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1.  Lifetime Risk for Heart Failure Among White and Black Americans: Cardiovascular Lifetime Risk Pooling Project 
Objective
To estimate lifetime risk for HF by sex and race.
Background
Prior estimates of lifetime risk for developing heart failure (HF) range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.
Methods
Using public-release and internal datasets from NHLBI-sponsored cohorts, we estimated lifetime risks for developing HF to age 95, with death free of HF as the competing event, among participants in Chicago Heart Association Detection Project in Industry (CHA), Atherosclerosis Risk in Communities (ARIC), and Cardiovascular Health Study (CHS) cohorts.
Results
There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30-42% in white men, 20-29% in black men, 32-39% in white women, and 24-46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher BP and BMI at all ages in both blacks and whites and did not diminish substantially with advancing index age.
Conclusions
These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.
doi:10.1016/j.jacc.2013.01.022
PMCID: PMC3618527  PMID: 23500287
lifetime risk; heart failure; epidemiology
2.  Interaction between Loop Diuretic Associated Mortality and Blood Urea Nitrogen Concentration in Chronic Heart Failure 
Objectives
The purpose of this study was to investigate if a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high dose loop diuretics (HDLD).
Background
Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and are associated with worsened survival.
Methods
Subjects in the Beta-Blocker Evaluation of Survival Trial receiving loop diuretics at baseline were analyzed (n=2456). The primary outcome was the interaction between BUN and HDLD associated mortality.
Results
In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (HR=1.56, 95% CI 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR=1.06, 95% CI 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR=1.59, 95% CI 1.34 to 1.88) and adjusted (HR=1.29, 95% CI 1.07 to 1.60) risk for death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR=0.99, 95% CI 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR=0.71, 95% CI 0.49 to 0.96) (p interaction=0.018).
Conclusion
The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with elevated BUN and improved survival in patients with normal BUN. These data suggest a role for neurohormonal activation in loop diuretic associated mortality.
doi:10.1016/j.jacc.2011.01.052
PMCID: PMC3980479  PMID: 21757114
Congestive heart failure; Loop diuretics; Kidney; Mortality
3.  Anger-induced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators 
Objective
To determine whether T-wave alternans (TWA) induced by anger in a laboratory setting predicts future ventricular arrhythmias (VT/VF) in patients with implantable cardioverter-defibrillators (ICDs).
Background
Anger can precipitate spontaneous VT/VF, and induce TWA. Whether anger-induced TWA predicts future arrhythmias is unknown.
Methods
Sixty-two patients with ICDs underwent ambulatory ECG during a mental stress protocol, three months post-implant. TWA was analyzed using time-domain methods. After ≥ 1 year follow-up, ICD stored data was reviewed to determine incidence of ICD-terminated VT/VF.
Results
Patients with ICD-terminated arrhythmias during follow-up (N=10) had higher TWA induced by anger, 13.2uV (iqr 9.3-16), compared to 9.3uV (7.5-11.5) (p<0.01). Patients in the highest quartile of anger-induced TWA (>11.9uV, N=15) were more likely to experience arrhythmias by one year than those in the lower quartiles, (33% versus 4%), and during extended follow-up (40% versus 9%, p<0.01 for both.) In multivariable regression controlling for ejection fraction, prior clinical arrhythmia, and wide QRS, anger-induced TWA remained a significant predictor of arrhythmia, with likelihood in the top quartile 10.8 times that of other patients (CI 1.6-113, p<0.05.)
Conclusion
Anger-induced TWA predicts future ventricular arrhythmias in patients with ICDs, suggesting that emotion-induced repolarization instability may be one mechanism linking stress and sudden death. Whether there is a clinical role for anger-induced TWA testing requires further study.
doi:10.1016/j.jacc.2008.10.053
PMCID: PMC3979284  PMID: 19245968
tachyarrhythmias (ventricular); anger; implantable cardioverter-defibrillator
4.  Natural History of Experimental Arterial Chronic Total Occlusions 
Objectives
We sought to perform the first systematic study of the natural history of chronic total arterial occlusions (CTOs) in an experimental model.
Background
Angioplasty of CTOs has low success rates. The structural and perfusion changes during CTO maturation, which may adversely affect angioplasty outcome, have not been systematically studied.
Methods
Occlusions were created in 63 rabbit femoral arteries by thrombin injection. Histology, contrast-enhanced magnetic resonance imaging, relative blood volume (RBV) index, and micro-computed tomography imaging were analyzed at 2, 6, 12, and 18 to 24 weeks.
