 clinical features and 5 ECG diagnoses showed the highest performance for 3‐year new‐onset AF prediction (C‐statistic, 0.796 [95% CI, 0.785–0.806]). A more simplified model using age, sex, and 5 ECG diagnoses (atrioventricular block, fusion beats, marked sinus arrhythmia, supraventricular premature complex, and wide QRS complex) had comparable predictive power (C‐statistic, 0.777 [95% CI, 0.766–0.788]). The simplified model showed a similar or better predictive performance than the previous models. In the subgroup analysis, the models performed relatively better in patients without risk factors. Specifically, the predictive power was lower in patients with heart failure or decreased renal function.

Conclusions

Although the 3‐year AF prediction model using both clinical and ECG variables showed the highest performance, the simplified model using age, sex, and 5 ECG diagnoses also had a comparable prediction power with broad applicability for incident AF.

Background

Delayed brain development, brain injury, and neurodevelopmental disabilities are commonly observed in infants operated for complex congenital heart defect. Our previous findings of poorer neurodevelopmental outcomes in individuals operated for simple congenital heart defects calls for further etiological clarification. Hence, we examined the microstructural tissue composition in cerebral cortex and subcortical structures in comparison to healthy controls and whether differences were associated with neurodevelopmental outcomes.

Methods and Results

Adults (n=62) who underwent surgical closure of an atrial septal defect (n=33) or a ventricular septal defect (n=29) in childhood and a group of healthy, matched controls (n=38) were enrolled. Brain diffusional kurtosis imaging and neuropsychological assessment were performed. Cortical and subcortical tissue microstructure were assessed using mean kurtosis tensor and mean diffusivity and compared between groups and tested for associations with neuropsychological outcomes. Alterations in microstructural tissue composition were found in the parietal, temporal, and occipital lobes in the congenital heart defects, with distinct mean kurtosis tensor cluster‐specific changes in the right visual cortex (pericalcarine gyrus, P=0.002; occipital part of fusiform and lingual gyri, P=0.019). Altered microstructural tissue composition in the subcortical structures was uncovered in atrial septal defects but not in ventricular septal defects. Associations were found between altered cerebral microstructure and social recognition and executive function.

Conclusions

Children operated for simple congenital heart defects demonstrated altered microstructural tissue composition in the cerebral cortex and subcortical structures during adulthood when compared with healthy peers. Alterations in cerebral microstructural tissue composition were associated with poorer neuropsychological performance.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

Background

Neonates with heart disease requiring cardiopulmonary bypass surgery are at high risk for mortality and morbidity. As it is rare, short‐term mortality is difficult to use as a primary outcome for clinical studies. We proposed “ICU‐30” as a binary composite “poor” outcome consisting of: (1) mortality within 30 days, (2) intensive care unit (ICU) admission ≥30 days, or (3) ICU readmission before day 30. To measure the utility of this composite, we assessed its prognostic properties for 6‐ and 12‐month mortality.

Methods and Results

This was a retrospective single‐center cohort study of neonates requiring cardiopulmonary bypass between 2013 and 2020. Mortality among patients with and without the ICU‐30 outcome was compared using log‐rank tests and Cox regression. Areas under the receiver operating characteristic curves assessed the ability of the composite to predict 12‐month mortality. In 887 neonates, 232 (26.2%) experienced the ICU‐30 outcome, with more prolonged ICU stays and readmissions (both ≥9%) than 30‐day mortality (4.2%). ICU‐30 was associated with higher rates of 6‐ and 12‐month mortality (log‐rank P<0.001) and predicted 12‐month mortality with area under the receiver operating characteristic of 0.81 (95% CI, 0.77–0.85). In 30‐day survivors, both prolonged ICU stay (hazard ratio, 12.3; 95% CI, 6.70–22.7; P<0.001) and ICU readmission (hazard ratio, 2.99; 95% CI, 1.17–7.63; P=0.02) were associated with 12‐month mortality.

Conclusions

ICU‐30, a composite outcome of mortality, ICU length of stay, or ICU readmission by 30 days was associated with 6‐ and 12‐month mortality in neonates requiring cardiopulmonary bypass. ICU‐30 is captured in routine data collection and appears to be a valid binary patient‐centered outcome.

Background

Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex‐specific differential effect of genetically increased low‐density lipoprotein cholesterol (LDL‐C) on cardiovascular disease (CVD) and other lipid‐associated diseases.

Methods and Results

This is a 2‐sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80‐variant LDL‐C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex‐specific LDL‐C effects on lipids, carotid‐intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL‐C effect on CVD events was sex specific: per SD genetically increased LDL‐C, female participants had a higher LDL‐C increase but an attenuated CVD risk increase compared with male participants (LDL‐C: female participants 0.71 mmol/L, 95% CI, 0.70–0.72 and male participants 0.57 mmol/L, 95% CI, 0.56–0.59. P for interaction: 5.03×10⁻⁶⁰; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24–1.40 and male participants: OR, 1.52; 95% CI, 1.46–1.58. P for interaction: 9.88×10⁻⁵). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL‐C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL‐C was also associated with an attenuated carotid‐intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex‐specific weighted genetic scores showed similar results.

Conclusions

We found that genetically increased LDL‐C has a sex‐specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL‐C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL‐C targeted therapies for CVD management than female patients and warranting investigations into the sex‐specific relative contribution of risk factors for CVD.

Background

Cardiovascular diseases are the leading cause of death in the United States, yet a significant proportion of adults at high risk remain undetected by standard screening practices. Polygenic risk score for coronary artery disease (CAD‐PRS) improves precision in determining the 10‐year risk of atherosclerotic cardiovascular disease but health benefits and health care costs associated with CAD‐PRS are unknown. We examined the cost‐effectiveness of including CAD‐PRS as a risk‐enhancing factor in the pooled cohort equation (PCE)—the standard of care for determining the risk of atherosclerotic cardiovascular disease—versus PCE alone.

