Percutaneous coronary intervention for ULMCA stenosis is controversial; however, current use and outcomes of ULMCA PCI in routine U.S. clinical practice have not been described.

We evaluated 5,627 patients undergoing ULMCA PCI at 693 centers within the National Cardiovascular Data Registry Catheterization Percutaneous Coronary Intervention Registry for temporal trends in PCI use (2004 to 2008), patient characteristics, and in-hospital mortality. Thirty-month mortality and composite major adverse events (death, myocardial infarction, and revascularization) with drug-eluting versus bare-metal stents were compared using inverse probability weighted (IPW) hazard ratios (HRs) in a nonrandomized Medicare-linked (age ≥65 years) patient cohort (n = 2,765).

ULMCA PCI was performed in 4.3% of patients with ULMCA stenosis. Unadjusted in-hospital mortality rates ranged from 2.9% for elective cases to 45.1% for emergent/salvage cases. By 30 months, 57.9% of the elderly ULMCA PCI population experienced death, myocardial infarction, or revascularization, and 42.7% died. Patients receiving drug-eluting stents (versus bare-metal stents) had a lower 30-month mortality (IPW HR: 0.84, 95% confidence interval [CI]: 0.73 to 0.96), but the composite of major adverse events were similar (IPW HR: 0.95, 95% CI: 0.84 to 1.06).

In the United States, ULMCA PCI is performed in <5% of patients with ULMCA disease and is generally reserved for those at high procedural risk. Adverse events are common in elderly patients and are related to patient and procedural characteristics, including stent type.

Despite a typical clinical presentation with exercise-related anginal symptoms (chest pain or dyspnea) with or without occasional attacks of resting chest pain suggestive of coronary artery disease, 40% of patients undergoing diagnostic angiography have normal or "near" normal coronary arteriograms. Many of these patients are given a diagnosis of noncardiac chest pain, and some are considered to have microvascular angina. However, we speculate that abnormal coronary vasomotion (reduced vasodilatation with exercise = reduced coronary flow reserve and/or vasospasm at rest) might also represent a plausible explanation for the symptoms of the patient.

This was a prospective study in 304 consecutive patients (50% men, mean age 66 ± 10 years) with exertional anginal symptoms undergoing diagnostic angiography. A total of 139 patients (46%) had ≥50% coronary artery disease in at least 1 coronary artery, 21 patients (7%) had luminal narrowings ranging from >20% to 49%, and 144 patients (47%) had normal coronary arteries or only minimal irregularities (<20% diameter reduction).

One hundred twenty-four patients of the latter (86%) underwent intracoronary acetylcholine (ACH) testing, which elicited coronary spasm in 77 patients (62%), 35 patients (45%) with epicardial spasm (≥75% diameter reduction with reproduction of the symptoms of the patient) and 42 patients (55%) with microvascular spasm (reproduction of symptoms, ischemic electrocardiographic changes, and no epicardial spasm).

Nearly 50% of patients undergoing diagnostic angiography for assessment of stable angina had angiographically normal or near normal coronary arteriograms. The ACH test triggered epicardial or microvascular coronary spasm in nearly two-thirds of these patients. Our results suggest that abnormal coronary vasomotion plays a pathogenic role in this setting and that the ACH test might be useful to identify patients with cardiac symptoms, despite normal coronaries. (Abnormal Coronary Vasomotion in Patients With Suspected CAD But Normal Coronary Arteries; NCT00921856)

The relative and combined contributions of fitness and fatness to health are controversial, and few studies are available on the associations of changes in fitness and fatness with the development of CVD risk factors.

We followed up 3,148 healthy adults who received at least 3 medical examinations. Fitness was determined by using a maximal treadmill test. Fatness was expressed by percent body fat and body mass index. Changes in fitness and fatness between the first and second examinations were categorized into loss, stable, or gain groups.

During the 6-year follow-up after the second examination, 752, 426, and 597 adults developed hypertension, metabolic syndrome, and hypercholesterolemia, respectively. Maintaining or improving fitness was associated with lower risk of developing each outcome, whereas increasing fatness was associated with higher risk of developing each outcome, after adjusting for possible confounders and fatness or fitness for each other (all p for trend <0.05). In the joint analyses, the increased risks associated with fat gain appeared to be attenuated, although not completely eliminated, when fitness was maintained or improved. In addition, the increased risks associated with fitness loss were also somewhat attenuated when fatness was reduced.

Both maintaining or improving fitness and preventing fat gain are important to reduce the risk of developing CVD risk factors in healthy adults.

Among patients with preserved EF, factors leading to HF are not fully understood. Cross-sectional studies have demonstrated LA dysfunction at the time of HF, but longitudinal data on antecedent atrial function are lacking.

We performed resting transthoracic echocardiography in 855 subjects with coronary heart disease and EF ≥50%. Left atrial functional index (LAFI) was calculated as ([LA emptying fraction x left ventricular outflow tract-velocity time integral] / [indexed LA end-systolic volume]), where LA emptying fraction was defined as (LA end-systolic volume – LA end-diastolic volume) / LA end-systolic volume. We used Cox models to evaluate the association between LAFI and HF hospitalization.

Over a median follow-up of 7.9 years, 106 participants (12.4%) were hospitalized for HF. Rates of HF hospitalization were inversely proportional to quartile (Q) of LAFI: Q1, 47 per 1,000 person-years; Q2, 18.3; Q3, 9.6; and Q4, 5.3 (p < 0.001). Each standard deviation decrease in LAFI was associated with a 2.6-fold increased hazard of adverse cardiovascular outcomes (unadjusted hazard ratio: 2.6, 95% confidence interval: 2.1 to 3.3, p < 0.001), and the association persisted even after adjustment for clinical risk factors, N-terminal pro–B-type natriuretic peptide, and a wide range of echocardiographic parameters (adjusted hazard ratio: 1.5, 95% confidence interval: 1.0 to 2.1, p = 0.05).

Left atrial dysfunction independently predicts HF hospitalization in subjects with coronary heart disease and preserved baseline EF. The LAFI may be useful for HF risk stratification, and LA dysfunction may be a potential therapeutic target.

The CIED infection rate has increased at a time of increased device use. LAE is associated with significant morbidity and mortality.

The clinical presentation and course of LAE were evaluated by the MEDIC (Multicenter Electrophysiologic Device Cohort) registry, an international registry enrolling patients with CIED infection. Consecutive LAE patients enrolled in the Multicenter Electrophysiologic Device Cohort registry between January 2009 and May 2011 were analyzed. The clinical features and outcomes of 2 groups were compared based on the time from the most recent CIED procedure (early, <6 months; late, >6 months).

The Multicenter Electrophysiologic Device Cohort registry entered 145 patients with LAE (early = 43, late = 102). Early LAE patients presented with signs and symptoms of local pocket infection, whereas a remote source of bacteremia was present in 38% of patients with late LAE but only 8% of early LAE (p < 0.01). Staphylococcal species were the most frequent pathogens in both early and late LAE. Treatment consisted of removal of all hardware and intravenous administration of antibiotics. In-hospital mortality was low (early = 7%, late = 6%).

The clinical presentation of LAE is influenced by the time from the most recent CIED procedure. Although clinical manifestations of pocket infection are present in the majority of patients with early LAE, late LAE should be considered in any CIED patient who presents with fever, bloodstream infection, or signs of sepsis, even if the device pocket appears uninfected. Prompt recognition and management may improve outcomes.

Recent data suggest that only a third of patients undergoing ICA have obstructive coronary artery disease (CAD); accurate pre-ICA risk stratification is needed.

At 47 centers participating in the ACIC (Advanced Cardiovascular Imaging Consortium) in Michigan, patients without known CAD who were undergoing CCTA within 3 months of a stress test were studied. Demographics, risk factors, symptoms, and stress test results were correlated with obstructive CAD (>50% stenosis) on CCTA and ICA.

Among 6,198 patients (age 56 ± 12 years, 48% men), >50% stenosis was seen in 1,158 (18.7%) on CCTA. Independent predictors included male sex (odds ratio [OR]: 2.37, 95% confidence interval [CI]: 1.83 to 3.06), current smoking (OR: 2.23, 95% CI: 1.57 to 3.17), older age (OR per 10-year increment: 2.14, 95% CI: 1.89 to 2.41), hypertension (OR: 1.8, 95% CI: 1.37 to 2.34), and typical angina (OR: 1.48, 95% CI: 1.03 to 2.12). Stress test results were not predictive. Among patients undergoing ICA (n = 621), there was a strong correlation of ICA with CCTA findings (OR: 9.09, 95% CI: 5.57 to 14.8, p < 0.001), but not stress results (OR: 0.79, 95% CI: 0.56 to 1.11, p = 0.17).

