The impact of bleeding avoidance strategies on post-PCI bleeding rates over time is unknown.

Using the CathPCI Registry, we examined temporal trends in post-PCI bleeding from 2005 to 2009 among patients with elective PCI (n = 599,524), UA/NSTEMI (n = 836,103), and STEMI (n = 267,632). We quantified the linear time trend in bleeding using 3 sequential logistic regression models: 1) clinical factors; 2) clinical + vascular access strategies (femoral vs. radial, use of closure devices); and 3) clinical, vascular strategies + antithrombotic treatments (anticoagulant ± glycoprotein IIb/IIIa inhibitor [GPI]). Changes in the odds ratio for time trend in bleeding were compared using bootstrapping and converted to risk ratio.

An approximate 20% reduction in post-PCI bleeding was seen (elective PCI: 1.4% to 1.1%; UA/NSTEMI: 2.3% to 1.8; STEMI: 4.9% to 4.5%). Radial approach remained low (<3%), and closure device use increased marginally from 44% to 49%. Bivalirudin use increased (17% to 30%), whereas any heparin + GPI decreased (41% to 28%). There was a significant 6% to 8% per year reduction in annual bleeding risk in UA/NSTEMI and elective PCI, but not in STEMI. Antithrombotic strategies were associated with roughly half of the reduction in annual bleeding risk: change in risk ratio from 7.5% to 4% for elective PCI, and 5.7% to 2.8% for UA/NSTEMI (both p <0.001).

The nearly 20% reduction in post-PCI bleeding over time was largely due to temporal changes in antithrombotic strategies. Further reductions in bleeding complications may be possible as bleeding avoidance strategies evolve, especially in STEMI.

The American College of Cardiology Foundation (ACCF) and 6 other societies recently published joint appropriateness criteria for coronary revascularization.

Data from patients who underwent CABG surgery and PCI without acute coronary syndrome or previous CABG surgery in New York in 2009 and 2010 were used to assess appropriateness and to examine the variation across hospitals in inappropriateness ratings.

Of the 8,168 patients undergoing CABG surgery in New York without ACS/prior CABG who could be rated, 90.0% were appropriate for revascularization, 1.1% were inappropriate, and 8.6% were uncertain. Of the 33,970 PCI patients eligible for rating, 28% lacked sufficient information to be rated. Of the patients who could be rated, 36.1% were appropriate, 14.3% were inappropriate, and 49.6% were uncertain. A total of 91% of the patients undergoing PCI who were classified as inappropriate had 1- or 2-vessel disease without proximal left anterior descending artery disease and had no or minimal anti-ischemic medical therapy.

For patients without ACS/prior CABG, only 1% of patients undergoing CABG surgery who could be rated were found to be inappropriate for the procedure according to the ACCF appropriateness criteria, but 14% of the PCI patients who could be rated were found to be inappropriate, and 28% lacked enough noninvasive test information to be rated.

Percutaneous coronary intervention is often complicated by post-procedural myocardial necrosis manifested by elevated cardiac biomarkers.

Stable angina patients (n = 107) with normal pre-PCI cTnT levels underwent 64-slice MDCT before PCI to evaluate plaque characteristics of culprit lesions. Patients were divided into 2 groups according to presence (group I, n = 36) or absence (group II, n = 71) of post-PCI cTnT elevation ≥3 times the upper limit of normal (0.010 ng/ml) at 24 h after PCI.

Computed tomography attenuation values were significantly lower in group I than in group II (43.0 [26.5 to 75.7] HU vs. 94.0 [65.0 to 109.0] HU, p < 0.001). Remodeling index was significantly greater in group I than in group II (1.20 ± 0.18 vs. 1.04 ± 0.15, p < 0.001). Spotty calcification was observed significantly more frequently in group I than in group II (50% vs. 11%, p < 0.001). Multivariate analysis showed presence of positive remodeling (remodeling index >1.05; odds ratio: 4.54; 95% confidence interval: 1.36 to 15.9; p = 0.014) and spotty calcification (odds ratio: 4.27; 95% confidence interval: 1.30 to 14.8; p = 0.016) were statistically significant independent predictors for cTnT elevation. For prediction of cTnT elevation, the presence of all 3 variables (CT attenuation value <55 HU; remodeling index >1.05, and spotty calcification) showed a high positive predictive value of 94%, and their absence showed a high negative predictive value of 90%.

MDCT may be useful in detecting which lesions are at high risk for myocardial necrosis after PCI.

As the HIV-infected population ages, cardiovascular disease prevalence and mortality are increasing, but the incidence and features of SCD have not yet been described.

The records of 2,860 consecutive patients in a public HIV clinic in San Francisco between April 2000 and August 2009 were examined. Identification of deaths, causes of death, and clinical characteristics were obtained by search of the National Death Index and/or clinic records. SCDs were determined using published retrospective criteria: 1) the International Classification of Diseases-10th Revision, code for all cardiac causes of death; and (2) circumstances of death meeting World Health Organization criteria.

Of 230 deaths over a median of 3.7 years of follow-up, 30 (13%) met SCD criteria, 131 (57%) were due to acquired immune deficiency syndrome (AIDS), 25 (11%) were due to other (natural) diseases, and 44 (19%) were due to overdoses, suicides, or unknown causes. SCDs accounted for 86% of all cardiac deaths (30 of 35). The mean SCD rate was 2.6 per 1,000 person-years (95% confidence interval: 1.8 to 3.8), 4.5-fold higher than expected. SCDs occurred in older patients than did AIDS deaths (mean 49.0 vs. 44.9 years, p = 0.02). Compared with AIDS and natural deaths combined, SCDs had a higher prevalence of prior myocardial infarction (17% vs. 1%, p < 0.0005), cardiomyopathy (23% vs. 3%, p < 0.0005), heart failure (30% vs. 9%, p = 0.004), and arrhythmias (20% vs. 3%, p = 0.003).

SCDs account for most cardiac and many non-AIDS natural deaths in HIV-infected patients. Further investigation is needed to ascertain underlying mechanisms, which may include inflammation, antiretroviral therapy interruption, and concomitant medications.

Cardiac function is an important determinant of therapy and is a major predictor for long-term survival in patients with coronary artery disease. A number of methods are available for assessment of function, but there are limited data on the comparison between these multiple methods in the same patients.

A total of 36 patients prospectively underwent 64-row CT, CVG, 2D Echo, 3D Echo, and MRI (as the reference standard). Global and regional LV wall motion and ejection fraction (EF) were measured. In addition, assessment of interobserver agreement was performed.

For the global EF, Bland-Altman analysis showed significantly higher agreement between CT and MRI (p < 0.005, 95% confidence interval: ±14.2%) than for CVG (±20.2%) and 3D Echo (±21.2%). Only CVG (59.5 ± 13.9%, p = 0.03) significantly overestimated EF in comparison with MRI (55.6 ± 16.0%). CT showed significantly better agreement for stroke volume than 2D Echo, 3D Echo, and CVG. In comparison with MRI, CVG—but not CT—significantly overestimated the end-diastolic volume (p < 0.001), whereas 2D Echo and 3D Echo significantly underestimated the EDV (p < 0.05). There was no significant difference in diagnostic accuracy (range: 76% to 88%) for regional LV function assessment between the 4 methods when compared with MRI. Interobserver agreement for EF showed high intraclass correlation for 64-row CT, MRI, 2D Echo, and 3D Echo (intraclass correlation coefficient >0.8), whereas agreement was lower for CVG (intraclass correlation coefficient = 0.58).

64-row CT may be more accurate than CVG, 2D Echo, and 3D Echo in comparison with MRI as the reference standard for assessment of global LV function.

Exposure to SHS impairs endothelial function in humans. The concentration-dependent relationship for aged SHS effects on endothelial function after an exposure of short duration is unknown.

Thirty-three healthy nonsmokers were exposed to 1 of 2 low levels of aged SHS or to conditioned filtered air for 30 min. The primary end point was change in maximal percent brachial artery flow-mediated dilation after exposure.

