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3.  Race–Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography
4.  Late Systolic Central Hypertension as a Predictor of Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis 
Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.
Methods and Results
We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001).
Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.
PMCID: PMC4392425  PMID: 25736440
arterial hemodynamics; heart failure; late systolic load; left ventricular afterload
5.  Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial 
In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.
Methods and Results
We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted.
TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported.
Clinical Trial Registration
URL: Unique identifier: NCT00403767.
PMCID: PMC4392426  PMID: 25736441
anticoagulants; arrhythmia; embolism; prevention; risk factors
6.  Ten‐Year Blood Pressure Trajectories, Cardiovascular Mortality, and Life Years Lost in 2 Extinction Cohorts: the Minnesota Business and Professional Men Study and the Zutphen Study 
Blood pressure (BP) trajectories derived from measurements repeated over years have low measurement error and may improve cardiovascular disease prediction compared to single, average, and usual BP (single BP adjusted for regression dilution). We characterized 10‐year BP trajectories and examined their association with cardiovascular mortality, all‐cause mortality, and life years lost.
Methods and Results
Data from 2 prospective and nearly extinct cohorts of middle‐aged men—the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study (n=632)—were used. BP was measured annually during 1947–1957 in Minnesota and 1960–1970 in Zutphen. BP trajectories were identified by latent mixture modeling. Cox proportional hazards and linear regression models examined BP trajectories with cardiovascular mortality, all‐cause mortality, and life years lost. Associations were adjusted for age, serum cholesterol, smoking, and diabetes mellitus. Mean initial age was about 50 years in both cohorts. After 10 years of BP measurements, men were followed until death on average 20 years later. All Minnesota men and 98% of Zutphen men died. Four BP trajectories were identified, in which mean systolic BP increased by 5 to 49 mm Hg in Minnesota and 5 to 20 mm Hg in Zutphen between age 50 and 60. The third systolic BP trajectories were associated with 2 to 4 times higher cardiovascular mortality risk, 2 times higher all‐cause mortality risk, and 4 to 8 life years lost, compared to the first trajectory.
Ten‐year BP trajectories were the strongest predictors, among different BP measures, of cardiovascular mortality, all‐cause mortality, and life years lost in Minnesota. However, average BP was the strongest predictor in Zutphen.
PMCID: PMC4392427  PMID: 25753924
blood pressure; cardiovascular disease; epidemiology; prospective cohort study
7.  Moderate‐to‐Vigorous Physical Activity With Accelerometry is Associated With Visceral Adipose Tissue in Adults 
We examined the relation between objectively measured physical activity with accelerometry and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community‐based sample.
Methods and Results
We evaluated 1249 participants of the Framingham Third Generation and Omni II cohorts (mean age 51.7 years, 47% women) who underwent assessment of moderate‐to‐vigorous physical activity (MVPA) with accelerometry over 5 to 7 days, and multi‐detector computed tomography for measurement of SAT and VAT volume; fat attenuation was estimated by SAT and VAT hounsfield units (HU). In women, higher levels of MVPA were associated with decreased SAT (P<0.0001) and VAT volume (P<0.0001). The average decrement in VAT per 30 minute/day increase in MVPA was −453 cm3 (95% CI −574, −331). The association was attenuated but persisted upon adjustment for BMI (−122 cm3, P=0.002). Higher levels of MVPA were associated with higher SAT HU (all P≤0.01), a marker of fat quality, even after adjustment for SAT volume. Similar findings were observed in men but the magnitude of the association was less. Sedentary time was not associated with SAT or VAT volume or quality in men or women.
MVPA was associated with less VAT and SAT and better fat quality.
