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1.  Aldosterone and Myocardial Extracellular Matrix Expansion in Type 2 Diabetes Mellitus 
Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m2, mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II–stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.
doi:10.1016/j.amjcard.2013.02.060
PMCID: PMC3957437  PMID: 23597770
2.  Effect of Left Ventricular Assist Device Implantation and Heart Transplantation on Habitual Physical Activity and Quality of Life☆ 
The present study defined the short- and long-term effects of left ventricular assist device (LVAD) implantation and heart transplantation (HT) on physical activity and quality of life (QoL). Forty patients (LVAD, n = 14; HT, n = 12; and heart failure [HF], n = 14) and 14 matched healthy subjects were assessed for physical activity, energy expenditure, and QoL. The LVAD and HT groups were assessed postoperatively at 4 to 6 weeks (baseline) and 3, 6, and 12 months. At baseline, LVAD, HT, and HF patients demonstrated low physical activity, reaching only 15%, 28%, and 51% of that of healthy subjects (1,603 ± 302 vs 3,036 ± 439 vs 5,490 ± 1,058 vs 10,756 ± 568 steps/day, respectively, p <0.01). This was associated with reduced energy expenditure and increased sedentary time (p <0.01). Baseline QoL was not different among LVAD, HT, and HF groups (p = 0.44). LVAD implantation and HT significantly increased daily physical activity by 60% and 52%, respectively, from baseline to 3 months (p <0.05), but the level of activity remained unchanged at 3, 6, and 12 months. The QoL improved from baseline to 3 months in LVAD implantation and HT groups (p <0.01) but remained unchanged afterward. At any time point, HT demonstrated higher activity level than LVAD implantation (p <0.05), and this was associated with better QoL. In contrast, physical activity and QoL decreased at 12 months in patients with HF (p <0.05). In conclusion, patients in LVAD and HT patients demonstrate improved physical activity and QoL within the first 3 months after surgery, but physical activity and QoL remain unchanged afterward and well below that of healthy subjects. Strategies targeting low levels of physical activity should now be explored to improve recovery of these patients.
doi:10.1016/j.amjcard.2014.04.008
PMCID: PMC4061472  PMID: 24925802
3.  Temporal Trends in Medical Therapies for ST- and Non-ST Elevation Myocardial Infarction: (From The Atherosclerosis Risk in Communities [ARIC] Surveillance Study) 
The American journal of cardiology  2012;111(3):305-311.
Reports from large studies using administrative datasets and event registries have characterized recent temporal trends and treatment patterns for AMI. However, few are population-based and fewer have examined differences in patterns of treatment for patients presenting with ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). We examined 22-year trends in the use of 10 medical therapies and procedures by STEMI and NSTEMI classification in 30986 definite or probable MIs in the ARIC Community Surveillance Study from 1987 to 2008. We used weighted multivariable Poisson regression controlling for sex, race/center classification, age, and PREDICT score to estimate average annual percent changes in medical therapy use. From 1987 – 2008, 6106 (19.7%) hospitalized events were classified as STEMI, and 20302 (65.5%) were classified as NSTEMI. Among STEMI patients, increases (%; 95% CI) were noted in the use of ACE inhibitors (6.4; 5.7, 7.2), non-aspirin anti-platelets (5.0; 4.0, 6.0), lipid-lowering medications (4.5; 3.1, 5.8), beta blockers (2.7; 2.4, 3.0), aspirin (1.2; 1.0, 1.3), and heparin (0.8; 0.4, 1.3). Among NSTEMI patients, the use of ACE inhibitors (5.5; 5.0, 6.1), non-aspirin anti-platelets (3.7; 2.7, 4.7), lipid-lowering medications (3.0; 1.9, 4.1), beta blockers (4.2; 3.9, 4.4), aspirin (1.9, 1.6; 2.1), and heparin (1.7; 1.3, 2.1) increased. Among STEMI patients, we observed decreases in the use of thrombolytics (-7.2; -7.9, -6.6) and CABG (-2.4%; -3.6, -1.2). We noted similar increases in PCI and decreases in the use of thrombolytics and CABG among all patients. In conclusion, we found trends of increasing use of evidence-based therapies for both STEMI and NSTEMI patients over the past 22 years.
doi:10.1016/j.amjcard.2012.09.032
PMCID: PMC4075033  PMID: 23168284
Epidemiology; myocardial infarction; treatment patterns; reperfusion; temporal trends
4.  Relation of Preoperative Serum Albumin Levels to Survival in Patients Undergoing Left Ventricular Assist Device Implantation 
The American journal of cardiology  2013;112(9):1484-1488.