Stress test findings did not predict obstructive CAD on CCTA, observed in <20% of patients in this large study group. The strong association of CCTA with ICA suggests that it may serve as an effective "gatekeeper" to invasive testing in patients needing adjudication of stress test results. (Advanced Cardiovascular Imaging Consortium: A Collaborative Quality Improvement Project [ACIC]; NCT00640068)

Although TAVI is becoming a mature technique, the impact of sex differences remains unclear.

The TAVI patients were included prospectively in a dedicated database from October 2006. The proportion of women (n = 131) was similar to that of men (n = 129). The Edwards valve (85.4%) and CoreValve (14.6%) were used through the transfemoral (65.0%), subclavian (3.1%), or transapical (31.9%) approach. All events were defined according to Valve Academic Research Consortium criteria.

Age was similar (83.1 ± 6.3 years), but women had less coronary and peripheral disease, less previous cardiac surgery, higher ejection fraction, and lower EuroSCORE (European System for Cardiac Operative Risk Evaluation [22.3 ± 9.0% vs. 26.2 ± 13.0%, p = 0.005]). Minimal femoral size (7.74 ± 1.03 mm vs. 8.55 ± 1.34 mm, p < 0.001), annulus size (20.9 ± 1.4 vs. 22.9 ± 1.7 mm, p < 0.001), and valve size (23.9 ± 1.6 mm vs. 26.3 ± 1.5 mm, p < 0.001) were smaller in women. Device success was similar (90.8% vs. 88.4%, p = 0.516) despite more frequent iliac complications (9.0% vs. 2.5%, p = 0.030). Residual mean aortic pressure gradient (11.6 ± 4.9 vs. 10.9 ± 4.9, p = 0.279) was also similar. The 1-year survival rate was higher for women, 76% (95% confidence interval: 72% to 80%), than for men, 65% (95% confidence interval: 60% to 69%); and male sex (hazard ratio: 1.62, 95% confidence interval: 1.03 to 2.53, p = 0.037) was identified as a predictor of midterm mortality by Cox regression analysis.

Female sex is associated with better baseline clinical characteristics and improved survival, and is identified as a predictor of midterm survival after TAVI.

Published data reviews have suggested that statins might not be as effective in women as in men in decreasing cardiovascular events.

Published data searches and contacts with investigators identified 18 randomized clinical trials of statins with sex-specific outcomes (N = 141,235, 40,275 women, 21,468 cardiovascular events). Odds ratios (ORs) and 95% confidence intervals (CIs) for cardiovascular events were calculated for women and men separately with random effects meta-analyses.

The cardiovascular event rate was lower among those randomized to statin intervention than in those randomized to control (low-dose statin in 4 studies, placebo in 11 studies, usual care in 3 studies) and similar in women and men (OR: 0.81, 95% CI: 0.75 to 0.89; p < 0.0001, and OR: 0.77, 95% CI: 0.71 to 0.83, p < 0.0001, respectively). The benefit of statins was statistically significant in both sexes, regardless of the type of control, baseline risk, or type of endpoint and in both primary and secondary prevention. All-cause mortality was also lower with statin therapy both in women and men without significant interaction by sex (p for interaction = 0.4457).

Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men. Statin therapy should be used in appropriate patients without regard to sex.

Endothelial dysfunction is commonly observed in patients with CHF, and it contributes to the limitation in exercise capacity that accompanies this condition. Bacterial lipopolysaccharide may trigger proinflammatory cytokine release and promote further endothelial dysfunction. UDCA, a bile acid used in the treatment of cholestatic liver disease, has anti-inflammatory and cytoprotective properties and may contribute to the formation of mixed micelles around lipopolysaccharide. These properties may help to improve peripheral blood flow in patients with CHF.

We performed a prospective, single-center, double-blind, randomized, placebo-controlled crossover study of UDCA in 17 clinically stable male patients with CHF (New York Heart Association functional class II/III, left ventricular ejection fraction <45%). Patients received in random order 500 mg UDCA twice daily for 4 weeks and placebo for another 4 weeks. The primary endpoint was post-ischemic peak peripheral arm blood flow as assessed by strain-gauge plethysmography.

Sixteen patients completed the study. UDCA was well tolerated in all patients. Compared with placebo, UDCA improved peak post-ischemic blood flow in the arm (+18%, p = 0.038), and a trend for improved peak post-ischemic blood flow in the leg was found (+17%, p = 0.079). Liver function improved: compared with placebo, levels of -glutamyl transferase, aspartate transaminase, and soluble tumor necrosis factor α receptor 1 were lower after treatment with UDCA than after placebo (all p < 0.05). There was no change in 6-min walk test or New York Heart Association functional class, and levels of tumor necrosis factor α and interleukin-6 were unchanged or increased compared with placebo.

UDCA is well tolerated in patients with CHF. UDCA improves peripheral blood flow and is associated with improved markers of liver function. (Ursodeoxycholic Acid in Chronic Heart Failure; NCT00285597)

Few studies have identified functional determinants of AF initiation. Because conduction slowing is required for reentry, we hypothesized that AF from pulmonary vein triggers might initiate at sites exhibiting rate-dependent slowing in conduction velocity (CV restitution) or local slowing evidenced by signal fractionation.

In 28 patients with AF (left atrial size 43 ± 5 mm; n = 13 persistent) and 3 control subjects (no AF) at electrophysiological study, we measured bi-atrial conduction time (CT) electrogram fractionation at 64 or 128 electrodes with baskets in left (n = 17) or both (n = 14) atria during superior pulmonary vein pacing at cycle lengths (CL) accelerating from 500 ms (120 beats/min) to AF onset.

Atrial fibrillation initiated in 19 of 28 AF patients and no control subjects. During rate acceleration, conduction slowed in 23 of 28 AF patients (vs. no control subjects, p = 0.01) at the site of AF initiation (15 of 19) or latest activated site (20 of 28). The CT lengthened from 79 ± 23 ms to 107 ± 39 ms (p < 0.001) on acceleration, in a spectrum from persistent AF (greatest slowing) to control subjects (least slowing; p < 0.05). Three patterns of CV restitution were observed: 1) broad (gradual CT prolongation, 37% patients); 2) steep (abrupt prolongation, at CL 266 ± 62 ms, 42%); and 3) flat (no prolongation, 21% AF patients, all control subjects). The AF initiation was more prevalent in patients with CV restitution (17 of 23 vs. 2 of 8; p = 0.03) and immediately followed abrupt re-orientation of the activation vector in patients with broad but not steep CV restitution (p < 0.01). Patients with broad CV restitution had larger atria (p = 0.03) and were more likely to have persistent AF (p = 0.04). Notably, neither amplitude nor duration (fractionation) of the atrial signal at the AF initiation site were rate-dependent (both p = NS).

Acceleration-dependent slowing of atrial conduction (CV restitution) precedes AF initiation, whereas absence of CV restitution identifies inability to induce AF. Conduction restitution, but not fractionated electrograms, may thus track the functional milieu enabling AF initiation and has implications for guiding AF ablation and pharmacological therapy.

The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk of SCD will help to define who may benefit most from implantable cardioverter-defibrillators.

The cohort was 1,803 children in the PCMR (Pediatric Cardiomyopathy Registry) with a diagnosis of DCM from 1990 to 2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using Classification and Regression Tree methodology.

The 5-year incidence rates were 29% for heart transplantation, 12.1% non-SCD, 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD, and the cause was unknown for 56. The 5-year incidence rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving antiarrhythmic medication were at higher risk of SCD (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.3, p = 0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all these criteria: left ventricular (LV) end-systolic dimension z-score >2.6, age at diagnosis younger than 14.3 years, and the LV posterior wall thickness to end-diastolic dimension ratio <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD.

The 5-year incidence rate of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included age at diagnosis younger than 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for implantable cardioverter-defibrillator placement. (Pediatric Cardiomyopathy Registry; NCT00005391)

OSE are critical in the initiation, progression, and destabilization of atherosclerotic plaques. Gadolinium [Gd(III)]-based MRI agents can be associated with systemic toxicity. Mn is an endogenous, biocompatible, paramagnetic metal ion that has poor MR efficacy when chelated, but strong efficacy when released within cells.

Multimodal Mn micelles were generated to contain rhodamine for confocal microscopy and conjugated with either the murine monoclonal IgG antibody MDA2 targeted to malondialdehyde (MDA)-lysine epitopes or the human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes ("targeted micelles"). Micelle formulations were characterized in vitro and in vivo, and their MR efficacy (9.4-T) evaluated in apolipoprotein-deficient (apoE ^–/–) and low-density lipoprotein receptor negative (LDLR ^–/–) mice (0.05 mmol Mn/kg dose) (total of 120 mice for all experiments). In vivo competitive inhibition studies were performed to evaluate target specificity. Untargeted, MDA2-Gd, and IK17-Gd micelles (0.075 mmol Gd/kg) were included as controls.