PMCID: PMC4392428  PMID: 25736442
accelerometry; physical activity; visceral adipose tissue
8.  Beyond Blood Pressure: Percutaneous Renal Denervation for the Management of Sympathetic Hyperactivity and Associated Disease States 
PMCID: PMC4392429  PMID: 25801757
atrial fibrillation; clinical trials; heart failure; metabolic syndrome; renal denervation; ventricular tachycardia
9.  Differential Time Trends of Outcomes and Costs of Care for Acute Myocardial Infarction Hospitalizations by ST Elevation and Type of Intervention in the United States, 2001–2011 
Little is known whether time trends of in‐hospital mortality and costs of care for acute myocardial infarction (AMI) differ by type of AMI (ST‐elevation myocardial infarction [STEMI] vs. non‐ST‐elevation [NSTEMI]) and by the intervention received (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], or no intervention) in the United States.
Methods and Results
We conducted a serial cross‐sectional study of all hospitalizations for AMI aged 30 years or older using the Nationwide Inpatient Sample, 2001–2011 (1 456 154 discharges; a weighted estimate of 7 135 592 discharges). Hospitalizations were stratified by type of AMI and intervention, and the time trends of in‐hospital mortality and hospital costs were examined for each combination of the AMI type and intervention, after adjusting for both patient‐ and hospital‐level characteristics. Compared with 2001, adjusted in‐hospital mortality improved significantly for NSTEMI patients in 2011, regardless of the intervention received (PCI odds ratio [OR] 0.68, 95% CI 0.56 to 0.83; CABG OR 0.57, 0.45 to 0.72; without intervention OR 0.61, 0.57 to 0.65). As for STEMI, a decline in adjusted in‐hospital mortality was significant for those who underwent PCI (OR 0.83; 0.73 to 0.94); however, no significant improvement was observed for those who received CABG or without intervention. Hospital costs per hospitalization increased significantly for patients who underwent intervention, but not for those without intervention.
In the United States, the decrease in in‐hospital mortality and the increase in costs differed by the AMI type and the intervention received. These non‐uniform trends may be informative for designing effective health policies to reduce the health and economic burdens of AMI.
PMCID: PMC4392430  PMID: 25801759
acute myocardial infarction; hospital costs; in‐hospital mortality; time trend
10.  Dipeptidyl‐Peptidase‐4 Inhibitor, Alogliptin, Attenuates Arterial Inflammation and Neointimal Formation After Injury in Low‐Density Lipoprotein (LDL) Receptor‐Deficient Mice 
The results of recent studies suggest that dipeptidyl‐peptidase‐4 inhibitors have antiatherogenic effects. However, whether or not dipeptidyl‐peptidase‐4 inhibitors could suppress arterial inflammation and intimal hyperplasia after injury remains undetermined. The present study aims to clarify the anti‐inflammatory effects of the dipeptidyl‐peptidase‐4 inhibitor, alogliptin (AGP), on the arteries of atherogenic low‐density lipoprotein receptor‐deficient (LKO) mice.
Methods and Results
We compared intimal hyperplasia in LKO mice 2 weeks after femoral artery injury using an external vascular cuff model. All mice received oral injection of AGP (20 mg/kg per day) or normal saline (control) once daily for 14 days. Fasting blood sugar levels, serum cholesterol levels, or blood pressure did not significantly differ between the 2 groups. Plasma levels of active glucagon‐like peptide‐1 were higher in the AGP than in the control LKO mice (22.2±1.9 versus 15.6±0.9 pg/mL; P<0.05). Compared with saline, AGP significantly reduced intimal hyperplasia (1087±127 versus 1896±140 μm2; P<0.001) as well as the intima/media ratio (0.08±0.01 versus 0.16±0.02; P<0.001). Immunostaining showed that AGP reduced proliferating cells (proliferating cell nuclear antigen–positive nuclei; P<0.001), percent smooth‐muscle cell area (α‐SMA‐positive cells; P<0.001), inflammatory cells infiltration (lymphocyte antigen 6 complex–positive cells; P<0.05), tumor necrosis factor‐α expression (P<0.05), and percent phospho‐NF‐κB‐positive cell compared with saline. Levels of tumor necrosis factor ‐α (0.5‐fold P<0.05), monocyte chemoattractant protein 1 (0.3‐fold P<0.01), and interleukin‐1β (0.2‐fold P<0.05) mRNA were lower in the injured arteries of the AGP than in the control group.
