Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Brain arterial dilatation modifies the association between extracranial pulsatile hemodynamics and brain perivascular spaces: the Northern Manhattan Study.

Pulsatile hemodynamics are associated with brain small perivascular spaces (SPVS). It is unknown whether the stiffness of intermediary arteries connecting the aorta and brain modifies this association. Participants from the Northern Manhattan Study were assessed for SPVS (defined as ≤3 mm T1 voids) and white matter hyperintensity volume (WMH) using MRI. Middle (MCA) and anterior cerebral arterial (ACA) diameters (measured on time-of-flight MRA) and CCA strain (assessed by ultrasound) were used as surrogates of stiffness. Brachial and aortic pulse pressure (PP) and aortic augmentation index (Aix, assessed by applanation tonometry) were used as markers of pulsatility. We tested whether stiffness in intermediary arteries modifies the association between extracranial pulsatility with SPVS and WMH. We found that among 941 participants (mean age 71 ± 9 years, 60% women, 66% Hispanic), the right MCA/ACA diameter was associated with right anterior SPVS (B = 0.177, P = 0.002). Brachial PP was associated with right anterior SPVS (B = 0.003, P = 0.02), and the effect size was bigger with right MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). The association between right CCA strain and ipsilateral SPVS was modified by MCA/ACA diameter, with the largest effect size in those with ipsilateral MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). Similar dose-effects and statistical interactions were replicated using aortic AIx or aortic PP. We found no evidence of effect modification between pulsatile measures and WMH by stiffness measures. In summary, pulsatile hemodynamics relate to brain SPVS, and the association is the strongest among individuals with dilated brain arteries.

Early Use of Echocardiography in Patients With Acute Pulmonary Embolism: Findings From the RIETE Registry.

Background Transthoracic echocardiography ( TTE ) is often considered for risk stratification of patients with acute pulmonary embolism ( PE ). We sought to determine the contemporary utilization of early TTE (within 72 hours of PE diagnosis) and explored the association between TTE findings and PE -related mortality. Methods and Results Data from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry, a multicenter registry of consecutive patients with acute PE , were used (2001-July 2017). We used a generalized linear mixed model to determine predictors of early TTE performance. Moreover, the association between 3 TTE variables (right atrial enlargement, right ventricular hypokinesis, and presence of right heart thrombi) and 30-day PE -related mortality was assessed in generalized linear mixed models adjusted for PE severity index, and other comorbidities. Among 35 935 enrollees with acute PE , 15 375 (42.8%) underwent early TTE . There was an increase in early TTE utilization rate over time ( P<0.001 for trend). Younger age, female sex, enrollment in countries other than Spain, history of coronary disease, heart failure, atrial fibrillation, tachycardia, and hypotension were the main predictors of early TTE ( P<0.01 for all). In multivariable analyses, right atrial enlargement (adjusted odds ratio: 3.74; 95% confidence interval, 2.10-6.66), right ventricular hypokinesis (adjusted odds ratio: 3.11, 95% confidence interval: 1.85-5.21) and right heart thrombi (adjusted odds ratio: 4.39, 95% confidence interval, 1.99-9.71) were associated with increased odds for PE -related mortality. Conclusions Early TTE is commonly performed for acute PE and utilization rates have increased over time. Right atrial enlargement, right ventricular hypokinesis, and right heart thrombi are predictive of worse outcomes. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02832245.

Electrocardiographic Findings in National Basketball Association Athletes.

