BACKGROUND:

Most methods for assessing microvascular function are not readily available in the cardiac catheterization laboratory. The aim of this study is to determine whether the Index of Microcirculatory Resistance (IMR), measured at the time of primary percutaneous coronary intervention (PCI) is predictive of death and rehospitalization for heart failure.

METHODS AND RESULTS:

IMR was measured immediately after primary PCI in 253 patients from 3 institutions using a pressure-temperature sensor wire. The primary endpoint was the rate of death or rehospitalization for heart failure. The prognostic value of IMR was compared to coronary flow reserve, TIMI myocardial perfusion grade and clinical variables. The mean IMR was 40.3 ±32.5. Patients with an IMR>40 had a higher rate of the primary end point at one year compared to patients with an IMR≤40 (17.1% vs. 6.6%, p=0.027). During a median follow-up period of 2.8 years, 13.8% suffered the primary end point and 4.3% died. An IMR>40 was associated with an increased risk of death or rehospitalization for heart failure (HR 2.1, p=0.034) and of death alone (HR 3.95, p=0.028). On multivariate analysis, independent predictors of death or rehospitalization for heart failure included IMR>40 (HR 2.2, p=0.026), fractional flow reserve ≤0.8 (HR 3.24, p=0.008) and diabetes (HR 4.4, p<0.001). An IMR>40 was the only independent predictor of death alone (HR 4.3, p=0.02).

CONCLUSIONS:

An elevated IMR at the time of primary PCI predicts poor long term outcomes.

Epicardial coronary arteries are called conductance arteries(1) (or "macrocirculation") as their normal intrinsic resistance is close to zero(2) and their main function is to transport blood. They are visible at invasive coronary angiography with an unsurpassed spatial and temporal resolution. Coronary arteries smaller than 500 µm are usually referred to as resistance arteries (or "microvasculature") because, by continuously modifying their resistance, they match blood flow to the requirements of the myocytes. At coronary angiography the microvasculature appear at best in the form of myocardial blush, a term which says something about its inaccuracy. The microvasculature consists of extramyocardial prearterioles ranging from 100 to 500 µm and intramural arterioles smaller than 100 µm where the largest pressure drop takes place. The resistance of the microvasculature - and thus myocardial blood flow - is controlled by mechanisms(3) which are "multiple, interactive, cumulative and nonlinear"(4). Changes to one factor will affect many others. This renders the study of the regulation of myocardial blood flow difficult, even in animal models. This also makes it obvious that - as in most biological systems - "resting" conditions is an elusive concept, especially in humans, not to mention in awake patients in a catheterization laboratory.

Background-Little is known as to whether long-term outcomes of acute ischemic stroke (AIS) vary by race/ethnicity. Using the American Heart Association Get With The Guidelines-Stroke registry linked with Medicare claims data set, we examined whether 30-day and 1-year outcomes differed by race/ethnicity among older patients with AIS.Methods and Results-We analyzed 200 900 patients with AIS >65 years of age (170 694 non-Hispanic whites, 85.0%; 20 514 non-Hispanic blacks, 10.2%; 6632 Hispanics, 3.3%; 3060 non-Hispanic Asian Americans, 1.5%) from 926 US centers participating in the Get With The Guidelines-Stroke program from April 2003 through December 2008. Compared with whites, other racial and ethnic groups were on average younger and had a higher median score on the National Institutes of Health Stroke Scale. Whites had higher 30-day unadjusted mortality than other groups (white versus black versus Hispanic versus Asian=15.0% versus 9.9% versus 11.9% versus 11.1%, respectively). Whites also had higher 1-year unadjusted mortality (31.7% versus 28.6% versus 28.1% versus 23.9%, respectively) but lower 1-year unadjusted all-cause rehospitalization (54.7% versus 62.5% versus 60.0% versus 48.6%, respectively). After risk adjustment, Asian American patients with AIS had lower 30-day and 1-year mortality than white, black, and Hispanic patients. Relative to whites, black and Hispanic patients had higher adjusted 1-year all-cause rehospitalization (black: adjusted odds ratio, 1.28 [95% confidence interval, 1.21-1.37]; Hispanic: adjusted odds ratio, 1.22 [95% confidence interval, 1.11-1.35]), whereas Asian patients had lower odds (adjusted odds ratio, 0.83 [95% confidence interval, 0.74-0.94]).Conclusions-Among older Medicare beneficiaries with AIS, there were significant differences in long-term outcomes by race/ethnicity, even after adjustment for stroke severity, other prognostic variables, and hospital characteristics.