AGP appeared to suppress neointimal formation by inhibiting inflammation, independently of its effects on glucose or cholesterol metabolism in atherogenic LKO mice.
PMCID: PMC4392431  PMID: 25770025
cytokine; dipeptidyl‐peptidase‐4 inhibitor; inflammation; intimal hyperplasia; smooth muscle cell
11.  American Heart Association's Life's Simple 7 and Risk of Venous Thromboembolism: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (CVH) toward a 2020 goal for improvement. The metric includes body mass index (BMI), blood pressure, cholesterol, glucose, physical activity (PA), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (VTE) with favorable Life's Simple 7 scores.
Methods and Results
REGARDS recruited 30 239 black and white participants ≥45 years of age across the United States in 2003–2007. A 14‐point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (HRs) of incident VTE were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison, HRs of VTE were calculated using the Framingham 10‐year coronary risk score. There were 263 incident VTE cases over 5.0 years of follow‐up; incidence rates per 1000 person‐years declined from 2.9 (95% confidence interval [CI], 2.3 to 3.7) among those in the inadequate category to 1.8 (95% CI, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower VTE risk (95% CI, 11 to 57) and participants in the optimal category had a 44% lower risk (95% CI, 18 to 62). The individual score components related to lower VTE risk were ideal PA and BMI. There was no association of Framingham Score with VTE.
Life's Simple 7, a CVH metric, was associated with reduced VTE risk. Findings suggest that efforts to improve the population's CVH may reduce VTE incidence.
PMCID: PMC4392432  PMID: 25725088
epidemiology; risk; thrombosis
12.  Efficacy and Safety of Vorapaxar as Approved for Clinical Use in the United States 
Vorapaxar is a protease‐activated receptor‐1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA).
Methods and Results
We examined the efficacy and safety of vorapaxar in the intended use population, considering 20 170 patients randomized in the multinational, double‐blinded, placebo‐controlled TRA 2°P‐TIMI 50 trial. Of these, 16 897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70.
In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long‐term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding.
Clinical Trial Registration
URL: Unique Identifier: NCT00526474.
PMCID: PMC4392433  PMID: 25792124
antiplatelet therapy; atherosclerosis; myocardial infarction; peripheral arterial disease; secondary prevention; vorapaxar
13.  Physical Activity Measured by Accelerometry and its Associations With Cardiac Structure and Vascular Function in Young and Middle‐Aged Adults 
Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated.
Measures and Results
We related objective measures of moderate‐ to vigorous‐intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P=0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m2]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes.
In our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.
PMCID: PMC4392434  PMID: 25792127
echocardiography; epidemiology; physical activity; vascular measures
14.  Angiotensin‐Converting Enzyme‐2 Overexpression Improves Atrial Remodeling and Function in a Canine Model of Atrial Fibrillation 
Atrial fibrosis is an important factor in initiating and maintaining atrial fibrillation. The purpose of this study was to test the hypothesis that atrial angiotensin‐converting enzyme‐2 (ACE2) overexpression might inhibit atrial collagen accumulation and improve atrial remodeling in a canine atrial pacing model.
Methods and Results
Thirty‐two mongrel dogs of both genders were divided randomly into 4 groups: sham‐operated, control, gene therapy with adenovirus‐enhanced green fluorescent protein (Ad‐EGFP), and gene therapy with Ad‐ACE2. All of the dogs in the control, Ad‐EGFP, and Ad‐ACE2 groups were paced at 450 bpm for a period of 14 days. The dogs in the sham group were instrumented without pacing. After 2 weeks, all of the dogs underwent a thoracotomy operation and received epicardial gene painting. On post–gene transfer day 21, the animals underwent electrophysiology, histology, and molecular studies. The percentage of fibrosis in the Ad‐ACE2 group was markedly lower than the percentage in the control and Ad‐EGFP groups. Compared with the other groups, ACE2 expression was increased significantly in the Ad‐ACE2 group. Compared with the sham and Ad‐ACE2 groups, the expression levels of transforming growth factor‐β1 and Smad3 were significantly higher in the Ad‐EGFP and control groups; however, the expression levels of Smad7 were lower in the atrial tissue as detected by Western blot and reverse transcription polymerase chain reaction.