In a linear regression model for each increase in SHS exposure by 100 μg/m³ respirable suspended particles, the absolute maximal percent brachial artery flow-mediated dilation was reduced by 0.67%. We did not find evidence of a threshold for the effect of SHS on flow-mediated dilation.

Short-term exposure to real-world levels of aged SHS for 30 min resulted in a concentration-dependent decrease in endothelial function as measured by flow-mediated dilation.

Ischemic complications of PCI are infrequent but prognostically important. How often these events are a consequence of intraprocedural complications is unknown, with only limited data assessing the occurrence and importance of IPTE.

A total of 3,428 patients who underwent PCI for non–ST-segment elevation acute coronary syndrome in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial underwent detailed frame-by-frame core laboratory angiographic analysis. An IPTE, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, or distal embolization at any time during the procedure, occurred in 121 patients (3.5%).

Patients with IPTE had higher in-hospital, 30-day, and 1-year major adverse cardiac event rates than patients without IPTE (25.6% vs. 6.3% in-hospital, 30.6% vs. 9.3% at 30 days, and 37.0% vs. 20.5% at 1 year; p < 0.0001 for each). An IPTE was strongly associated with Q-wave myocardial infarction and out-of-laboratory definite/probable stent thrombosis (in-hospital 3.3% vs. 0.5%, p = 0.006; 30 days 5.8% vs. 1.3%, p < 0.0001; and 1 year 6.7% vs. 2.0%, p = 0.0002). Unplanned revascularization, target vessel revascularization, and major bleeding not associated with coronary artery bypass graft surgery were also increased among patients with IPTE, as was overall 30-day mortality (3.3% vs. 0.7%, p = 0.002). Moreover, IPTE was an independent predictor of 30-day and 1-year composite death/myocardial infarction, stent thrombosis, and major adverse cardiac events.

Although infrequent among patients undergoing early PCI for moderate and high-risk non–ST-segment elevation acute coronary syndrome, IPTE was strongly associated with subsequent adverse outcomes including death, myocardial infarction, and stent thrombosis.

Whether the prognosis of in-hospital and out-of-hospital ST are similar is uncertain, with conflicting data reported from prior studies.

A total of 3,602 STEMI patients undergoing primary percutaneous coronary intervention (PCI) were randomized to bivalirudin (n = 1,800) versus unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) (UFH+GPI; n = 1,802). Stents were implanted in 3,202 patients, 156 (4.9%) of whom developed Academic Research Consortium definite/probable ST during 3-year follow-up. We investigated the 1-year clinical outcomes after ST in 54 patients with in-hospital ST compared with 102 patients with out-of-hospital ST.

One year after the ST event, patients with in-hospital compared with out-of-hospital ST had significantly greater mortality (27.8% vs. 10.8%, p < 0.01); most deaths in both groups occurred within 1 week of the ST event. Patients with in-hospital ST also had higher rates of major bleeding (21.2% vs. 6.0%, p < 0.01), but a lower rate of myocardial infarction (56.6% vs. 77.5%, p < 0.01). Subgroup analysis within both in-hospital and out-of-hospital ST groups indicated that subacute ST had the highest mortality. By multivariable analysis, 1-year mortality was significantly increased in patients with in-hospital compared with out-of-hospital ST (adjusted hazard ratio: 4.62, 95% confidence interval: 1.98 to 10.77, p < 0.01). Additional correlates of increased mortality after an ST event included diabetes and randomization to UFH+GPI (vs. bivalirudin).

Following primary PCI for STEMI, more than one-third of all ST events during 3-year follow-up occurred during the index hospital phase. Mortality and major bleeding were significantly higher after in-hospital ST compared with out-of-hospital ST. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966)

Either modified ANP plasma levels or peptide structural alterations have been involved in development of cardiovascular events.

Three hundred ninety-three control subjects and 1,004 patients undergoing coronary angiography for suspected CAD (432 stable angina [SA], 572 acute coronary syndrome [ACS]) were genotyped for rs5065 ANP gene variant. Data in SA and ACS groups were replicated in an independent population of 482 stable angina patients (rSA) and of 675 ACS patients, respectively. Clinical follow-up was available for both SA and rSA patients. Plasma N-terminal-proANP, myeloperoxidase, lipoprotein-associated phospholipase A2, and oxidized low-density lipoprotein were assessed in a subgroup of rSA patients.

rs5065 minor allele (MA) was an independent predictor of ACS (odds ratio: 1.90; 95% confidence interval: 1.40 to 2.58, p < 0.001). At follow-up, rs5065 MA was independently associated with a significantly higher rate of major adverse cardiovascular events in the SA group, p < 0.001. Data were replicated in the rSA group at follow-up (p = 0.008). Cox proportional hazard analysis tested by 4 models confirmed higher major adverse cardiovascular events risk in rs5065 MA carriers in both SA and rSA cohorts. Significantly higher myeloperoxidase levels were detected in rs5065 MA carriers (n = 597 [345 to 832 μg/l] vs. n = 488 [353 to 612 μg/l], p = 0.038). No association of rs5065 was observed with N-terminal-proANP levels.

The MA of rs5065 ANP gene variant associates with increased susceptibility to ACS and has unfavorable prognostic value in CAD.

Hypertension and CV complications are more severe in men and post-menopausal women than in pre-menopausal women. C-PP is lower than B-PP, and the B/C-PP ratio is a physiological marker of PP amplification between B and C arteries that tends toward 1.0 with age.

The study involved 72,437 men (ages 41.0 ± 11.1 years) and 52,714 women (39.5 ± 11.6 years). C-PP was calculated for each sex by a multiple regression analysis including B-PP, age, height and risk factors, and a method validated beforehand in a subgroup of 834 subjects. During the 12 years of follow-up, 3,028 men and 969 women died.

In the total population, the adjusted hazard ratios (HR) (95% confidence interval [CI]) of B/C-PP ratio were: 1) for all-cause mortality: men, HR: 1.51 (95% CI: 1.47 to 1.56), women; HR: 2.46 (95% CI: 2.27 to 2.67) (p < 0.0001); and 2) for CV mortality: men, HR 1.81 (95% CI: 1.70 to 1.93); women, HR: 4.46 (95% CI: 3.66 to 5.45) (p < 0.0001). The B/C-PP impact on mortality did not significantly increase from younger men to those ≥55 years of age, from: HR: 1.44 (95% CI: 1.31 to 1.58) to HR 1.65 (95% CI: 1.48 to 1.84), but increased significantly with age in women: HR: 3.19 (95% CI: 2.08 to 4.89) versus HR: 5.60 (95% CI: 4.17 to 7.50) (p < 0.01). Thus, the mortality impact of B/C-PP ratio was 3-fold higher in women than in men ≥55 years old.

PP amplification is highly predictive of differences in CV risk between men and women. In post-menopausal women, the attenuation of PP amplification, mainly related to increased aortic stiffness, contributes to the significant increase in CV risk.

Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects.

We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major cardiovascular events (MCVEs).

Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1 year post-randomization did not change upon increase of the statin dose.

PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691)

Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF).

Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤40% vs. >40%) and presence (or absence) of AF at baseline.

After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001).

Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.

Despite its growing use in clinical laboratories, the accuracy of 3DE has not been studied on a large scale. It is unclear if this technology offers an advantage over traditional two-dimensional (2D) methods.

We searched for studies that compared LV volumes and EF measured by 3DE and cardiac magnetic resonance (CMR) imaging. A subset of those also compared standard 2D methods with CMR. We used meta-analyses to determine the overall bias and limits of agreement of LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF measured by 3DE and 2D echocardiography (2DE).