Results
Early changes were characterized by an acute inflammatory response and negative arterial remodeling, with >70% reduction of arterial cross-sectional area (CSA) from 2 to 6 weeks. Intraluminal neovascularization of the CTO occurred with a 2-fold increase in total (media + intima) microvessel CSA from 2 to 6 weeks (0.014 ± 0.002 mm2 to 0.023 ± 0.005 mm2, p = 0.0008) and a 3-fold increase in RBV index (5.1 ± 1.9% to 16.9 ± 2.7%, p = 0.0008). However at later time periods, there were significant reductions in both RBV (3.5 ± 1.1%, p = 0.0001) and total microvessel CSA (0.017 ± 0.002 mm2, p = 0.011). Micro-computed tomography imaging demonstrated a corkscrew-like recanalization channel at the proximal end at 6 weeks that regressed at later time points. These vascular changes were accompanied by a marked decrease in proteoglycans and accumulation of a collagen-enriched extracellular matrix, particularly at the entrance (“proximal fibrous cap”).
Conclusions
This study is the first to systematically analyze compositional changes occurring during CTO maturation, which may underlie angioplasty failure. Negative remodeling, regression of intraluminal channels, and CTO perfusion, together with the accumulation of dense collagen, may represent important targets for novel therapeutic interventions.
doi:10.1016/j.jacc.2008.09.064
PMCID: PMC3976676  PMID: 19324261 CAMSID: cams4144
chronic total occlusions; magnetic resonance imaging; angioplasty; collagen
5.  Electroanatomic Remodeling of the Left Stellate Ganglion After Myocardial Infarction 
Objectives
The purpose of this study was to evaluate the changes of left stellate ganglionic nerve activity (SGNA) and left thoracic vagal nerve activity (VNA) after acute myocardial infarction (MI).
Background
Whether MI results in remodeling of extracardiac nerve activity remains unclear.
Methods
We implanted radiotransmitters to record the SGNA, VNA, and electrocardiogram in 9 ambulatory dogs. After baseline monitoring, MI was created by 1-h balloon occlusion of the coronary arteries. The dogs were then continuously monitored for 2 months. Both stellate ganglia were stained for growth-associated protein 43 and synaptophysin. The stellate ganglia from 5 normal dogs were used as control.
Results
MI increased 24-h integrated SGNA from 7.44 ± 7.19 Ln(Vs)/day at baseline to 8.09 ± 7.75 Ln(Vs)/day after the MI (p < 0.05). The 24-h integrated VNA before and after the MI was 5.29 ± 5.04 Ln(Vs)/day and 5.58 ± 5.15 Ln(Vs)/day, respectively (p < 0.05). A significant 24-h circadian variation was noted for the SGNA (p < 0.05) but not the VNA. The SGNA/VNA ratio also showed significant circadian variation. The nerve densities from the left SG were 63,218 ± 34,719 μm2/mm2 and 20,623 ± 4,926 μm2/mm2 for growth-associated protein 43 (p < 0.05) and were 32,116 ± 8,190 μm2/mm2 and 16,326 ± 4,679 μm2/mm2 for synaptophysin (p < 0.05) in MI and control groups, respectively. The right SG also showed increased nerve density after MI (p < 0.05).
Conclusions
MI results in persistent increase in the synaptic density of bilateral stellate ganglia and is associated with increased SGNA and VNA. There is a circadian variation of the SGNA/VNA ratio. These data indicate significant remodeling of the extracardiac autonomic nerve activity and structures after MI.
doi:10.1016/j.jacc.2011.11.030
PMCID: PMC3975658  PMID: 22381432
acute myocardial infarction; autonomic nervous system; nerve recordings
6.  Cost-Effectiveness of Statins for Primary Cardiovascular Prevention in Chronic Kidney Disease 
Objectives
To evaluate the cost-effectiveness of statins for primary prevention of myocardial infarction (MI) and stroke in patients with chronic kidney disease (CKD).
Background
Patients with CKD have an elevated risk of MI and stroke. Although HMG Co-A reductase inhibitors (“statins”) may prevent cardiovascular events in patients with non-dialysis-requiring CKD, adverse drug effects and competing risks could materially influence net effects and clinical decision-making.
Methods
We developed a decision-analytic model of CKD and cardiovascular disease (CVD) to determine the cost-effectiveness of low-cost generic statins for primary CVD prevention in men and women with hypertension and mild-to-moderate CKD. Outcomes included MI and stroke rates, discounted quality adjusted life years (QALYs) and lifetime costs (2010 USD), and incremental cost-effectiveness ratios.