Hypoalbuminemia has been recognized as a prognostic indicator in patients with heart failure. We aimed to investigate the association of hypoalbuminemia with postoperative mortality in patients undergoing left ventricular assist device (LVAD) implantation. We studied 272 consecutive patients undergoing LVAD implantation from 2000 to 2010 at our institution. Preoperative clinical characteristics and laboratory variables associated with mortality were analyzed. Postoperative survival of patients with preoperative hypoalbuminemia (<3.5 g/dl, n = 125) and those with normal albumin concentration (≥3.5 g/dl, n = 147) was compared. Survival after LVAD surgery was better in patients with normal albumin levels compared with those with hypoalbuminemia before surgery (3 and 12 months: 93.2% vs 82.4% and 88.4% vs 75.2%, respectively, p <0.001). Multivariate analysis revealed that preoperative albumin was independently associated with mortality after LVAD implantation (hazard ratio 0.521, 95% confidence interval 0.290 to 0.934; p = 0.029.) Furthermore, the impact of normalization of albumin levels during LVAD support on postoperative survival was analyzed in both groups. Subgroup analysis of patients with preoperative hypoalbuminemia and postoperative normalization of albumin levels (n = 81) showed improved survival compared with those who remained hypoalbuminemia (n = 44) or those who had decreasing albumin levels during LVAD support (n = 40; 3-month survival: 92.6% vs 63.6% and 65.0%; p <0.01). In conclusion, preoperative hypoalbuminemia is associated with poor prognosis after LVAD surgery. Postoperative normalization of albumin level is associated with improved survival. Attention to albumin levels by correcting nutrition, inflammation, and hepatic function could be an effective way to improve prognosis in patients evaluated for LVAD implantation.
doi:10.1016/j.amjcard.2013.06.023
PMCID: PMC4074378  PMID: 23891248
5.  Usefulness of High-Sensitivity C-Reactive Protein to Predict Mortality in Patients with Atrial Fibrillation (From the Atherosclerosis Risk in Communities [ARIC] Study) 
High-sensitivity C-reactive protein (hs-CRP) is a marker for risk of cardiovascular and overall mortality, but information about the association between hs-CRP and mortality in atrial fibrillation (AF) patients is scarce. A total of 293 participants of the Atherosclerosis Risk in Communities (ARIC) Study with a history of AF and available hs-CRP levels were studied. During a median time follow-up of 9.4 years, 134 participants died (46%). The hazard ratio (HR) of all-cause mortality associated with the highest vs. the lowest tertile of hs-CRP was 2.52; 95% CI 1.49–4.25 after adjusting for age, sex, history of cardiovascular diseases and cardiovascular risk factors. A similar trend was observed for cardiovascular mortality (57 events) (HR=1.90; 95% CI 0.81–4.45). CHADS2 score was also associated with all-cause and cardiovascular mortality: the adjusted HR were, respectively, 3.39 (95% CI 1.91–6.01) and 8.71, (95% CI 2.98–25.47) comparing those with CHADS2>2 versus CHADS2=0. Adding hs-CRP to a predictive model including CHADS2 score was associated with an improvement of the C-statistic for total mortality (from 0.627 to 0.677) and for cardiovascular mortality (from 0.700 to 0.718). In conclusion, high levels of hs-CRP constitute an independent marker for risk of mortality in AF patients.
doi:10.1016/j.amjcard.2011.08.010
PMCID: PMC4062871  PMID: 21962993
Atrial fibrillation; Cardiovascular risk factor; Reactive protein C
6.  Cardiogenic SHOCK Without Flow-Limiting Angiographic Coronary Artery Disease – (From The SHOCK Trial And Registry) 
Myocardial infarction (MI) often develops when thrombosis occurs at lesions which have not previously been flow-limiting. However, the development of cardiogenic shock complicating acute myocardial infarction in such circumstances has received little attention. We studied the characteristics of 15 patients with cardiogenic shock who had no flow-limiting angiographic stenosis compared to 767 patients with at least one stenosis, who were enrolled in the SHOCK Trial and Registry. Compared to patients with at least one flow-limiting stenosis, patients with no flow-limiting stenosis were less likely to have pulmonary edema on chest x-ray (29% v 62%, P=0.008), and to have white ethnicity (53% v 82%, P = 0.011), and had lower median highest creatine kinase levels (702 v 2731 u/l; P = 0.018). For SHOCK Trial patients 1-year survival was 49% for patients with at least one flow-limiting stenosis and 71% for those with no flow-limiting stenosis (P= 0.268).
doi:10.1016/j.amjcard.2009.03.002
PMCID: PMC4060258  PMID: 19576316
no flow-limiting stenosis; myocardial infarction; cardiogenic shock
7.  Dose Effect of Cardiorespiratory Exercise on Metabolic Syndrome in Postmenopausal Women 
The American journal of cardiology  2013;111(12):1805-1811.