Our results demonstrate that the overexpression of ACE2 inhibits atrial collagen accumulation and improves left atrial remodeling and function in a canine model of atrial fibrillation. Thus, targeted gene ACE2 therapy provides a promising approach for the treatment of atrial fibrillation.
PMCID: PMC4392435  PMID: 25792125
angiotensin II; angiotensin‐converting enzyme 2; atrial fibrillation; atrial fibrosis; extracellular matrix; transforming growth factor‐β1
15.  Subclinical Atherosclerosis and Obesity Phenotypes Among Mexican Americans 
Data on the influence of obesity on atherosclerosis in Hispanics are inconsistent, possibly related to varying cardiometabolic risk among obese individuals. We aimed to determine the association of obesity and cardiometabolic risk with subclinical atherosclerosis in Mexican‐Americans.
Methods and Results
Participants (n=503) were drawn from the Cameron County Hispanic Cohort. Metabolic health was defined as <2 of the following: blood pressure ≥130/85; triglyceride ≥150 mg/dL; high‐density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women); fasting glucose ≥100 mg/dL; homeostasis model assessment of insulin resistance value >5.13; or high‐sensitivity C‐reactive protein >3 mg/L. Carotid intima media thickness (cIMT) was measured. A high proportion of participants (77.8%) were metabolically unhealthy; they were more likely to be male, older, with fewer years of education, and less likely to meet daily recommendations regarding fruit and vegetable servings. One‐third (31.8%) had abnormal carotid ultrasound findings. After adjusting for covariates, mean cIMT varied across the obesity phenotypes (P=0.0001); there was no difference among the metabolically unhealthy regardless of whether they were obese or not. In multivariable analysis, after adjusting for covariates, cardiometabolic risk (P=0.0159), but not obesity (P=0.1446), was significantly associated with subclinical atherosclerosis.
In Mexican‐Americans, cardiometabolic risk has a greater effect on early atherosclerosis development than body mass index. Non‐obese but metabolically unhealthy participants had similar development of subclinical atherosclerosis as their obese counterparts. Interventions to maintain metabolic health among obese and non‐obese patients may be a more important goal than weight loss alone.
PMCID: PMC4392436  PMID: 25787312
atherosclerosis; carotid intima‐media thickness; obesity; population; risk factors
16.  Circulating Brain‐Derived Neurotrophic Factor Concentrations and the Risk of Cardiovascular Disease in the Community 
Brain‐derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD).
Methods and Results
We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome‐Wide Replication And Meta‐Analysis) consortium (>22 000 coronary artery disease [CAD] cases, >60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow‐up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable‐adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1‐SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect).
Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD.
PMCID: PMC4392437  PMID: 25762803
cardiovascular disease; growth factors; Mendelian randomization; mortality; risk factors
17.  Three‐Dimensional Echocardiography and 2D‐3D Speckle‐Tracking Imaging in Chronic Pulmonary Hypertension: Diagnostic Accuracy in Detecting Hemodynamic Signs of Right Ventricular (RV) Failure 
Our aim was to compare three‐dimensional (3D) and 2D and 3D speckle‐tracking (2D‐STE, 3D‐STE) echocardiographic parameters with conventional right ventricular (RV) indexes in patients with chronic pulmonary hypertension (PH), and investigate whether these techniques could result in better correlation with hemodynamic variables indicative of heart failure.
