HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.

Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.

Development and calibration of a new point-of-care test for the determination of NT-proBNP in whole blood.

A new point-of-care test for the determination of NT-proBNP in whole blood was developed based on the existing gold-label rapid immunoassay technology of the Roche Cardiac reader system. The novel gold-labelled monoclonal antibody recognizes NT-proBNP at amino acid sequence 27 to 31, the biotinylated polyclonal antibody recognizes sequence 39 to 50. In a model assay based upon the reference method Elecsys proBNP and with an R & D lot of the point-of-care test, this newly selected and developed combination of antibodies showed a very good correlation with the standard Elecsys proBNP assay with correlations of 0.96 or 0.94, respectively. The test was calibrated according to the existing masterlot concept of the Roche CARDIAC tests with Elecsys proBNP as a reference. In a preliminary method comparison with Elecsys proBNP the accuracy of the calibration was confirmed; the bias was between 1 and 6%. Possible reasons of approximately 1% outliers (> +/- 100%) were discussed.

Cardiac troponin T for prediction of short- and long-term morbidity and mortality after elective open heart surgery.

BACKGROUND: Increased cardiac troponins in blood are observed after virtually every open heart surgery, indicating perioperative myocardial cell injury. We sought to determine the optimum time point for blood sampling and the respective cutoff value of cardiac troponin T (cTnT) for risk assessment in patients undergoing cardiac surgery. METHODS: In a series of 204 patients undergoing scheduled open heart surgery, mainly for coronary artery bypass grafting (n = 132) or valve repair (n = 27), cTnT concentrations were measured before and 4 and 8 h after cross-clamping and then daily for 7 days. Individual risk was assessed by use of the Cleveland Clinic Foundation Risk score and intraoperative risk indicators such as duration of cardiopulmonary bypass, cross-clamping, and perioperative release of cardiac markers. Patients were followed for 28 months. RESULTS: Cardiac mortality, all-cause mortality rates, and rates of nonfatal acute myocardial infarction (AMI) at 28 months were 6.9%, 8.8%, and 6.8%, respectively. cTnT was higher in patients with Q-wave AMI or postoperative heart failure requiring inotropic support, and in nonsurvivors. The ROC curve revealed a cTnT > or = 0.46 microg/L at 48 h as the optimum discriminator for long-term cardiac mortality. Stepwise logistic regression identified higher Cleveland Clinic Risk Score [odds ratio (OR) = 2.6 per point], cross-clamp time >65 min (OR = 6.6), and cTnT (OR = 4.9) as significant and independent predictors of long-term cardiac mortality. CONCLUSIONS: A single postoperative cTnT measurement can be used to estimate myocardial cell injury that impacts long-term survival after open heart surgery. It adds independently to established risk indicators.

Prognostic significance of admission cardiac troponin T in patients treated successfully with direct percutaneous interventions for acute ST-segment elevation myocardial infarction.

BACKGROUND: Cardiac troponin T (cTnT) elevations at admission indicate a high-risk subgroup of patients with acute ST-segment elevation myocardial infarction, possibly due to a higher failure rate of reperfusion therapies. OBJECTIVE: We sought to determine the predictive role of admission cTnT in patients with ST-segment elevation myocardial infarction undergoing successful direct percutaneous coronary intervention. METHODS: A total of 218 consecutive patients with ST-segment elevation myocardial infarction were enrolled. Patients were stratified according to admission cTnT and infarct location. They were followed prospectively for short-term and long-term outcomes. RESULTS A positive cTnT (47.7%) was associated with higher mortality rates at 30 days (14.4% vs. 3.5%, p = .003) and 12 months (17.3% vs. 4.4%, p =.007). cTnT allowed discrimination of patients at high and low risk for cardiac death at 30 days and 12 months among anterior (19.2% vs. 7.9%, p = .19, and 25% vs. 13.2%, p = .22, respectively) and, more impressively, among nonanterior acute myocardial infarction (9.6% vs. 1.3%, p = .04, and 11.5% vs. 1.3%, p = .017, respectively). In multivariate analysis, older age, anterior infarct location, and depressed left ventricular function were the most potent independent predictors of future risk. Among clinical variables available at admission, cTnT indicated independently a higher risk of cardiac death (odds ratio, 3.1 [1.07-9.01], p =.038). This increased risk associated with a positive cTnT was almost independent of time delays from onset of symptoms to admission (3.8 vs. 2.3 hrs in cTnT-positive vs. cTnT-negative patients, p <.001). CONCLUSIONS: Admission cTnT is a strong predictor of future cardiac risk in patients with ST-segment elevation myocardial infarction, despite successful restoration of Thrombolysis in Myocardial Infarction grade 3 coronary flow by direct percutaneous coronary intervention.