As an ancillary report to a large National Institutes of Health (NIH)–funded trial, we examined the effects of 6 months of exercise training at 50%, 100%, and 150% of the NIH Consensus Recommendations for physical activity (i.e., 4, 8, and 12 kcal/kg of energy expenditure/wk [KKW]) versus a nonexercise control group on the metabolic syndrome (MS) in sedentary, overweight, moderately hypertensive, postmenopausal women. We examined the clinically defined National Cholesterol Education Program MS, individual components scores, and summed z-scores, expressed as a continuous variable (zMS), using chi-square and general linear models to assess the clinical and progressive nature of MS, respectively. Our results showed significant improvements in zMS for all exercise groups and MS for the 8- and 12 KKW groups only (all, p for trend = 0.02). Post hoc analyses showed that 12 KKW for zMS and 8 and 12 KKW for MS was significant versus the control group (all, p <0.05). When examining the composite scores, we observed significant trends for improvement in waist circumference (p for trend = 0.001), fasting glucose (p for trend = 0.01), and systolic blood pressure (p for trend = 0.02), which appeared to be dose dependent, given the additive nature for incorporating the within-group improvements in waist circumference (4, 8, and 12 KKW), fasting glucose (8 and 12 KKW), and systolic blood pressure (12 KKW). Our results suggest that low-to-moderate intensity cardiorespiratory exercise appears to improve components of the MS in postmenopausal women at levels at or greater than NIH recommendations and that zMS improves at half the NIH recommendations. Greater levels of energy expenditure appear to enhance this effect by incorporating a greater number of requisite MS composite scores.
doi:10.1016/j.amjcard.2013.02.037
PMCID: PMC3755613  PMID: 23578351
8.  Comparison of Clinical Presentation, Left Ventricular Morphology and Hemodynamics, and Exercise Tolerance in Obese versus Non-Obese Patients with Hypertrophic Cardiomyopathy 
The American journal of cardiology  2013;112(8):1182-1189.
Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index, BMI≥30 kg/m2) and 154 non-obese (BMI<30 kg/m2) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p=0.04) and chest pain (p=0.002), and had higher prevalence of hypertension (p=0.008). LV posterior wall thickness (p=0.01) but not the septal wall (p≥0.21) was significantly higher in obese patients, resulting in an increased LV mass index (p=0.003). No significant differences in LV systolic and diastolic function were observed, but obesity was associated with higher LV stroke volume (p=0.03), inducible LV outflow tract gradients (p=0.045) and chance of developing LV outflow tract obstruction during stress (p=0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (β=0.15, p=0.02) and LV mass index (β=0.18, p=0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.
doi:10.1016/j.amjcard.2013.05.070
PMCID: PMC4042005  PMID: 24079444
hypertrophic cardiomyopathy; obesity; hypertension; body mass index; left ventricular mass
9.  Competing Cardiovascular Outcomes Associated with Subclinical Atherosclerosis (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;111(11):1541-1546.
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
doi:10.1016/j.amjcard.2013.02.003
PMCID: PMC3657323  PMID: 23499272
coronary artery calcium; competing risks
10.  A Pilot Study Identifying Statin Non-adherence With Visit-to-visit Variability of Low Density Lipoprotein-Cholesterol 
The American journal of cardiology  2013;111(10):1437-1442.
Non-adherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication non-adherence. The visit-to-visit variability (VVV) of LDL-C may represent an opportunity to identify statin non-adherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center (BMC) Health Plan, seen at either BMC or its affiliated Community Health Centers, who were taking statins and had at least 3 LDL-C measurements between 2008 and 2011. The LDL-C VVV (defined by the within-patient standard deviation) was categorized into quintiles. Multivariable logistic regression models were generated with statin non-adherence (defined by the standard 80% pharmacy refill based medication possession ratio threshold) as the dependent variable. The proportion of statin non-adherence increased across quintiles of LDL-C VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL-C VVV had a strong positive association with statin non-adherence with an adjusted odds ratio of 3.4 (CI: 1.7–7.1) in the highest versus lowest quintile of LDL-C VVV. The age and gender adjusted model had poor discrimination [C-statistic 0.62 (CI: 0.57, 0.67)] while the final adjusted (age, gender, race, mean LDL-C) model demonstrated good discrimination [C-statistic 0.75 (CI: 0.71, 0.79)] between adherent and non-adherent patients. In conclusion, the VVV of LDL-C demonstrated a strong association with statin non-adherence in a clinic setting. Further, a VVV- of LDL-C based model has good discrimination characteristics for statin non-adherence. Research is needed to validate and generalize these findings to other populations and biomarkers.
doi:10.1016/j.amjcard.2013.01.297
PMCID: PMC3644321  PMID: 23433758
Visit-to-visit variability; statins; medication adherence
11.  Distribution, Determinants,and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (From the Framingham Heart Study) 
The American journal of cardiology  2013;111(10):1510-1516.