Methods and Results
Seventy‐three adult patients (mean age, 53±13 years; 44% male) with chronic PH of different etiologies were studied by echocardiography and cardiac catheterization (25 precapillary PH from pulmonary arterial hypertension, 23 obstructive pulmonary heart disease, and 23 postcapillary PH from mitral regurgitation). Thirty healthy subjects (mean age, 54±15 years; 43% male) served as controls. Standard 2D measurements (RV–fractional area change–tricuspid annular plane systolic excursion) and mitral and tricuspid tissue Doppler annular velocities were obtained. RV 3D volumes and global and regional ejection fraction (3D‐RVEF) were determined. RV strains were calculated by 2D‐STE and 3D‐STE. RV 3D global‐free‐wall longitudinal strain (3DGFW‐RVLS), 2D global‐free‐wall longitudinal strain (GFW‐RVLS), apical‐free‐wall longitudinal strain, basal‐free‐wall longitudinal strain, and 3D‐RVEF were lower in patients with precapillary PH (P<0.0001) and postcapillary PH (P<0.01) compared to controls. 3DGFW‐RVLS (hazard ratio 4.6, 95% CI 2.79 to 8.38, P=0.004) and 3D‐RVEF (hazard ratio 5.3, 95% CI 2.85 to 9.89, P=0.002) were independent predictors of mortality. Receiver operating characteristic curves showed that the thresholds offering an adequate compromise between sensitivity and specificity for detecting hemodynamic signs of RV failure were 39% for 3D‐RVEF (AUC 0.89), −17% for 3DGFW‐RVLS (AUC 0.88), −18% for GFW‐RVLS (AUC 0.88), −16% for apical‐free‐wall longitudinal strain (AUC 0.85), 16 mm for tricuspid annular plane systolic excursion (AUC 0.67), and 38% for RV‐FAC (AUC 0.62).
In chronic PH, 3D, 2D‐STE and 3D‐STE parameters indicate global and regional RV dysfunction that is associated with RV failure hemodynamics better than conventional echo indices.
PMCID: PMC4392438  PMID: 25792128
chronic pulmonary hypertension; echocardiography; right ventricular function; speckle‐tracking echocardiography; three‐dimensional echocardiography
18.  Renal Tubule Angiotensin II Type 1 Receptor–Associated Protein Promotes Natriuresis and Inhibits Salt‐Sensitive Blood Pressure Elevation 
Angiotensin II type 1 receptor (AT1R)–associated protein (ATRAP; Agtrap gene) promotes AT1R internalization along with suppression of pathological AT1R activation. In this study, we examined whether enhancement of ATRAP in the renal distal tubules affects sodium handling and blood pressure regulation in response to high salt (HS) loading, using ATRAP transgenic mice on a salt‐sensitive C57BL/6J background.
Methods and Results
Renal ATRAP transgenic (rATRAP‐Tg) mice, which exhibit renal tubule–dominant ATRAP enhancement, and their wild‐type littermate C57BL/6J mice on a normal salt diet (0.3% NaCl) at baseline were subjected to dietary HS loading (4% NaCl) for 7 days. In rATRAP‐Tg mice, the dietary HS loading–mediated blood pressure elevation was suppressed compared with wild‐type mice, despite similar baseline blood pressure. Although renal angiotensin II level was comparable in rATRAP‐Tg and wild‐type mice with and without HS loading, urinary sodium excretion in response to HS loading was significantly enhanced in the rATRAP‐Tg mice. In addition, functional transport activity of the amiloride‐sensitive epithelial Na+ channel was significantly decreased under saline volume–expanded conditions in rATRAP‐Tg mice compared with wild‐type mice, without any evident change in epithelial Na+ channel protein expression. Plasma membrane AT1R expression in the kidney of rATRAP‐Tg mice was decreased compared with wild‐type mice.
These results demonstrated that distal tubule–dominant enhancement of ATRAP inhibits pathological renal sodium reabsorption and blood pressure elevation in response to HS loading. The findings suggest that ATRAP‐mediated modulation of sodium handling in renal distal tubules could be a target of interest in salt‐sensitive blood pressure regulation.