In vitro studies demonstrated that targeted Mn micelles accumulate in macrophages when pre-exposed to MDA-LDL with ~10x increase in longitudinal relativity. Following intravenous injection, strong MR signal enhancement was observed 48 to 72 h after administration of targeted Mn micelles, with colocalization within intraplaque macrophages. Co-injection of free MDA2 with the MDA2-Mn micelles resulted in full suppression of MR signal in the arterial wall, confirming target specificity. Similar MR efficacy was noted in apoE ^–/– and LDLR ^–/– mice with aortic atherosclerosis. No significant differences in MR efficacy were noted between targeted Mn and Gd micelles.

This study demonstrates that biocompatible multimodal Mn-based molecular imaging probes detect OSE within atherosclerotic plaques and may facilitate clinical translation of noninvasive imaging of human atherosclerosis.

There is no proven therapy for HFpEF. In the absence of data, medicines with established benefit in HFrEF such as vasodilators are frequently prescribed for HFpEF.

We compared baseline hemodynamics and acute responses to vasodilation with intravenous sodium nitroprusside in patients with HFrEF (n = 174) and HFpEF (n = 83), determined invasively by cardiac catheterization.

Baseline blood pressure, stroke volume, and cardiac output were greater in HFpEF than HFrEF, while pulmonary artery mean and pulmonary wedge pressures were similar. Left ventricular filling pressures were reduced to a similar extent in each group with nitroprusside, but the drop in systemic arterial pressure was 2.6-fold greater in HFpEF (p < 0.0001), and improvements in stroke volume and cardiac output were each ~60% lower in HFpEF compared to HFrEF (p < 0.0001). Despite similarly elevated filling pressures, HFpEF patients were fourfold more likely than HFrEF to experience a reduction in stroke volume with nitroprusside (p < 0.0001), suggesting greater vulnerability to preload reduction. Pulmonary artery systolic pressure dropped more in HFpEF than in HFrEF despite similar reduction in pulmonary mean pressure and resistance, suggesting higher right ventricular systolic elastance in HFpEF.

As compared to patients with HFrEF, patients with HFpEF experience greater blood pressure reduction, less enhancement in cardiac output, and greater likelihood of stroke volume drop with vasodilators. These findings emphasize fundamental differences in the 2 HF phenotypes and suggest that more pathophysiologically targeted therapies are needed for HFpEF.

HFpEF is associated with ventriculoarterial stiffening.

We compared 23 patients with stable chronic HFpEF, left ventricular ejection fraction >45%, and impaired relaxation with 15 controls without cardiac disease. Patients were compared at rest and during a 30-W exercise. The following variables were measured or calculated by Doppler echocardiography and tonometry: left ventricular volumes and end-systolic elastance (Ees), peripheral resistance, arterial elastance (Ea), arterial compliance, aortic pulse wave velocity, and carotid Peterson modulus (Ep).

Patients with HFpEF were comparable to controls in age, sex ratio, blood pressure, and heart rate. Ventriculoarterial coupling, assessed by Ees/Ea and Ees/Ep ratios, was moderately impaired at rest in patients compared with controls (both p < 0.01). HFpEF was associated during exercise with a major increase in Ep (+155 ± 193% vs. –5 ± 28%), pulse wave velocity (+20 ± 30% vs. –7 ± 24%), and Ea (+12 ± 15% vs. –5 ± 10%), and a lower decrease in peripheral resistance (–17 ± 12% vs. –26 ± 12%) (p < 0.05 for all). In addition, HFpEF patients showed a lower increase in stroke volume (+10 ± 16% vs. +21 ± 12%) despite a greater increase in Ees (+20 ± 18% vs. +3 ± 12%) (p < 0.05 for all). Also during exercise, adaptation of proximal ventriculoarterial coupling was impaired in HFpEF patients (Ees/Ep: –26 ± 47% vs. +20 ± 47% for controls) (p < 0.01), with no difference in Ees/Ea.

In HFpEF patients, moderate exercise leads to a steep increase in proximal afterload that is underestimated at rest and is associated with unfavorable ventriculoarterial coupling and exercise intolerance.

Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear.

We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography.

Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results.

Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomy's Role in Coronary Artery [CAD] [SPARC]; NCT00321399)

cPP can be partitioned into height of the first systolic shoulder (P1), generated by a forward pressure wave and related to arterial stiffness, and augmentation pressure (AP), thought to be influenced by pressure wave reflection from muscular arteries and/or aortic reservoir.

Using a longitudinal cohort design, cPP, P1, and AP were estimated (using the SphygmoCor System [AtCor Medical Pty Ltd., West Ryde, Australia]) in 411 female twins over a mean follow-up of 10.8 years. In a subsample (n = 42), cPP, arterial stiffness (using pulse wave velocity [PWV]) and arterial diameters (using ultrasonography) were measured before and after nitroglycerin administration (400 μg s/l).

cPP increased more than peripheral pulse pressure (10.3 and 9.2 mm Hg, respectively; p < 0.0001). In women <60 years of age at follow-up, AP contributed more to the increase in cPP than did P1 (increases of 6.5 ± 6.4 mm Hg and 4.2 ± 7.8 mm Hg, respectively). P1 was significantly positively correlated to PWV (p < 0.0001); AP was correlated to aorto-femoral tapering (p < 0.0001) but not PWV. Nitroglycerin reduced cPP by 10.0 ± 6.0 mm Hg (p < 0.0001), equivalent to a decade of aging. The reduction in cPP was entirely explained by a decrease in AP, with no significant change in P1 or PWV but an increase in large artery diameters of 4% to 18% (p < 0.0001).

Age-related widening of cPP is driven in large part by an increase in AP, which can be reversed by selective dilation of muscular arteries, independent of PWV.

Hyperglycemia is associated with an increased risk of cardiac events, but limited information is available on its relationship to subclinical myocardial damage. Elevated cardiac troponin T even below traditional detection levels can be detected by a novel high-sensitivity assay.

We examined the association between baseline glycated hemoglobin (HbA1c) and high-sensitivity cardiac troponin T (hs-cTnT) in 9,661 participants free of CHD and heart failure in the ARIC (Atherosclerosis Risk in Communities) study. Multivariable logistic regression models characterized the association between clinical categories of HbA1c (<5.7%, 5.7% to 6.4%, and ≥6.5%) and our primary outcome of elevated hs-cTnT (≥14 ng/l).

Higher baseline values of HbA1c were associated in a graded fashion with elevated hs-cTnT (p for trend < 0.001). After adjusting for traditional risk factors, compared to persons with HbA1c <5.7%, the odds ratios of elevated hs-cTnT for persons with HbA1c 5.7% to 6.4% and ≥6.5% were 1.26 (95% confidence interval: 1.01 to 1.56) and 1.97 (95% confidence interval: 1.44 to 2.70), respectively.

Higher HbA1c is associated with elevated hs-cTnT among persons without clinically evident CHD, suggesting that hyperglycemia contributes to myocardial injury beyond its effects on development of clinical atherosclerotic coronary disease.

LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA.

In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment.

In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor.

Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

Anemia is an independent prognostic marker in patients with heart failure. The effect of anemia on mortality decreases with increasing creatinine levels.

Multivariate Cox regression analyses were used to investigate the prognostic effect of anemia in 4,144 patients with heart failure from 21 outpatient heart failure clinics in Norway. Severe renal failure was defined as estimated glomerular filtration rate ≤45 ml/min/1.73 m² and advanced heart failure as New York Heart Association functional classes IIIb and IV.

Baseline anemia was present in 24% and was a strong predictor of all-cause mortality (adjusted hazard ratio [HR]: 1.30, 95% CI: 1.09 to 1.56, p = 0.004). Baseline anemia did not predict mortality in the 752 patients with severe renal dysfunction (adjusted HR: 1.08, 95 % CI: 0.77 to 1.51, p = 0.662) and the 528 patients with advanced heart failure (adjusted HR: 0.87, 95% CI: 0.56 to 1.34, p = 0.542). In the 1,743 patients who attended subsequent visits, sustained anemia independently predicted worse prognosis (adjusted HR: 1.47, 95% CI: 1.10 to 1.94, p = 0.008), whereas transient and new-onset anemia did not.

According to our study, baseline anemia was not an independent predictor of all-cause mortality in outpatients with heart failure and accompanied severe renal dysfunction or advanced heart disease. Sustained anemia after optimizing heart failure treatment might imply worse prognosis independently of renal function and New York Heart Association functional class.

The ability of CTA to exclude obstructive CAD in patients of different pre-test probabilities and in presence of coronary calcification remains uncertain.

For the CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) study, 371 patients underwent CTA and cardiac catheterization for the detection of obstructive CAD, defined as ≥50% luminal stenosis by quantitative coronary angiography (QCA). This analysis includes 80 initially excluded patients with a calcium score ≥600. Area under the receiver-operating characteristic curve (AUC) was used to evaluate CTA diagnostic accuracy compared to QCA in patients according to calcium score and pre-test probability of CAD.