Current screening and detection of asymptomatic aortic aneurysms is largely based on uniform cut-point diameters. Our objective was to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease (CVD).Measurements of the diameter of the ascending aorta(AA), descending thoracic aorta (DTA), infrarenal abdominal (IRA) and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study participants. Mean diameters were stratified by sex, age, and body surface area (BSA). Univariate associations with risk factor levels were examined and multivariable linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameter was 34.1 mm for AA, 25.8 mm for DTA, 19.3 mm for IRA and 18.7 mm for LAA.For women, the average diameter was 31.9 mm for AA, 23.1 mm for DTA, 16.7 mm for IRA, and 16.0 mm for LAA. The mean aorticdiameters were strongly correlated (p<0.0001) with age and BSA in age-adjusted analyses, and these relations remained significant in multivariable regression analyses. Positive associations of diastolic BP with AA and DTA in both sexes and pack years of cigarette smoking with DTA in women and with IRA in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by CT are larger in men compared with women, vary significantly with age and BSA, and are associated with modifiable CVD risk factors including diastolic blood pressure and cigarette smoking.
doi:10.1016/j.amjcard.2013.01.306
PMCID: PMC3644324  PMID: 23497775
Aortic diameter; computed tomography; sex; age; body surface area
12.  Relation between Optimism and Lipids in Midlife 
The American journal of cardiology  2013;111(10):1425-1431.
This research examined optimism’s relationship with total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides. The hypothesis that optimism is associated with a healthier lipid profile was tested. Participants were 990 mostly white men and women from the Midlife in the United States study who were on average 55.1 years old. Optimism was assessed by self-report with the Life Orientation Test. A fasting blood sample was used to assess serum lipid levels. Linear and logistic regression models examined the cross-sectional association between optimism and lipids accounting for covariates such as demographic characteristics (e.g., education) and health status (e.g., chronic medical conditions). After adjusting for covariates, results suggested that greater optimism was associated with higher HDL cholesterol and lower triglycerides. Optimism was not associated with LDL or total cholesterol. Findings were robust to a variety of modeling strategies that took into consideration the effect of treatment for cholesterol problems. Results further indicated that diet and body mass index may link optimism with lipids. In conclusion, this is the first study to suggest that optimism is associated with a healthy lipid profile; moreover, these associations may be explained, in part, by having healthier behaviors and a lower body mass index.
doi:10.1016/j.amjcard.2013.01.292
PMCID: PMC3644345  PMID: 23433765
optimism; lipids; cholesterol; triglycerides
13.  Comparison of Electrocardiographic QTc Duration in Patients With Supravalvar Aortic Stenosis With Versus Without Williams Syndrome 
The American journal of cardiology  2013;111(10):1501-1504.
Cardiovascular abnormalities in Williams syndrome (WS) are largely attributable to elastin haploinsufficiency resulting from a large deletion of the elastin-containing region on chromosome 7q11.23. The risk of sudden death in patients with WS is 25- to 100-fold greater than that in the general population. The corrected QT (QTc) interval is prolonged in 14% of patients with WS. Patients with nonsyndromic supravalvar aortic stenosis (NSVAS) have elastin mutations resulting in elastin haploinsufficiency and a vascular phenotype nearly identical to that of WS. No previous studies have evaluated the QTc duration in NSVAS. A retrospective review of all electrocardiograms (ECGs) performed on consecutive patients with NSVAS at Arkansas Children's Hospital from January 1, 1985 to January 1, 2012 was completed. ECGs with nonsinus rhythm or unmeasurable intervals were excluded. The ECGs were read by 1 reader who was unaware of previous readings. A QTc interval of ≥460 ms was defined as prolonged. The NSVAS cohort was compared to previously published WS and control groups using the mixed model for continuous electrocardiographic variables and the generalized estimating equation for binary indicators for prolonged QTc. The generalized estimating equation used bootstrapping with 1,000 replicates. A total of 300 ECGs (median 6, range 1 to 27) from the 35 identified patients with NSVAS met the inclusion criteria. A total of 482 ECGs from patients with WS and 1,522 ECGs from controls were included. The mean age of the patients with NSVAS at ECG was 7.3 ± 6.9 years; 64% were male. The mean QTc duration was 409 ± 20 ms in the NSVAS group, 418 ± 17 ms in the control group (p <0.001), and 436 ± 27 ms in the WS group (p <0.001 compared to the control group). The prevalence of QTc prolongation was 0.3% in the NSVAS group, 2.0% in the control group (p <0.001), and 14.8% in the WS group (p <0.001 compared to controls). No patients with NSVAS died. In conclusion, cardiac repolarization is normal in patients with NSVAS. Elastin haploinsufficiency does not appear to be the etiology of QTc prolongation in patients with WS. The possible contribution of other genes on 7q11.23 to QTc prolongation in WS should be investigated.
doi:10.1016/j.amjcard.2013.01.308
PMCID: PMC3984918  PMID: 23433766
14.  Functional Aerobic Capacity in Patients With Sleep-Disordered Breathing 
The American journal of cardiology  2013;111(11):1650-1654.
