Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. METHODS AND RESULTS: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. CONCLUSIONS: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.

Impact of electrocardiographic interpretability on outcome in patients referred for stress testing.

BACKGROUND: There is limited insight into the association of electrocardiographic interpretability with outcome in patients referred for stress testing. METHODS: Exercise echocardiography was performed in 8226 patients with known or suspected coronary artery disease. Electrocardiograms were considered uninterpretable in the presence of left bundle-branch block (LBBB), left ventricular hypertrophy (LVH) with strain, repolarization abnormalities because of digitalis therapy, ventricular paced rhythm, preexcitation or ST depression ≥ 0.1 mV because of other causes. End points were all-cause mortality, cardiac death and hard cardiac events (i.e. cardiac death or nonfatal myocardial infarction). RESULTS: A total of 2450 patients had uninterpretable electrocardiograms. During a follow-up period of 4.1 ± 3.5 years, there were 1011 deaths (of which 478 were cardiac deaths) and 1069 patients experienced a hard cardiac event. The 5-year rates of death, cardiac death and hard cardiac events were, respectively, 18.7%, 10.9% and 18.8% in patients with uninterpretable ECGs, compared with 9.5%, 4.1% and 10.9% in those with interpretable ECGs (P < 0.001). After covariate adjustment, lack of ECG interpretability remained an independent predictor of all-cause mortality (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.08-1.44, P = 0.002), cardiac death (HR 1.63, 95% CI 1.32-2.01, P < 0.001) and hard cardiac events (HR 1.28, 95% CI 1.11-1.47, P < 0.001). When the specific ECG abnormalities were included as covariates, LBBB, LVH and digitalis therapy remained predictors of cardiac death; LBBB and LVH were predictors of hard cardiac events, and LVH remained predictive of all-cause mortality. CONCLUSION: Uninterpretable ECGs portend a worse prognosis in patients referred for stress testing.

Cardiotrophin-1 plasma levels are associated with the severity of hypertrophy in hypertrophic cardiomyopathy.

AIMS: Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spirito's LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm). CONCLUSIONS: These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.

Safety and efficacy of femoral vascular closure devices in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction.

BACKGROUND: The use of vascular closure devices (VCDs) for the reduction of access site complications following percutaneous coronary intervention (PCI) remains controversial. Patients undergoing primary PCI for acute ST-segment elevation myocardial infarction (STEMI) are at high risk of femoral artery complications. A lack of information exists regarding the use of VCDs in this group of patients because they have been routinely excluded from randomized trials. This study sought to evaluate the safety and efficacy of the routine use of VCDs after primary PCI. METHODS: A total of 558 consecutive patients undergoing primary PCI for STEMI via femoral route were studied for in-hospital outcomes through a prospective registry from January 2003 to December 2008. The primary end point was the presence of major vascular complication (MVC) defined as a composite of fatal access site bleeding, access site complication requiring interventional or surgical correction, or access site bleeding with ≥3 g/dL drop in hemoglobin or requiring blood transfusion. RESULTS: Of the total patients, 464 (83.2%) received a VCD; and manual compression was used in 94 patients (16.8%). Major vascular complication occurred in 5.2% of patients. The risk of MVC was significantly lower with VCDs compared with manual compression (4.3% vs 9.6%, P = .036). Multivariable logistic regression analysis determined that VCD use remained an independent predictor of lower rate of MVC (odds ratio 0.38, 95% CI 0.17-0.91). CONCLUSIONS: The use of VCDs in patients undergoing primary PCI for STEMI is safe and is associated with lower rates of MVC compared with manual compression.

Left atrial size and risk for all-cause mortality and ischemic stroke.