Methods and Results

We applied a Markov model on a cohort of 40‐year‐old individuals with borderline or intermediate 10‐year risk (5% to <20%) for atherosclerotic cardiovascular disease to identify those in the top quintile of the CAD‐PRS distribution who are at high risk and eligible for statin prevention therapy. Health outcomes examined included coronary artery disease (CAD; ie, myocardial infarction) and ischemic stroke. The model projected medical costs (2019 US$) of screening for CAD, statin prevention therapy, treatment, and monitoring patients living with CAD or ischemic stroke and quality‐adjusted life‐years for PCE+CAD‐PRS versus PCE alone. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed to examine uncertainty in parameter inputs. PCE+CAD‐PRS was dominant compared with PCE alone in the 5‐ and 10‐year time horizons. We found that, respectively, PCE+CAD‐PRS had 0.003 and 0.011 higher mean quality‐adjusted life‐years and $40 and $181 lower mean costs per person screened, with 29 and 50 fewer events of CAD and ischemic stroke in a cohort of 10 000 individuals compared with PCE alone. The risk of developing CAD, the effectiveness of statin prevention therapy, and the cost of treating CAD had the largest impact on the cost per quality‐adjusted life‐year gained. However, this cost remained below the $50 000 willingness‐to‐pay threshold except when the annual risk of developing CAD was <0.006 in the 5‐year time horizon. Results from Monte Carlo simulation indicated that PCE+CAD‐PRS would be cost‐effective. with the probability of 94% and 99% at $50 000 willingness‐to‐pay threshold in the 5‐ and 10‐year time horizon, respectively.

Conclusions

Implementing CAD‐PRS as a risk‐enhancing factor in the PCE to determine the risk of atherosclerotic cardiovascular disease reduced the mean cost per individual, improved quality‐adjusted life‐years, and averted future events of CAD and ischemic stroke when compared with PCE alone.

Background

Hypertension and diabetes disproportionately affect older non‐Hispanic Black and Hispanic adults in the United States. Chronic stress may partially explain these disparities. This study identified underlying stress profiles of older US adults, analyzed stress profiles in relation to hypertension and diabetes, examined the distribution of stress profiles by race and ethnicity, and assessed patterns of change in latent classes of stress over time.

Methods and Results

Latent class analysis was conducted with a nationally representative sample of older US adults who completed 3 waves of the HRS (Health and Retirement Study) (ie, 2010 [n=6863], 2014 [n=4995], and 2018 [n=3089]). Latent classes of stress in 2010 (ie, stress profiles) were identified using 15 indicators of unmet needs within 5 categories (ie, physiological, safety/security, belonging, esteem, and self‐fulfillment). Hypertension and diabetes status were examined as outcomes of latent class membership at 3 time points, and race and ethnicity were examined in association with class membership, adjusting for sociodemographic covariates. Finally, a latent transition analysis examined the stability of latent class membership and racial and ethnic differences in the patterns of stress profiles experienced from 2010 to 2018. Five classes were identified: Generally Unmet Needs (13% of sample), Generally Met Needs (42% of sample), Unmet Self‐Efficacy/Goal Needs (12% of sample), Unmet Financial Needs (20% of sample), and Unmet Social Belonging Needs (13% of sample). Compared with the Generally Met Needs class, the Generally Unmet Needs class had higher odds of hypertension (odds ratio [OR], 1.80; [95% CI, 1.35–2.39]) and diabetes (OR, 1.94; [95% CI, 1.45–2.59]), and the Unmet Financial Needs class had higher odds of diabetes (OR, 1.50; [95% CI, 1.10–2.05]). Non‐Hispanic Black participants compared with non‐Hispanic White participants had higher odds of being members of the Generally Unmet Needs, Unmet Self‐Efficacy/Goal Needs, and Unmet Financial Needs classes (OR, 2.70; [95% CI, 1.59–4.58]; OR, 1.99; [95% CI, 1.15–3.43]; and OR, 4.74; [95% CI, 3.32–6.76], respectively). Class membership remained relatively stable over time, with 93% of participants remaining in Generally Met Needs and 78% of participants remaining in Generally Unmet Needs across time points. Compared with non‐Hispanic White participants, non‐Hispanic Black participants had lower odds of Generally Met Needs class membership at any time point (OR, 0.60; [95% CI, 0.42–0.84]) and had lower odds of moving into the Generally Met Needs class and higher odds of moving into the Unmet Financial Needs class from 2010 to 2014 (OR, 0.33; [95% CI, 0.13–0.86]; and OR, 3.02; [95% CI, 1.16–7.87], respectively).

Conclusions

Underlying classes of stress based on unmet needs were associated with hypertension and diabetes status. Racial and ethnic differences were observed for both latent class membership and transitions between classes over time. Latent classes of stress associated with unmet needs, hypertension, and diabetes and the ability to transition between classes may explain the perpetuation of racial and ethnic disparities in cardiovascular health. Interventions targeting unmet needs may be used to confront these disparities.

Background

There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID‐19.

Methods and Results

The French National Healthcare Data System database was used to conduct a matched‐cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID‐19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long‐term medications. Its association with in‐hospital death from COVID‐19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID‐19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81–0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low‐ and moderate‐intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71–0.86] and HR, 0.84 [95% CI, 0.80–0.89], respectively), whereas high‐intensity statins did not (HR, 1.01; 95% CI, 0.86–1.18). We found similar results with in‐hospital death from COVID‐19.

Conclusions

Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID‐19 and of in‐hospital death from COVID‐19.

Background

Prior studies have reported disparities by race in the management of acute myocardial infarction (MI), with many studies having limited covariates or now dated. We examined racial and ethnic differences in the management of MI, specifically non–ST‐segment‐elevation MI (NSTEMI), in a large, socially diverse cohort of insured patients. We hypothesized that the racial and ethnic disparities in the receipt of coronary angiography or percutaneous coronary intervention would persist in contemporary data.

Methods and Results

We identified individuals presenting with incident, type I NSTEMI from 2017 to 2019 captured by a health claims database. Race and ethnicity were categorized by the database as Asian, Black, Hispanic, or White. Covariates included demographics (age, sex, race, and ethnicity); Elixhauser variables, including cardiovascular risk factors and other comorbid conditions; and social factors of estimated annual household income and educational attainment. We examined rates of coronary angiography and percutaneous coronary intervention by race and ethnicity and income categories and in multivariable‐adjusted models. We identified 87 094 individuals (age 73.8±11.6 years; 55.6% male; 2.6% Asian, 13.4% Black, 11.2% Hispanic, 72.7% White) with incident NSTEMI events from 2017 to 2019. Individuals of Black race were less likely to undergo coronary angiography (odds ratio [OR], 0.93; [95% CI, 0.89–0.98]) and percutaneous coronary intervention (OR, 0.86; [95% CI, 0.81–0.90]) than those of White race. Hispanic individuals were less likely (OR, 0.88; [95% CI, 0.84–0.93]) to undergo coronary angiography and percutaneous coronary intervention (OR, 0.85; [95% CI, 0.81–0.89]) than those of White race. Higher annual household income attenuated differences in the receipt of coronary angiography across all racial and ethnic groups.