Few studies have examined exercise capacity or cardiovascular responses to maximal exercise testing and recovery in patients with sleep-disordered breathing (SDB), and results from these studies are conflicting. The objective of this cross-sectional study conducted at a tertiary referral center was to examine the association between SDB and exercise testing outcomes independent of body mass index (BMI) and other cardiopulmonary risk factors. Between January 1, 2005 and January 1, 2010, 1,424 adults underwent exercise testing and within 6 months before first-time diagnostic polysomnography. Subjects were categorized by apnea-hypopnea index (AHI) into 4 groups: <5, 5 to 14, 15 to 29, and ≥30. A logistic regression model incorporated age, gender, BMI, smoking, hypertension, diabetes, beta-blocker use, and cardiac and pulmonary disease as covariates. The primary variable of interest was functional aerobic capacity (FAC). Mean age was 56.4 ± 12.4 years; 75% were men. Mean BMI was 32.4 ± 7.1 kg/m2, and mean AHI 19.5 ± 22.1 per hour. On multivariate analysis, AHI as a continuous variable showed a negative correlation with FAC (R2adj = 0.30, p <0.001) and postexercise SBP (R2adj = 0.23, p = 0.03), and positively correlated with resting and peak DBP (R2adj = 0.09, p = 0.01 and R2adj = 0.09, p = 0.04 respectively). When comparing patients with severe SDB (AHI ≥30) with those without SDB (AHI <5), FAC and heart rate recovery were significantly lower, and resting, peak, and postexercise DBP were higher in those with severe apnea (all p <0.05), after accounting for confounders. In conclusion, SDB severity was associated with reduced FAC and increased resting and peak DBP. Even after accounting for confounders, severe SDB was associated with attenuated FAC, impaired heart rate recovery, and higher resting, peak, and postexercise DBP.
doi:10.1016/j.amjcard.2013.02.008
PMCID: PMC4014074  PMID: 23578347
15.  Prospective, Head-to-Head Comparison of Quantitative Coronary Angiography, Quantitative Computed Tomography Angiography, and Intravascular Ultrasound for the Prediction of Hemodynamic Significance in Intermediate and Severe Lesions, Using Fractional Flow Reserve as Reference Standard (from the ATLANTA I and II Study) 
The objective of this study was to compare the diagnostic accuracy of quantitative coronary angiography (QCA), coronary computed tomography angiography (CTA), and intravascular ultrasound (IVUS) with fractional flow reserve (FFR) measurements. Eighty-five lesions (40% to 99% diameter stenosis) in 85 patients were prospectively interrogated by QCA, CTA, IVUS, and FFR. Minimal lumen diameter (MLD), percent diameter stenosis (%DS), minimal lumen area (MLA), and percent area stenosis (%AS) were measured. Correlation, receiver operating characteristic analysis, kappa statistics, and multivariable logistic regression was used to assess relation between anatomic measurements and FFR. Average age was 61.3 ± 7.8; 62% were men. QCA-derived mean %DS was 55.3% ± 19.5%; mean FFR 0.81 ± 0.17; 27% had FFR ≤0.75. QCA had the strongest correlation, followed by CTA and then IVUS for MLD (r = 0.67, 0.47, and 0.29, respectively) and for %DS (r = −0.63, −0.52, and −0.22, respectively); QCA-derived MLD had area under the curve of 0.96, with 95% sensitivity and 82% specificity. Cut-point, area under the curve, sensitivity, and specificity for CTA-MLA and IVUS-MLA were 3.11 mm2, 0.86, 81%, and 81% and 2.68 mm2, 0.75, 70%, and 80%. In multivariable analysis for each modality, MLD on QCA (odds ratio [OR]: 0.002), %AS on CTA (OR: 1.09) and MLA on IVUS (OR: 0.28) remained independent predictors. In conclusion, in intermediate-to-severe lesions, QCA-, CTA-, and IVUS-derived quantitative anatomic measurements correlated with FFR. CTA-derived cut-points were similar to respective measurements on QCA and IVUS and had similar or better diagnostic performance compared with IVUS.
doi:10.1016/j.amjcard.2013.09.010
PMCID: PMC4007350  PMID: 24238960
16.  Comparison of Medication Practices in Patients with Heart Failure and Preserved vs those with Reduced Ejection Fraction (from the Cardiovascular Research Network) 
The American journal of cardiology  2013;111(9):1324-1329.
Limited data exist describing differences in the medical management of patients with heart failure with preserved ejection fraction (HF-PEF) from those with heart failure with reduced ejection fraction (HF-REF) in more generalizable population-based cohorts. We studied individuals with incident HF diagnosed between 2005 and 2008 from 4 sites participating in the Cardiovascular Research Network. These persons, their medication profile, and left ventricular systolic function status were identified based on hospital discharge and ambulatory visit diagnoses, pharmacy dispensing information, and imaging reports found in health plan electronic databases and through chart review. The study population consisted of 6,210 patients with newly diagnosed HF-PEF and 3,914 patients with newly diagnosed HF-REF. The mean age of our study population was 73 years, 48% were women, and 74% were Caucasian. Patients with HF-REF were less likely to have been treated with various cardiac and HF related medications prior to their index HF event, but were significantly more likely to have been treated with new cardiac medications and HF therapies after the diagnosis of HF, than patients with HF-PEF. After controlling for several potentially confounding factors, patients with HF-PEF were significantly less likely to have been treated with multiple cardiac drug regimens (adjusted odds ratio (OR) = 0.69; 95% CI 0.59, 0.81) and multiple HF related therapies (OR = 0.40; 95% 0.38,0.42) than patients with HF-REF. The present results from a large, population-based sample suggest considerable variation in the prior and new use of different cardiac medication classes of drugs in patients with HF-PEF vs. HF-REF.