BACKGROUND: Limited data are available on the relation between left atrial size and outcome among patients referred for clinically indicated echocardiograms. Our aim was to assess the association of left atrial size with all-cause mortality and ischemic stroke in a large cohort of patients referred for echocardiography. METHODS: Left atrial diameter was measured in 52 639 patients aged 18 years or older (mean age 61.8 [standard deviation (SD) 16.3] years; 52.9% men) who underwent a first transthoracic echocardiogram for clinical reasons at our institution between April 1990 and March 2008. The outcomes were all-cause mortality and nonfatal ischemic stroke. RESULTS: Based on the criteria of the American Society of Echocardiography, 50.4% of the patients had no left atrial enlargement, whereas 24.5% had mild, 13.3% had moderate and 11.7% had severe left atrial enlargement. Over a mean follow-up period of 5.5 (SD 4.1) years, 12 527 patients died, and 2314 patients had a nonfatal ischemic stroke. Cumulative 10-year survival was 73.7% among patients with normal left atrial size, 62.5% among those with mild enlargement, 54.8% among those with moderate enlargement and 45% among those with severe enlargement (p < 0.001). After adjustment in multivariable Cox proportional hazard analysis, left atrial diameter remained a predictor of all-cause mortality in both sexes (hazard ratio [HR] per 1-cm increment in left atrial size 1.17, 95% confidence interval [CI] 1.12-1.22, p < 0.001 in women, and HR 1.09, 95% CI 1.05-1.13, p < 0.001 in men) and of ischemic stroke in women (HR 1.25, 95% CI 1.14-1.37, p < 0.001). INTERPRETATION: Left atrial diameter has a graded and independent association with all-cause mortality in both sexes and with ischemic stroke in women.

Prognostic value of peak and post-exercise treadmill exercise echocardiography in patients with known or suspected coronary artery disease.

AIMS: Although peak may have higher sensitivity than post-treadmill exercise echocardiography (EE) for the detection of coronary artery disease (CAD), its prognostic value remains unknown. We sought to assess the relative values of peak and post-EE for predicting outcome in patients with known/suspected CAD. METHODS AND RESULTS: We studied 2947 patients who underwent EE. Wall motion score index (WMSI) was evaluated at rest, peak, and post-exercise. Ischaemia was defined as the development of new or worsening wall motion abnormalities with exercise. Separate analyses for all-cause mortality and major cardiac events (MACE) were performed. Ischaemia developed in 544 patients (18.5%). Among them, ischaemia was detected only at peak exercise in 124 patients (23%), whereas 414 (76%) had ischaemia at peak plus post-exercise imaging and six patients (1%) had ischaemia only at post-exercise. During follow-up, 164 patients died. The 5-year mortality rate was 3.5% in patients without ischaemia, 15.3% in patients with peak ischaemia alone, and 14% in patients with post-exercise ischaemia (P < 0.001 normal vs. ischaemic groups). In the multivariate analysis, post-exercise WMSI was an independent predictor of MACE [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.09-2.19, P = 0.02]. Peak exercise WMSI was an independent predictor of MACE (HR 2.19, 95% CI 1.30-3.69, P = 0.003) and mortality (HR 1.58, 95% CI 1.07-2.35, P = 0.02). The addition of peak EE results to clinical, resting echocardiography, exercise variables, and post-EE provided incremental prognostic information for MACE (P = 0.04) and mortality (P = 0.04). CONCLUSION: Peak treadmill EE provides significant incremental information over post-EE for predicting outcome in patients with known or suspected CAD.

Prognostic value of exercise echocardiography in patients with left ventricular systolic dysfunction and known or suspected coronary artery disease.

BACKGROUND: The prognostic value of exercise echocardiography (ExE) in patients with left ventricular systolic dysfunction (LVSD) has not been characterized. We sought to assess the value of ExE for predicting outcome in patients with LVSD and known/suspected coronary artery disease. METHODS: This study is a retrospective analysis of a prospectively collected database of 1,107 patients who underwent treadmill ExE and had resting LVSD (left ventricular ejection fraction <50%). Ischemia was defined as an increase in wall motion score index from rest to exercise. The end points were all-cause mortality and major cardiac events (MACE). RESULTS: Overall, 494 patients (44.6%) developed new or worsening wall motion abnormalities. During a mean follow-up of 4.1 +/- 3.4 years, 301 patients died and 166 had a MACE. In patients with mild LVSD, the 5-year mortality rate was 8.8% in those without ischemia and 21% in those with ischemia (P < .001). For patients with moderate LVSD without ischemia, the 5-year mortality rate was 18.3%, whereas it was 29.2% when ischemia was present (P = .009). In those with severe LVSD, the 5-year mortality rate was 23.9% without ischemia and 35.7% with ischemia (P = .03). In the multivariate analysis, increase in wall motion score index was an independent predictor of mortality (hazard ratio 2.25, 95% CI 1.26-2.06, P = .001) and MACE (hazard ratio 2.60, 98% CI 1.34-5.04, P = .005). The addition of the ExE results to clinical, resting echocardiography and exercise variables provided significant incremental prognostic information for predicting mortality (P = .001) and MACE (P = .005). CONCLUSIONS: The ExE provides significant information for predicting outcome in patients with LVSD and known/suspected coronary artery disease.