PMCID: PMC4392439  PMID: 25792129
angiotensin receptors; basic science; gene expression/regulation; hypertension (kidney); receptors; salt‐sensitive; sodium transport (kidney)
19.  Impaired Right Ventricular Hemodynamics Indicate Preclinical Pulmonary Hypertension in Patients With Metabolic Syndrome 
Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease.
Methods and Results
A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m2), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e′ (right ventricular diastolic function parameter), shorter PAAT, shorter ejection time, and larger pulmonary artery diameter compared with controls (P<0.05 for all). Estimated pulmonary artery systolic pressure based on PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls (P for ANOVA <0.0001). After adjustment for age, sex, hypertension, diabetes, body mass index, and triglycerides, MetS remained associated with a 20‐ms–shorter PAAT (β=−20.4, SE=6.5, P=0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea.
MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.
PMCID: PMC4392440  PMID: 25758604
echocardiography; metabolic syndrome; obesity; pulmonary hypertension
20.  Pulmonary Vascular and Right Ventricular Reserve in Patients With Normalized Resting Hemodynamics After Pulmonary Endarterectomy 
Patients with normalized mean pulmonary artery pressure (mPAP) after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) do not always regain normal exercise capacity. We evaluated right ventricular function, its interaction with both pulsatile and resistive afterload, and the effect of sildenafil during exercise in these patients.
Methods and Results
Fourteen healthy controls, 15 CTEPH patients, and 7 patients with normalized resting mPAP (≤25 mm Hg) post‐PEA underwent cardiopulmonary exercise testing, followed by cardiac magnetic resonance imaging with simultaneous invasive mPAP measurement during incremental supine cycling exercise. Peak oxygen consumption and peak heart rate were significantly reduced in post‐PEA and CTEPH patients compared to controls. The mPAP–cardiac output slope was steeper in post‐PEA patients than in controls and similar to CTEPH. Relative to controls, resting right ventricular ejection fraction was reduced in CTEPH, but not in post‐PEA patients. In contrast, peak exercise right ventricular ejection fraction was reduced both in post‐PEA and CTEPH patients. Exercise led to reduction of pulmonary arterial compliance in all groups. Nevertheless, resting pulmonary arterial compliance values in CTEPH and post‐PEA patients were even lower than those in controls at peak exercise. In post‐PEA patients, sildenafil did not affect resting hemodynamics nor right ventricular function, but decreased the mPAP/cardiac output slope and increased peak exercise right ventricular ejection fraction.
Exercise intolerance in post‐PEA patients is explained by abnormal pulmonary vascular reserve and chronotropic incompetence. The mPAP/cardiac output slope and pulmonary arterial compliance are sensitive measures demonstrating abnormal resistive and pulsatile pulmonary vascular function in post‐PEA patients. These abnormalities are partially attenuated with sildenafil.
PMCID: PMC4392441  PMID: 25801760
cardiac magnetic resonance imaging; chronic thromboembolic pulmonary hypertension; exercise; pulmonary arterial compliance; pulmonary vascular resistance; right ventricle
21.  Plasma Pro‐Endothelin‐1 Peptide Concentrations Rise in Chronic Kidney Disease and Following Selective Endothelin A Receptor Antagonism 
Endothelin 1 (ET‐1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET‐1 peptides, endothelin‐like domain peptide (ELDP) and C‐terminal pro‐ET‐1 (CT‐proET‐1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists.
Methods and Results
We assessed plasma and urine ELDP and plasma CT‐proET‐1 in CKD patients with minimal comorbidity. Next, in a randomized double‐blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT‐proET‐1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT‐proET‐1. Sitaxentan increased both plasma ELDP and CT‐proET‐1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT‐proET‐1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET‐1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT‐proET‐1 correlated negatively with 24‐hour urinary sodium excretion.
ELDP and CT‐proET‐1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents.