Twenty-three studies (1,638 echocardiograms) were included. The pooled biases ± 2 SDs for 3DE were –19.1 ± 34.2 ml, –10.1 ± 29.7 ml, and – 0.6 ± 11.8% for EDV, ESV, and EF, respectively. Nine studies also included data from 2DE, where the pooled biases were –48.2 ± 55.9 ml, –27.7 ± 45.7 ml, and 0.1 ± 13.9% for EDV, ESV, and EF, respectively. In this subset, the difference in bias between 3DE and 2D volumes was statistically significant (p = 0.01 for both EDV and ESV). The difference in variance was statistically significant (p < 0.001) for all 3 measurements.

Three-dimensional echocardiography underestimates volumes and has wide limits of agreement, but compared with traditional 2D methods in these carefully performed studies, 3DE is more accurate for volumes and more precise in all 3 measurements.

Severe aortic stenosis reduces the length and quality of a patient's life. Transcatheter aortic valve implantation (TAVI) is superior to standard medical therapy and noninferior to surgical aortic valve replacement for 1-year mortality. HRQOL is an important outcome measure for which there is limited evidence in TAVI populations.

A total of 102 patients (mean age 80 ± 0.6 years; 49% male) undergoing TAVI consented to participate. Two HRQOL questionnaires—the social functioning (SF)-12v2 with physical component summaries (PCS) and mental component summaries (MCS) and the EQ-5D (with a visual analog scale [VAS])—were completed at baseline, 30 days, 6 months, and 1 year according to the recommendations of the Valve Academic Research Consortium. A SF-6D utility measure was calculated from the SF-12 survey.

HRQOL significantly improved over 1 year (PCS p = 0.02; EQ-5D p = 0.02; VAS p = 0.01; SF-6D p = 0.03), becoming similar to age-adjusted U.S. population norms. The greatest change occurred from baseline to 30 days (p < 0.001), with further significant improvements to 6 months (p < 0.01). An insignificant decline occurred between 6 months and 1 year (p > 0.05), but a linear pattern of change remained for PCS, EQ-5D, and VAS (p < 0.05). Male sex (SF-6D p = 0.01) and increased operator experience (PCS, EQ-5D, and VAS p < 0.05) were independent predictors of a greater improvement in HRQOL.

HRQOL significantly improved early after TAVI and was maintained out to 1 year. Patient factors, procedural complications, and operator experience are predictors of health benefit at 1 year.

There are a growing number of patients on chronic prasugrel therapy regimens, leading to questions about the dosing regimen of prasugrel to administer if percutaneous coronary intervention is required.

This is a prospective pharmacodynamic study in patients (n = 64) receiving maintenance prasugrel therapy who were randomly allocated to a 10 mg, 30 mg, or 60 mg dose of prasugrel. Pharmacodynamic assessments using multiple assays were conducted at 3 timepoints (baseline and 1 h and 4 h after dosing).

Intragroup comparisons showed that a 60 mg dose reduced the platelet reactivity index (PRI) after 1 h (p = 0.004) and 4 h (p < 0.001, primary endpoint; p = 0.002 between 1 h and 4 h). A 30 mg dose also reduced PRI levels at 1 h (p = 0.006) and 4 h (p < 0.001; p = 0.044 between 1 h and 4 h). A 10 mg dose was associated with modest pharmacodynamic effects. Intragroup comparisons showed similar findings with VerifyNow-P2Y12 and light transmission aggregometry. Intergroup comparisons showed that a 60 mg dose achieved lower PRI levels than 30 mg at 4 h (p = 0.05), and a numerical trend toward better pharmacodynamic effects at 1 h (p = 0.171). Intergroup comparisons were similar with VerifyNow-P2Y12, but not light transmission aggregometry.

For patients on maintenance prasugrel therapy, a 60 mg dosing strategy is associated with faster and higher platelet inhibition compared with lower doses, as assessed by P2Y₁₂ specific assays. (Impact of Prasugrel Re-load on Platelet Aggregation in Patients on Chronic Prasugrel Therapy; NCT01201772)

Fetuin-A is a circulating inhibitor of calcium deposition in the vasculature and of insulin action in muscle and fat, and may be involved in the pathogenesis of CVD.

This is a population-based prospective study of 633 men and 1,025 women (median age = 73 years) who had fetuin-A levels and CVD risk factors evaluated in 1992 to 1996 and were followed for vital status through 2010.

Plasma fetuin-A (g/l ± SD) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI]: 1.34 to 2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI: 0.19 to 0.98; p = 0.046) for participants with diabetes.

Low fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms leading to CVD death in those with versus without diabetes.

Serum levels of resistin, an adipose tissue–derived adipokine, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular diseases. However, the function of resistin in humans is enigmatic.

Human hepatocytes (HepG2 and primary) were treated (24 h) with the following: 1) purified human resistin at various concentrations, with and without lovastatin; and 2) obese human serum with elevated resistin levels or serum from which resistin was removed via antibody-immunoprecipitation. The effect of the treatments on cellular low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger ribonucleic acid and protein levels were determined by using real-time polymerase chain reaction and Western blotting, respectively.

Resistin, at physiological levels observed in human obesity, down-regulated hepatocyte LDLR expression substantially (by 40%). A key mechanism by which human resistin inhibited LDLR levels was by increased cellular expression of the recently identified protease, PCSK9, which enhances intracellular LDLR lysosomal degradation. The quantitatively important role of human resistin in LDLR expression was demonstrated by antibody-immunoprecipitation removal of resistin in human serum, which decreased serum stimulation of hepatocyte LDLRs markedly (by 80%). Furthermore, resistin diminished statin-mediated up-regulation of the LDLR by 60%, implicating resistin in the relative ineffectiveness of statins in selective target populations.

These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum low-density lipoprotein and, thereby, atherosclerotic cardiovascular diseases in obese humans.

Patients with both HF and renal insufficiency have a poor prognosis. Three formulas are mostly used to assess renal function: Cockroft-Gault formula, MDRD-4 (Modification of Diet in Renal Disease Study) formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The prognostic values of these formulas have not been adequately compared in HF patients.

A total of 925 patients (72% men; age 69 years; interquartile range: 59 to 75.5 years) with a left ventricular ejection fraction of 31% (interquartile range: 23.5% to 39%) were studied. Follow-up was 1,202 days (interquartile range: 627.5 to 2,156.5 days). Measures of performance were evaluated using continuous data and by dividing patients into 4 subgroups according to the eGFR: ≥90, 89 to 60, <60 to 30, and <30 ml/min/1.73 m².

The 3 formulas correlated significantly, with the best correlation found between the MDRD-4 and CKD-EPI formulas. The 3 formulas afforded independent prognostic information over long-term follow-up. However, risk prediction was most accurate using the Cockroft-Gault formula as evaluated by Cox proportional hazards models (hazard ratio: 0.75 vs. 0.81 with the MDRD-4 formula and 0.80 with the CKD-EPI equation), area under the curve (0.67 vs. 0.62 and 0.64, respectively), and Bayesian information criterion (both analyzing eGFR as a continuous or categorical variable). Indeed, net reclassification improvement and integrated discrimination improvement using the Cockroft-Gault formula were 21% and 5.04, respectively, versus the MDRD-4 formula (the most used) and 13.1% and 3.77 respectively versus CKD-EPI equation (the more recent) (all p values <0.001).

In this ambulatory, real-life cohort of HF patients, the Cockroft-Gault formula was the most accurate of the 3 used eGFR formulas to improve the risk stratification for death.

Accurate detection of obstructive CAD is important for effective therapy. Noninvasive myocardial perfusion imaging is increasingly being applied to gauge the severity of CAD.

Studies published between 1990 and 2010 identified by PubMed search and citation tracking were examined. A study was included if a perfusion imaging modality was used as a diagnostic test for the detection of obstructive CAD and coronary angiography as the reference standard (≥50% diameter stenosis).