doi:10.1016/j.amjcard.2013.01.276
PMCID: PMC3640739  PMID: 23380451
heart failure; management practices; drug therapy; population research
17.  Relation of Patients Living Without a Partner or Spouse to Being Physical Active after Acute Coronary Syndromes (From the PULSE Accelerometry Substudy) 
The American journal of cardiology  2013;111(9):1264-1269.
Living alone is associated with adverse outcomes after an acute coronary syndrome (ACS). One potential mediator of the relationship between partner status and outcomes after an ACS is physical activity. To evaluate the association of partner status with physical activity after an ACS we analyzed data from 107 participants enrolled in the Prescription Use, Lifestyle, and Stress Evaluation Study, a prospective observational study of post-ACS patients. Accelerometers were employed to measure physical activity following hospital discharge. The primary outcome measure was maximum 10 hours of daytime activity one month after discharge. One month after discharge from an ACS hospitalization, participants without a partner or spouse exhibited 24.4% lower daytime activity than those with a partner or spouse (p=0.003). After controlling for age, gender, body mass index, Charlson comorbidity index, and traditional psychosocial and clinical cardiovascular correlates of post-ACS physical activity, partner status remained an independent predictor of post-ACS physical activity (20.5% lower daytime activity among those without partner or spouse, p=0.008). In conclusion, in this study of accelerometer-measured physical activity after an ACS hospitalization, those without a partner or spouse exhibit significantly less physical activity than those with a partner or spouse one month after discharge from the hospital. Low physical activity may be an important mediator of the prognosis associated with partner status after an ACS.
doi:10.1016/j.amjcard.2013.01.272
PMCID: PMC3640672  PMID: 23411104
Partner status; physical activity; acute coronary syndrome; accelerometer
18.  Risk of Cardiac Events in Patients with Asthma and Long QT Syndrome Treated with β2-agonists 
The American journal of cardiology  2008;102(7):871-874.
The clinical course and risk factors associated with β2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to β2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc≥450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent β2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent β-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of β2-agonist therapy (HR = 3.53; p = 0.006). The combined use of β2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). β-blocker therapy was associated with a reduction in cardiac events in those using β2-agonists (HR = 0.14; P = 0.05). In conclusion, β2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving β-blockers.
doi:10.1016/j.amjcard.2008.05.029
PMCID: PMC4005827  PMID: 18805113
19.  Usefulness of Biventricular Volume as a Predictor of Mortality in Patients with Diabetes Mellitus (From the Diabetes Heart Study) 
The American journal of cardiology  2013;111(8):1152-1158.
Individuals with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. This study examined the relationship between BiVV and risk for mortality in European Americans with type 2 DM from the Diabetes Heart Study. BiVV was calculated from 771 non-contrast computed tomography scans performed to image coronary artery calcified plaque (CAC). Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional hazards regression was performed to determine risk for mortality (all-cause and CVD-mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years (mean ± SD) of follow-up, 23% of the sample were deceased. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, CAC, history of hypertension and prior myocardial infarction (p<0.0001–0.012). BiVV was significantly associated with all-cause (HR: 2.45; CI: 1.06–5.67; p=0.036) and CVD-mortality (HR: 4.36; CI: 1.36–14.03; p=0.014) in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p=0.04) and 0.74 to 0.77 (p=0.02) for all-cause and CVD-mortality on inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contra-indicated, BiVV from computed tomography may be considered as a tool for stratification of high-risk individuals, such as those with type 2 DM.
doi:10.1016/j.amjcard.2012.12.044
PMCID: PMC3618594  PMID: 23351459
cardiovascular disease; heart size; diabetes; risk-prediction
20.  Volumetric Left Ventricular Ejection Fraction is Superior to 2-Dimensional Echocardiography for Risk Stratification of Patients for Primary Prevention Implantable Cardioverter-Defibrillator Implantation 
The American journal of cardiology  2013;111(8):1175-1179.