Results
For 65 year-old men with moderate hypertension and mild-to-moderate CKD, statins reduced the combined rate of MI and stroke, yielded 0.10 QALYs, and increased costs by $1,800 ($18,000 per QALY gained). For patients with lower baseline cardiovascular risks, health and economic benefits were smaller; for 65 year-old women, statins yielded 0.06 QALYs and increased costs by $1,900 ($33,400 per QALY gained). Results were sensitive to rates of rhabdomyolysis and drug costs. Statins are less cost-effective when obtained at average retail prices, particularly in patients at lower CVD risk.
Conclusions
While statins reduce absolute CVD risk in patients with CKD, increased risk of rhabdomyolysis, and competing risks associated with progressive CKD, partly offset these gains. Low-cost generic statins appear cost-effective for primary prevention of CVD in patients with mild-to-moderate CKD and hypertension.
doi:10.1016/j.jacc.2012.12.034
PMCID: PMC3688058  PMID: 23500327
chronic kidney disease; statins; cardiovascular disease; cost-effectiveness; guidelines
7.  Heart Failure Associated Hospitalizations in the United States 
Journal of the American College of Cardiology  2013;61(12):10.1016/j.jacc.2012.12.038.
Objective
We sought to characterize temporal trends in hospitalizations with heart failure as a primary or secondary diagnosis.
Background
Heart failure patients are frequently admitted for both heart failure and other causes.
Methods
Using the Nationwide Inpatient Sample (NIS), we evaluated trends in heart failure hospitalizations between 2001 and 2009. Hospitalizations were categorized as either primary or secondary heart failure hospitalizations based the location of heart failure in the discharge diagnosis. National estimates were calculated using the sampling weights of the NIS. Age- and gender-standardized hospitalization rates were determined by dividing the number of hospitalizations by the United States population in a given year and using direct standardization.
Results
The number of primary heart failure hospitalizations in the United States decreased from 1,137,944 in 2001 to 1,086,685 in 2009, while secondary heart failure hospitalizations increased from 2,753,793 to 3,158,179 over the same period. Age- and gender-adjusted rates of primary heart failure hospitalizations decreased steadily over 2001–2009, from 566 to 468 per 100,000 people. Rates of secondary heart failure hospitalizations initially increased, from 1370 to 1476 per 100,000 from 2001–2006, then decreased to 1359 per 100,000 in 2009. Common primary diagnoses for secondary heart failure hospitalizations included pulmonary disease, renal failure, and infections.
Conclusions
Although primary heart failure hospitalizations declined, rates of hospitalizations with a secondary diagnosis of heart failure were stable in the past decade. Strategies to reduce the high burden of hospitalizations of heart failure patients should include consideration of both cardiac disease and non-cardiac conditions.
doi:10.1016/j.jacc.2012.12.038
PMCID: PMC3838728  PMID: 23500328
Heart failure; hospitalizations; comorbidity
8.  Cardiovascular and Systemic Microvascular Effects of Anti-Vascular Endothelial Growth Factor Therapy for Cancer 
Objectives
This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy.
Background
Hypertension is a common side effect of VEGF inhibitors used in cancer medicine.
Methods
Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties.
Results
Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF–treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension–pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF–treated mice.
Conclusions
Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.
doi:10.1016/j.jacc.2012.02.053
PMCID: PMC3963486  PMID: 22703929
contrast; echocardiography; VEGF; ventricular; hypertrophy
9.  Use of Stress Testing and Diagnostic Catheterization after Coronary Stenting: Association of Site-level Patterns with Patient Characteristics and Outcomes in 247,052 Medicare Beneficiaries 
Objectives
To determine diagnostic testing patterns after percutaneous coronary intervention (PCI).
Background
Little is known about patterns of diagnostic testing after PCI in the U.S. or the relationship of these patterns with clinical outcomes.
Methods
We linked Centers for Medicare & Medicaid Services inpatient and outpatient claims to the National Cardiovascular Data Registry® CathPCI Registry® data from 2005–2007. Hospital quartiles of the cumulative incidence of diagnostic testing use within 12 and 24 months post-PCI were compared for patient characteristics, repeat revascularization, acute myocardial infarction (AMI), and death.
Results
A total of 247,052 patients underwent PCI at 656 institutions. Patient and site characteristics were similar across testing use quartiles. There was a 9% and 20% higher adjusted risk of repeat revascularization in Quartile 3 and Quartile 4 (highest testing rate), respectively, when compared to Quartile 1 (lowest testing rate) (p=0.020 and <0.0001, respectively). The adjusted risk for death or AMI did not differ among quartiles.