Analysis of patient-based quantitative CTA accuracy revealed an AUC of 0.93 (95% confidence interval [CI]: 0.90 to 0.95). The AUC remained 0.93 (95% CI: 0.90 to 0.96) after excluding patients with known CAD but decreased to 0.81 (95% CI: 0.71 to 0.89) in patients with calcium score ≥600 (p = 0.077). While AUCs were similar (0.93, 0.92, and 0.93, respectively) for patients with intermediate, high pre-test probability for CAD, and known CAD, negative predictive values were different: 0.90, 0.83, and 0.50, respectively. Negative predictive values decreased from 0.93 to 0.75 for patients with calcium score <100 or ≥100, respectively (p = 0.053).

Both pre-test probability for CAD and coronary calcium scoring should be considered before using CTA for excluding obstructive CAD. For that purpose, CTA is less effective in patients with calcium score ≥600 and in patients with a high pre-test probability for obstructive CAD.

The KATP channels play a vital role in preserving the metabolic integrity of the stressed heart. However, the mechanisms that govern the expression of their subunits (e.g., potassium inward rectifier [Kir] 6.2) in adult pathologies are mostly unknown.

We collected biopsies from the 4 cardiac chambers and 50 clinical parameters from 30 surgical patients with severe mitral dysfunction. Proteins and messenger ribonucleic acids (mRNAs) of KATP pore subunits and mRNAs of their known transcriptional regulators (forkhead box [FOX] F2, FOXO1, FOXO3, and hypoxia inducible factor [HIF]-1α) were measured respectively by Western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction, and submitted to statistical analysis.

In all heart chambers, Kir6.2 mRNA correlated with HIF-1α mRNA. Neither Kir6.1 nor Kir6.2 proteins positively correlated with their respective mRNAs. The HIF-1α mRNA related in the left ventricle to aortic pressure, in the left atrium to left atrial pressure, and in all heart chambers to a decreased Kir6.2 protein/mRNA ratio. Interestingly, in the left heart, Kir6.2 protein and its immunohistochemical detection in myocytes were maximal at low venous PO₂. In the left ventricle, the Kir6.2 protein/mRNA ratio was also significantly higher at low venous PO₂, suggesting that tissue hypoxia might stabilize the Kir6.2 protein.

Results suggest that post-transcriptional events determine Kir6.2 protein expression in the left ventricle of patients with severe mitral dysfunction and low venous PO₂. Mechanical stress mainly affects transcription of HIF-1α and Kir6.2. This study implies that new therapies could aim at the proteasome for stabilizing the left ventricular Kir6.2 protein.

Limited data are available regarding survival in patients with PCA identified in the clinical setting by noninvasive lower extremity arterial evaluation.

We conducted a historical cohort study of consecutive patients who underwent outpatient, noninvasive lower extremity arterial evaluation at the Mayo Clinic, Rochester, Minnesota, from January 1998 through December 2007, and who were followed for a mean duration of 5.8 ± 3.1 years. An ABI 1.00 to 1.30 was considered normal, PAD was defined as a resting or post-exercise ABI ≤0.90, and PCA defined as an ABI ≥1.4 and/or an ankle systolic blood pressure >255 mm Hg. Patients were followed for all-cause mortality through September 30, 2009.

Of 16,493 individuals (mean age 67.8 ± 13.0 years, 59% male); 29% had normal ABI, 54% had PAD, and 17% had PCA. During follow-up (mean duration 5.8 ± 3.1 years), 4,365 patients (26%) died. The percent alive at the end of the study period was 88%, 70%, and 60% for normal ABI, PAD, and PCA, respectively. After adjustment for age, sex, cardiovascular risk factors, comorbid conditions, and medication use, the hazard ratios (95% confidence intervals) of death associated with PCA were 2.0 (1.8 to 2.2) and 1.3 (1.2 to 1.4) compared with the normal ABI and PAD groups, respectively.

Patients identified by noninvasive vascular testing to have poorly compressible leg arteries have poor survival, worse than those with a normal ABI or those with PAD.

Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood.

We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice.

We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men.

E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease.

Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown.

The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro.

Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that T lymphocytes but not CD4⁺ helper T cells were a major source of IL-17A. Anti–IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression.

IL-17A mainly produced by T cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.

The surgical strategy of conventional aortic valve replacement does not accept paraprosthetic leakage and requires immediate action to eliminate it. However, paravalvular leakage is the major concern after TAVI.

A total of 358 patients underwent transapical TAVI with balloon-expandable prostheses. The modified procedural strategy consisted of precise positioning of the prosthesis using a modified TAVI technique and immediate additional intraprocedural treatment to eliminate relevant paravalvular leakage.

Balloon redilation of the transcatheter valve was performed in 18 patients (5%), and additional second valves were implanted in 13 (4%). At the end of the procedure, 186 patients (52%) had no paravalvular or transvalvular regurgitation. In the remaining 172 patients, paravalvular leakage was observed in 113 (32%), transvalvular leakage in 47 (13%), and both in 12 (3%). Leakage was trace in 88 patients (25%), mild in 82 (23%), and moderate in 2 (0.6%). Multivariate analysis identified male sex, New York Heart Association functional class IV, and no previous aortic valve replacement as predictors of post-procedural leakage. Cumulative survival was not dependent on post-procedural regurgitation rate. Overall mortality was 5 ± 1% at 30 days, 14 ± 2% at 6 months, 17 ± 2% at 1 year, and 33 ± 4% at 2 years.

The modified procedural strategy of transapical TAVI with a balloon-expandable prosthesis was associated with a low incidence of relevant prosthetic regurgitation.

Although several studies have focused on idiopathic pulmonary arterial hypertension, less is known about pulmonary hypertension among patients with HF, particularly about its prognostic value in the community.

Between 2003 and 2010, Olmsted County residents with HF prospectively underwent assessment of ejection fraction, diastolic function, and PASP by Doppler echocardiography.

PASP was recorded in 1,049 of 1,153 patients (mean age 76 ± 13; 51% women). Median PASP was 48 mm Hg (25th to 75th percentile: 37.0 to 58.0). There were 489 deaths after a follow-up of 2.7 ± 1.9 years. There was a strong positive graded association between PASP and mortality. Increasing PASP was associated with an increased risk of death (hazard ratio [HR]: 1.45, 95% confidence interval [CI]: 1.13 to 1.85 for tertile 2; HR: 2.07, 95% CI: 1.62 to 2.64 for tertile 3 vs. tertile 1), independently of age, sex, comorbidities, ejection fraction, and diastolic function. Adding PASP to models including these clinical characteristics resulted in an increase in the c-statistic from 0.704 to 0.742 (p = 0.007), an integrated discrimination improvement gain of 4.2% (p < 0.001), and a net reclassification improvement of 14.1% (p = 0.002), indicating that PASP improved prediction of death over traditional prognostic factors. All results were similar for cardiovascular death.

Among community patients with HF, PASP strongly predicts death and provides incremental and clinically relevant prognostic information independently of known predictors of outcomes.

The management of patients with asymptomatic severe AS remains controversial. Moreover, under the same denomination of severe AS, several entities might be identified according to transvalvular flow rates and pressure gradients, resulting in 4 flow-gradient patterns.

Transthoracic echocardiography and measurement of B-type natriuretic peptide level from venous blood sample were performed in 150 consecutive patients with asymptomatic severe AS and normal exercise test. Patients were classified in 4 groups, depending on left ventricular flow state (normal flow [NF] vs. low flow [LF]: 35 ml/m²) and pressure gradient levels (low gradient [LG] vs. high gradient [HG]: 40 mm Hg).

Patients with NF/LG had significantly lower B-type natriuretic peptide than those with LF/HG and LF/LG. The mean follow-up was 27 ± 12 months. At 2 years, cardiac event-free survival was 83 ± 6%, 44 ± 6%, 30 ± 12%, and 27 ± 13% in NF/LG, NF/HG, LF/HG, and LF/LG groups, respectively (p < 0.0001). On multivariable analysis, LF/LG (hazard ratio [HR]: 5.26, 95% confidence interval [CI]: 2.04 to 14.3, p = 0.045) and LF/HG (HR: 2.38, 95% CI: 1.02 to 5.55, p = 0.001) were identified as strong independent determinants of poor prognosis as compared with NF/HG. By limiting the multivariable analysis to patients with LF, LF/LG was an independent predictor of markedly reduced cardiac event-free survival when compared with LF/HG (HR: 5.4, 95% CI: 1.03 to 28.6, p = 0.046).

The use of the new proposed AS grading classification integrating valve area and flow-gradient patterns allows a better characterization of the clinical outcome of patients with asymptomatic severe AS.

Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI.

In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase–associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization.