Conclusions

We identified significant racial and ethnic differences in the management of individuals presenting with NSTEMI that were marginally attenuated by higher household income. Our findings suggest continued evidence of health inequities in contemporary NSTEMI treatment.

Background

Exercise is associated with a reduced risk of cardiovascular disease. Increased high‐density lipoprotein cholesterol (HDL‐C) levels are thought to contribute to these benefits, but much of the research in this area has been limited by lack of well‐controlled subject selection and exercise interventions. We sought to study the effect of moderate and high‐intensity exercise on HDL function, lipid/lipoprotein profile, and other cardiometabolic parameters in a homogeneous population where exercise, daily routine, sleep patterns, and living conditions were carefully controlled.

Methods and Results

Male Army recruits (n=115, age 22±0.3 years) completed a 12‐week moderate‐intensity exercise program. A subset of 51 subsequently completed a 15‐week high‐intensity exercise program. Fitness increased and body fat decreased after moderate‐ and high‐intensity exercise (P<0.001). Moderate‐intensity exercise increased HDL‐C and apolipoprotein A‐I levels (6.6%, 11.6% respectively), and decreased low‐density lipoprotein cholesterol and apolipoprotein B levels (7.2%, 4.9% respectively) (all P<0.01). HDL‐C and apolipoprotein A‐I levels further increased by 8.2% (P<0.001) and 6.3% (P<0.05) after high‐intensity exercise. Moderate‐intensity exercise increased ABCA‐1 (ATP‐binding cassette transporter A1) mediated cholesterol efflux by 13.5% (P<0.001), which was sustained after high‐intensity exercise. In a selected subset the ability of HDLs to inhibit ICAM‐1 (intercellular adhesion molecule‐1) expression decreased after the high (P<0.001) but not the moderate‐intensity exercise program.

Conclusions

When controlling for exercise patterns, diet, and sleep, moderate‐intensity exercise improved HDL function, lipid/lipoprotein profile, fitness, and body composition. A sequential moderate followed by high‐intensity exercise program showed sustained or incremental benefits in these parameters. Improved HDL function may be part of the mechanism by which exercise reduces cardiovascular disease risk.

Background

Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension.

Methods and Results

We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self‐identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable‐adjusted regression modeling. Multivariable‐adjusted genotype‐stratified differences in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and BNP (B‐type natriuretic peptide) levels were assessed. Genotype‐stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; −1.24±0.82), diastolic BP (0.51±0.33; −0.41±0.46), mean arterial pressure (0.48±0.38; −0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80–1.09]; OR, 0.79 [95% CI, 0.61–1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; −1.26±0.81), diastolic BP (0.52±0.33; −0.33±0.45), mean arterial pressure (0.50±0.38; −0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84–1.23]; OR, 0.87 [95% CI, 0.67–1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94–1.93]; OR, 0.95 [95% CI, 0.64–1.39]) in the study cohorts. The NT‐proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups.

Conclusions

Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Background

Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We investigated whether common and rare genetic variants in HMGCR are associated with cataract risk, to gauge the likely long‐term effects of statin treatment on lenticular opacities.

Methods and Results

We used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of HMGCR and cataract risk. First, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low‐density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss‐of‐function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >402 000 individuals, a 38.7 mg/dL (1 mmol/L) reduction in low‐density lipoprotein C by the HMGCR genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00–1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06–1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we identified 32 participants (0.02%), who carried a rare HMGCR predicted loss‐of‐function variant. Compared with noncarriers, heterozygous carriers of HMGCR predicted loss‐of‐function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96–10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27–12.25], P=5.37×10⁻⁴). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low‐density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk.

Conclusions

We found that genetically proxied inhibition of the HMGCR gene mimicking long‐term statin treatment associated with higher risk of cataract. Clinical trials with longer follow‐up are needed to confirm these findings.

Background

Determine the prevalence and predictors associated with underdiagnosis and undertreatment of modifiable cardiovascular disease (CVD) risk factors (hypertension, dyslipidemia, glucose intolerance/diabetes) among adult survivors of childhood cancer at high risk of premature CVD.

Methods and Results

This was a cross‐sectional study of adult‐aged survivors of childhood cancer treated with anthracyclines or chest radiotherapy, recruited across 9 US metropolitan regions. Survivors completed questionnaires and in‐home clinical assessments. The comparator group was a matched sample from the National Health and Nutrition Examination Survey. Multivariable logistic regression estimated the risk (odds ratios) of CVD risk factor underdiagnosis and undertreatment among survivors compared with the National Health and Nutrition Examination Survey. Survivors (n=571; median age, 37.7 years and 28.5 years from cancer diagnosis) were more likely to have a preexisting CVD risk factor than the National Health and Nutrition Examination Survey (n=345; P<0.05 for all factors). While rates of CVD risk factor underdiagnosis were similar (27.1% survivors versus 26.1% National Health and Nutrition Examination Survey; P=0.73), survivors were more likely undertreated (21.0% versus 13.9%, P=0.007; odds ratio, 1.8, 95% CI, 1.2–2.7). Among survivors, the most underdiagnosed and undertreated risk factors were hypertension (18.9%) and dyslipidemia (16.3%), respectively. Men and survivors who were overweight/obese were more likely to be underdiagnosed and undertreated. Those with multiple adverse lifestyle factors were also more likely undertreated (odds ratio, 2.2, 95% CI, 1.1–4.5). Greater health‐related self‐efficacy was associated with reduced undertreatment (odds ratio, 0.5; 95% CI, 0.3–0.8).

Conclusions

Greater awareness of among primary care providers and cardiologists, combined with improving self‐efficacy among survivors, may mitigate the risk of underdiagnosed and undertreated CVD risk factors among adult‐aged survivors of childhood cancer.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03104543.