Conclusions
While patient characteristics were largely independent of rates of post-PCI testing, higher testing rates was not associated with lower risks of myocardial infarction or death, but repeat revascularization was significantly higher at these sites. Additional studies should examine whether increased testing is a marker for improved quality of post-PCI care or simply increased healthcare utilization.
doi:10.1016/j.jacc.2013.02.093
PMCID: PMC3962793  PMID: 23727207
stress testing; diagnostic catheterization; site-level patterns; patient outcomes
10.  End Points for Clinical Trials in Acute Heart Failure Syndromes 
Acute heart failure syndromes (AHFS) remain a major cause of morbidity and mortality, in part because the development of new therapies for these disorders has been marked by frequent failure and little success. The heterogeneity of current approaches to AHFS drug development, particularly with regard to end points, remains a major potential barrier to progress in the field. End points involving hemodynamic status, biomarkers, symptoms, hospital stay, end organ function, and mortality have all been employed either alone or in combination in recent randomized clinical trials in AHFS. In this review, we will discuss the various end point domains from both a clinical and a statistical perspective, summarize the wide variety of end points used in completed and ongoing AHFS studies, and suggest steps for greater standardization of end points across AHFS trials.
doi:10.1016/j.jacc.2008.12.079
PMCID: PMC3961583  PMID: 19520247
acute heart failure syndromes/acute decompensated heart failure; end points; randomized controlled trial design
11.  Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion 
Objectives
The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR).
Background
Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship.
Methods
We evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFRregional) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease.
Results
Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFRregional. Importantly, MFRregional varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFRregional (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFRglobal.
Conclusions
Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.
doi:10.1016/j.jacc.2011.06.051
PMCID: PMC3951833  PMID: 21996395
atherosclerosis; coronary computed tomography angiography; myocardial flow reserve; positron emission tomography
12.  Serum Phosphate Concentrations 
doi:10.1016/j.jacc.2011.01.047
PMCID: PMC3951850  PMID: 21737023
aortic valve calcification; lipids; phosphate; renal disease
13.  Human Degenerative Valve Disease Is Associated With Up-Regulation of Low-Density Lipoprotein Receptor-Related Protein 5 Receptor-Mediated Bone Formation 
OBJECTIVES
The goal of this research was to define the cellular mechanisms involved in myxomatous mitral valve disease and calcific aortic valve disease and to redefine the term degenerative valve disease in terms of an active cellular biology.
BACKGROUND
“Degenerative” valvular heart disease is the primary cause of regurgitant and stenotic valvular lesion in the U.S. However, the signaling pathways are not known. We hypothesize that valve degeneration occurs due to an osteoblastic differentiation process mediated by the low-density lipoprotein receptor-related protein 5 (Lrp5) signaling pathway to cause valve thickening.
METHODS
We examined human diseased valves: myxomatous mitral valves (n = 23), calcified tricuspid aortic valves (n = 27), calcified bicuspid aortic valves (n = 23), and control tissue from mitral and aortic valves (n = 40). The valves were examined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry for signaling markers important in osteoblast differentiation: Sox9 and Cbfa1 (transcription factors for osteoblast differentiation); Lrp5 and Wnt3 (osteoblast differentiation signaling marker), osteopontin and osteocalcin (osteoblast endochrondral bone matrix proteins), and proliferating cell nuclear antigen (a marker of cell proliferation). Cartilage development and bone formation was measured by Alcian blue stain and Alizarin red stain. Computed Scano MicroCT-40 (Bassersdorf, Switzerland) analysis measured calcium burden.
RESULTS
Low-density lipoprotein receptor-related protein 5, osteocalcin, and other osteochrondrogenic differentiation markers were increased in the calcified aortic valves by protein and gene expression (p > 0.001). Sox9, Lrp5 receptor, and osteocalcin were increased in myxomatous mitral valves by protein and gene expression (p > 0.001). MicroCT was positive in the calcified aortic valves and negative in the myxomatous mitral valves.
CONCLUSIONS
The mechanism of valvular heart disease involves an endochondral bone process that is expressed as cartilage in the mitral valves and bone in the aortic valves. Up-regulation of the Lrp5 pathway may play a role in the mechanism for valvular heart disease.
doi:10.1016/j.jacc.2006.02.040
PMCID: PMC3951851  PMID: 16631011
14.  Rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progression of Aortic Stenosis 
Objectives
The objective of this study was to test the effect of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor on the progression of moderate to severe aortic stenosis as measured by echocardiography.
Background
Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis.