Importance: While it is known that long-term intensive athletic training is associated with cardiac structural changes that can be reflected on surface electrocardiograms (ECGs), there is a paucity of sport-specific ECG data. This study seeks to clarify the applicability of existing athlete ECG interpretation criteria to elite basketball players, an athlete group shown to develop significant athletic cardiac remodeling. Objective: To generate normative ECG data for National Basketball Association (NBA) athletes and to assess the accuracy of athlete ECG interpretation criteria in this population. Design, Setting, and Participants: The NBA has partnered with Columbia University Medical Center to annually perform a review of policy-mandated annual preseason ECGs and stress echocardiograms for all players and predraft participants. This observational study includes the preseason ECG examinations of NBA athletes who participated in the 2013-2014 and 2014-2015 seasons, plus all participants in the 2014 and 2015 NBA predraft combines. Examinations were performed from July 2013 to May 2015. Data analysis was performed between December 2015 and March 2017. Exposures: Active roster or draft status in the NBA and routine preseason ECGs and echocardiograms. Main Outcomes and Measures: Baseline quantitative ECG variables were measured and ECG data qualitatively analyzed using 3 existing, athlete-specific interpretation criteria: Seattle (2012), refined (2014), and international (2017). Abnormal ECG findings were compared with matched echocardiographic data. Results: Of 519 male athletes, 409 (78.8%) were African American, 96 (18.5%) were white, and the remaining 14 (2.7%) were of other races/ethnicities; 115 were predraft combine participants, and the remaining 404 were on active rosters of NBA teams. The mean (SD) age was 24.8 (4.3) years. Physiologic, training-related changes were present in 462 (89.0%) athletes in the study. Under Seattle criteria, 131 (25.2%) had abnormal findings, compared with 108 (20.8%) and 81 (15.6%) under refined and international criteria, respectively. Increased age and increased left ventricular relative wall thickness (RWT) on echocardiogram were highly associated with abnormal ECG classifications; 17 of 186 athletes (9.1%) in the youngest age group (age 18-22 years) had abnormal ECGs compared with 36 of the 159 athletes (22.6%) in the oldest age group (age 27-39 years) (odds ratio, 2.9; 95% CI, 1.6-5.4; P < .001). Abnormal T-wave inversions (TWI) were present in 32 athletes (6.2%), and this was associated with smaller left ventricular cavity size and increased RWT. One of the 172 athletes (0.6%) in the lowest RWT group (range, 0.24-0.35) had TWIs compared with 24 of the 163 athletes (14.7%) in the highest RWT group (range, 0.41-0.57) (odds ratio, 29.5; 95% CI, 3.9-221.0; P < .001). Conclusions and Relevance: Despite the improved specificity of the international recommendations over previous athlete-specific ECG criteria, abnormal ECG classification rates remain high in NBA athletes. The development of left ventricular concentric remodeling appears to have a significant influence on the prevalence of abnormal ECG classification and repolarization abnormalities in this athlete group.

Effect of Parathyroidectomy Upon Left Ventricular Mass in Primary Hyperparathyroidism: A Meta-Analysis.

CONTEXT: Primary hyperparathyroidism (PHPT) has been associated with increased left ventricular mass (LVM) in many studies. Most studies have been inadequately powered to assess the effect of parathyroidectomy (PTX) on LVM. OBJECTIVE: The objective was to evaluate whether PTX has a benefit on LVM in patients with PHPT. DATA SOURCES: Sources included PubMed, Medline, Cochrane Library, clinicaltrials.gov, review articles, and abstracts from meetings. STUDY SELECTION: Eligible studies included prospective studies of PTX vs observation or PTX alone in patients with PHPT who had LVM measured by echocardiography. DATA EXTRACTION: Two investigators independently identified eligible studies and extracted data. Random-effects models were used to obtain final pooled estimates. DATA SYNTHESIS: Fifteen studies (four randomized controlled trials and 11 observational) of 457 participants undergoing PTX were included. PTX was associated with a reduction in LVM (crude Hedges gu -0.290 ± 0.070, 95% confidence interval [CI] -0.423 to -0.157) of 11.6 g/m(2) (12.5%) on average. Effect size estimates differed by study duration (P < .001), with improvements seen in shorter (≤ 6 mo) but not longer studies. There was a trend toward greater improvement in observational studies vs randomized controlled trials (P = .07), and both serum calcium and PTH were higher in the former. Using random-effects models, the estimated effect size remained significant (Hedges gu -0.250, 95% CI -0.450 to -0.050). Higher preoperative PTH but not calcium was associated with a greater decline in LVM (ß = -.039, 95% CI -0.075 to -0.004). CONCLUSION: PTX reduced LVM in PHPT, and higher preoperative PTH levels were associated with greater improvements. Because the benefit was limited to short-term studies and PHPT disease severity was not independent of study design, further work is needed to clarify the factors that influence the change in LVM and whether the benefit persists beyond 6 months after PTX. Although the clinical significance of the LVM improvement is unclear, these data indicate that PTH may underlie increased LVM in PHPT.

Race-ethnic differences in the association between lipid profile components and risk of myocardial infarction: The Northern Manhattan Study.