Background

Extracellular vesicles (EVs) are a popular treatment candidate for myocardial injury. This work investigated the effects of mesenchymal stem cells (MSCs)–secreted EVs–derived miR‐200b‐3p on cardiomyocyte apoptosis and inflammatory response after myocardial infarction (MI) through targeting BCL2L11 (Bcl‐2–like protein 11) .

Methods and Results

EVs from MSCs were isolated and identified. EVs from MSCs with transfection of miR‐200b‐3p for overexpression were injected into MI mice. The effect of miR‐200b‐3p on cardiac function, infarction area, myocardial fibrosis, cardiomyocyte apoptosis, and inflammatory response was determined in MI mice. The targeting relationship between miR‐200b‐3p and BCL2L11 was verified, and the interaction between BCL2L11 and NLR family pyrin domain containing 1 (NLRP1) was also verified. MI mice were injected with an overexpressing BCL2L11 lentiviral vector to clarify whether BCL2L11 can regulate the effect of miR‐200b‐3p on MI mice. EVs from MSCs were successfully extracted. MSCs‐EVs improved cardiac function and reduced infarction area, apoptosis of cardiomyocytes, myocardial fibrosis, and inflammation in MI mice. Upregulation of miR‐200b‐3p further enhanced the effects of MSCs‐EVs on the myocardial injury of MI mice. BCL2L11 was targeted by miR‐200b‐3p and bound to NLRP1. Upregulation of BCL2L11 negated the role of miR‐200b‐3p–modified MSCs‐EVs in MI mice.

Conclusions

A summary was obtained that miR‐200b‐3p–encapsulated MSCs‐EVs protect against MI‐induced apoptosis of cardiomyocytes and inflammation via suppressing BCL2L11.

Background

We aimed to characterize the occurrence of major adverse cardiovascular and limb events (MACE and MALE) among patients with peripheral artery disease (PAD) undergoing peripheral vascular intervention (PVI), as well as associated factors in patients with chronic limb threatening ischemia (CLTI).

Methods and Results

Patients undergoing PVI in the American College of Cardiology’s (ACC) National Cardiovascular Data Registry’s PVI Registry who could be linked to Centers for Medicare and Medicaid Services data were included. The primary outcomes were MACE, MALE, and readmission within 1 month and 1 year following index CLTI‐PVI or non‐CLTI‐PVI. Cox proportional hazards regression was used to identify factors associated with the development of the primary outcomes among patients undergoing CLTI‐PVI. There were 1758 (49.7%) patients undergoing CLTI‐PVI and 1779 (50.3%) undergoing non‐CLTI‐PVI. By 1 year, MACE occurred in 29.5% of patients with CLTI (n=519), and MALE occurred in 34.0% of patients with CLTI (n=598). By 1 year, MACE occurred in 8.2% of patients with non‐CLTI (n=146), and MALE occurred in 26.1% of patients with non‐CLTI (n=465). Predictors of MACE at 1 year in CLTI‐PVI included end‐stage renal disease on hemodialysis, congestive heart failure, prior CABG, and severe lung disease. Predictors of MALE at 1 year in CLTI‐PVI included treatment of a prior bypass graft, profunda femoral artery treatment, end‐stage renal disease on hemodialysis, and treatment of a previously treated lesion.

Conclusions

Patients ≥65 years old undergoing PVI experience high rates of MACE and MALE. A range of modifiable and non‐modifiable patient factors, procedural characteristics, and medications are associated with the occurrence of MACE and MALE following CLTI‐PVI.

Background

Several imaging parameters and biomarkers provide diagnostic and prognostic information for wild‐type transthyretin amyloid cardiomyopathy. However, the relevance of these parameters and their association with cardiac amyloid load requires further substantiation. We aimed to elucidate the association of imaging parameters obtained using ^99mTc‐labeled pyrophosphate scintigraphy, cardiovascular magnetic resonance imaging, global longitudinal strain (GLS), and cardiac biomarkers with cardiac amyloid load in patients with wild‐type transthyretin amyloid cardiomyopathy.

Methods and Results

Eighty‐eight patients with wild‐type transthyretin amyloid cardiomyopathy who underwent ^99mTc‐labeled pyrophosphate scintigraphy and cardiovascular magnetic resonance were retrospectively evaluated. Quantitative cardiac amyloid load was obtained from 61 patients after myocardial biopsy. Correlations were assessed using Pearson’s correlation coefficient applied to medical record data. The mean heart to contralateral ratio, native T1, extracellular volume, and GLS were 1.91±0.36, 1419.4±56.4 ms, 56.5±13.6%, and −9.4±2.5%, respectively. Median high‐sensitivity cardiac troponin T (hs‐cTnT) and BNP (B‐type natriuretic peptide) levels were 0.0478 (0.0334‐0.0691) ng/mL and 213.8 (125.8–392.7) pg/mL, respectively. The mean cardiac amyloid load was 22.9±15.0%. The heart to contralateral ratio correlated significantly with native T1 (r=0.397), extracellular volume (r=0.477), GLS (r=0.363), cardiac amyloid load (r=0.379), and Ln (hs‐cTnT) (r=0.247). Further, cardiac amyloid load correlated significantly with native T1 (r=0.509), extracellular volume (r=0.310), GLS (r=0.446), and Ln (hs‐cTnT) (r=0.354). Compared with BNP, hs‐cTnT levels better correlated with several imaging parameters and cardiac amyloid load.

Conclusions

Increased cardiac amyloid load correlated with increased ^99mTc‐labeled pyrophosphate positivity, native T1, extracellular volume, and hs‐cTnT levels, and an impaired GLS, suggesting that imaging parameters and cardiac biomarkers may reflect histological and functional changes attributable to amyloid deposition in the myocardium.

Background

Epigenetic modulators have been proposed as promising new drug targets to treat adverse remodeling in heart failure. Here, we evaluated the potential of 4 epigenetic drugs, including the recently developed histone deacetylase 6 (HDAC6) inhibitor JS28, to prevent endothelin‐1 induced pathological gene expression in cardiac myocytes and analyzed the chromatin binding profile of the respective inhibitor targets.