All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase–associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase–associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events.

Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.

Cardiac dysfunction after acute myocardial infarction is a major cause of heart failure. Current therapy relies on prompt reperfusion and blockage of secondary maladaptive pathways by small molecules. Platelet gels are biomaterials rich in cytokines and growth factors, which can be manufactured in an autologous manner and are effective in various models of wound healing. However, the potential utility of platelet gel in cardiac regeneration has yet to be tested.

Platelet gel was derived from syngeneic rats and its morphology, biocompatibility, secretion of beneficial factors, and in vivo degradation profile were characterized.

After delivery into infarcted rat hearts, the gel was efficiently infiltrated by cardiomyocytes and endothelial cells. Gel-treated hearts exhibited enhanced tissue protection, greater recruitment of endogenous regeneration, higher capillary density, and less compensatory myocyte hypertrophy. The cardiac function of control-injected animals deteriorated over the 6-week time course, while that of platelet gel-injected animals did not. In addition, the gel did not exacerbate inflammation in the heart.

Intramyocardial injection of autologous platelet gel ameliorated cardiac dysfunction after myocardial infarction. The striking functional benefits, the simplicity of manufacturing, and the potentially autologous nature of this biomaterial provide impetus for further translation.

The new class of anti–type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.

Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.

DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10^–4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).

A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.

Anecdotal evidence suggests that patient selection for TAVI is shifting toward lower surgical risk patients. The extent of this shift and its impact on clinical outcomes, however, are currently unknown.

We conducted a single-center study that subcategorized TAVI patients into quartiles (Q1 to Q4) defined by enrollment date. These subgroups were subsequently examined for differences in baseline characteristics and 30-day and 6-month mortality rate. The relationship between quartiles and mortality rate was examined using unadjusted and adjusted (for baseline characteristics) Cox proportional hazard models.

Each quartile included 105 patients (n = 420). Compared with Q4 patients, Q1 patients had higher logistic EuroSCORES (25.4 ± 16.1% vs. 17.8 ± 12.0%, p < 0.001), higher Society of Thoracic Surgeons scores (7.1 ± 5.5% vs. 4.8 ± 2.6%, p > 0.001), and higher median N-terminal pro–B-type natriuretic peptide levels (3,495 vs. 1,730 ng/dl, p < 0.046). From Q1 to Q4, the crude 30-day and 6-month mortality rate decreased significantly from 11.4% to 3.8% (unadjusted hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.11 to 1.01; p = 0.053) and from 23.5% to 12.4% (unadjusted HR: 0.49; 95 CI: 0.25 to 0.95; p = 0.07), respectively. After adjustment for baseline characteristics, there were no significant differences between Q1 and Q4 in 30-day mortality rate (adjusted HR ratio: 0.29; 95% CI: 0.08 to 1.08; p = 0.07) and 6-month mortality rate (HR: 0.67; 95% CI: 0.25 to 1.77; p = 0.42).

The results of this study demonstrate an important paradigm shift toward the selection of lower surgical risk patients for TAVI. Significantly better clinical outcomes can be expected in lower than in higher surgical risk patients undergoing TAVI.

Despite an aging population, little is known about the comparative effectiveness of DES versus BMS among patients age ≥85 years undergoing percutaneous coronary intervention (PCI).

We examined 471,006 PCI patients age ≥65 years at 947 hospitals in the National Cardiovascular Data Registry between 2004 and 2008 and linked to Medicare claims data. Long-term outcomes (median follow-up 640.8 ± 423.5 days) were compared between users of DES and BMS.

Patients age ≥85 years comprise an increasing proportion of PCIs performed among elderly subjects, yet rates of DES use declined the most in this age group. Compared with BMS, use of DES was associated with lower mortality: age ≥85 years, 29% versus 38% (adjusted hazard ratio [HR]: 0.80 [95% confidence interval (CI): 0.77 to 0.83]); age 75 to 84 years, 17% versus 25% (HR: 0.77 [95% CI: 0.75 to 0.79]); and age 65 to 74 years, 10% versus 16% (HR: 0.73 [95% CI: 0.71 to 0.75]). However, the adjusted mortality difference narrowed with increasing age (p_interaction <0.001). In contrast, the adjusted HR for myocardial infarction rehospitalization associated with DES use was significantly lower with increasing age: age ≥85 years, 9% versus 12% (HR: 0.77 [95% CI: 0.71 to 0.83]); age 75 to 84 years, 7% versus 9% (HR: 0.81 [95% CI: 0.77 to 0.84]); and age 65 to 74 years, 7% versus 8% (HR: 0.84 [95% CI: 0.80 to 0.88]) (p_interaction <0.001).

In this national study of older patients undergoing PCI, declines in DES use were most pronounced among those aged ≥85 years, yet lower adverse-event rates associated with DES versus BMS use were observed.

Vascular complications have been the major cause of mortality and morbidity associated with PAVR. Both open surgical and fully percutaneous access site strategies have been advocated.

All patients undergoing transfemoral PAVR during fiscal years 2009 and 2010 were prospectively evaluated at baseline, after the procedure, and at 30 days.

PAVR was performed in 137 consecutive patients. All but 1 patient underwent planned arteriotomy closure using a percutaneous pre-closure technique. Smaller sheaths, rigorous angiographic and computed tomographic screening and patient selection, and percutaneous vascular repair techniques were increasingly used over this period. From 2009 to 2010, major vascular complications decreased from 8% to 1% (p = 0.06), minor vascular complications decreased from 24% to 8% (p < 0.01), major bleeds fell from 14% to 1% (p < 0.01), and unplanned surgery decreased from 28% to 2% (p < 0.01). A minimal artery diameter smaller than the external sheath diameter, moderate or severe calcification, and peripheral vascular disease were associated with higher vascular complication rates.

Vascular complications occur more often if the minimal artery diameter is smaller than the external sheath diameter, in the presence of moderate or severe calcification, and in patients with peripheral vascular disease. With careful patient selection, advanced interventional techniques, and a fully percutaneous procedure, marked reductions in vascular and bleeding complications can be achieved.

Understanding dynamic aspects of functional aortic valve anatomy is important for beating-heart transcatheter aortic valve implantation.

Thirty-five patients with aortic stenosis and 11 normal subjects underwent 256-slice computed tomography. The aortic annulus plane was reconstructed in 10% increments over the cardiac cycle. For each phase, minimum diameter, ellipticity index, cross-sectional area (CSA), and perimeter (Perim) were measured. In a subset of 10 patients, Young's elastic module was calculated from the stress-strain relationship of the annulus.

In both subjects with normal and with calcified aortic valves, minimum diameter increased in systole (12.3 ± 7.3% and 9.8 ± 3.4%, respectively; p < 0.001), and ellipticity index decreased (12.7 ± 8.8% and 10.3 ± 2.7%, respectively; p < 0.001). The CSA increased by 11.2 ± 5.4% and 6.2 ± 4.8%, respectively (p < 0.001). Perim increase was negligible in patients with calcified valves (0.56 ± 0.85%; p < 0.001) and small even in normal subjects (2.2 ± 2.2%; p = 0.01). Accordingly, relative percentage differences between maximum and minimum values were significantly smallest for Perim compared with all other parameters. Young's modulus was calculated as 22.6 ± 9.2 MPa in patients and 13.8 ± 6.4 MPa in normal subjects.

The aortic annulus, generally elliptic, assumes a more round shape in systole, thus increasing CSA without substantial change in perimeter. Perimeter changes are negligible in patients with calcified valves, because tissue properties allow very little expansion. Aortic annulus perimeter appears therefore ideally suited for accurate sizing in transcatheter aortic valve implantation.

Patients with severe MR (3 to 4+) at high risk of surgery may benefit from percutaneous mitral leaflet repair, a potentially safer approach to reduce MR.

Patients with severe symptomatic MR and an estimated surgical mortality rate of ≥12% were enrolled. A comparator group of patients screened concurrently but not enrolled were identified retrospectively and consented to compare survival in patients treated by standard care.

Seventy-eight patients underwent the MitraClip procedure. Their mean age was 77 years, >50% had previous cardiac surgery, and 46 had functional MR and 32 degenerative MR. MitraClip devices were successfully placed in 96% of patients. Protocol-predicted surgical mortality rate in the HRS and concurrent comparator group was 18.2% and 17.4%, respectively, and Society of Thoracic Surgeons calculator estimated mortality rate was 14.2% and 14.9%, respectively. The 30-day procedure-related mortality rate was 7.7% in the HRS and 8.3% in the comparator group (p = NS). The 12-month survival rate was 76% in the HRS and 55% in the concurrent comparator group (p = 0.047). In surviving patients with matched baseline and 12-month data, 78% had an MR grade of ≤2+. Left ventricular end-diastolic volume improved from 172 ml to 140 ml and end-systolic volume improved from 82 ml to 73 ml (both p = 0.001). New York Heart Association functional class improved from III/IV at baseline in 89% to class I/II in 74% (p < 0.0001). Quality of life was improved (Short Form-36 physical component score increased from 32.1 to 36.1 [p = 0.014] and the mental component score from 45.5 to 48.7 [p = 0.065]) at 12 months. The annual rate of hospitalization for congestive heart failure in surviving patients with matched data decreased from 0.59 to 0.32 (p = 0.034).