OBJECTIVE: The aim of this study was to explore race-ethnic differences in the association between plasma lipid components and risk of incident myocardial infarction (MI). DESIGN/METHODS: As part of the Northern Manhattan Study, 2,738 community residents without cardiovascular disease were prospectively evaluated. Baseline fasting blood samples were collected, and lipid panel components were analyzed as continuous and categorical variables. Cox proportional hazards models were used to calculate HRs and 95% CIs for incident MI after adjusting for demographic and cardiovascular risk factors. RESULTS: The mean age was 68.8 ± 10.4 years; 36.7% were men. Of the participants, 19.9% were non-Hispanic white; 24.9%, non-Hispanic black; and 52.8%, Hispanic (>80% from the Caribbean). Hispanics had lower mean high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TG)/HDL-C. During a mean 8.9 years of follow-up, there were 163 incident MIs. In the whole cohort, all lipid profile components were associated with risk of MI in the expected directions. However, HDL-C (adjusted HR per 10 mg/dL increase 0.93, 95% CI 0.76-1.12) and TG/HDL-C >2 (adjusted HR 0.89, 95% CI 0.51-1.55) were not predictive of MI among Hispanics but were predictive among non-Hispanic blacks and whites. Triglycerides/HDL-C per unit increase was associated with an 8% higher risk of MI among Hispanics (adjusted HR 1.08, 95% CI 1.04-1.12). CONCLUSIONS: In Hispanics, low HDL-C and TG/HDL-C >2 were not associated with MI risk. Our data suggest that a different TG/HDL ratio cutoff may be needed among Hispanics to predict MI risk.

Ethnic differences in aortic valve thickness and related clinical factors.

BACKGROUND: Prior studies suggest that the causes of calcific aortic valve (AV) disease involve chronic inflammation, lipoprotein levels, and calcium metabolism, all of which may differ among race-ethnic groups. We sought to determine whether AV thickness differs by race-ethnicity in a large multiethnic population-based cohort. METHODS: The Northern Manhattan Study includes stroke-free community-based Hispanic (57%), non-Hispanic black (22%), and non-Hispanic white (21%) participants. The relation between AV thickness on transthoracic echocardiography and clinical risk factors for atherosclerosis was evaluated among 2,085 participants using polytomous logistic regression models. Aortic valve thickness was graded in 3 categories (normal, mild, and moderate/severe) based on leaflet thickening and calcification. RESULTS: Mild AV thickness was present in 44.4% and moderate/severe thickness in 5.7% of the cohort, with the lowest frequency of moderate/severe thickness seen particularly among Hispanic women. In multivariate models adjusting for age, sex, race-ethnicity, body mass index, hypertension, coronary artery disease, blood glucose, and high-density lipoprotein cholesterol, Hispanics had significantly less moderate/severe AV thickness (odds ratio 0.43, 95% CI 0.25-0.73) than non-Hispanic whites. Men were almost 2-fold as likely to have moderate/severe AV thickness compared with women (odds ratio 1.96, 95% CI 1.24-3.10). CONCLUSIONS: In this large multiethnic population-based cohort, there were ethnic differences in the degree of AV thickness. Hispanic ethnicity was strongly protective against AV thickness. This effect was not related to traditional risk factors, suggesting that unmeasured factors related to Hispanic ethnicity and AV thickness may be responsible.

Metabolic syndrome and ischemic stroke risk: Northern Manhattan Study.

BACKGROUND AND PURPOSE: More than 47 million individuals in the United States meet the criteria for the metabolic syndrome. The relation between the metabolic syndrome and stroke risk in multiethnic populations has not been well characterized. METHODS: As part of the Northern Manhattan Study, 3298 stroke-free community residents were prospectively followed up for a mean of 6.4 years. The metabolic syndrome was defined according to guidelines established by the National Cholesterol Education Program Adult Treatment Panel III. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% CIs for ischemic stroke and vascular events (ischemic stroke, myocardial infarction, or vascular death). The etiologic fraction estimates the proportion of events attributable to the metabolic syndrome. RESULTS: More than 44% of the cohort had the metabolic syndrome (48% of women vs 38% of men, P<0.0001), which was more prevalent among Hispanics (50%) than whites (39%) or blacks (37%). The metabolic syndrome was associated with increased risk of stroke (HR=1.5; 95% CI, 1.1 to 2.2) and vascular events (HR=1.6; 95% CI, 1.3 to 2.0) after adjustment for sociodemographic and risk factors. The effect of the metabolic syndrome on stroke risk was greater among women (HR=2.0; 95% CI, 1.3 to 3.1) than men (HR=1.1; 95% CI, 0.6 to 1.9) and among Hispanics (HR=2.0; 95% CI, 1.2 to 3.4) compared with blacks and whites. The etiologic fraction estimates suggest that elimination of the metabolic syndrome would result in a 19% reduction in overall stroke, a 30% reduction of stroke in women; and a 35% reduction of stroke among Hispanics. CONCLUSIONS: The metabolic syndrome is an important risk factor for ischemic stroke, with differential effects by sex and race/ethnicity.