Methods and Results

Cardiac myocytes were differentiated and puromycin‐selected from mouse embryonic stem cells and treated with endothelin‐1 to induce pathological gene expression (938 differentially expressed genes, q<0.05). Dysregulation of gene expression was at least in part prevented by epigenetic inhibitors, including the pan‐BRD (bromodomain‐containing protein) inhibitor bromosporine (290/938 genes), the BET (bromodomain and extraterminal) inhibitor JQ1 (288/938), the broad‐spectrum HDAC inhibitor suberoylanilide hydroxamic acid (227/938), and the HDAC6 inhibitor JS28 (210/938). Although the 4 compounds were similarly effective toward pathological gene expression, JS28 demonstrated the least adverse effects on physiological gene expression. Genome‐wide chromatin binding profiles revealed that HDAC6 binding sites were preferentially associated with promoters of genes involved in RNA processing. In contrast, BRD4 binding was associated with genes involved in core cardiac myocyte functions, for example, myocyte contractility, and showed enrichment at enhancers and intronic regions. These distinct chromatin binding profiles of HDAC6 and BRD4 might explain the different effects of their inhibitors on pathological versus physiological gene expression.

Conclusions

In summary, we demonstrated, that the HDAC6 inhibitor JS28 effectively prevented the adverse effects of endothelin‐1 on gene expression with minor impact on physiological gene expression in cardiac myocytes. Selective HDAC6 inhibition by JS28 appears to be a promising strategy for future evaluation in vivo and potential translation into clinical application.

Background

There are limited data on the use of angiotensin receptor neprilysin inhibitors (ARNIs) in minority populations with heart failure (HF) with reduced ejection fraction. We used data from the CHAMP‐HF (Change the Management of Patients With Heart Failure) registry to evaluate ARNI initiation and associated changes in health status and clinical outcomes across different races and ethnicities.

Methods and Results

CHAMP‐HF was a prospective, observational registry of US outpatients with chronic HF with reduced ejection fraction. We compared patients starting ARNI with patients not starting ARNI using a propensity‐matched analysis. Patients were grouped as Hispanic, non‐Hispanic Black, non‐Hispanic White, or non‐Hispanic other individuals, where “non‐Hispanic other” consists of all patients who did not identify as Hispanic, Black, or White. Health status was assessed using the 12‐item Kansas City Cardiomyopathy Questionnaire. Outcomes were analyzed with multivariable models that included race and ethnicity, ARNI initiation, and an interaction term between race and ethnicity and ARNI initiation. Cox proportional hazards models were used for death/HF hospitalization, and multiple regression was used for change in Kansas City Cardiomyopathy Questionnaire score. The analysis included 1516 patients, with 758 patients in each group (ARNI and no ARNI). Changes in Kansas City Cardiomyopathy Questionnaire score after ARNI initiation were similar among all race and ethnicity groups (mean [SD], non‐Hispanic White individuals, 3.5 [19.0]; non‐Hispanic Black individuals, 2.0 [17.0]; non‐Hispanic other individuals, 5.5 [20.3]; and Hispanic individuals, 3.2 [20.1]), with no statistically significant interaction between race and ethnicity and ARNI initiation (P=0.21). There was similarly no statistically significant interaction between race and ethnicity and ARNI initiation for HF hospitalization (P=0.82) or all‐cause mortality (P=0.92).

Conclusions

In a large registry of outpatients with HF with reduced ejection fraction, the association between ARNI initiation and outcomes did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HF with reduced ejection fraction irrespective of race and ethnicity.

Background

Sacubitril/valsartan improves health outcomes for heart failure with reduced ejection fraction relative to angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers, but it carries higher out‐of‐pocket costs. Neither the impact of cost nor how to integrate cost into medical decisions is well studied.

Methods and Results

To evaluate the impact of out‐of‐pocket costs and a novel cost‐priming intervention on willingness to take sacubitril/valsartan for heart failure with reduced ejection fraction, participants with self‐reported heart disease were surveyed using the online Ipsos Knowledge Panel. Participants were presented with a modified decision aid for sacubitril/valsartan and then, in a 3×2 factorial design, randomly assigned to 1 of 3 cost conditions ($10, $50, or $100/month) and to a control group or cost‐priming intervention, defined by being asked questions about their financial situation before learning about the benefits of sacubitril/valsartan. Of the 1013 participants included in the analysis, 85% of respondents were willing to take sacubitril/valsartan at $10, 62% at $50, and 33% at $100 (P<0.0001). In a multivariable logistic regression model, participants were more likely to take sacubitril/valsartan at $10 versus $100 (odds ratio [OR], 14.3 [95% CI, 9.4–21.8]) and $50 compared with $100 (OR, 3.6 [95% CI, 2.5–5.1]). Overall, participants in the cost‐primed group were more willing to take sacubitril/valsartan than those not primed to consider their financial situation (63% versus 56%, P=0.04). There was no statistically significant interaction between cost conditions and cost priming. Perceived benefit of sacubitril/valsartan over angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers decreased as cost increased but did not vary by cost priming.

Conclusions

Commonly encountered out‐of‐pocket costs of sacubitril/valsartan may impact individuals’ willingness to take the medication even when recommended by their physicians. Priming individuals to consider personal finances before learning about the drug increased willingness to take sacubitril/valsartan.

Background

Blood pressure associates with arterial stiffness, but the contribution of blood pressure at different life stages is unclear. We examined the relative contribution of childhood, young‐ and mid‐adulthood blood pressure to mid‐adulthood large artery stiffness.

Methods and Results

The sample comprised 1869 participants from the Cardiovascular Risk in Young Finns Study who had blood pressure measured in childhood (6–18 years), young‐adulthood (21–30 years), and mid‐adulthood (33–45 years). Markers of large artery stiffness were pulse wave velocity and carotid distensibility recorded in mid‐adulthood. Bayesian relevant life course exposure models were used. For each 10‐mm Hg higher cumulative systolic blood pressure across the life stages, pulse wave velocity was 0.56 m/s higher (95% credible interval: 0.49 to 0.63) and carotid distensibility was 0.13%/10 mm Hg lower (95% credible interval: −0.16 to −0.10). Of these total contributions, the highest contribution was attributed to mid‐adulthood systolic blood pressure (relative weights: pulse wave velocity, childhood: 2.6%, young‐adulthood: 5.4%, mid‐adulthood: 92.0%; carotid distensibility, childhood: 5.6%; young‐adulthood: 10.1%; mid‐adulthood: 84.3%), with the greatest individual contribution coming from systolic blood pressure at the time point when pulse wave velocity and carotid distensibility were measured. The results were consistent for diastolic blood pressure, mean arterial pressure, and pulse pressure.