Of the 3,635 citations, 166 articles (n = 17,901) met the inclusion criteria: 114 SPECT, 37 CMR, and 15 PET articles. There were not enough publications on other perfusion techniques such as perfusion echocardiography and computed tomography to include these modalities into the study. The patient-based analysis per imaging modality demonstrated a pooled sensitivity of 88% (95% confidence interval [CI]: 88% to 89%), 89% (95% CI: 88% to 91%), and 84% (95% CI: 81% to 87%) for SPECT, CMR, and PET, respectively; with a pooled specificity of 61% (95% CI: 59% to 62%), 76% (95% CI: 73% to 78%), and 81% (95% CI: 74% to 87%). This resulted in a pooled diagnostic odds ratio (DOR) of 15.31 (95% CI: 12.66 to 18.52; I ² 63.6%), 26.42 (95% CI: 17.69 to 39.47; I ² 58.3%), and 36.47 (95% CI: 21.48 to 61.92; I ² 0%). Most of the evaluated test and study characteristics did not affect the ranking of diagnostic performances.

SPECT, CMR, and PET all yielded a high sensitivity, while a broad range of specificity was observed. SPECT is widely available and most extensively validated; PET achieved the highest diagnostic performance; CMR may provide an alternative without ionizing radiation and a similar diagnostic accuracy as PET. We suggest that referring physicians consider these findings in the context of local expertise and infrastructure.

Although extensively calcified atherosclerotic lesions have been proposed to be clinically quiescent, the presence of spotty calcification within plaque has been reported to be associated with an increased incidence of ischemic cardiovascular events. The relationship between spotty calcification and disease progression has not been investigated.

A total of 1,347 stable patients with angiographic coronary artery disease underwent serial evaluation of atheroma burden with intravascular ultrasound imaging. Patients with spotty calcification were identified based on the presence of lesions (1 to 4 mm in length) containing an arc of calcification of <90°. Clinical characteristics and disease progression were compared between patients with spotty calcification (n = 922) and those with no calcification (n = 425).

Patients with spotty calcification were older (age 56 years vs. 54 years; p = 0.001), more likely to be male (68% vs. 54%; p = 0.01), and have a history of diabetes mellitus (30% vs. 24%; p = 0.01) and myocardial infarction (28% vs. 20%; p = 0.004), and have lower on-treatment high-density lipoprotein cholesterol levels (48 ± 16 mg/dl vs. 51 ± 17 mg/dl; p = 0.001). Patients with spotty calcification demonstrated a greater percent atheroma volume (PAV) (36.0 ± 7.6% vs. 29.0 ± 8.5%; p < 0.001) and total atheroma volume (174.6 ± 71.9 mm³ vs. 133.9 ± 64.9 mm³; p < 0.001). On serial evaluation, spotty calcification was associated with greater progression of PAV (+0.43 ± 0.07% vs. +0.02 ± 0.11%; p = 0.002). Although intensive low-density lipoprotein cholesterol and blood pressure lowering therapy slowed disease progression, these efficacies were attenuated in patients with spotty calcification.

The presence of spotty calcification is associated with more extensive and diffuse coronary atherosclerosis and accelerated disease progression despite use of medical therapies.

Aldosterone antagonism in heart failure might influence atrial fibrosis and remodeling and, therefore, risk of developing AFF. The development of new AFF was a pre-specified secondary endpoint in the EMPHASIS-HF study.

Patients in New York Heart Association functional class II and with ejection fraction ≤35% were eligible for EMPHASIS-HF. History of AFF at baseline was reported by investigators using the study case report form. New onset AFF (in those with no history of AFF at baseline) was reported using a specific endpoint form; in a sensitivity analysis we also examined the effect of eplerenone on AFF reported as an adverse event.

New onset AFF was significantly reduced by eplerenone: 25 of 911 (2.7%) versus 40 of 883 (4.5%) in the placebo group (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.35 to 0.96; p = 0.034). The reduction in the primary endpoint with eplerenone was similar among patients with and without AFF at baseline (HR: 0.60, 95% CI: 0.46 to 0.79 vs. HR: 0.70, 95% CI: 0.57 to 0.85, respectively; p for interaction = 0.41). The risk of cardiovascular (CV) death or hospital admission for worsening heart failure, the primary endpoint, was not significantly different in subjects with and without AFF at baseline (both study groups combined: HR: 1.23, 95% CI: 0.81 to 1.86; p = 0.33).

In patients with systolic heart failure and mild symptoms, eplerenone reduced the incidence of new onset AFF. The effects of eplerenone on the reduction of major CV events were similar in patients with and without AFF at baseline.

Long-term mortality of viral myocarditis, as well as potential risk factors for poor clinical outcome, are widely unknown.

A total of 222 consecutive patients with biopsy-proven viral myocarditis and CMR were enrolled. A total of 203 patients were available for clinical follow-up, and 77 patients underwent additional follow-up CMR. The median follow-up was 4.7 years. Primary endpoints were all-cause mortality and cardiac mortality.

We found a relevant long-term mortality in myocarditis patients (19.2% all cause, 15% cardiac, and 9.9% sudden cardiac death [SCD]). The presence of late gadolinium enhancement (LGE) yields a hazard ratio of 8.4 for all-cause mortality and 12.8 for cardiac mortality, independent of clinical symptoms. This is superior to parameters like left ventricular (LV) ejection fraction, LV end-diastolic volume, or New York Heart Association (NYHA) functional class, yielding hazard ratios between 1.0 and 3.2 for all-cause mortality and between 1.0 and 2.2 for cardiac mortality. No patient without LGE experienced SCD, even if the LV was enlarged and impaired. When focusing on the subgroup undergoing follow-up CMR, we found an initial NYHA functional class >I as the best independent predictor for incomplete recovery (p = 0.03).

Among our population with a wide range of clinical symptoms, biopsy-proven viral myocarditis is associated with a long-term mortality of up to 19.2% in 4.7 years. In addition, the presence of LGE is the best independent predictor of all-cause mortality and of cardiac mortality. Furthermore, initial presentation with heart failure may be a good predictor of incomplete long-term recovery.

CIED infection is sometimes challenging to diagnose. Because extraction is associated with significant morbidity/mortality, new imaging modalities to confirm the infection and its dissemination would be of clinical value.

Three groups were compared. In Group A, 42 patients with suspected CIED infection underwent ¹⁸F-FDG PET/CT. Positive PET/CT was defined as abnormal uptake along cardiac devices. Group B included 12 patients without infection who underwent PET/CT 4 to 8 weeks post-implant. Group C included 12 patients implanted for >6 months without infection who underwent PET/CT for another indication. Semi-quantitative ratio (SQR) was obtained from the ratio between maximal uptake and lung parenchyma uptake.

In Group A, 32 of 42 patients with suspected CIED infection had positive PET/CT. Twenty-four patients with positive PET/CT underwent extraction with excellent correlation. In 7 patients with positive PET/CT, 6 were treated as superficial infection with clinical resolution. One patient with positive PET/CT but negative leukocyte scan was considered false positive due to Dacron pouch. Ten patients with negative-PET/CT were treated with antibiotics and none has relapsed at 12.9 ± 1.9 months. In Group B, patients had mild uptake seen at the level of the connector. There was no abnormal uptake in Group C patients. Median SQR was significantly higher in Group A (A = 2.02 vs. B = 1.08 vs. C = 0.57; p < 0.001).

PET/CT is useful in differentiating between CIED infection and recent post-implant changes. It may guide appropriate therapy.

Biochemical detection of MIS is a major challenge. The validation of novel biosignatures is of utmost importance.

High-resolution nuclear magnetic resonance spectroscopy was used to profile 32 blood serum metabolites obtained (before and after controlled ischemia) from swine (n = 9) and patients (n = 20) undergoing transitory MIS in the setting of planned coronary angioplasty. Additionally, blood serum of control patients (n = 10) was sequentially profiled. Preliminary clinical validation of the developed metabolomic biosignature was undertaken in patients with spontaneous acute chest pain (n = 30).