The MitraClip device reduced MR in a majority of patients deemed at high risk of surgery, resulting in improvement in clinical symptoms and significant left ventricular reverse remodeling over 12 months. (Pivotal Study of a Percutaneous Mitral Valve Repair System [EVEREST II]; NCT00209274)

AF is the most common clinically significant arrhythmia and is associated with increased morbidity and mortality. Radiofrequency or cryotherapy ablation of AF is a relatively new treatment option, and data on post-procedural outcomes in large general populations are limited.

Using data from the California State Inpatient Database, we identified all adult patients who underwent their first AF ablation from 2005 to 2008. We used multivariable logistic regression to identify predictors of complications and/or 30-day readmissions and Kaplan-Meier analyses to estimate rates of all-cause and arrhythmia readmissions.

Among 4,156 patients who underwent an initial AF ablation, 5% had periprocedural complications, most commonly vascular, and 9% were readmitted within 30 days. Older age, female, prior AF hospitalizations, and less hospital experience with AF ablation were associated with higher adjusted risk of complications and/or 30-day readmissions. The rate of all-cause hospitalization was 38.5% by 1 year. The rate of readmission for recurrent AF, atrial flutter, and/or repeat ablation was 21.7% by 1 year and 29.6% by 2 years.

Periprocedural complications occurred in 1 of 20 patients undergoing AF ablation, and all-cause and arrhythmia-related rehospitalizations were common. Older age, female sex, prior AF hospitalizations, and recent hospital procedure experience were associated with a higher risk of complications and/or 30-day readmission after AF ablation.

Innate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes.

Acute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose (¹⁸FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology.

Gd-DTPA–enhanced infarcts showed high ¹⁸FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b⁺ cells had 4-fold higher ¹⁸FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 10⁴/mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation.

This study shed light on the innate inflammatory response in remote myocardium after MI.

Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown.

We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage.

Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor–positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport.

Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport.

Very few data exist on the occurrence of NOAF following TAVI.

A total of 138 consecutive patients with no prior history of atrial fibrillation (AF) underwent TAVI with a balloon-expandable valve. Patients were on continuous electrocardiogram monitoring until hospital discharge, and NOAF was defined as any episode of AF lasting >30 s. All clinical, echocardiographic, procedural, and follow-up data were prospectively collected.

NOAF occurred in 44 patients (31.9%) at a median time of 48 h (interquartile range: 0 to 72 h) following TAVI. The predictive factors of NOAF were left atrial (LA) size (odds ratio [OR]: 1.21 for each increase in 1 mm/m², 95% confidence interval [CI]: 1.09 to 1.34, p < 0.0001) and transapical approach (OR: 4.08, 95% CI: 1.35 to 12.31, p = 0.019). At 30-day follow-up, NOAF was associated with a higher rate of stroke/systemic embolism (13.6% vs. 3.2%, p = 0.021, p = 0.047 after adjustment for baseline differences between groups), with no differences in mortality rate between groups (NOAF: 9.1%, no-NOAF: 6.4%, p = 0.57). At a median follow-up of 12 months (interquartile range: 5 to 20 months), a total of 27 patients (19.6%) had died, with no differences between the NOAF (15.9%) and no-NOAF (21.3%) groups, p = 0.58. The cumulative rate of stroke and stroke/systemic embolism at follow-up were 13.6% and 15.9%, respectively, in the NOAF group versus 3.2% in the no-NOAF group (p = 0.039, adjusted p = 0.037 for stroke; p = 0.020, adjusted p = 0.023 for stroke/systemic embolism).

NOAF occurred in about one-third of the patients with no prior history of AF undergoing TAVI and its incidence was increased in patients with larger LA size and those undergoing transapical TAVI. NOAF was associated with a higher rate of stroke/systemic embolism, but not a higher mortality, at 30 days and at 1-year follow-up.

In-stent restenosis after FP stenting is an unsolved problem. The incidence and predictors of refractory restenosis remain unclear.

This study was a multicenter, retrospective observational study. From September 2000 to December 2009, 133 restenotic lesions after FP artery stenting were classified by angiographic pattern: class I included focal lesions (≤50 mm in length), class II included diffuse lesions (>50 mm in length), and class III included totally occluded ISR. All patients were treated by balloon angioplasty for at least 60 s. Recurrent ISR or occlusion was defined as ISR or occlusion after target lesion revascularization. Restenosis was defined as >2.4 of the peak systolic velocity ratio by duplex scan or >50% stenosis by angiography.

Sixty-four percent of patients were male, 67% had diabetes mellitus, and 24% underwent hemodialysis. Class I pattern was found in 29% of the limbs, class II in 38%, and class III in 33%. Mean follow-up period was 24 ± 17 months. All-cause death occurred in 14 patients; bypass surgery was performed in 11 limbs, and major amputation was performed in 1 limb during the follow-up. Kaplan-Meier survival curves showed that the rate of recurrent ISR at 2 years was 84.8% in class III patients compared with 49.9% in class I patients (p < 0.0001) and 53.3% in class II patients (p = 0.0003), and the rate of recurrent occlusion at 2 years was 64.6% in class III patients compared with 15.9% in class I patients (p < 0.0001) and 18.9% in class II patients (p < 0.0001).

Restenotic patterns after FP stenting are important predictors of recurrent ISR and occlusion.

Renal dysfunction before LVAD placement is frequent, and it is unclear whether it is due to primary renal disease or to poor perfusion.

A retrospective single-center analysis was conducted in 83 consecutive patients implanted with HeartMate II continuous-flow LVADs (Thoratec Corp., Pleasanton, California). Calculated glomerular filtration rate (GFR) was assessed on admission and 1, 3, and 6 months after implantation. To define predictors for improvement in GFR, clinical variables were examined in patients with decreased renal function (GFR <60 ml/min/1.73 m²) before LVAD, surviving and dialysis-free at 1 month (n = 44).

GFR significantly increased from admission (53.2 ± 21.4 ml/min/1.73 m²) to 1 month after LVAD implantation (87.4 ± 27.9 ml/min/1.73 m²) (p < 0.0001). Subsequently, at 3 and 6 months, GFR remained significantly (p < 0.0001) above pre-LVAD values. Of the 51 patients with GFRs <60 ml/min/1.73 m² before LVAD surviving at 1 month, 34 (67%) improved to GFRs >60 ml/min/1.73 m². Univariate pre-operative predictors for improvement in renal function at 1 month included younger age (p = 0.049), GFR improvement with optimal medical therapy (p < 0.001), intra-aortic balloon pump use (p = 0.004), kidney length above 10 cm (p = 0.023), no treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (p = 0.029), higher bilirubin (p = 0.002), higher Lietz-Miller score (p = 0.019), and atrial fibrillation (p = 0.007). Multivariate analysis indicated pre-operative improved GFR (slope = 0.5 U per unit improved; 95% confidence interval: 0.2 to 0.8; p = 0.003), atrial fibrillation (slope = 27; 95% confidence interval: 8 to 46; p = 0.006), and intra-aortic balloon pump use (slope = 14; 95% confidence interval: 2 to 26; p = 0.02) as independent predictors.

In most patients with end-stage heart failure considered for LVAD implantation, renal dysfunction is reversible and likely related to poor renal perfusion.

Brugada syndrome is a genetic disease associated with increased risk of sudden cardiac death. Even though its value has been questioned, inducibility of VTs/VF is widely used to select candidates to receive a prophylactic implantable defibrillator, and its accuracy has never been addressed in prospective studies with homogeneous enrolling criteria.

Patients with a spontaneous or drug-induced type I electrocardiogram (ECG) and without history of cardiac arrest were enrolled. The registry included 308 consecutive individuals (247 men, 80%; median age 44 years, range 18 to 72 years). Programmed electrical stimulation was performed at enrollment, and patients were followed-up every 6 months.

During a median follow-up of 34 months, 14 arrhythmic events (4.5%) occurred (13 appropriate shocks of the implantable defibrillator, and 1 cardiac arrest). Programmed electrical stimulation performed with a uniform and pre-specified protocol induced ventricular tachyarrhythmias in 40% of patients: arrhythmia inducibility was not a predictor of events at follow-up (9 of 14 events occurred in noninducible patients). History of syncope and spontaneous type I ECG (hazard ratio [HR]: 4.20), ventricular refractory period <200 ms (HR: 3.91), and QRS fragmentation (HR: 4.94) were significant predictors of arrhythmias.