Methods
We performed an open-label, prospective study evaluating 121 consecutive patients with asymptomatic moderate to severe aortic stenosis (aortic valve area ≥ 1.0 cm2; mean age 73.7 ± 8.9 years; 57 men and 64 women), treated with and without rosuvastatin according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Echocardiographic, serum lipid, and inflammatory markers were measured at baseline and every 6 months for 18 months.
Results
Sixty-one patients (50.4%) with elevated LDL (159.7 ± 33.4 mg/dl), aortic valve velocity (3.65 ± 0.64 m/s), and aortic valve area (1.23 ± 0.42 cm2) received rosuvastatin (20 mg/day), and 60 (49.6%) with a normal LDL (118.6 ± 37.4 mg/dl), aortic valve velocity (3.62 ± 0.61 m/s), and aortic valve area (1.20 ± 0.35 cm2) received no statin. During a mean follow-up of 73 ± 24 weeks, the change in aortic valve area in the control group was −0.10 ± 0.09 cm2/year versus −0.05 ± 0.12 cm2/year in the rosuvastatin group (p = 0.041). The increase in aortic valve velocity was 0.24 ± 0.30 m/s/year in the control group and 0.04 ± 0.38 m/s/year in the rosuvastatin group (p = 0.007). There was significant improvement in serum lipid and echocardiographic measures of aortic stenosis in the statin group.
Conclusions
Prospective treatment of aortic stenosis with rosuvastatin by targeting serum LDL slowed the hemodynamic progression of aortic stenosis. This is the first prospective study that shows a positive effect of statin therapy for this disease process.
doi:10.1016/j.jacc.2006.07.072
PMCID: PMC3951859  PMID: 17276178
15.  Modest Visceral Fat Gain Causes Endothelial Dysfunction In Healthy Humans 
Objective
This study sought to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans.
Background
Endothelial dysfunction has been identified as an independent predictor of cardiovascular events. Whether fat gain impairs endothelial function is unknown.
Methods
A randomized controlled study to assess the effects of fat gain on endothelial function. We recruited 43 normal weight healthy volunteers (mean age 29 years; 18 women). Subjects were assigned to gain weight (approximately 4 kg) (n=35) or to maintain weight (n=8). Endothelial function (brachial artery flow mediated dilation -FMD) was measured at baseline, after fat gain (8 weeks) and after weight loss (16 weeks) for fat-gainers and at baseline and follow-up (8 weeks) for weight-maintainers. Body composition was measured by DXA and abdominal CT scans.
Results
After an average weight gain of 4.1 kg, fat-gainers significantly increased their total, visceral and subcutaneous fat. Blood pressure and overnight polysomnography did not change after fat gain or loss. FMD remained unchanged in weight-maintainers. FMD decreased in fat-gainers (9.1 ± 3% vs. 7.8 ± 3.2%, p =0.003), but recovered to baseline when subjects shed the gained weight. There was a significant correlation between the decrease in FMD and the increase in visceral fat gain (rho = −0.42, p=0.004), but not with subcutaneous fat gain (rho = −0.22, p=0.15).
Conclusions
In normal weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction.
doi:10.1016/j.jacc.2010.03.063
PMCID: PMC3951914  PMID: 20705223
weight gain; endothelial function; visceral fat
16.  Treatment Differences by Health Insurance Among Outpatients with Coronary Artery Disease: Insights from the NCDR® 
Objectives
To compare treatment rates by insurance status for 5 quality-of-care indicators for coronary artery disease (CAD) care related to medication treatment.
Method
Within the NCDR's PINNACLE Registry, we identified 60,814 outpatients with CAD from 30 U.S. practices. Hierarchical modified Poisson regression models with practice site as a random effect were used to study the association between health insurance (no insurance, public or private health insurance) and 5 CAD quality measures.
Results
Of 60,814 patients, 5716 (9.4%) patients were uninsured and 11,962 (19.7%) had public insurance, whereas 43,136 (70.9%) were privately insured. After accounting for exclusions, uninsured patients with CAD were 9%, 12%, and 6% less likely to receive treatment with beta-blocker, ACE-I/ARB, and lipid lowering therapy, respectively, than privately insured patients, whereas patients with public insurance were 9% less likely to be prescribed ACE-I/ARB therapy. Most differences by insurance status were attenuated after adjusting for the site providing care. For example, whereas uninsured patients with left ventricular dysfunction and CAD were less likely to receive ACE-I/ARB therapy (unadjusted RR=0.88; 95% CI 0.84-0.93), this difference was eliminated after adjustment for site (adjusted RR=0.95; 95% CI 0.88-1.03; P=0.18).