Striking differences were detected in the blood profiles of swine and patients immediately after MIS. MIS induced early increases (10 min) of circulating glucose, lactate, glutamine, glycine, glycerol, phenylalanine, tyrosine, and phosphoethanolamine; decreases in choline-containing compounds and triacylglycerols; and a change in the pattern of total, esterified, and nonesterified fatty acids. Creatine increased 2 h after ischemia. Using multivariate analyses, a biosignature was developed that accurately detected patients with MIS both in the setting of angioplasty-related MIS (area under the curve 0.94) and in patients with acute chest pain (negative predictive value 95%).

This study reports, to the authors' knowledge, the first metabolic biosignature of acute MIS developed under highly controlled coronary flow restriction. Metabolic profiling of blood plasma appears to be a promising approach for the early detection of MIS in patients.

Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues.

Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (T) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed.

T was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher T compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher T compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher T compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher T compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01).

MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation.

Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care.

A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure–related hospitalization.

The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031).

Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure–related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943)

Guidelines focus on LDL-C as the primary target of therapy, yet residual risk for cardiovascular disease (CVD) among statin-treated individuals remains high and not fully explained.

Participants in the randomized placebo-controlled JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial were adults without diabetes or CVD, with baseline LDL-C levels <130 mg/dl, high-sensitivity C-reactive protein levels ≥2 mg/l, and triglyceride concentrations <500 mg/dl. Individuals allocated to receive rosuvastatin 20 mg daily with baseline and on-treatment lipids and lipoproteins were examined in relation to the primary endpoint of incident CVD (nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death).

Using separate multivariate Cox models, statistically significant associations of a similar magnitude with residual risk of CVD were found for on-treatment LDL-C, non–HDL-C, apolipoprotein B, total cholesterol/HDL-C, LDL-C/HDL-C, and apolipoprotein B/A-I. The respective adjusted standardized hazard ratios (95% confidence intervals) for each of these measures were 1.31 (1.09 to 1.56), 1.25 (1.04 to 1.50), 1.27 (1.06 to 1.53), 1.22 (1.03 to 1.44), 1.29 (1.09 to 1.52), and 1.27 (1.09 to 1.49). The overall residual risk and the risk associated with these measures decreased among participants achieving on-treatment LDL-C ≤70 mg/dl, on-treatment non–HDL-C ≤100 mg/dl, or on-treatment apolipoprotein B ≤80 mg/dl. In contrast, on-treatment triglycerides showed no association with CVD.

In this primary prevention trial of nondiabetic individuals with low LDL-C and elevated high-sensitivity C-reactive protein, on-treatment LDL-C was as valuable as non–HDL-C, apolipoprotein B, or ratios in predicting residual risk. (JUPITER—Crestor 20mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681)

Optimal endpoints for VT ablation are not well defined.

Of 200 consecutive patients with VT and structural heart disease undergoing ablation, 11 had clinical VT inducible at the end of ablation and 11 recurred spontaneously. Of the remaining 178 patients, 132 underwent NIPS through their implantable cardioverter-defibrillator 3.1 ± 2.1 days after ablation. At 2 drive cycle lengths, single, double, and triple right ventricular extrastimuli were delivered to refractoriness. Clinical VT was defined by comparison with 12-lead electrocardiograms and stored implantable cardioverter-defibrillator electrograms from spontaneous VT episodes. Patients were followed for 1 year.

Fifty-nine patients (44.7%) had no VT inducible at NIPS; 49 (37.1%) had inducible nonclinical VT only; and 24 (18.2%) had inducible clinical VT. Patients with inducible clinical VT at NIPS had markedly decreased 1-year VT-free survival compared to those in whom no VT was inducible (<30% vs. >80%; p = 0.001), including 33% recurring with VT storm. Patients with inducible nonclinical VT only, had intermediate 1-year VT-free survival (65%).

When patients with VT and structural heart disease have no VT or nonclinical VT only inducible at the end of ablation or their condition is too unstable to undergo final programmed stimulation, NIPS should be considered in the following days to further define risk of recurrence. If clinical VT is inducible at NIPS, repeat ablation may be considered because recurrence over the following year is high.

The noninvasive assessment of coronary artery plaque biology would be a major advance particularly in the identification of vulnerable plaques, which are associated with specific pathological characteristics, including micro-calcification and inflammation.

We prospectively recruited 119 volunteers (72 ± 8 years of age, 68% men) with and without aortic valve disease and measured their coronary calcium score and 18F-NaF and 18F-FDG uptake. Patients with a calcium score of 0 were used as control subjects and compared with those with calcific atherosclerosis (calcium score >0).

Inter-observer repeatability of coronary 18F-NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99). Activity was higher in patients with coronary atherosclerosis (n = 106) versus control subjects (1.64 ± 0.49 vs. 1.23 ± 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p < 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p = 0.023) and higher Framingham risk scores (p = 0.011). Quantification of coronary 18F-FDG uptake was hampered by myocardial activity and was not increased in patients with atherosclerosis versus control subjects (p = 0.498).

18F-NaF is a promising new approach for the assessment of coronary artery plaque biology. Prospective studies with clinical outcomes are now needed to assess whether coronary 18F-NaF uptake represents a novel marker of plaque vulnerability, recent plaque rupture, and future cardiovascular risk. (An Observational PET/CT Study Examining the Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis; NCT01358513)

The use of endovascular stents are a common clinical intervention for the treatment of arteries occluded due to vascular disease. Both heparin and heparan sulfate are known to be potent inhibitors of thrombosis. Heparanase is the major enzyme that degrades heparan sulfate in mammalian cells. This study examined the role of heparanase in controlling thrombosis following vascular injury and stent-induced flow disturbance.

This study used mice overexpressing human heparanase and examined the time to thrombosis using a laser-induced arterial thrombosis model in combination with vascular injury. An ex vivo system was used to examine the formation of thrombus to stent-induced flow disturbance.

In the absence of vascular injury, wild type and heparanase overexpressing (HPA Tg) mice had similar times to thrombosis in a laser-induced arterial thrombosis model. However, in the presence of vascular injury, the time to thrombosis was dramatically reduced in HPA Tg mice. An ex vivo system was used to flow blood from wild type and HPA Tg mice over stents and stented arterial segments from both animal types. These studies demonstrate markedly increased thromboses on stents with blood isolated from HPA Tg mice in comparison to blood from wild type animals. We found that blood from HPA Tg animals had markedly increased thrombosis when applied to stented arterial segments from either wild type or HPA Tg mice.

Taken together, this study's results indicate that heparanase is a powerful mediator of thrombosis in the context of vascular injury and stent-induced flow disturbance.

OxPL measured on apolipoprotein B-100 (OxPL/apoB), primarily reflecting OxPL on Lp(a), independently predict cardiovascular disease (CVD) events.

The authors examined plasminogen from commercially available preparations and plasma from chimpanzees; gorillas; bonobos; cynomolgus monkeys; wild-type, apoE ^–/– , LDLR ^–/– , and Lp(a)-transgenic mice; healthy humans; and patients with familial hypercholesterolemia, stable CVD, and acute myocardial infarction (AMI). Phosphocholine (PC)-containing OxPL (OxPC) present on plasminogen were detected directly with liquid chromatography–mass spectrometry (LC-MS/MS) and immunologically with monoclonal antibody E06. In vitro clot lysis assays were performed to assess the effect of the OxPL on plasminogen on fibrinolysis.

LC-MS/MS revealed that OxPC fragments were covalently bound to mouse plasminogen. Immunoblot, immunoprecipitation, density gradient ultracentrifugation, and enzyme-linked immunosorbent assay analyses demonstrated that all human and animal plasma samples tested contained OxPL covalently bound to plasminogen. In plasma samples subjected to density gradient fractionation, OxPL were present on plasminogen (OxPL/plasminogen) in non-lipoprotein fractions but on Lp(a) in lipoprotein fractions. Plasma levels of OxPL/apoB and OxPL/apo(a) varied significantly (>25x) among subjects and also strongly correlated with Lp(a) levels. In contrast, OxPL/plasminogen levels were distributed across a relatively narrow range and did not correlate with Lp(a). Enzymatic removal of OxPL from plasminogen resulted in a longer lysis time for fibrin clots (16.25 vs. 11.96 min, p = 0.007). In serial measurements over 7 months, OxPL/plasminogen levels did not vary in normal subjects or in patients with stable CVD, but increased acutely over the first month and then slowly decreased to baseline in patients following AMI.