Current guidelines recommend an implantable cardioverter-defibrillator (ICD) according to the left ventricular ejection fraction (LVEF). However, they do not mandate volumetric LVEF assessment. We sought to determine whether volumetric LVEF measurement using cardiovascular magnetic resonance imaging (CMR-LVEF) is superior to conventional LVEF measurement using 2-dimensional transthoracic echocardiography (Echo-LVEF) for risk stratifying patients referred for primary prevention ICD. Patients who underwent primary prevention ICD implantation at our institution and had undergone preimplantation CMR-LVEF from November 2001 to February 2011 were identified. Volumetric CMR-LVEF was determined from cine short-axis data sets. CMR-LVEF and Echo-LVEF were extracted from the clinical reports. The end point was appropriate ICD discharge (shock and/or antitachycardia pacing). Of 48 patients, appropriate ICD discharge occurred in 9 (19%) within 29 – 25 months (range 1 to 99, median 20). All patients met the Echo-LVEF criteria for ICD implantation; however 25% (95% confidence interval 13% to 37%) did not meet the CMR-LVEF criteria. None (0%) of these latter patients had received an appropriate ICD discharge. Using CMR-LVEF ≤30% as a threshold for ICD eligibility, 19 patients (40%) with a qualifying Echo-LVEF would not have been referred for ICD, and none (0%) received an ICD discharge. For primary prevention ICD implantation, volumetric CMR-LVEF might be superior to clinical Echo-LVEF for risk stratification and can identify a large minority of subjects in whom ICD implantation can be safely avoided. In conclusion, if confirmed by larger prospective series, volumetric methods such as CMR should be considered a superior “gatekeeper” for the identification of patients likely to benefit from primary prevention ICD implantation.
doi:10.1016/j.amjcard.2012.12.051
PMCID: PMC3619203  PMID: 23375599
21.  Effect of Morbid Obesity on In-Hospital Mortality and Coronary Revascularization Outcomes after Acute Myocardial Infarction in the United States 
The American journal of cardiology  2013;111(8):10.1016/j.amjcard.2012.12.033.
We sought to investigate the impact of morbid obesity (body mass index (BMI ≥ 40 kg/m2)] on in-hospital mortality and coronary revascularization outcomes on patients presenting with acute myocardial infarction (AMI). We used the Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project (HCUP) and reviewed 413,673 patients hospitalized with acute myocardial infarction (AMI) in 2009. The morbidly obese comprised 3.7% of all AMI patients. Analysis of the unadjusted data revealed that morbidly obese patients compared to those not morbidly obese were more likely to undergo any invasive cardiac procedures when presenting with either STEMI (97.4% vs 93.8%, p<0.0001) or NSTEMI (85.5% vs 80.6%, p<0.0001). The unadjusted mortality rate for morbidly obese patients with AMI was 3.5% compared to 5.5% (p<.0.0001) of those not obese. In adjusted analyses also, patients with morbid obesity had lower odds of in-hospital mortality compared to non-morbidly obese patients consistent with the phenomenon of "the obesity paradox."
doi:10.1016/j.amjcard.2012.12.033
PMCID: PMC3885329  PMID: 23360768
morbid obesity; mortality; acute myocardial infarction; percutaneous coronary intervention
22.  Relation between Leukocyte Telomere Length and Incident Coronary Heart Disease Events (From the 1995 Canadian Nova Scotia Health Survey) 
The American journal of cardiology  2013;111(7):962-967.
Leukocyte telomere length has been proposed as a biomarker of cellular aging and atherosclerosis. We sought to determine whether leukocyte telomere length is independently associated with incident coronary heart disease (CHD) in the general population. Telomere length was measured using a polymerase chain reaction method for participants enrolled in the 1995 Nova Scotia Health Survey (n=1,917). The primary endpoint was first occurrence of fatal and non-fatal CHD events. During a mean follow-up of 8.7 years, 164 fatal or non-fatal CHD events occurred. Compared to participants in the longest tertile of telomere length, those in the middle and shortest tertiles had increased incidence of CHD events (6.2, 11.2 and 12.2 per 1000 person-years, respectively). After adjustment for demographics, traditional risk factors and inflammatory markers including hs-CRP, IL-6, and sICAM-1, those in the middle tertile had significantly elevated risk for incident CHD (hazard ratio [HR] 1.63, 95% CI 1.07–2.51, p=0.02) compared to the longest tertile, whereas the risk for those in the shortest tertile was non-significantly elevated (HR 1.25, 95% CI 0.82–1.90, p=0.30). In conclusion, these findings do not support a linear association between leukocyte telomere length and incident CHD risk in the general population.
doi:10.1016/j.amjcard.2012.12.017
PMCID: PMC3602395  PMID: 23375186
coronary heart disease; telomere; risk prediction
23.  Infarct Artery Distribution and Clinical Outcomes in Occluded Artery Trial Subjects Presenting with Non ST elevation Myocardial Infarction (From the Long Term Follow-up of the Occluded Artery Trial) 
The American journal of cardiology  2013;111(7):930-935.