Conclusions

Although mid‐adulthood blood pressure contributed most to mid‐adulthood large artery stiffness, we observed small contributions from childhood and young‐adulthood blood pressure. These findings suggest that the burden posed by arterial stiffness might be reduced by maintaining normal blood pressure levels at each life stage, with mid‐adulthood a critical period for controlling blood pressure.

Background

TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study.

Methods and Results

Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P=0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P=0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value (P_int=0.59) or BARC bleeding (P_int=0.47) nor for sex and genotype (MACE P_int=0.15, and BARC bleeding P_int=0.60).

Conclusions

CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01742117.

Background

The role of invasive management compared with medical management in patients with non–ST‐segment–elevation myocardial infarction (NSTEMI) and advanced chronic kidney disease (CKD) is uncertain, given the increased risk of procedural complications in patients with CKD. We aimed to compare clinical outcomes of invasive management with medical management in patients with NSTEMI‐CKD.

Methods and Results

We identified NSTEMI and CKD stages 3, 4, 5, and end‐stage renal disease admissions using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) codes from the Nationwide Readmission Database 2016 to 2018. Patients were stratified into invasive and medical management. Primary outcome was mortality (in‐hospital and 6 months after discharge). Secondary outcomes were in‐hospital postprocedural complications (acute kidney injury requiring dialysis, major bleeding) and postdischarge 6‐month safety and major adverse cardiovascular events. Out of 141 052 patients with NSTEMI‐CKD, 85 875 (60.9%) were treated with invasive management, whereas 55 177 (39.1%) patients were managed medically. In propensity‐score matched cohorts, invasive strategy was associated with lower in‐hospital (CKD 3: odds ratio [OR], 0.47 [95% CI, 0.43–0.51]; P<0.001; CKD 4: OR, 0.79 [95% CI, 0.69–0.89]; P<0.001; CKD 5: OR, 0.72 [95% CI, 0.49–1.06]; P=0.096; end‐stage renal disease: OR, 0.51 [95% CI, 0.46–0.56]; P<0.001) and 6‐month mortality. Invasive management was associated with higher in‐hospital postprocedural complications but no difference in postdischarge safety outcomes. Invasive management was associated with a lower hazard of major adverse cardiovascular events at 6 months in all CKD groups compared with medical management.

Conclusions

Invasive management was associated with lower mortality and major adverse cardiovascular events but minimal increased in‐hospital complications in patients with NSTEMI‐CKD compared with medical management, suggesting patients with NSTEMI‐CKD should be offered invasive management.

Background

There are few studies on the association with Kawasaki disease in children and the family’s history of cardiovascular disease (CVD). The aim of this study was to identify the association of increased risks for Kawasaki disease in children with a family history of CVD.

Methods and Results

Clinical data of children born in 2008 and 2009 (n=917 707) were obtained from the National Health Insurance Service and the National Health Screening Program for Infants and Children for this study. The cohort consisted of 495 215 participants (53.8%) who completed the family history questionnaire for children 54 to 60 months old. Family history of CVD included 5 medical conditions: hypertension, dyslipidemia, myocardial infarction, stroke, and diabetes. Kawasaki disease was defined using the disease code, intravenous immunoglobulin prescription, and use of antipyretics for more than 25 days. Severe Kawasaki disease was defined as diagnosis of accompanied cardiac/coronary artery complications or intravenous immunoglobulin use ≥2 times. The incidence rate of Kawasaki disease was 124/100 000 person‐years (95% CI, 117.5–131.5) for children <2 years old, 95/100 000 person‐years (95% CI, 90.5–100.4) in children 2 to 5 years old, and 14/100 000 person‐years (95% CI, 12.6–15.6) in children >5 years old. After propensity‐score matching, 829 participants with a family history of CVD were diagnosed as having Kawasaki disease (0.68% [95% CI, 0.63–0.72]), and 690 patients with Kawasaki disease (0.56% [95% CI, 0.52–0.61]) had no family history of CVD. The family history of CVD was associated with increased risk for Kawasaki disease (risk ratio, 1.20 [95% CI, 1.08–1.32]) but not for severe Kawasaki disease (risk ratio, 1.23 [95% CI, 0.92–1.65]).

Conclusions

In this nationwide propensity‐score matched study, those with a family history of CVD had a significantly greater risk of Kawasaki disease compared with those who had no family history of CVD.

Background

Evidence of scaled‐up physical activity interventions is scarce. This study evaluates the uptake, engagement, and effectiveness of one such intervention program.

Methods and Results

The program was open to individuals aged ≥17 years in Singapore. The main intervention components comprised device‐based daily physical activity recording paired with step count goals and financial rewards. According to the different reward opportunities, we divided the evaluation period (August 2017 to June 2018) into the baseline monitoring phase, the main challenge phase, and the maintenance phase. Uptake was assessed by the number of individuals registered, and engagement by the step recording duration after registration. The effectiveness was defined as changes in mean daily step count from baseline to the main challenge phase and the maintenance phase. A total of 696 907 participants registered, including more Singapore citizens (versus noncitizens), women, and younger (aged 17–39 years) individuals. The evaluation of engagement and effectiveness included 421 388 (60.5%) participants who provided plausible characteristic information and step count data. The median duration of engagement was 74 (IQR, 14–149) days. Compared with the baseline of 7509 (SD, 3467) steps, mean daily step count increased by 1579 (95% CI, 1564–1594) steps during the main challenge phase and 934 (95% CI, 916–952) steps during the maintenance phase. Greater engagement and activity increase were found in participants who are citizens, women, aged ≥40 years, non‐obese, and using separate wearables (versus smartphones).

Conclusions

Mobile health physical activity interventions can successfully reach a large population and be effective in increasing physical activity, despite declining program engagement over time.

Background

Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long‐term cardiovascular outcomes in pre‐transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long‐term cardiovascular outcomes in kidney transplant candidates.