Background-Cardiologists are distributed unevenly across regions of the United States. It is unknown whether patients in regions with fewer cardiologists have worse outcomes after hospitalization for acute myocardial infarction (AMI) or heart failure (HF).Methods and Results-Using Medicare administrative claims data from 2010, we examined the relationship between regional density of cardiologists and risk of death after hospitalization for AMI and HF using hospitalizations for pneumonia as a comparison. We defined density as the number of cardiologists divided by population aged≥65 years within hospital referral regions, categorized into quintiles. Among 171 126 admissions for AMI, 352 853 admissions for HF, and 343 053 admissions for pneumonia, we tested associations between density of cardiologists and 30-day and 1-year mortality for each condition. We used 2-level hierarchical logistic regression models that adjusted for characteristics of patients and hospital referral regions. Patients hospitalized for AMI (odds ratios [OR], 1.13; 95% confidence interval [CI], 1.06-1.21) and HF (OR, 1.19; 95% CI, 1.12-1.27) in the lowest quintile of density had modestly higher 30-day mortality risk compared with patients in the highest quintile, unlike patients hospitalized for pneumonia (OR, 1.02; 95% CI, 0.96-1.09). Patients hospitalized for AMI (OR, 1.06; 95% CI, 1.00-1.12) and HF (OR, 1.09; 95% CI, 1.04-1.13) in the lowest quintile had slightly higher 1-year mortality risk, unlike patients hospitalized for pneumonia (OR, 1.00; 95% CI, 0.95-1.05).Conclusions-Patients hospitalized for AMI and HF in regions with a low density of cardiologists experienced modestly higher 30-day and 1-year mortality risk, unlike patients with pneumonia.

BACKGROUND:

-Multiple studies have demonstrated strong associations between cardiorespiratory fitness and lower cardiovascular disease mortality. In contrast, little is known about associations of fitness with non-fatal cardiovascular events.

METHODS AND RESULTS:

-Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20,642 participants (21% women) with fitness measured at mean age 49 years and who survived to receive Medicare coverage from 1999 to 2009. Fitness was categorized into age- and sex-specific quintiles (Q) according to Balke protocol treadmill time with Q1 as low fitness. Fitness was also estimated in metabolic equivalents according to treadmill time. Associations between midlife fitness and hospitalizations for heart failure and acute myocardial infarction after age 65 were assessed by applying a proportional hazards model to the multivariate failure time data. After 133,514 person-years of Medicare follow-up, we observed 1,051 hospitalizations for heart failure and 832 hospitalizations for acute myocardial infarction. Compared to high fitness (Q4-5), low fitness (Q1) was associated with a higher rate of heart failure hospitalization (14.3% vs. 4.2%) and hospitalization for myocardial infarction (9.7% vs. 4.5%). After multivariable adjustment for baseline age, blood pressure, diabetes, body mass index, smoking status and total cholesterol, a 1 unit greater fitness level in metabolic equivalents (METs) achieved in midlife was associated with approximately a 20% lower risk for heart failure hospitalization after age 65 [Men, hazard ratio (95% confidence intervals): 0.79 (0.75-0.83), p<0.001; Women: 0.81 (0.68-0.96), P=0.01] but just a 10% lower risk for acute myocardial infarction in men [0.91 (0.87-0.95), p< 0.001] and no association in women [0.97 (0.83-1.13), p=0.68].

CONCLUSIONS:

-Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age.

BACKGROUND:

-Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive.

METHODS AND RESULTS:

-We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with "genotype-negative/phenotype-positive" LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2's PEST domain.

CONCLUSIONS:

-This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.

BACKGROUND:

-Loss-of-function mutations in CHD7 cause CHARGE syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 66%-92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development.

METHODS AND RESULTS:

-We have collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1,007 equally classified non-syndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects (AVSD) and conotruncal heart defects are overrepresented. Gender did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (chi-square, p<0.001).

CONCLUSIONS:

-CHD7 plays a very important role in cardiac development because we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and AVSDs are overrepresented in patients with CHD7 mutations compared to patients with non-syndromic heart defects.

BACKGROUND:

-Two endophenotypes of arterial calcification, calcification on arterial wall and calcification in atherosclerotic plaques, are associated with different types of cardiovascular events. Mgp-deficient mice showed MGP is strongly associated with calcification on arterial wall without atherosclerotic plaques, and MGP variants were not significantly associated with myocardial infarction. MGP may play different roles in the two endophenotypes.