Conclusions
Within this national outpatient cardiac registry, uninsured patients were less likely to receive evidence-based medications for CAD. These disparities were explained by the site providing care. Efforts to reduce treatment differences by insurance status among cardiac outpatients may additionally need to focus on improving rates of evidence-based treatment at sites with high proportions of uninsured patients.
doi:10.1016/j.jacc.2012.11.058
PMCID: PMC3641586  PMID: 23375933
Quality of Care; Disparities; Cardiovascular; Outpatient Care
17.  Association Between Statin Medications and Mortality, Major Adverse Cardiovascular Event, and Amputation-Free Survival Rates in Patients with Critical Limb Ischemia 
Objectives
To determine the associations between statin use and major adverse cardiovascular and cerebrovascular events (MACCE) and amputation-free survival in critical limb ischemia (CLI) patients.
Background
CLI is an advanced form of peripheral arterial disease (PAD) associated with nonhealing arterial ulcers and high rates of MACCE and major amputation. While statin medications are recommended for secondary prevention in PAD, their effectiveness in CLI is uncertain.
Methods
We reviewed 380 CLI patients who underwent diagnostic angiography or therapeutic endovascular intervention from 2006–2012. Propensity scores and inverse probability of treatment weighting were used to adjust for baseline differences between patients taking and not taking statins.
Results
246 (65%) patients were prescribed statins. The mean serum low-density lipoprotein (LDL) level was lower in patients prescribed statins (75±28 vs. 96±40 mg/dL, P<0.001). Patients prescribed statins had more baseline comorbidities including diabetes, coronary artery disease, and hypertension, as well as more extensive lower extremity disease (all P <0.05). After propensity weighting, statin therapy was associated with lower one-year rates of MACCE (stroke, myocardial infarction, or death; hazard ratio [HR] 0.53, 95% CI 0.28–0.99), mortality (HR 0.49, 95% CI 0.24–0.97), and major amputation or death (HR 0.53, 95% CI 0.35–0.98). Statin use was also associated with improved lesion patency among patients undergoing infrapopliteal angioplasty. Patients with LDL levels above 130mg/dL had increased hazards of MACCE and mortality compared to patients with lower levels of LDL.
Conclusions
Statins are associated with lower mortality and MACCE and increased amputation-free survival in CLI patients.
doi:10.1016/j.jacc.2013.09.073
PMCID: PMC3944094  PMID: 24315911
Peripheral artery disease; statin therapy; major adverse cardiac event; lipids and lipoproteins; secondary prevention
18.  Metformin Impairs Vascular Endothelial Recovery After Stent Placement in the Setting of Locally Eluted Mammalian Target of Rapamycin Inhibitors Via S6 Kinase-Dependent Inhibition of Cell Proliferation 
Objectives
This study sought to examine the effect of oral metformin (Mf) therapy on endothelialization in the setting of drug-eluting stents (DES).
Background
Mf is a commonly used therapy in diabetic patients receiving DES. Mf and locally eluted mammalian target of rapamycin (mTOR) inhibitors used in DES have convergent molecular signaling; however, the impact of this drug interaction on stent endothelialization is unknown.
Methods
We examined human endothelial aortic cells (HAECs) and a rabbit model of stenting to determine points on molecular convergence between these 2 agents and their impact on stent endothelialization.
Results
Western blotting of HAECs treated with Mf and the mTOR inhibitor sirolimus and 14-day rabbit iliacs treated with the combination of zotarolimus-eluting stents (ZES) and oral Mf demonstrated greater inhibition of S6 kinase (S6K), a downstream effector of mTOR complex 1, than either treatment alone. HAEC proliferation was significantly inhibited by Mf or sirolimus treatments alone and further reduced when they were combined. Knockdown of S6K via short interfering RNA in HAECs impaired cell proliferation via a cyclin D1–dependent mechanism, whereas its overexpression rescued the antiproliferative effects of both agents. Last, endothelialization and endothelial cell proliferation at 14 days were assessed in rabbits receiving ZES or bare-metal stents and Mf or placebo by scanning electron microscopy and bromodeoxyuridine/CD31 labeling, respectively. Both endpoints were inhibited by ZES treatment alone and were further reduced by the combination of Mf and ZES.
Conclusions
Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K. This further impairs endothelial recovery/proliferation via an S6K-dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk of delayed endothelial healing and stent thrombosis.
doi:10.1016/j.jacc.2012.12.018
PMCID: PMC3942872  PMID: 23449430
cell proliferation; drug-eluting stents; endothelium; metformin; S6K
19.  National Trends in Heart Failure Hospitalization Rates, 2001–2009 
Objective
This study sought to analyze recent trends over time in heart failure (HF) hospitalization rates, length of stay (LOS), and in-hospital mortality by age groups using a large national dataset of U.S. hospital discharges.