Methods and Results

We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom‐limited exercise stress echocardiography for pre‐transplant cardiovascular assessment. Exercise capacity was measured by age‐ and sex‐predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non‐fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time‐varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow‐up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29–0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30–0.91], P=0.02). Patients achieving predicted METs on pre‐transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32–1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42–2.25], P=0.95).

Conclusions

Achievement of predicted METs on pre‐transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

Background

Predicting a spontaneous rhythm change from nonshockable to shockable before hospital arrival in patients with out‐of‐hospital cardiac arrest can help emergency medical services develop better strategies for prehospital treatment. The aim of this study was to identify predictors of spontaneous rhythm change before hospital arrival in patients with out‐of‐hospital cardiac arrest and develop a predictive scoring system.

Methods and Results

We retrospectively reviewed data of eligible patients with out‐of‐hospital cardiac arrest with an initial nonshockable rhythm registered in a nationwide registry between June 2014 and December 2017. We performed a multivariable analysis using a Cox proportional hazards model to identify predictors of a spontaneous rhythm change, and a ridge regression model for predicting it. The data of 25 804 patients were analyzed (derivation cohort, n=17 743; validation cohort, n=8061). The rhythm change event rate was 4.1% (724/17 743) in the derivation cohort, and 4.0% (326/8061) in the validation cohorts. Age, sex, presence of a witness, initial rhythm, chest compression by a bystander, shock with an automated external defibrillator by a bystander, and cause of the cardiac arrest were all found to be independently associated with spontaneous rhythm change before hospital arrival. Based on this finding, we developed and validated the Rhythm Change Before Hospital Arrival for Nonshockable score. The Harrell’s concordance index values of the score were 0.71 and 0.67 in the internal and external validations, respectively.

Conclusions

Seven factors were identified as predictors of a spontaneous rhythm change from nonshockable to shockable before hospital arrival. We developed and validated a score to predict rhythm change before hospital arrival.

Background

The small GTPase RhoA (Ras homolog gene family, member A) regulates a variety of cellular processes, including cell motility, proliferation, survival, and permeability. In addition, there are reports indicating that RhoA‐ROCK (rho associated coiled‐coil containing protein kinase) activation is essential for VEGF (vascular endothelial growth factor)‐mediated angiogenesis, whereas other work suggests VEGF‐antagonistic effects of the RhoA‐ROCK axis.

Methods and Results

To elucidate this issue, we examined human umbilical vein endothelial cells and human coronary artery endothelial cells after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant‐negative (T19N), or wild‐type RhoA using a series of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a human umbilical vein endothelial cells xenograft assay in immune‐incompetent NOD scid gamma mice in vivo. Here, we report that expression of active and wild‐type RhoA but not dominant‐negative RhoA significantly inhibited endothelial cell proliferation, migration, tube formation, and angiogenic sprouting in vitro. Moreover, active RhoA increased endothelial cell death in vitro and decreased human umbilical vein endothelial cell‐related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized the inhibitory effects of RhoA and strongly enhanced VEGF‐induced angiogenic sprouting in control‐treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 (LIM domain kinase 1/2) did not significantly affect RhoA‐related effects, but increased angiogenic sprouting and migration of control‐treated cells. In agreement with these data, VEGF did not activate RhoA in human umbilical vein endothelial cells as measured by a Förster resonance energy transfer–based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology enrichment analyses revealed that constitutively active RhoA induced a differentially expressed gene pattern that was enriched for gene ontology biological process terms associated with mitotic nuclear division, cell proliferation, cell motility, and cell adhesion, which included a significant decrease in VEGFR‐2 (vascular endothelial growth factor receptor 2) and NOS3 (nitric oxide synthase 3) expression.

Conclusions

Our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and antiangiogenic effects independently of its well‐characterized downstream effectors ROCK and LIMK.

Background

Despite high female prevalence of peripheral artery disease (PAD), little is known about sex‐based outcomes after lower extremity revascularization (LER) for symptomatic PAD. The effects of rivaroxaban according to sex following LER have not been fully reported.

Methods and Results

In VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease), low‐dose rivaroxaban versus placebo on a background of aspirin reduced the composite primary efficacy outcome of cardiovascular and limb events in patients with PAD undergoing LER. Unplanned index limb revascularization was prespecified and prospectively ascertained. The primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding. Analyses of outcomes and treatment effects by sex were performed using Cox proportional hazards models. Among 6564 randomly assigned patients followed for a median of 28 months, 1704 (26.0%) were women. Among patients administered placebo, women were at similar risk for the primary efficacy outcome (hazard ratio [HR], 0.90; [95% CI, 0.74–1.09]; P=0.29) as men, while female sex was associated with a trend toward higher risk of unplanned index limb revascularization (HR, 1.18; [95% CI, 1.00–1.40]; P=0.0499). Irrespective of sex, effects of rivaroxaban were consistent for the primary efficacy outcome (P‐interaction=0.22), unplanned index limb revascularization (P‐interaction=0.64), and bleeding (P‐interaction=0.61). Women were more likely than men to discontinue study treatment (HR, 1.13; [95% CI, 1.03–1.25]; P=0.0099).

Conclusions

Among >1700 women with PAD undergoing LER, women and men were at similar risk for the primary outcome, but a trend for greater risk of unplanned index limb revascularization among women was observed. Effects of rivaroxaban were consistent by sex, though women more often discontinued treatment. Better understanding of sex‐based outcomes and treatment adherence following LER is needed.

Registration

URL: http://clinicaltrials.gov; Unique identifier: NCT02504216.

Background

Fibromuscular dysplasia (FMD) is a disease of unknown etiology that causes stenosis, aneurysmal dilatation, and dissection of vascular beds. Known to affect medium‐sized arteries, FMD is not typically considered to affect the aorta. We tested the hypothesis that aortic size in FMD is abnormal compared with age‐ and sex‐matched controls.

