Although exercise echocardiography may assess left ventricular (LV) function and LV outflow tract (LVOT) gradients during exercise in patients with hypertrophic cardiomyopathy (HCM), its value for ...predicting outcomes has not been studied. The aim of this study was to determine whether exercise echocardiography predicts outcomes in patients with HCM.
LV function and LVOT gradients were evaluated during exercise echocardiography in 239 patients with HCM.
Sixty patients (25.1%) had LVOT obstruction at rest, and 43 (18%) developed exercise-induced LVOT obstruction. The mean resting LV ejection fraction was 69 ± 9%, and the mean resting wall motion score index was 1.00 ± 0.06. Wall motion abnormalities during exercise were seen in 19 patients (7.9%). During follow-up of 4.1 ± 2.6 years, 19 patients had hard events (cardiac death, cardiac transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, or hospitalization for heart failure), and 41 patients had composite end points of hard or soft events (including atrial fibrillation and syncope). Exercise wall motion abnormalities occurred in 31.5% of patients with hard events compared with 5.9% of patients without hard events (P < .001). After adjustment, LV wall thickness (hazard ratio HR, 1.13; 95% confidence interval CI, 1.05-1.21; P = .002), resting wall motion score index (HR, 21.59; 95% CI, 2.38-196.1, P = .006), and metabolic equivalents (HR, 0.74; 95% CI, 0.63-0.88; P = .001) remained independent predictors of hard events. Change in wall motion score index was also independently associated with hard events (HR, 52.30; 95% CI, 3.81-718.5; P = .003) and with the composite end point (HR, 39.51; 95% CI, 3.79-412.4; P = .002). LVOT obstruction was not associated with either end point.
Assessment of exercise capacity and LV systolic function during exercise echocardiography may have a role in risk stratification of patients with HCM.
Objectives We sought to assess the value of exercise echocardiography (EE) for predicting outcome in patients with known or suspected coronary artery disease and normal exercise electrocardiogram ...(ECG) testing. Background The prognostic value of EE in patients with normal exercise ECG testing has not been characterized. Methods We studied 4,004 consecutive patients (2,358 men, mean age ± SD 59.6 ± 12.5 years) with interpretable ECG who underwent treadmill EE and did not develop chest pain or ischemic ECG abnormalities during the tests. Wall motion score index (WMSI) was evaluated at rest and with exercise, and the difference (ΔWMSI) was calculated. Ischemia was defined as the development of new or worsening wall motion abnormalities with exercise. End points were all-cause mortality and major cardiac events (MACE). Results Overall, 669 patients (16.7%) developed ischemia with exercise. During a mean follow-up of 4.5 ± 3.4 years, 313 patients died, and 183 patients had a MACE before any revascularization procedure. The 5-year mortality and MACE rates were 6.4% and 4.2% in patients without ischemia versus 12.1% and 10.1% in those with ischemia, respectively (p < 0.001). In the multivariate analysis, ΔWMSI remained an independent predictor of mortality (hazard ratio HR: 2.73, 95% confidence interval CI: 1.40 to 5.32, p = 0.003) and MACE (HR: 3.59, 95% CI: 1.42 to 9.07, p = 0.007). The addition of the EE results to the clinical, resting echocardiographic and exercise hemodynamic data significantly increased the global chi-square of the models for the prediction of mortality (p = 0.005) and MACE (p = 0.009). Conclusions The use of EE provides significant prognostic information for predicting mortality and MACE in patients with interpretable ECG and normal exercise ECG testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Objective Evaluation of renal function (RF) is important for management of patients with non-ST elevation acute coronary syndrome (NSTE-ACS). Cystatin C, a sensitive marker of RF, appears to ...be also a marker of cardiovascular risk. Little is known regarding its predictive role in NSTE-ACS patients. Methods We assessed 525 patients taking part in the “Systemic Inflammation Evaluation in patients with NSTE-ACS” (SIESTA) study. Patients were subdivided in quartiles according to cystatin C plasma concentrations (mg/L), i.e., Q1 < 0.81; Q2 = 0.81–0.92; Q3 = 0.93–1.10; Q4 ≥ 1.11. Glomerular filtration rate (eGFR) was estimated using the modification of diet in renal disease (MDRD) equation. The study end-point was the composite of cardiac death, non-fatal myocardial infarction and unstable angina at 1-year follow up. Results Few patients (0.8%) had severely impaired RF (MDRD < 30 ml/min/1.73 m2 ). 157 patients reached (30%) the study end-point. Patients in Q3 and Q4 showed a higher cumulative probability of cardiac events compared to patients in the lowest quartile. On multivariable analysis, patients in Q3 and Q4 had an increased incidence of cardiac events (adjusted HR = 1.57 95%CI 1.04–2.49; p = 0.036). Patients with TIMI risk score ≥3 or in-hospital heart failure were also at higher risk for acute cardiac events. Conventional markers of RF, i.e., serum creatinine and eGRF, were not predictors for the study end-point. Conclusions Increased levels of cystatin C were an independent predictor of cardiac events at 1-year follow up in this contemporary series of Mediterranean patients with NSTE-ACS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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. (Circ J 2013; 77: 2358–2365)
We identified 2 compound heterozygous mutations (p.D1690N and p.G1748D) in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) in a proband diagnosed with Brugada syndrome type 1. Furthermore, in ...the allele encoding the p.D1690N mutation, the p.H558R polymorphism was also detected.