Design of a family study among high-risk Caribbean Hispanics: the Northern Manhattan Family Study.

Stroke continues to kill disproportionately more Blacks and Hispanics than Whites in the United States. Racial/ethnic variations in the incidence of stroke and prevalence of stroke risk factors are probably explained by both genetic and environmental influences. Family studies can help identify genetic predisposition to stroke and potential stroke precursors. Few studies have evaluated the heritability of these stroke risk factors among non-White populations, and none have focused on Caribbean Hispanic populations. The aim of the Northern Manhattan Family Study (NOMAFS) is to investigate the gene-environment interaction of stroke risk factors among Caribbean Hispanics. The unique recruitment and methodologic approaches used in this study are relevant to the design and conduct of genetic aggregation studies to investigate complex genetic disorders in non-White populations. The aim of this paper is to describe the NOMAFS and report enrollment and characteristics of the participants. The NOMAFS will provide a data resource for the exploration of the genetic determinants of highly heritable stroke precursor phenotypes that are less complex than the stroke phenotype. Understanding the gene environment interaction is the critical next step toward the development of new and unique approaches to disease prevention and interventions.

Effect of clenbuterol on cardiac and skeletal muscle function during left ventricular assist device support.

BACKGROUND: High-dose clenbuterol (a selective beta2-adrenergic agonist) has been proposed to promote myocardial recovery during left ventricular assist device (LVAD) support, but its effects on cardiac and skeletal muscle are largely unknown. METHODS: Seven subjects with heart failure (5 ischemic, 2 non-ischemic) were started on oral clenbuterol 5 to 46 weeks post-LVAD implantation and up-titrated to daily doses of 720 microg. The following procedures were performed at baseline and after 3 months of therapy: echocardiography at reduced support (4 liters/min); cardiopulmonary exercise testing; body composition analysis; and quadriceps maximal voluntary contraction (MVC). Myocardial histologic analysis was measured at device implantation and explantation. RESULTS: There were no serious adverse events or arrhythmias. Creatine phosphokinase (CPK) was elevated in 4 subjects, with no clinical sequelae. No change in ejection fraction was seen. End-diastolic dimension increased significantly (4.73 +/- 0.67 vs 5.24 +/- 0.66; p < 0.01), despite a trend toward increased LV mass. Body weight and lean mass increased significantly (75.5 +/- 17.9 vs 79.2 +/- 25.1 kg, 21.1 +/- 8.9 vs 23.6 +/- 9.7 kg, respectively; both p < 0.05). Exercise capacity did not change, but MVC improved significantly from 37.0 +/- 15.7 to 45.8 +/- 20.6 kg (p < 0.05). No significant change in myocyte size or collagen deposition was seen. CONCLUSIONS: Cardiac function did not improve in this cohort of LVAD patients treated with high-dose clenbuterol. However, clenbuterol therapy increased skeletal muscle mass and strength and prevented the expected decrease in myocyte size during LVAD support. Further study will clarify its potential for cardiac and skeletal muscle recovery.

Mechanical unloading leads to echocardiographic, electrocardiographic, neurohormonal, and histologic recovery.

BACKGROUND: Mechanical unloading during left ventricular assist device (LVAD) support may lead to cardiac recovery. Predictors of recovery, however, have not been identified. We aimed to evaluate the time course and durability of echocardiographic, electrocardiographic (ECG), histologic, and neurohormonal changes that occur with LVAD support and to screen for non-invasive markers of cardiac recovery. METHODS: LVAD patients underwent monthly testing, including echocardiographic, ECG, and serum B-type natriuretic peptide (BNP) measurement. Paired myocardial tissue samples from implant and explant were also analyzed. RESULTS: Thirty-six LVAD patients were prospectively followed for an average of 101 +/- 99 days. Left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD) significantly improved at 30 days compared with pre-LVAD (19% +/- 6.6% vs 33% +/- 8.1%, 7.1 +/- 1.2 cm vs 4.9 +/- 1.0 cm, respectively; both p < 0.001), with no improvement thereafter. At 30 days, QRS duration and QTc interval were significantly decreased from pre-LVAD (both p < 0.05). There was a marked reduction in BNP, myocyte size, and collagen deposition with LVAD support (all p < 0.01). In screening for markers of recovery, the decrease in QTc was inversely related to LVEDD at 60 days. Changes in QRS and myocyte diameter also correlated with the improvement in LVEF at 30 days. No patients had sufficient recovery for device explantation. CONCLUSIONS: We demonstrate echocardiographic, ECG, histologic, and neurohormonal improvement during LVAD support. Cardiac recovery peaked by 60 days, and there was a trend toward progressive improvement in QRS duration with ongoing support. We report the association of ECG changes with echocardiographic and histologic improvements. Future prospective studies may yield important markers of recovery.