Our data show that VT/VF inducibility is unable to identify high-risk patients, whereas the presence of a spontaneous type I ECG, history of syncope, ventricular effective refractory period <200 ms, and QRS fragmentation seem useful to identify candidates for prophylactic implantable cardioverter defibrillator.

Randomized studies have shown that ventricular rate control is an acceptable treatment strategy in patients with AF. However, identification of patients who will adequately respond to rate-control therapy remains a challenge.

We studied 543 subjects (63% men; age 61.8 ± 14 years) prospectively enrolled in the Vanderbilt AF registry and managed with rate-control strategy. A "responder" displayed adequate ventricular rate control based on the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) criteria: average heart rate (HR) at rest ≤80 beats/min; and maximum HR during a 6-min walk test ≤110 beats/min or average HR during 24-h Holter ≤100 beats/min.

A total of 295 (54.3%) patients met the AFFIRM criteria. Baseline clinical characteristics were similar in responders and nonresponders except for mean resting HR (76 ± 20 beats/min vs. 70 ± 15 beats/min; p < 0.01) and smoking (6% vs. 1%; p < 0.01). Multiple clinical variables (age, gender, hypertension) failed to predict response to rate-control therapy. By contrast, carriers of Gly variant at 389 were more likely to respond favorably to rate-control therapy; 60% versus 51% in the Arg389Arg genotype, p = 0.04. This association persisted after correction for multiple clinical factors (odds ratio: 1.42, 95% confidence interval: 1.00 to 2.03, p < 0.05). Among responders, subjects carrying the Gly389 variant required the lowest doses of rate-control medications; atenolol: 92 mg versus 68 mg; carvedilol: 44 mg versus 20 mg; metoprolol: 80 mg versus 72 mg; diltiazem: 212 mg versus 180 mg, and verapamil: 276 mg versus 200 mg, respectively (p < 0.01 for all comparisons).

We have identified a common β1-AR polymorphism, G389R, that is associated with adequate response to rate-control therapy in AF patients. Gly389 is a loss-of-function variant; consequently, for the same adrenergic stimulation, it produces reduced levels of adenyl cyclase, and hence, attenuates the β-adrenergic cascade. Mechanistically, the effect of rate-control drugs will be synergistic with that of the Gly389 variant, which could possibly explain our findings. These findings represent a step forward in the development of a long-term strategy of selecting treatment options in AF based on genotype.

Statins improve clinical outcome after cardiac surgery, but it is unclear whether they exert their effects by modifying the myocardial redox state.

We quantified myocardial superoxide anion (O₂ ^–) and peroxynitrite (ONOO^–) and their enzymatic sources in samples of the right atrial appendage (RAA) from 303 patients undergoing cardiac surgery who were followed up until discharge, and in 42 patients who were randomized to receive 3-day treatment with atorvastatin 40 mg/d or placebo before surgery. The mechanisms by which atorvastatin modifies myocardial redox state were investigated in 26 RAA samples that were exposed to atorvastatin ex vivo.

Atrial O₂ ^– (derived mainly from nicotinamide adenine dinucleotide phosphate [NADPH] oxidases) and ONOO^– were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O₂ ^– and ONOO^– production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase.

There is a strong independent association between myocardial O₂ ^–/ONOO^– and in-hospital complications after cardiac surgery. Both myocardial O₂ ^– and ONOO^– are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103)

Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients.

A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components.

The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg.

The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients. (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; NCT00153101)

Data on long-term prognostic value of high on-treatment platelet reactivity (HTPR) on clopidogrel after PCI are limited. As a distinct biological pathway, CRP has been suggested to be associated with post-PCI atherothrombotic events.

We evaluated 2,849 patients who received drug-eluting stents (DES) and had post-PCI VerifyNow P2Y12 assays (Accumetrics, San Diego, California) performed. Among them, baseline CRP measurement was available in 2,546 patients. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction, stent thrombosis, and stroke.

During follow-up (median, 2.2 years), the occurrence of the primary endpoint did not significantly differ among patients with and without HTPR (2.8% vs. 2.4% at 2 years; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.88 to 2.01; p = 0.18). By contrast, patients with elevated CRP levels were at significantly higher risk for the primary endpoint, as compared with those with nonelevated CRP levels (5.6% vs. 1.7% at 2 years; HR: 2.81, 95% CI:, 1.83 to 4.31; p < 0.001). The VerifyNow test had no incremental usefulness to classify long-term risk. However, the incorporation of CRP into a model with conventional clinical and procedural risk factors significantly improved the C-statistic for the prediction of the primary endpoint (0.729 to 0.759; p = 0.03).

We failed to identify that HTPR measured by VerifyNow P2Y12 assay was significantly associated with long-term atherothrombotic risks in patients receiving DES. However, elevated CRP levels were significantly associated with worse outcomes and had incremental predictive values over conventional risk factors.

Although its prevalence is increasing rapidly, little is known about the impact of extreme obesity on STEMI presentation, treatments, complication rates, and outcomes.

The relationship between BMI and baseline characteristics, treatment patterns, and risk-adjusted in-hospital outcomes was quantified for 50,149 patients with STEMI from the National Cardiovascular Data Registry (NCDR) ACTION Registry–GWTG.

The proportions of patients with STEMI by BMI category were as follows: underweight (BMI <18.5 kg/m²) 1.6%, normal weight (18.5 kg/m² ≤BMI <25 kg/m²) 23.5%, overweight (25 kg/m² ≤BMI <30 kg/m²) 38.7%, class I obese (30 kg/m² ≤BMI <35 kg/m²) 22.4%, class II obese (35 kg/m² ≤BMI <40 kg/m²) 8.7%, and class III obese 5.1%. Extreme obesity was associated with younger age at STEMI presentation (median age 55 years for class III obese vs. 66 years for normal weight); a higher prevalence of diabetes, hypertension, and dyslipidemia; a lower prevalence of smoking; and less extensive coronary artery disease and higher left ventricular ejection fraction. Process-of-care measures were similar across BMI categories, including the extremely obese. Using class I obesity as the referent, risk-adjusted in-hospital mortality rates were significantly higher only for class III obese patients (adjusted odds ratio: 1.64; 95% confidence interval: 1.32 to 2.03).

Patients with extreme obesity present with STEMI at younger ages and have less extensive coronary artery disease, better left ventricular systolic function, and similar processes and quality of care. Despite these advantages, extreme obesity remains independently associated with higher in-hospital mortality.

Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels <2 mg/l and thus would be ineligible for these treatments?

We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies <6 h from symptoms onset in order to limit acute event-related increases.

hsCRP values were similar in samples obtained <2 h, 2 to 4 h, and 4 to 6 h from symptoms onset in all ethnic groups, consistent with the delayed hsCRP elevation after myocardial necrosis and thus indicative of pre-infarction levels. Median hsCRP values were significantly higher in patients than in control subjects: 2.49 (interquartile range [IQR]: 1.18 to 5.55) mg/l versus 1.32 (IQR: 0.58 to 3.10) mg/l (p < 0.0001), which is consistent with previous findings. However, 41% of patients had hsCRP levels <2 mg/l and conversely, 37% of control subjects had values ≥2 mg/l.

The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk.

Controversy surrounds the optimal treatment for native coarctation of the aorta. This is the first multicenter study evaluating acute and follow-up outcomes of these 3 treatment options in children weighing >10 kg.

This is a multicenter observational study. Baseline, acute, short-term (3 to 18 months), and intermediate (>18 months) follow-up hemodynamic, imaging data, and complications were recorded.

Between June 2002 and July 2009, 350 patients from 36 institutions were enrolled: 217 underwent stent, 61 underwent BA, and 72 underwent surgery. All 3 arms showed significant improvement acutely and at follow-up in resting systolic blood pressure and upper to lower extremity systolic blood pressure gradient (ULG). Stent was superior to BA in achieving lower ULG acutely. Surgery and stent were superior to BA at short-term follow-up in achieving lower ULG. Stent patients had shorter hospitalization than surgical patients (2.4 vs. 6.4 days; p < 0.001) and fewer complications than surgical and BA patients (2.3%, 8.1%, and 9.8%; p < 0.001). The BA patients were more likely to encounter aortic wall injury, both acutely and at follow-up (p < 0.001).

Stent patients had significantly lower acute complications compared with surgery patients or BA patients, although they were more likely to require a planned reintervention. At short-term and intermediate follow-up, stent and surgical patients achieved superior hemodynamic and integrated aortic arch imaging outcomes compared with BA patients. Because of the nonrandomized nature of this study, these results should be interpreted with caution.

No study has examined the effects of these genetic variants on CHD in diabetic patients.