Background
HF hospitalization rates, LOS, and mortality have fallen over the past decade for older Medicare beneficiaries, but whether this holds true for younger adults is unknown.
Methods
From the National Inpatient Sample (NIS), we calculated HF hospitalization rates, LOS, and in-hospital mortality from 2001–2009 using survey data analysis techniques.
Results
1,686,089 hospitalizations with a primary discharge diagnosis of HF were identified from NIS data between 2001 and 2009. The overall national hospitalization rate decreased from 633 to 463 hospitalizations per 100,000 persons, (− 26.9%, p-for-trend<0.001). However, statistically significant declines (p<0.001) were only observed for patients age 55–64 years (−36.5%) 65–74 years (−37.4%), and ≥75 years (−28.3%), but not for patients age 18–44 years (−12.8%, p=0.57) or 45– 55 years (−16.2%, p=0.04). Statistically significant declines in LOS were only observed for patients age 65 years and older. Overall in-hospital mortality fell from 4.5% to 3.3%, a relative decline of 27.4%, (p-for-trend <0.001), but patients age 18 to 44 years did not exhibit a significant decline (−8.1%, p-for-trend=0.18). In secondary analyses significant declines in HF hospitalization rate over time were observed for white men, white women, and black women, but not for black men (−9.5%, p-for-trend=0.43).
Conclusions
Younger patients have not experienced comparable declines in HF hospitalization, LOS, and in-hospital mortality as older patients. Black men remain a vulnerable population for HF hospitalization.
doi:10.1016/j.jacc.2012.11.057
PMCID: PMC3939721  PMID: 23473413
congestive heart failure; epidemiology; hospitalization; mortality
21.  Natural History of the Early Repolarization Pattern in a Biracial Cohort: CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Objectives
The objective of this analysis was to determine the natural history and prospective association of cardiovascular risk factors with early repolarization (ER).
Background
ER is common and has been suggested to increase risk for cardiovascular mortality in middle-aged adults. Data are sparse regarding the natural history of ER from young adulthood to middle age.
Methods
We examined 5,069 participants (mean age 25 years at baseline; 40% black) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort over 20 years. Electrocardiograms were recorded at years 0 (Y0), 7 (Y7), and 20 (Y20) and coded as either definite, probable, possible, or no ER. Logistic regression was used to determine the association of cardiovascular risk factors with the presence of ER cross-sectionally and prospectively.
Results
A total of 941 of the 5,069 participants (18.6%) had definite ER at baseline, and only 119 of 2,505 participants (4.8%) at the Y20 examination still demonstrated the presence of ER. Younger age, black race, male sex, longer exercise duration and QRS duration, and lower body mass index (BMI), heart rate, QT index, and Cornell voltage were associated cross-sectionally with the presence of ER. Predictors of maintenance of ER from Y0 to Y20 were black race (odds ratio [OR]: 2.62; 95% CI; 1.61 to 4.25), BMI (OR: 0.62 per 1 SD; 95% CI: 0.40 to 0.94), serum triglyceride levels (OR: 0.66 per 1 SD; 95% CI: 0.45 to 0.98), and QRS duration (OR: 1.68 per 1 SD; 95% CI: 1.37 to 2.06) at baseline.
Conclusions
The prevalence of ER was significantly higher than previous estimates among asymptomatic young adults, and the majority of ER regressed by middle age. Black race, lower BMI, lower serum triglyceride levels, and longer QRS duration were independently associated with maintenance of ER over time.
doi:10.1016/j.jacc.2012.11.053
PMCID: PMC3748821  PMID: 23428218
early repolarization; electrocardiography; epidemiology
22.  Histopathologic Characteristics of Atherosclerotic Coronary Disease and Implications of the Findings for the Invasive and Noninvasive Detection of Vulnerable Plaques 
Objectives
The goal of this study was to identify histomorphologic characteristics of atherosclerotic plaques and to determine the amenability of some of these components to be used as markers for invasive and noninvasive imaging.
Background
Rupture of the atherosclerotic plaques is responsible for the majority of acute coronary events, and the culprit lesions demonstrate distinct histopathologic features. It has been tacitly believed that plaque rupture (PR) is associated with angiographically minimally occlusive lesions.