These data demonstrate that plasminogen contains covalently bound OxPL that influence fibrinolysis. OxPL/plasminogen represent a second major plasma pool of OxPL, in addition to those present on Lp(a). OxPL present on plasminogen may have pathophysiological implications in AMI and atherothrombosis.

Dyspnea is a key symptom and clinical trial endpoint in AHF, yet objective assessment is lacking.

In a clinical trial substudy, 421 patients (37 sites) underwent PEFR testing at baseline, 1, 6, and 24 h after randomization to nesiritide or placebo. DI (by Likert scale) was collected at hours 6 and 24.

Patients were median age 70 years, and 34% were female; no significant differences between nesiritide or placebo patients existed. Median baseline PEFR was 225 l/min (interquartile range [IQR]: 160 to 300 l/min) and increased to 230 l/min (2.2% increase; IQR: 170 to 315 l/min) by hour 1, 250 l/min (11.1% increase; IQR: 180 to 340 l/min) by hour 6, and 273 l/min (21.3% increase; IQR: 200 to 360 l/min) by 24 h (all p < 0.001). The 24-h PEFR change related to moderate or marked dyspnea improvement by DI (adjusted odds ratio: 1.04 for each 10 l/min improvement [95% confidence interval (CI): 1.07 to 1.10]; p < 0.01). A model incorporating time and treatment over 24 h showed greater PEFR improvement after nesiritide compared with placebo (p = 0.048).

PEFR increases over the first 24 h in AHF and could serve as an AHF endpoint. Nesiritide had a greater effect than placebo on PEFR, and this predicted patients with moderate/marked improvement in dyspnea, thereby providing an objective metric for assessing AHF. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

Valvular calcification is associated with the development and progression of aortic stenosis. Bisphosphonates have been suggested to slow this progression.

Female patients older than the age of 60 years with an aortic valve area (AVA) between 1.0 and 2.0 cm² were identified and studied retrospectively. Only those who had follow-up echocardiograms at least a year apart were included. Primary outcomes were the change in AVA and valvular gradients over time. Mortality and freedom from aortic valve replacement were also studied. A propensity-matching method was applied for the probability of the use of bisphosphonates.

The study included 801 female patients (mean age, 76 ± 7.6 years) with a mean follow-up of 5.1 ± 2.4 years. The mean duration of bisphosphonate use was 3.1 ± 2.6 years. At the time of the initial echocardiogram, 323 patients (38%) were taking bisphosphonates. The mean ejection fraction at baseline was 56.7 ± 9.6% with a mean AVA of 1.32 ± 0.25 cm². Peak and mean gradients were 28.4 ± 11 mm Hg and 15.6 ± 6.8 mm Hg, respectively. Propensity matching was successfully performed for 438 patients. On follow-up, there were no differences in the rate of change in AVA or peak and mean gradients when patients were stratified based on the use of bisphosphonates. Bisphosphonates also had no impact on survival or freedom from aortic valve replacement.

In this retrospective analysis of older female patients, bisphosphonates do not have a significant impact on the hemodynamic or clinical progression of aortic stenosis.

Unlike cardiovascular morbidity and mortality, little is known about the relationship between QTc and risk of stroke.

A total of 27,411 participants age 45 years and older without previous stroke from the REGARDS (REasons for Geographic and Racial Differences in Stroke) study were included in this analysis. QTc was calculated using Framingham formula (QTc_Fram)_. Stroke cases were identified and adjudicated during up to 8.2 years of follow-up (median, 5.1 years).

The risk of incident stroke in study participants with prolonged QTc_Fram was almost 3 times the risk in those with normal QTc_Fram (hazard ratio [HR] [95% confidence interval (CI)]: 2.88 [2.12 to 3.92], p < 0.0001). After adjustment for demographics (age, race, and sex), traditional stroke risk factors (antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, and previous cardiovascular disease), warfarin use, aspirin use, QRS duration and use of QTc-prolonging drugs, the risk of stroke remained significantly high (HR [95% CI]: 1.67 [1.16 to 2.41], p = 0.0061) and was consistent across several subgroups of REGARDS study participants. Similar results were obtained when the risk of stroke was estimated per 1-SD increase in QTc_Fram, (HR [95% CI]: 1.12 [1.03 to 1.21], p = 0.0053 in multivariable-adjusted model) and when other QTc correction formulas including those of Hodge, Bazett, and Fridericia were used.

QTc prolongation is associated with a significantly increased risk of incident stroke independent of traditional stroke risk factors. Examining the risk of stroke associated with QTc-prolonging drugs may be warranted.

Catheter perforation for PAIVS is now an established procedure. However, the management of the borderline right ventricle (RV) is controversial, and there may be a place for novel techniques such as stenting of the arterial duct.

There were 37 successful valve perforations (total 39 patients). Median length of follow-up was 9.2 years (range 2.2 to 21.0 years). Seventeen patients had stenting of the arterial duct. The mean (SD) initial z-score for the tricuspid valve was –5.1 (±3.4), and a further 142 sets of measurements were taken to assess the growth of the RV of survivors.

There were 8 deaths (21%), and no deaths after the first 35 days. There were no late arrhythmias or ischemic events. Twenty-five patients (83% of survivors) have a biventricular circulation. For patients who had stenting of the arterial duct, significant reductions in early reintervention (0 vs. 7 patients, p = 0.009) and hospital stay (17.4 ± 18.1 days vs. 33.8 ± 28.6 days, p = 0.012) occurred, with no increase in mortality or morbidity. There was no catch-up growth of the RV in patients who had a biventricular outcome (z-score increase +0.08/year, p = 0.26).

Long-term survival is good, and even small RVs may be amenable to this procedure. Multiple interventions may be required to achieve biventricular circulation, but stenting of the arterial duct may reduce hospital stay and repeat procedures.

The mechanism for alcoholic cardiomyopathy remains largely unknown.

The chronic cardiac effects of alcohol were examined in mice feeding with alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced cardiac cell death were examined in H9c2 cells.

Compared with controls, hearts from alcohol-fed mice exhibited increased apoptosis, along with significant nitrative damage, demonstrated by 3-nitrotyrosine abundance. Alcohol exposure to H9c2 cells induced apoptosis, accompanied by 3-nitrotyrosine accumulation and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation. Pre-incubation of H9c2 cells with urate (peroxynitrite scavenger), N ^G-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor), manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (a superoxide dismutase mimetic), and apocynin (NOX inhibitor) abrogated alcohol-induced apoptosis. Furthermore, alcohol exposure significantly increased the expression of angiotensin II and its type 1 receptor (AT1). A protein kinase C (PKC)-α/β1 inhibitor or PKC-β1 small interfering RNA and an AT1 blocker prevented alcohol-induced activation of NOX, and the AT1 blocker losartan significantly inhibited the expression of PKC-β1, indicating that alcohol-induced activation of NOX is mediated by PKC-β1 via AT1. To define the role of AT1-mediated PKC/NOX-derived superoxide generation in alcohol-induced cardiotoxicity, mice with knockout of the AT1 gene and wild-type mice were simultaneously treated with alcohol for 2 months. The knockout AT1 gene completely prevented cardiac nitrative damage, cell death, remodeling, and dysfunction. More importantly, pharmacological treatment of alcoholic mice with superoxide dismutase mimetic also significantly prevented cardiac nitrative damage, cell death, and remodeling.