Methods and Results

Medical records and computed tomography angiography images were reviewed in female patients with a diagnosis of FMD who were seen in the vascular medicine clinic at Emory Healthcare. Aortic dimensions were measured at 6 different landmarks. Using 2 sample t tests, the aortic measurements and height‐indexed measurements were compared with published normal values in healthy women of a similar age. A total of 94 female patients were included in the study. The median age was 57 (interquartile range, 50–65). FMD involvement was present most commonly in the extracranial carotid (77.7%) and renal (43.6%) arteries. All 6 aortic segments were found to be larger in both absolute measures and height‐indexed measures in the FMD population (P<0.001). The largest differences were observed within the absolute measures of the sinotubular junction with mean±SD (mm) (29.9±4.1) versus (27±2.5), ascending aorta (32.7±4.4) versus (30.0±3.5), and descending aorta (24.7±3.0) versus (22.0±2.0) (P<0.001).

Conclusions

Aortic diameters in female patients with FMD are larger when compared with published age‐ and sex‐matched normal values. These findings suggest that FMD may also affect the large‐sized arteries.

Background

There is a concern that resheathing/repositioning of transcatheter heart valves during transcatheter aortic valve implantation (TAVI) may lead to an increased risk of periprocedural complications. We aimed to evaluate the short‐ and long‐term impact on clinical outcomes of resheathing for repositioning of transcatheter heart valves during TAVI procedures.

Methods and Results

We conducted a systematic search of Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases to identify studies comparing outcomes between patients requiring resheathing/repositioning during TAVI and those who did not. Random‐effects meta‐analyses were used to estimate the association of resheathing compared with no resheathing with clinical outcomes after TAVI. Seven studies including 4501 participants (pooled mean age, 80.9±7.4 years; 54% women; and 1374 [30.5%] patients requiring resheathing/repositioning) were included in this study. No significant differences between the 2 groups were identified with regards to safety: 30‐day mortality (n=3125; odds ratio [OR], 0.74 [95% confidence interval [CI], 0.41–1.33]; I²=0%), stroke (n=4121; OR, 1.09 [95% CI, 0.74–1.62]; I²=0%), coronary obstruction (n=3000; OR, 2.35 [95% CI, 0.17–33.47]; I²=75%), major vascular complications (n=3125; OR, 0.92 [95% CI, 0.66–1.33]; I²=0%), major bleeding (n=3125; OR, 1.13 [95% CI, 0.94–2.01]; I²=39%), acute kidney injury (n=3495; OR, 1.30 [95% CI, 0.64–2.62]; I²=44%), and efficacy outcomes: device success (n=1196; OR, 0.77 [95% CI, 0.51–1.14]; I²=0%), need for a second valve (n=3170; OR, 2.86 [95% CI, 0.96–8.48]; I²=62%), significant (moderate or higher) paravalvular leak (n=1151; OR, 1.53 [95% CI, 0.83–2.80]; I²=0%), and permanent pacemaker implantation (n=1908; OR, 1.04 [95% CI, 0.68–1.57]; I²=58%). One‐year mortality was similar between groups (n=1972; OR, 1.00 [95% CI, 0.68–1.47]; I²=0%).

Conclusions

Resheathing of transcatheter heart valves during TAVI is associated with similar periprocedural risk compared with no resheathing in several patient‐important outcomes. These data support the safety of current self‐expanding transcatheter heart valves with resheathing features.

Registration

URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021273715.

Background

Cerebral small‐vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best‐known gene, several others have been reported. We aimed to summarize the cerebral phenotypes associated with these more recent cSVD genes.

Methods and Results

We performed a systematic review (PROSPERO [International Prospective Register of Systematic Reviews]: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals’ characteristics and clinical and vascular radiological cerebral phenotypes. We summarized phenotype frequencies per gene, comparing patterns across genes. We screened 6485 publications including 402, and extracted data on 390 individuals with COL4A1, 123 with TREX1, 44 with HTRA1 homozygous, 41 with COL4A2, 346 with ADA2, 82 with HTRA1 heterozygous, and 14 with CTSA. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke, 9% (TREX1) to 52% (HTRA1 heterozygotes); cognitive features, 0% (ADA2) to 64% (HTRA1 homozygotes); and psychiatric features, 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischemic and hemorrhagic lesions dominated, respectively.

Conclusions

There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterization of associated phenotypes, as well as insights from population‐based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.

Background

Bifurcation lesions account for 20% of all percutaneous coronary interventions and represent a complex subset which are associated with lower procedural success and higher rates of restenosis. The ideal bifurcation technique, however, remains elusive.

Methods and Results

Extensive search of the literature was performed to pull data from randomized clinical trials that met predetermined inclusion criteria. Conventional meta‐analysis produced pooled relative risk (RR) and 95% CI of 2‐stent technique versus provisional stent on prespecified outcomes. Both frequentist and Bayesian network meta‐analyses were performed to compare bifurcation techniques. A total of 8318 patients were included from 29 randomized clinical trials. Conventional meta‐analysis showed no significant differences in all‐cause mortality, cardiac death, major adverse cardiac events, myocardial infarction, stent thrombosis, target lesion revascularization, and target vessel revascularization between 2‐stent techniques and provisional stenting. Frequentist network meta‐analysis revealed that double kissing crush was associated with lower cardiac death (RR, 0.57; 95% CI, 0.38–0.84), major adverse cardiac events (RR, 0.50; 95% CI, 0.39–0.64), myocardial infarction (RR, 0.60; 95% CI, 0.39–0.90), stent thrombosis (RR, 0.50; 95% CI, 0.28–0.88), target lesion revascularization, and target vessel revascularization when compared with provisional stenting. Double kissing crush was also superior to other 2‐stent techniques, including T‐stent or T and protrusion, dedicated bifurcation stent, and culotte.

Conclusions

Double kissing crush was associated with lower risk of cardiac death, major adverse cardiac events, myocardial infarction, stent thrombosis, target lesion revascularization, and target vessel revascularization compared with provisional stenting and was superior to other 2‐stent techniques. Superiority of 2‐stent strategy over provisional stenting was observed in subgroup meta‐analysis stratified to side branch lesion length ≥10 mm.

Severe mental illnesses, such as schizophrenia or bipolar disorder, affect ≈1% of the population who, as a group, experience significant disadvantage in terms of physical health and reduced life expectancy. In this review, we explore the interaction between race, ethnicity, severe mental illness, and cardiovascular disease, with a focus on cardiovascular care pathways. Finally, we discuss strategies to investigate and address disparities in cardiovascular care for patients with severe mental illness.