METHODS AND RESULTS:

-We analyzed the associations of MGP variants rs4236, rs1800801, and rs1800802 with the two endophenotypes determined by multi-detector computed tomography angiography. Total 585 with calcification on coronary artery wall, 675 with calcification in coronary atherosclerotic plaques, 454 with calcification on aortic wall, and 725 controls were enrolled. After Bonferroni correction, rs4236 and rs1800801 were still associated with calcification on arterial wall, the odds ratios were 0.708(95%CI, 0.540-0.928) for rs4236 and 0.652(95%CI, 0.479-0.888) for rs1800801 in coronary artery wall calcification, and 0.699(95%CI, 0.525-0.931) for rs4236 and 0.650(95%CI, 0.467-0.905) for rs1800801 in aortic wall calcification, respectively. The variants were correlated with calcification severity by ln(CAC Agatston score+1) in coronary artery wall calcification, but not in atherosclerotic plaque calcification. In accordance with their associations with calcification on arterial wall, rs4236C and rs1800801A were associated with higher MGP plasma levels while rs1800802C with lower MGP levels in normal controls. Due to the role of calcification in plaque vulnerability, their associations with acute myocardial infarction were also determined in 771 controls and 752 patients, no association was found.

CONCLUSIONS:

-MGP genetic variants showed association with calcification on arterial wall but not calcification in atherosclerotic plaques.

BACKGROUND:

Clinicians need to identify coronary artery disease patients for whom the benefits of high-dose versus usual-dose statin therapy outweigh potential harm. We therefore aimed to develop and validate a model for prediction of the incremental treatment effect of high-dose statins for individual patients in terms of reduction of 5-year absolute risk for myocardial infarction, stroke, coronary death or cardiac resuscitation.

METHODS AND RESULTS:

Based on data from the Treating to New Targets trial (TNT; n=10,001), a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (i.e. atorvastatin 80mg or 10mg). External validation in the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL; n=8,888) confirmed adequate goodness-of-fit and calibration, but moderate discrimination (C-statistic 0.63; 95%CI 0.62-0.65). Still, among participants of both trials combined, the model identified a group of 11.7% whose predicted 5-year number needed to treat (NNT) was 25 or lower and a group of 41.9% whose predicted NNT was 50 or higher. A decision curve shows that making treatment decisions on the basis of predictions using our model may improve net benefit.

CONCLUSIONS:

Estimation of the incremental treatment effect of high-dose versus usual-dose statin therapy in individual coronary artery disease patients enables selection of high-risk patients that benefit most from more aggressive therapy. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifiers: NCT00327691 and NCT00159835.

BACKGROUND:

Several randomized clinical trials (RCTs) support the use of coronary artery bypass grafting (CABG) for patients with unprotected left main coronary artery disease (ULMCAD). Studies suggesting the equivalence of percutaneous coronary intervention (PCI) with CABG for this indication indirectly support the 2011 American College of Cardiology Foundation/American Heart Association Class IIa recommendation for PCI to improve survival in patients with ULMCAD. We tested whether Bayesian approaches uphold the new recommendation.

METHODS AND RESULTS:

We performed a Bayesian cross-design and network meta-analysis of 12 studies (4 RCTs and 8 observational studies) comparing CABG with PCI (N=4,574 patients) and of 7 studies (2 RCTs and 5 observational studies) comparing CABG with medical therapy (MT, N=3,224 patients). The odds ratios (ORs) of 1-year mortality after PCI compared with CABG using Bayesian cross-design meta-analysis were not different among RCTs (OR 0.99, 95% Bayesian credible interval [BCI] 0.67-1.43), matched cohort studies (OR 1.10, 95% BCI 0.76-1.73), and other types of cohort studies (OR 0.93, 95% BCI 0.58-1.35). A network meta-analysis suggested that MT is associated with higher 1-year mortality than the use of PCI for patients with ULMCAD (OR 3.22, 95% BCI 1.96-5.30).

CONCLUSIONS:

Bayesian methods support the current guidelines, which were based on traditional statistical methods and have proposed that PCI like CABG, as compared with MT, improves survival for patients with ULMCAD. An integrated approach using both direct and indirect evidence may yield new insights to enhance the translation of clinical-trial data into practice.