The purpose of this study was to analyze the functional properties of the mutated channels as well as the putative modulator effects produced by the presence of the polymorphism.
Wild-type and mutated human Nav1.5 channels were expressed in Chinese hamster ovary cells and recorded using whole-cell patch-clamp technique.
Separately, both p.D1690N and p.G1748D mutations produced a marked reduction in peak Na(+) current density (>80%), mainly due to their limited trafficking toward the membrane. Furthermore, p.G1748D mutation profoundly affected channel gating. Both p.D1690N and p.G1748D produced a marked dominant negative effect when cotransfected with either wild-type or p.H558R channels. Conversely, p.H558R was able to rescue defective trafficking of p.D1690N channels toward the membrane when both polymorphism and mutation were in the same construct. Surprisingly, cotransfection with p.D1690N, either alone or together with the polymorphism (p.H558R-D1690N), completely restored the profound gating defects exhibited by p.G1748D channels but only slightly rescued their trafficking.
Our results add further support to the hypothesis that Nav1.5 subunits interact among them before trafficking toward the membrane and suggest that a missense mutation can "rescue" the defective gating produced by another missense mutation.
A high frequency of venous thromboembolism (VTE) has been observed after lung, kidney, and liver transplantation. However, data about the incidence of this complication among heart transplant (HT) ...recipients are lacking.
We analyzed the incidence, recurrence, and predisposing factors of VTE in a single-center cohort of 635 patients who underwent HT from April 1991 to April 2013. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were considered as VTE episodes.
During a median post-transplant follow-up of 8.4 years, 62 VTE episodes occurred in 54 patients (8.5%). Incidence rates of VTE, DVT, and PE were, respectively, 12.7 (95% confidence interval CI, 9.7-16.3), 8.4 (95% CI, 6.0-11.4), and 7.0 (95% CI 4.8-9.7) episodes per 1,000 patient-years. Incidence rates of VTE during the first post-transplant year and beyond were, respectively, 45.1 (95% CI, 28.9-67.1) and 8.7 (95% CI 6.2-11.2) episodes per 1,000 patient-years. The incidence rate of VTE recurrence after a first VTE episode was 30.5 (95% CI, 13.2-60.2) episodes per 1,000 patient-years. By means of multivariable Cox regression, chronic renal dysfunction, older age, obesity, and the use of mammalian target of rapamycin inhibitors were identified as independent risk factors for VTE among HT recipients.
VTE is a frequent complication after HT, mainly during the first post-operative year. In view of a high recurrence rate, long-term anti-coagulation should be considered in HT recipients who experience a first VTE episode.
Supine bicycle exercise (SBE) echocardiography and treadmill exercise (TME) echocardiography have been used for evaluation of coronary artery disease (CAD). Although peak imaging acquisition has been ...considered unfeasible with TME, higher sensitivity for the detection of CAD has been recently found with this method compared with post-TME echocardiography. However, peak TME echocardiography has not been previously compared with the more standardized peak SBE echocardiography. The aim of this study was to compare peak TME echocardiography, peak SBE echocardiography, and post-TME echocardiography for the detection of CAD.
A series of 116 patients (mean age, 61 ± 10 years) referred for evaluation of CAD underwent SBE (starting at 25 W, with 25-W increments every 2-3 min) and TME with peak and postexercise imaging acquisition, in a random sequence. Digitized images at baseline, at peak TME, after TME, and at peak SBE were interpreted in a random and blinded fashion. All patients underwent coronary angiography.