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy.

BACKGROUND: MyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients. METHODS: Screening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families. RESULTS: 16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9]. CONCLUSIONS: Mutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

Value of exercise echocardiography for predicting mortality in elderly patients.

BACKGROUND: Elderly patients with suspected or known coronary artery disease are often referred for pharmacological stress testing. Data on the value of exercise echocardiography (ExEcho) for predicting outcome (particularly all-cause mortality) in these patients are scarce. METHODS: Peak treadmill ExEcho was performed in 2159 patients ≥ 70 years of age with known or suspected coronary artery disease. Left ventricular wall motion was evaluated at baseline and with exercise, and the increase in wall motion score index from rest to peak exercise (ΔWMSI) was calculated. Ischaemia was diagnosed when new or worsening wall motion abnormalities developed with exercise. The end points were all-cause mortality and major cardiac events (cardiac death or myocardial infarction). RESULTS: Ischaemia developed in 844 patients (38·6%) during exercise. Over a mean follow-up of 3·5 ± 3·1 years, 439 deaths occurred. The cumulative 5-year mortality rate was 29·3% in patients with ischaemia versus 16·8% in those without ischaemia (P < 0·001). After covariate adjustment, ΔWMSI remained an independent predictor of mortality [hazard ratio (HR) 2·37, 95% confidence interval (CI) 1·66-3·39, P < 0·001] and major cardiac events (HR 3·48, 95% CI 2·11-5·74, P < 0·001). These results remained significant even in patients with chronotropic incompetence. When added to a model with clinical, resting echocardiographic and exercise electrocardiogram variables, ExEcho results provided incremental value for the prediction of both end points (P < 0·001). CONCLUSIONS: ExEcho is feasible in elderly patients with suspected or known coronary artery disease and provides useful information for risk stratification in these patients.

The effect of post-discharge educational intervention on patients in achieving objectives in modifiable risk factors six months after discharge following an episode of acute coronary syndrome, (CAM-2 Project): a randomized controlled trial.

OBJECTIVES: We investigated whether an intervention mainly consisting of a signed agreement between patient and physician on the objectives to be reached, improves reaching these secondary prevention objectives in modifiable cardiovascular risk factors six-months after discharge following an acute coronary syndrome. BACKGROUND: There is room to improve mid-term adherence to clinical guidelines' recommendations in coronary heart disease secondary prevention, specially non-pharmacological ones, often neglected. METHODS: In CAM-2, patients discharged after an acute coronary syndrome were randomly assigned to the intervention or the usual care group. The primary outcome was reaching therapeutic objectives in various secondary prevention variables: smoking, obesity, blood lipids, blood pressure control, exercise and taking of medication. RESULTS: 1757 patients were recruited in 64 hospitals and 1510 (762 in the intervention and 748 in the control group) attended the six-months follow-up visit. After adjustment for potentially important variables, there were, between the intervention and control group, differences in the mean reduction of body mass index (0.5 vs. 0.2; p < 0.001) and waist circumference (1.6 cm vs. 0.6 cm; p = 0.05), proportion of patients who exercise regularly and those with total cholesterol below 175 mg/dl (64.7% vs. 56.5%; p = 0.001). The reported intake of medications was high in both groups for all the drugs considered with no differences except for statins (98.1% vs. 95.9%; p = 0.029). CONCLUSIONS: At least in the short term, lifestyle changes among coronary heart disease patients are achievable by intensifying the responsibility of the patient himself by means of a simple and feasible intervention.