Alcohol-induced nitrative stress and apoptosis, which are mediated by angiotensin II interaction with AT1 and subsequent activation of a PKC-β1–dependent NOX pathway, are a causal factor in the development of alcoholic cardiomyopathy.

Only 1 randomized trial previously compared these stents.

This investigator-initiated, patient-blinded, randomized noninferiority study had limited exclusion criteria (acute ST-segment elevation myocardial infarctions not eligible). Patients (n = 1,391; 81.4% of eligible population) were randomly assigned to ZES (n = 697) or EES (n = 694). Liberal use of stent post-dilation was encouraged. Cardiac biomarkers were systematically assessed. The primary endpoint was target vessel failure (TVF), a composite of cardiac death, myocardial infarction not clearly attributable to non-target vessels, and clinically indicated target-vessel revascularization. An external independent research organization performed clinical event adjudication (100% follow-up data available). Analysis was by intention-to-treat.

Acute coronary syndromes were present in 52% and "off-label" feature in 77% of patients. Of the lesions, 70% were type B2/C; the post-dilation rate was very high (82%). In ZES and EES, TVF occurred in 8.2% and 8.1%, respectively (absolute risk-difference 0.1%; 95% confidence interval: –2.8% to 3.0%, p_{noninferiority} = 0.001). There was no significant between-group difference in TVF components. The definite-or-probable stent thrombosis rates were relatively low and similar for ZES and EES (0.9% and 1.2%, respectively, p = 0.59). Definite stent thrombosis rates were also low (0.58% and 0%, respectively, p = 0.12). In EES, probable stent thrombosis beyond day 8 was observed only in patients not adhering to dual antiplatelet therapy.

Resolute ZES were noninferior to Xience V EES in treating "real-world" patients with a vast majority of complex lesions and "off-label" indications for drug-eluting stents, which were implanted with liberal use of post-dilation. (The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting SteNt Study: Head-to-head Comparison of Clinical Outcome After Implantation of Second Generation Drug-eluting Stents in a Real World Scenario; NCT01066650)

Durable polymer coatings on drug-eluting stents have been associated with chronic inflammation and impaired healing. Bioabsorbable polymer-coated drug-delivery systems may reduce the risk of late adverse events, including stent thrombosis, and thus the need for prolonged dual-antiplatelet therapy.

A total of 291 patients with a de novo lesion ≤28 mm in length, in a coronary artery of ≥2.25 to ≤3.5 mm diameter, were enrolled in the EVOLVE study, a prospective, randomized, single-blind, noninferiority trial. Patients were randomly assigned in a 1:1:1 ratio to PROMUS Element, SYNERGY, or SYNERGY half dose. The primary clinical endpoint was the 30-day rate of target lesion failure, defined as cardiac death or myocardial infarction related to the target vessel, or target lesion revascularization. The primary angiographic endpoint was 6-month in-stent late loss measured by quantitative coronary angiography.

The 30-day primary clinical endpoint of target lesion failure occurred in 0%, 1.1%, and 3.1% of patients in the PROMUS Element, SYNERGY, and SYNERGY half dose groups, respectively. The 6-month in-stent late loss was 0.15 ± 0.34 mm for PROMUS Element, 0.10 ± 0.25 mm for SYNERGY, and 0.13 ± 0.26 mm for SYNERGY half dose (SYNERGY, difference –0.06, upper 95.2% confidence limit: 0.02, p for noninferiority <0.001; SYNERGY half dose, difference –0.03, upper 95.2% confidence limit: 0.05, p for noninferiority <0.001). Clinical event rates remained low and comparable between groups, with no stent thromboses in any group at 6 months.

The EVOLVE trial confirms the effective delivery of everolimus by a unique directional bioabsorbable polymer system utilizing the SYNERGY stent. (A Prospective Randomized Multicenter Single-Blind Noninferiority Trial to Assess the Safety and Performance of the Evolution Everolimus-Eluting Monorail Coronary Stent System [Evolution Stent System] for the Treatment of a De Novo Atherosclerotic Lesion [EVOLVE]; NCT01135225)

Although the efficacy of the drug-eluting stent has been well established, the risk-benefit balance is still suboptimal, and the safety of polymers remains uncertain.

Patients undergoing percutaneous coronary intervention for de novo lesions were randomly assigned 1:1 to Cre8 or Taxus Liberté stents. Primary endpoint was 6-month angiographic in-stent late lumen loss (LLL) within a noninferiority scope. Six-month intravascular ultrasound was performed in 20% of the patients. All patients will be clinically followed up to 5 years.

Out of 323 patients enrolled, 162 received Cre8 and 161 Taxus Liberté stents. In-stent LLL was significantly lower in Cre8 group (0.14 ± 0.36 mm vs. 0.34 ± 0.40 mm, p noninferiority <0.0001, p superiority <0.0001). Clinical endpoints (cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis) up to 12 months did not differ significantly between the groups.

The Cre8 stent in de novo lesions showed significantly lower in-stent LLL at 6 months than the Taxus Liberté stent did, with a trend toward better 12-month clinical safety and efficacy results. (International Randomized Comparison Between DES Limus Carbostent and Taxus Drug-Eluting Stents in the Treatment of De Novo Coronary Lesions [NEXT]; NCT01373502)

Drug-coated balloon angioplasty is associated with favorable results for treatment of bare-metal stent restenosis.

In this prospective, single-blind, multicenter, randomized trial, the authors randomly assigned 110 patients with drug-eluting stent restenoses located in a native coronary artery to paclitaxel-coated balloon angioplasty or uncoated balloon angioplasty. Dual antiplatelet therapy was prescribed for 6 months. Angiographic follow-up was scheduled at 6 months. The primary endpoint was late lumen loss. The secondary clinical endpoint was a composite of cardiac death, myocardial infarction attributed to the target vessel, or target lesion revascularization.

There was no difference in patient baseline characteristics or procedural results. Angiographic follow-up rate was 91%. Treatment with paclitaxel-coated balloon was superior to balloon angioplasty alone with a late loss of 0.43 ± 0.61 mm versus 1.03 ± 0.77 mm (p < 0.001), respectively. Restenosis rate was significantly reduced from 58.1% to 17.2% (p < 0.001), and the composite clinical endpoint was significantly reduced from 50.0% to 16.7% (p < 0.001), respectively.

Paclitaxel-coated balloon angioplasty is superior to balloon angioplasty alone for treatment of drug-eluting stent restenosis. (PEPCAD DES–Treatment of DES-In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting PTCA Catheter [PEPCAD-DES]; NCT00998439)

Randomized trials comparing filter-protected CAS with carotid endarterectomy revealed a higher periprocedural stroke rate after CAS. Proximal balloon occlusion may be more effective in preventing cerebral embolization during CAS than filters.

Patients undergoing CAS with cerebral embolic protection for internal carotid artery stenosis were randomly assigned to proximal balloon occlusion or filter protection. The primary endpoint was the incidence of new cerebral ischemic lesions assessed by diffusion-weighted magnetic resonance imaging. Secondary endpoints were the number and volume of new ischemic lesions and major adverse cardiovascular and cerebral events (MACCE).

Sixty-two consecutive patients (mean age: 71.7 years, 76.4% male) were randomized. Compared with filter protection (n = 31), proximal balloon occlusion (n = 31) resulted in a significant reduction in the incidence of new cerebral ischemic lesions (45.2% vs. 87.1%, p = 0.001). The number (median [range]: 2 [0 to 13] vs. 0 [0 to 4], p = 0.0001) and the volume (0.47 [0 to 2.4] cm³ vs. 0 [0 to 0.84] cm³, p = 0.0001) of new cerebral ischemic lesions were significantly reduced by proximal balloon occlusion. Lesions in the contralateral hemisphere were found in 29.0% and 6.5% of patients (filter vs. balloon occlusion, respectively, p = 0.047). The 30-day MACCE rate was 3.2% and 0% for filter versus balloon occlusion, respectively (p = NS).