Maximal heart rate was higher during TME, whereas systolic blood pressure was higher during SBE, resulting in similar rate-pressure products. On quantitative angiography, 75 patients had coronary stenosis (≥50%). In these patients, wall motion score indexes at maximal exercise were higher at peak TME (median, 1.45; interquartile range IQR, 1.13-1.75) than at peak SBE (median, 1.25; IQR, 1.0-1.56) or after TME (median, 1.13; IQR, 1.0-1.38) (P = .002 between peak TME and peak SBE imaging, P < .001 between post-TME imaging and the other modalities). The extent of myocardial ischemia (number of ischemic segments) was also higher during peak TME (median, 5; IQR, 2-12) compared with peak SBE (median, 3; IQR, 0-8) or after TME (median, 2; IQR, 0-4) (P < .001 between peak TME and peak SBE imaging, P < .001 between post-TME imaging and the other modalities). ST-segment changes in patients with CAD and normal baseline ST segments were higher during TME (median, 1 mm IQR, 0-1.9 mm vs 0 mm IQR, 0-1.5 mm; P = .006). The sensitivity of peak TME, peak SBE, and post-TME echocardiography for CAD was 84%, 75%, and 60% (P = .001 between post-TME and peak TME echocardiography, P = .055 between post-TME and peak SBE echocardiography), with specificity of 63%, 80%, and 78%, respectively (P = NS) and accuracy of 77%, 77%, and 66%, respectively (P = NS). Peak TME echocardiography diagnosed multivessel disease in 27 of the 40 patients with stenoses in more than one coronary artery, in contrast to 17 patients with peak SBE imaging and 12 with post-TME imaging (P < .05 between peak TME imaging and the other modalities). Image quality was similar with the three techniques. The duration of the test was longer with SBE echocardiography (9.5 ± 3.8 vs 7.6 ± 2.5 min, P < .001).
During TME and SBE, patients achieve similar double products. Ischemia is more extensive and frequent with peak TME, which makes peak TME a more valuable exercise echocardiographic modality to increase sensitivity. However, peak SBE should be preferred to TME if the latter is performed with postexercise imaging acquisition.
Our aim was to assess the association of left ventricular mass with mortality and nonfatal cardiovascular events.
Left ventricular mass was measured by echocardiography in 40138 adult patients (mean ...age 61.1 ± 16.4 years, 52.5% male). The primary endpoint was all-cause mortality. Secondary endpoints included nonfatal myocardial infarction and nonfatal stroke. During a mean follow-up period of 5.6 ± 3.9 years, 9181 patients died, 901 patients had a nonfatal myocardial infarction, and 2139 patients had a nonfatal stroke. Cumulative 10-year mortality was 26.8%, 31.9%, 37.4% and 46.4% in patients with normal, mildly, moderately and severely increased left ventricular mass, respectively (p<0.001). Ten-year rates of nonfatal myocardial infarction and stroke ranged from 3.2% and 6.7% in patients with normal left ventricular mass to 5.3% and 12.7% in those with severe increase in left ventricular mass, respectively. After multivariate adjustment, left ventricular mass remained an independent predictor of all-cause mortality (hazard ratio HR per 100 g increase 1.21, 95% confidence interval CI 1.14-1-27, p<0.001 in women, and HR 1.09, 95% CI 1.04-1-13, p<0.001 in men), myocardial infarction (HR 1.60, 95% CI 1.31-1.94, p<0.001 in women and HR 1.15, 95% CI 1.02-1.29, p=0.019 in men) and stroke (HR 1.26, 95% CI 1.13-1.40, p<0.001 in women and HR 1.19, 95% CI 1.09-1.30, p<0.001 in men).
Left ventricular mass has a graded and independent association with all-cause mortality, myocardial infarction and stroke.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests ...humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991–December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post‐HT of 21.3 ± 24.7 months (range: 2–72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
Phospholamban is an endogenous sarcoplasmic reticulum calcium ATPase inhibitor with a regulatory effect on cardiac contraction/relaxation coupling. Mutations in the phospholamban gene ...(PLN) have been associated with primary cardiomyopathies.
Aims:
To screen for PLN mutations in our population of patients with primary cardiomyopathies and to perform functional analysis of the mutations identified.
Methods:
We performed SSCP mutational screening and DNA sequencing of the PLN gene in 186 patients with either hypertrophic or dilated cardiomyopathy. To study promoter strength we constructed reporter plasmids containing the luciferase gene and performed transient transfection analysis in C6 and C2C12 cell lines.
Results:
The PLN -42 C>G mutation was found in one patient with late onset familial apical hypertrophic cardiomyopathy. This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively. One son had mild apical hypertrophic cardiomyopathy and carried the mutation, another son with normal ECG and echocardiogram also had the mutation.
Conclusion:
The PLN -42 C>G mutation is associated with a benign form of apical hypertrophic cardiomyopathy in this family, though the presence of a healthy adult carrier suggests that other genetic and environmental factors could be involved. Otherwise, mutations in the PLN gene are not a frequent cause of cardiomyopathies in our population.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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