Clinical Trial Registration
URL: Unique identifier: NCT00810732
PMCID: PMC4392442  PMID: 25801761
antagonists; CKD; endothelin; fluid retention
22.  Outcomes After Acute Ischemic Stroke in the United States: Does Residential ZIP Code Matter? 
We sought to analyze the impact of socioeconomic status (SES) on in‐hospital outcomes, cost of hospitalization, and resource use after acute ischemic stroke.
Methods and Results
We used the 2003–2011 Nationwide Inpatient Sample database for this analysis. All admissions with a principal diagnosis of acute ischemic stroke were identified by using International Classification of Diseases, Ninth Revision codes. SES was assessed by using median household income of the residential ZIP code for each patient. Quartile 1 and quartile 4 reflect the lowest‐income and highest‐income SES quartile, respectively. During a 9‐year period, 775 905 discharges with acute ischemic stroke were analyzed. There was a progressive increase in the incidence of reperfusion on the first admission day across the SES quartiles (P‐trend<0.001). In addition, we observed a significant reduction in discharge to nursing facility, across the SES quartiles (P‐trend<0.001). Although we did not observe a significant difference in in‐hospital mortality across the SES quartiles in the overall cohort (P‐trend=0.22), there was a significant trend toward reduced in‐hospital mortality across the SES quartiles in younger patients (<75 years) (P‐trend<0.001). The mean length of stay in the lowest‐income quartile was 5.75 days, which was significantly higher compared with other SES quartiles. Furthermore, the mean adjusted cost of hospitalization among quartiles 2, 3, and 4, compared with quartile 1, was significantly higher by $621, $1238, and $2577, respectively. Compared with the lowest‐income quartile, there was a significantly higher use of echocardiography, invasive angiography, and operative procedures, including carotid endarterectomy, in the highest‐income quartile.
Patients from lower‐income quartiles had decreased reperfusion on the first admission day, compared with patients from higher‐income quartiles. The cost of hospitalization of patients from higher‐income quartiles was significantly higher than that of patients from lowest‐income quartiles, despite longer hospital stays in the latter group. This might be partially attributable to a lower use of key procedures among patients from lowest‐income quartile.
PMCID: PMC4392443  PMID: 25773298
acute ischemic stroke; cost of illness; mortality; socioeconomic status; ZIP code
23.  QRS Fragmentation and Sudden Cardiac Death in the Obese and Overweight 
Obesity has been associated with significantly greater risk of sudden cardiac death (SCD); however, identifying the obese patient at highest risk remains a challenge. We evaluated the association between QRS fragmentation on the 12‐lead electrocardiogram and SCD, in obese/overweight subjects.
Methods and Results
In the ongoing prospective, community‐based Oregon Sudden Unexpected Death Study (population approximately 1 million), we performed a case‐control analysis, comparing obese/overweight SCD victims with obese/overweight controls from the same geographic region. Archived ECGs prior and unrelated to the SCD event were used for cases and all ECG measurements were assessed in blinded fashion. Fragmentation was defined as the presence of RSR’ patterns and/or notching of the R/S wave in at least 2 contiguous leads. Analysis was limited to ECGs with QRS duration <120 ms. Overall prevalence of fragmentation was higher in cases (n=185; 64.9±13.8 years; 67.0% male) compared with controls (n=405; 64.9±11.0 years; 64.7% male) (34.6% versus 26.9%, P=0.06). Lateral fragmentation was significantly more frequent in cases (8.1% versus 2.5%; P<0. 01), with non‐significant differences in anterior and inferior territories. Fragmentation in multiple territories (≥2) was also more likely to be observed in cases (9.7% versus 4.9%, P=0.02). In multivariable analysis with consideration of established SCD risk factors, lateral fragmentation was significantly associated with SCD (OR 2.84; 95% CI 1.01 to 8.02; P=0.05).
QRS fragmentation, especially in the lateral territory is a potential risk marker for SCD independent of the ejection fraction, among obese/overweight subjects in the general population.