Methods
We obtained 295 coronary atherosclerotic plaques, including stable (fibroatheroma [FA]; n = 105), vulnerable (thin-cap fibroatheroma [TCFA]; n = 88), and disrupted plaques (plaque rupture [PR]; n = 102) from the hearts of 181 men and 32 women who had died suddenly. The hierarchical importance of fibrous cap thickness, percent luminal stenosis, macrophage area, necrotic core area, and calcified plaque area was evaluated by using recursive partitioning analysis. Because clinical assessment of fibrous cap thickness is not possible by noninvasive imaging, it was excluded from the second set of partitioning analysis.
Results
Thickness of the fibrous cap emerged as the best discriminator of plaque type; the cap thickness measured <55 μm in ruptured plaques, and all FA were associated with >84-μm cap thickness. Although the majority of TCFA were found in the 54- to 84-μm thickness group, those with <54-μm thickness were more likely to show <74% luminal stenosis (area under the curve: FA, 1.0; TCFA, 0.89; PR, 0.90). After exclusion of cap thickness, analysis of the plaque characteristics revealed macrophage infiltration and necrotic core to be the 2 best discriminators of plaque types (area under the curve: FA, 0.82; TCFA, 0.58; PR, 0.72). More than 75% cross-section area stenosis was seen in 70% of PR and 40% of TCFA; only 5% PR and 10% TCFA were <50% narrowed.
Conclusions
This postmortem study defines histomorphologic characteristics of vulnerable plaques, which may help develop imaging strategies for identification of such plaques in patients at a high risk of sustaining acute coronary events.
doi:10.1016/j.jacc.2012.10.054
PMCID: PMC3931303  PMID: 23473409
acute coronary syndrome; coronary artery disease; high-risk plaque; positive remodeling
23.  Haptoglobin Genotype Is a Consistent Marker of Coronary Heart Disease Risk Among Individuals With Elevated Glycosylated Hemoglobin 
Objectives
This study sought to investigate into the biologically plausible interaction between the common haptoglobin (Hp) polymorphism rs#72294371 and glycosylated hemoglobin (HbA1c) on risk of coronary heart disease (CHD).
Background
Studies of the association between the Hp polymorphism and CHD report inconsistent results. Individuals with the Hp2-2 genotype produce Hp proteins with an impaired ability to prevent oxidative injury caused by elevated HbA1c.
Methods
HbA1c concentration and Hp genotype were determined for 407 CHD cases matched 1:1 to controls (from the NHS [Nurses' Health Study]) and in a replication cohort of 2,070 individuals who served as the nontreatment group in the ICARE (Israel Cardiovascular Events Reduction With Vitamin E) study, with 29 CHD events during follow-up. Multivariate models were adjusted for lifestyle and CHD risk factors as appropriate. A pooled analysis was conducted of NHS, ICARE, and the 1 previously published analysis (a cardiovascular disease case-control sample from the Strong Heart Study).
Results
In the NHS, Hp2-2 genotype (39% frequency) was strongly related to CHD risk only among individuals with elevated HbA1c (≥6.5%), an association that was similar in the ICARE trial and the Strong Heart Study. In a pooled analysis, participants with both the Hp2-2 genotype and elevated HbA1c had a relative risk of 7.90 (95% confidence interval: 4.43 to 14.10) for CHD compared with participants with both an Hp1 allele and HbA1c <6.5% (p for interaction = 0.004), whereas the Hp2-2 genotype with HbA1c <6.5% was not associated with risk (relative risk: 1.34 [95% confidence interval: 0.73 to 2.46]).
Conclusions
Hp genotype was a significant predictor of CHD among individuals with elevated HbA1c.
doi:10.1016/j.jacc.2012.09.063
PMCID: PMC3678553  PMID: 23312704
acute myocardial infarction; coronary disease; epidemiology; genetic association; genotype; glycoproteins
24.  Prognostic Impact of the Presence and Absence of Angina on Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Stable Coronary Artery Disease 
Objectives
The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence of angina and angina equivalent symptoms.
Background
Data on the prognostic value of symptoms in these patients are limited.
Methods
Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline.
Results
There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p = 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p =0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48).
Conclusions
Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305)
doi:10.1016/j.jacc.2012.11.036
PMCID: PMC3701296  PMID: 23410541
angina; coronary artery disease; silent ischemia; type 2 diabetes
25.  Prevalence and Clinical Characteristics of Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Heart Disease 
Objectives
The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.
Background
Mental stress–induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia.
Methods
Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test.
Results
Mental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05).
Conclusions
Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)
doi:10.1016/j.jacc.2012.11.037
PMCID: PMC3913125  PMID: 23410543
mental and exercise stress; myocardial ischemia

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