Association of increased body mass index and impaired endothelial function among Hispanic women.

We tested the hypothesis that an increased body mass index was similarly associated with impaired endothelial function as measured by flow-mediated dilation in a high-risk, Hispanic population of men and women living in northern Manhattan. The association of flow-mediated dilation and body mass index was significant in women (beta -0.16 +/- 0.04, p <0.0001) but not in men (beta -0.02 +/- 0.06, p = 0.72). This is the first study to demonstrate a gender-specific difference in endothelial function associated with body mass index.

Age as a determinant of adverse events in medically treated cryptogenic stroke patients with patent foramen ovale.

BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) is associated with cryptogenic stroke. There is no study that assessed the effect of age on adverse event rates in cryptogenic stroke patients with PFO. The purpose of this retrospective analysis from PFO in Cryptogenic Stroke Study (PICSS) database was to assess the effect of age on the risk of adverse events in medically treated cryptogenic stroke patients with PFO. METHODS: 250 cryptogenic stroke patients from PICSS were followed-up for 24 months, with death and recurrent ischemic stroke as primary endpoints. Hazard ratios were calculated for determination of relative risk in cryptogenic stroke patients with and without PFO in 3 age groups (younger than 55, 55 to 64, and 65 years or older). RESULTS: Among the 2 younger age groups, the presence of PFO did not significantly affect the risk of adverse events (P=0.15; hazard ratio=0.21; 95% CI, 0.02 to 1.78; 2-year event rates, 2.0% versus 9.3%; and P=0.70; hazard ratio=0.72; 95% CI, 0.14 to 3.73; 2-year event rates, 10.0% versus 13.9%). However, in those aged 65 years or older, the risk of adverse events was significantly higher in the patients with PFO (P=0.01; hazard ratio=3.21; 95% CI, 1.33 to 7.75; 2-year event rates 37.9% versus 14.5%). CONCLUSIONS: In this exploratory analysis, the presence of PFO in the younger cryptogenic stroke patients did not increase the risk of adverse events. However, in the older patients, PFO significantly increased the risk of adverse events.

Relation between socioeconomic status, race-ethnicity, and left ventricular mass: the Northern Manhattan study.

Increased left ventricular mass (LVM) and lower socioeconomic status (SES) are predictors of cardiovascular morbidity and mortality. Blacks and Hispanics are more likely to have higher LVM and lower SES. The relation between SES, race-ethnicity, and LVM has not been fully explored. Data were used from the NOMAS population-based sample of 1916 subjects living in Northern Manhattan. SES was characterized on the basis of educational attainment and divided into 4 categories. Echocardiography-defined LVM was indexed according to height at the allometric power of 2.7 and analyzed as a continuous variable. LVM varied by race in our cohort (blacks 48.9 g/m2.7, Hispanics 48.4 g/m2.7, whites 45.6 g/m2.7; P=0.004). Using ANCOVA, there was a significant inverse and graded association between mean LVM and SES for the total cohort. Mean LVM was 48.4 g/m2.7, 48.6 g/m2.7, 47.1 g/m2.7, and 45.3 g/m2.7 for the lowest to the highest educational level category (P trend=0.0004). This relationship remained among normotensives (P trend=0.0005) and was present for blacks (P trend=0.009), but not for whites (P trend=0.86) or Hispanics (P trend=0.47). The difference in mean LVM between the highest and lowest categories of education was 5.3 g/m2.7 for blacks, 0.0 g/m2.7 for whites, and 1.0 g/m2.7 for Hispanics. Lower SES is an independent predictor of increased LVM among hypertensive and normotensive blacks.