PMCID: PMC4392444  PMID: 25762804
ECG; obesity; QRS fragmentation; sudden cardiac death
24.  Effect of Prehospital Induction of Mild Hypothermia on 3‐Month Neurological Status and 1‐Year Survival Among Adults With Cardiac Arrest: Long‐Term Follow‐up of a Randomized, Clinical Trial 
Randomized trials of prehospital cooling after cardiac arrest have shown that neither prehospital cooling nor targeted temperature management differentially affected short‐term survival or neurological function. In this follow‐up study, we assess the association of prehospital hypothermia with neurological function at least 3 months after cardiac arrest and survival 1 year after cardiac arrest.
Methods and Results
There were 508 individuals who were discharged alive from hospitals in King County, Washington; 373 (73%) were interviewed by telephone 123±43 days after the initial event. Overall, 59% of the treatment group and 58% of the control group had Cerebral Performance Category (CPC) 1 or 2 (P=0.70), and 50% of the treatment group and 49% of the control group had slight disability or better by the Modified Rankin Scale (MRS; (P=0.35). One‐year survival was 87% in the treatment group and 84% in the control group (P=0.42). Of those with CPC 1 at hospital discharge, 68% had CPC 1 or 2 at follow‐up, and 59% had MRS of slight disability or better. Of 41 patients with CPC 3 or 4 at discharge, only 12% had CPC 2 at follow‐up, and just 5% had MRS of slight disability or better. One‐year survival was 92% for CPC 1 at discharge, but only 40% for CPC 4.
In addition to excellent survival, patients who had good neurological function at discharge continued to have good function at least 3 months after the event.
Clinical Trial Registration
URL: Unique identifier: NCT00391469
PMCID: PMC4392445  PMID: 25762805
arrhythmia; cardiac arrest; follow‐up study
25.  Variation in Critical Care Unit Admission Rates and Outcomes for Patients With Acute Coronary Syndromes or Heart Failure Among High‐ and Low‐Volume Cardiac Hospitals 
Little is known about cross‐hospital differences in critical care units admission rates and related resource utilization and outcomes among patients hospitalized with acute coronary syndromes (ACS) or heart failure (HF).
Methods and Results
Using a population‐based sample of 16 078 patients admitted to a critical care unit with a primary diagnosis of ACS (n=14 610) or HF (n=1467) between April 1, 2003 and March 31, 2013 in Alberta, Canada, we stratified hospitals into high (>250), medium (200 to 250), or low (<200) volume based on their annual volume of all ACS and HF hospitalization. The percentage of hospitalized patients admitted to critical care units varied across low, medium, and high‐volume hospitals for both ACS and HF as follows: 77.9%, 81.3%, and 76.3% (P<0.001), and 18.0%, 16.3%, and 13.0% (P<0.001), respectively. Compared to low‐volume units, critical care patients with ACS and HF admitted to high‐volume hospitals had shorter mean critical care stays (56.6 versus 95.6 hours, P<0.001), more critical care procedures (1.9 versus 1.2 per patient, <0.001), and higher resource‐intensive weighting (2.8 versus 1.5, P<0.001). No differences in in‐hospital mortality (5.5% versus 6.2%, adjusted odds ratio 0.93; 95% CI, 0.61 to 1.41) were observed between high‐ and low‐volume hospitals; however, 30‐day cardiovascular readmissions (4.6% versus 6.8%, odds ratio 0.77; 95% CI, 0.60 to 0.99) and cardiovascular emergency‐room visits (6.6% versus 9.5%, odds ratio 0.80; 95% CI, 0.69 to 0.94) were lower in high‐volume compared to low‐volume hospitals. Outcomes stratified by ACS or HF admission diagnosis were similar.
Cardiac patients hospitalized in low‐volume hospitals were more frequently admitted to critical care units and had longer hospitals stays despite lower resource‐intensive weighting. These findings may provide opportunities to standardize critical care utilization for ACS and HF patients across high‐ and low‐volume hospitals.
PMCID: PMC4392446  PMID: 25725089
critical care; heart failure; acute coronary syndrome; hospital variation

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