In this randomized trial of patients undergoing CAS, proximal balloon occlusion as compared with filter protection significantly reduced the embolic load to the brain.

Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time.

A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine.

Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively.

Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481)

Recent studies have shown clear discrepancies between conventional 2-dimensional (2D) echocardiographic and CT measurements. In terms of aortic annular measurement for TAVR, such findings have lacked the outcome analysis required to inform clinical practice.

The discriminatory value of multiple CT annular measures for post-TAVR PV aortic regurgitation was compared with 2D echocardiographic measures. TAVR outcomes with device selection according to aortic annular sizing using a traditional 2D transesophageal echocardiography–guided or a novel CT-guided approach were also studied.

In receiver-operating characteristic models, cross-sectional CT parameters had the highest discriminatory value for post-TAVR PV regurgitation: This was with the area under the curve for [maximal cross-sectional diameter minus prosthesis size] of 0.82 (95% confidence interval: 0.69 to 0.94; p < 0.001) and that for [circumference-derived cross-sectional diameter minus prosthesis size] of 0.81 (95% confidence interval: 0.7 to 0.94; p < 0.001). In contrast, traditional echocardiographic measures were nondiscriminatory in relation to post-TAVR PV aortic regurgitation. The prospective application of a CT-guided annular sizing approach resulted in less PV aortic regurgitation of grade worse than mild after TAVR (7.5% vs. 21.9%; p = 0.045).

Our data lend strong support to 3-dimensional cross-sectional measures, using CT as the new gold standard for aortic annular evaluation for TAVR with the Edwards SAPIEN device.

Moderate or severe PAR after TAVR is associated with increased morbidity and mortality.

A total of 109 consecutive patients underwent MDCT pre-TAVR with a balloon expandable aortic valve. Differences between transcatheter heart valve (THV) size and MDCT measures of annular size (mean diameter, area, and circumference) were analyzed concerning prediction of PAR. Patients with THV malposition (n = 7) were excluded. In 50 patients, MDCT was repeated after TAVR to assess THV eccentricity (1 – short diameter/long diameter) and expansion (MDCT measured THV area/nominal THV area).

Moderate or severe PAR (13 of 102) was associated with THV undersizing (THV diameter – mean diameter = –0.7 ± 1.4 mm vs. 0.9 ± 1.8 mm for trivial to mild PAR, p < 0.01). The difference between THV size and MDCT annular size was predictive of PAR (mean diameter: area under the curve [AUC]: 0.81, 95% confidence interval [CI]: 0.68 to 0.88; area: AUC: 0.80, 95% CI: 0.65 to 0.90; circumference: AUC: 0.76, 95% CI: 0.59 to 0.91). Annular eccentricity was not associated with PAR (AUC: 0.58, 95% CI: 0.46 to 0.75). We found that 35.3% (36 of 102) and 45.1% (46 of 102) of THVs were undersized relative to the MDCT mean diameter and area, respectively. THV oversizing relative to the annular area was not associated with THV eccentricity or underexpansion (oversized vs. undersized THVs; expansion: 102.7 ± 5.3% vs. 106.1 ± 5.6%, p = 0.03; eccentricity: median: 1.7% [interquartile range: 1.4% to 3.0%] vs. 1.7% [interquartile range: 1.1% to 2.7%], p = 0.28).

MDCT-derived 3-dimensional aortic annular measurements are predictive of moderate or severe PAR following TAVR. Oversizing of THVs may reduce the risk of moderate or severe PAR.

MS, a proinflammatory state with hypertension, diabetes, dyslipidemia, and obesity, is presumed to be a close associate of AF.

In this prospective study, 1,496 consecutive patients with AF undergoing first ablation (29% with paroxysmal AF, 26% with persistent AF, and 45% with long-standing persistent AF) were classified into those with MS (group 1; n = 485) and those without MS (group 2; n = 1,011). Patients were followed for recurrence and QoL. The Medical Outcomes Study SF-36 Health Survey was used to assess QoL at baseline and 12 month after ablation.

After 21 ± 7 months of follow-up, 189 patients in group 1 (39%) and 319 in group 2 (32%) had arrhythmia recurrence (p = 0.005). When stratified by AF type, patients with nonparoxysmal AF in group 1 failed more frequently compared with those in group 2 (150 [46%] vs. 257 [35%], p = 0.002); no difference existed in the subgroup with paroxysmal AF (39 [25%] vs. 62 [22%], p = 0.295). Group 1 patients had significantly lower baseline scores on all SF-36 Health Survey subscales. At follow-up, both mental component summary (5.7 ± 2.5, p < 0.001) and physical component summary (9.1 ± 3.7, p < 0.001) scores improved in group 1, whereas only mental component summary scores (4.6 ± 2.8, p = 0.036) were improved in group 2. In the subgroup with nonparoxysmal AF, MS, sex, C-reactive protein ≥0.9 mg/dl, and white blood cell count were independent predictors of recurrence.

Baseline inflammatory markers and the presence of MS predicted higher recurrence after single-catheter ablation only in patients with nonparoxysmal AF. Additionally, significant improvements in QoL were observed in the post-ablation MS population.

Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel.

A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y₁₂ platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units.

Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units.

Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole. (A Study of the Effects of Multiple Doses of Dexlansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants; NCT00942175)

The EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) randomized controlled trial compared a less invasive catheter-based treatment for MR with surgery, providing an opportunity to assess the impact of AF on the outcomes of both the MitraClip procedure and surgical repair.

The study population included 264 patients with moderately severe or severe MR assessed by an independent echocardiographic core laboratory. Comparison of safety and effectiveness study endpoints at 30 days and 1 year were made using both intention-to-treat and per-protocol (cohort of patients with MR ≤2+ at discharge) analyses.

Pre-existing AF was present in 27% of patients. These patients were older, had more advanced disease, and were more likely to have a functional etiology. Similar reduction of MR to ≤2+ before discharge was achieved in patients with AF (83%) and in patients without AF (75%, p = 0.3). Freedom from death, mitral valve surgery for valve dysfunction, and MR >2+ was similar at 12 months for AF patients (64%) and for no-AF patients (61%, p = 0.3). At 12 months, MR reduction to <2+ was greater with surgery than with MitraClip, but there was no interaction between rhythm and MR reduction, and no difference in all-cause mortality between patients with and patients without AF.

Atrial fibrillation is associated with more advanced valvular disease and noncardiac comorbidities. However, acute procedural success, safety, and 1-year efficacy with MitraClip therapy is similar for patients with AF and without AF.

Single gene delivery of VEGF results in immature neovessels that ultimately regress. Endogenously, VEGF acts early to initiate angiogenesis, whereas Ang-1 acts later to induce vessel maturation. Timing VEGF and Ang-1 gene delivery to mimic endogenous angiogenesis might be more effective for sustained neovascularization.

Unilateral hindlimb ischemia was induced in 170 rats. Ultrasound-mediated gene delivery was performed with cationic microbubbles and plasmid deoxyribonucleic acid. Groups included VEGF at 2 weeks, VEGF/Ang-1 at 2 weeks, VEGF at 2 weeks with Ang-1 at 4 weeks, and untreated control subjects. At 2, 4, and 8 weeks after ligation, blood flow and flow reserve (FR) were assessed by contrast-enhanced ultrasound. Vascular density, organization, and supporting cell coverage were assessed by fluorescent microangiography and immunohistochemistry.

In untreated control subjects, blood flow, FR, and vessel density remained reduced. The VEGF delivery improved flow and vessel density at 4 weeks; however, FR remained low, supporting cell coverage was poor, and flow and vessel density regressed by 8 weeks. The VEGF/Ang-1 co-delivery marginally increased flow and vessel density; however, FR and supporting cell coverage improved. After temporally separated VEGF and Ang-1 delivery, blood flow, vessel density, and FR increased and were sustained, with improved pericyte coverage at 8 weeks.

In conclusion, temporally separated VEGF and Ang-1 gene therapy results in sustained and functional neovascularization.