We genotyped 15 genetic markers of 12 loci in 3 studies of diabetic patients: the prospective Nurses' Health Study (309 CHD cases, and 544 control subjects) and Health Professional Follow-up Study (345 CHD cases, and 451 control subjects) and the cross-sectional Joslin Heart Study (422 CHD cases, and 435 control subjects).

Five single-nucleotide polymorphisms, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the 3 studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p = 0.03 to 0.0002). None of the other single-nucleotide polymorphisms reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the 5 significantly associated loci. The OR of CHD/GRS unit was 1.19 (95% confidence interval: 1.13 to 1.26; p < 0.0001). Individuals with GRS ≥8 (19% of diabetic subjects) had almost a 2-fold increase in CHD risk (OR: 1.94, 95% confidence interval: 1.60 to 2.35) as compared with individuals with GRS ≤5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p < 0.001) when the GRS was added to a model including clinical predictors in the combined samples.

Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations.

Beta₃-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta₃-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability.

Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels.

Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta₃-AR ^–/–, eNOS^–/–, and in nNOS^–/– mice.

Our results indicate that beta₃-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta₃-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.

The recurrence of mitral regurgitation following surgical mitral valve (MV) repair in both adult and pediatric patients remains a significant clinical problem. Mitral annuloplasty rings are commonly used in MV repair procedures and may serve as secure landing zones for percutaneous valves.

Five sheep underwent surgical MV annuloplasty (24 mm, n = 2; 26 mm, n = 2; 28 mm, n = 1). Animals underwent cardiac catheterization with VIR implantation via a transfemoral venous, transatrial septal approach 1 week following surgery. Hemodynamic, angiographic, and echocardiographic data were recorded before and after VIR.

VIR was technically successful and required <1 h of procedure time in all animals. Fluoroscopy demonstrated securely positioned Melody valves within the annuloplasty ring in all animals. Angiography revealed no significant MV regurgitation in 4 and moderate central MV regurgitation in the animal with the 28-mm annuloplasty. All animals demonstrated vigorous left ventricular function, no outflow tract obstruction, and no aortic valve insufficiency.

This study demonstrated the feasibility of a purely percutaneous approach to MV replacement in patients with preexisting annuloplasty rings. This novel approach may be of particular benefit to patients with failed repair of ischemic mitral regurgitation and in pediatric patients with complex structural heart disease.

The role of low high-density lipoprotein cholesterol as a causal factor in atherogenesis has recently been questioned. LCAT plays a key role in high-density lipoprotein cholesterol metabolism.

Carotid 3.0-T MRI and B-mode ultrasound measurements were performed in 40 carriers of LCAT gene mutations and 40 controls, matched for age. Patients with cardiovascular disease were excluded.

Carriers had 31% lower LCAT activity levels and 38% decreased high-density lipoprotein cholesterol levels (both p < 0.001 vs. controls). Carriers presented with a 10% higher normalized wall index (0.34 ± 0.07 vs. 0.31 ± 0.04, p = 0.002), a 22% higher mean wall area (17.3 ± 8.5 mm² vs. 14.2 ± 4.1 mm², p = 0.01), and a 22% higher total wall volume (1,039 ± 508 mm³ vs. 851 ± 247 mm³, p = 0.01 vs. controls) as measured by MRI. The prevalence (20 vs. 5, p = 0.002) and the total volume (102 mm³ vs. 3 mm³) of atherosclerotic plaque components on MRI relating to lipid-rich tissue or calcification were also higher in carriers than in controls. All differences retained significance after adjustment for age, sex, blood pressure, low-density lipoprotein cholesterol, body mass index, smoking, and family history of cardiovascular disease. Common carotid intima-media thickness measured with ultrasound was increased in carriers by 12.5% (0.72 ± 0.33 mm vs. 0.64 ± 0.15 mm, p = 0.14).

Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies.

Post-infarction ventricular tachycardia can involve the endocardial myocardium, the intramural myocardium, the epicardium, or the His Purkinje system.

Among 74 consecutive patients with recurrent post-infarction VT, 33 patients (45%) were identified in whom the critical part of the VT involved the interventricular septum. A total of 206 VTs were induced in these 33 patients. In 46 of the 206 VTs, a critical component was identified in the interventricular septum. The critical isthmus of the re-entry circuit was identified by entrainment mapping, activation mapping, or pace-mapping.

In 32 of 46 VTs (70%), the critical component of the re-entry circuit was confined to the endocardium. In 9 of 46 VTs (20%), the critical component involved the Purkinje system, and in 5 of 46 VTs (11%), an intramural area was critical. Entrainment and/or pace-mapping helped to identify critical areas of endocardial VTs as well as VTs involving the Purkinje fibers, but neither of these mapping techniques localized intramural VTs. Electrocardiographic characteristics were specific for each of the septal locations. All VTs mapped to the interventricular septum were acutely successfully ablated. VTs recurred in 9 of 33 patients with septal VTs during a mean follow-up period of 40 ± 20 months.

Post-infarction VT involving the interventricular septum can involve the endocardial muscle, Purkinje fibers, or intramural muscle fibers. Electrocardiographic characteristics differ depending on the type of tissue involved.

Hypertrophic obstructive cardiomyopathy is an uncommon cause of left ventricular outflow tract obstruction in children. In symptomatic patients, open heart surgical myectomy has hitherto been the only therapeutic option.

In 32 children, at a median age of 11.1 (range 2.9 to 17.5) years and weight of 31 (15 to 68) kg, ablation of the hypertrophied septum was performed using a cool-tip ablation catheter via a femoral arterial approach. The median number of lesions was 27 (10 to 63) and fluoroscopic time was 24 (12 to 60) min.

The majority of patients demonstrated an immediate decrease in the catheter pullback gradient (mean 78.5 ± 26.2 mm Hg pre-RFCA versus mean 36.1 ± 16.5 mm Hg post-RFCA, p < 0.01) and a further reduction in the Doppler echocardiographic gradient (mean 96.9 ± 27.0 mm Hg pre-RFCA versus 32.7 ± 27.1 mm Hg post-RFCA, p < 0.01) at follow-up. One patient died due to a paradoxical increase in left ventricular outflow tract obstruction, and another had persistent atrioventricular block that required permanent pacing. Six patients required further procedures (surgery, pacing, or further RFCA) during a median follow-up of 48 (3 to 144) months.

The preliminary results of RFCA for septal reduction in children with hypertrophic cardiomyopathy are promising and merit further evaluation.

Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function.

A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy.

Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis.

After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Collagen is an essential constituent of aneurysms. Noninvasive MRI of collagen may represent an opportunity to help detect and better characterize AAAs and initiate intervention.

We used an AAA C57BL/6 mouse model in which a combination of angiotensin II infusion and transforming growth factor–β neutralization results in AAA formation with incidence of aortic rupture. High-resolution, multisequence MRI was performed to characterize the temporal progression of an AAA. To allow molecular MRI of collagen, paramagnetic/fluorescent micellar nanoparticles functionalized with a collagen-binding protein (CNA-35) were intravenously administered. In vivo imaging results were corroborated with immunohistochemistry and confocal fluorescence microscopy.

High-resolution, multisequence MRI allowed the visualization of the primary fibrotic response in the aortic wall. As the aneurysm progressed, the formation of a secondary channel or dissection was detected. Further analysis revealed a dramatic increase of the aortic diameter. Injection of CNA-35 micelles resulted in a significantly higher magnetic resonance signal enhancement in the aneurysmal wall compared with nonspecific micelles. Histological studies revealed the presence of collagen in regions of magnetic resonance signal enhancement, and confocal microscopy proved the precise co-localization of CNA-35 micelles with type I collagen. In addition, in a proof-of-concept experiment, we reported the potential of CNA-35 micelles to discriminate between stable AAA lesions and aneurysms that were likely to rapidly progress or rupture.

High-resolution, multisequence MRI allowed longitudinal monitoring of AAA progression while the presence of collagen was visualized by nanoparticle-enhanced MRI.

The frequency and clinical relevance of CAD in patients without CAC are unclear.

We identified 10,037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as <50%, ≥50%, and ≥70% stenosis. All-cause mortality and the composite endpoint of mortality, myocardial infarction, or late coronary revascularization (≥90 days after CCTA) were assessed.

Mean age was 57 years, 56% were men, and 51% had a CAC score of 0. Among patients with a CAC score of 0, 84% had no CAD, 13% had nonobstructive stenosis, and 3.5% had ≥50% stenosis (1.4% had ≥70% stenosis) on CCTA. A CAC score >0 had a sensitivity, specificity, and negative and positive predictive values for stenosis ≥50% of 89%, 59%, 96%, and 29%, respectively. During a median of 2.1 years, there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8,907 patients with follow-up for the composite endpoint, 3.9% with a CAC score of 0 and ≥50% stenosis experienced an event (hazard ratio: 5.7; 95% confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8% of patients with a CAC score of 0 and no obstructive CAD. Receiver-operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84).

In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.