We hypothesized that the insensitivity of the electrocardiogram (ECG) in identifying acute circumflex occlusion would result in differences in the distribution of the infarct related artery (IRA) between patients with non ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI) enrolled in the Occluded Artery Trial. We also sought to evaluate the impact of percutaneous intervention to the IRA on clinical outcomes for patients with NSTEMI. Overall NSTEMI subjects comprised 13% (n=283) of the trial population. The circumflex IRA was overrepresented in the NSTEMI group compared to patients enrolled with STEMI (42.5 vs. 11.2%; p<0.0001). The 7 year clinical outcomes for NSTEMI patients randomized to percutaneous intervention and optimal medical therapy versus optimal medical therapy alone were similar for the primary composite of Death, MI and Class IV Congestive Heart Failure (CHF) (22.3 vs. 20.23%, p=0.51, HR 1.20; 0.59-2.43); as well as the individual endpoints of Death (13.8 vs. 17.0%, p=0.51, HR 0.81;0.36-1.85); MI (6.1 vs. 5.1%, p=0.84, HR=1.11; 0.28-4.41); Class IV CHF (6.7 vs. 6.0%, p=0.45, HR 1.50;0.37-6.02). There was no interaction between MI type by ECG and treatment effect (p= NS). In conclusion the occluded circumflex IRA is overrepresented in the NSTEMI population. Consistent with the overall trial results, stable patients with NSTEMI and a totally occluded IRA did not benefit from randomization to PCI.
doi:10.1016/j.amjcard.2012.12.009
PMCID: PMC3619220  PMID: 23351464
Coronary artery disease; Myocardial Infarction; Percutaneous coronary intervention; Prognosis
24.  Impact of Fitness Versus Obesity on Routinely Measured Cardiometabolic Risk in Young, Healthy Adults 
The American journal of cardiology  2013;111(7):991-995.
Obesity demonstrates a direct relation with cardiovascular risk and all-cause mortality, while cardiorespiratory fitness demonstrates an inverse relation. In clinical practice, several cardiometabolic (“CM”) risk factors are commonly measured to gauge cardiovascular risk yet the interaction between fitness and obesity with regard CM risk has not been fully explored. We studied 2,634 Brazilian adults referred for an employer-sponsored heath exam. Obesity was defined as BMI >30 kg/m2 or waist circumference > 102cm (men) or >88cm (women) when BMI 25–30kg/m2. Fitness was quantified by stage achieved on an Ellestad treadmill stress test, with those completing stage 4 considered fit. Hepatic steatosis was determined by ultrasound. We compared CM risk factors after stratifying patients into 4 groups: fit/normal weight, fit/obese, unfit/normal weight & unfit/obese. Approximately 22% of patients were obese; 12% were unfit. Fitness and obesity were moderately correlated (ρ=0.38–50). 6.5% of the sample was unfit/normal weight, and 16% fit/obese. In overweight and obese patients, fitness was negatively associated with CM risk (p<0.01 for all values). In fit patients, increasing BMI was positively associated with CM risk (p<0.01 for all values). In instances of discordance between fitness and obesity, obesity was the stronger determinant of CM risk. Fitness and obesity are independently associated with CM risk. The effects of fitness and obesity are additive but obesity is more strongly associated with CM risk when fitness and obesity are discordant. These findings underscore the need for weight loss in obese individuals and suggest an unmeasured benefit of fitness.
doi:10.1016/j.amjcard.2012.12.022
PMCID: PMC3697077  PMID: 23340029
fitness; obesity; metabolic syndrome; liver fat; inflammation
25.  Usefulness of the addition of Beta-2-microglobulin, Cystatin C and C-reactive protein to an Established Risk Factors Model to Improve Mortality Risk Prediction in Patients Undergoing Coronary Angiography 
The American journal of cardiology  2013;111(6):851-856.
Evidence-based therapies are available to reduce the risk of death from cardiovascular disease, yet many patients go untreated. Novel methods are needed to identify those at highest risk of cardiovascular death. Here, the biomarkers beta-2-microglobulin, cystatin C and C-reactive protein were measured at baseline in a cohort of participants undergoing coronary angiography. Adjusted Cox proportional-hazards models were used to determine whether the biomarkers predicted all-cause and cardiovascular mortality. Additionally, improvements in risk reclassification and discrimination were evaluated by calculating the net reclassification improvement (NRI), C-index and the integrated discrimination improvement (IDI) with the addition of the biomarkers to a baseline model of risk factors for cardiovascular disease and death. During a median follow-up period of 5.6 years, there were 78 deaths among 470 participants. All biomarkers independently predicted future all-cause and cardiovascular mortality. A significant improvement in risk reclassification was observed for all-cause (NRI, 35.8%; P=0.004) and cardiovascular (NRI, 61.9%; P=0.008) mortality compared to the baseline risk factors model. Additionally, we observed significantly increased risk discrimination with a C-index of 0.777 (change in C-index [ΔC], 0.057; 95% CI, 0.016–0.097) and 0.826 (ΔC, 0.071; 95% CI, 0.010–0.133) for all-cause and cardiovascular mortality respectively. Improvements in risk discrimination were further supported using the integrated discrimination improvement index. In conclusion, we provide evidence that beta-2-microglobulin, cystatin C and C-reactive protein predict mortality and improve risk reclassification and discrimination for a high-risk cohort undergoing coronary angiography.
doi:10.1016/j.amjcard.2012.11.055
PMCID: PMC3594484  PMID: 23290308
Angiography; Cardiovascular diseases; Proteins; Mortality

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