Pavel Gregor

The Effects of Candesartan on Left Ventricular Hypertrophy and Function in Nonobstructive Hypertrophic Cardiomyopathy: A Pilot, Randomized Study

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.

Myocardial viability and cardiac dyssynchrony as strong predictors of perioperative mortality in high-risk patients with ischemic cardiomyopathy having coronary artery bypass surgery

OBJECTIVE Myocardial viability and left ventricular dyssynchrony are important predictors of long-term outcomes in patients with ischemic left ventricular dysfunction. The objective of this study was to test the hypothesis that assessment of myocardial viability and left ventricular dyssynchrony will predict perioperative mortality in high-risk patients with ischemic left ventricular dysfunction having coronary artery bypass surgery. METHODS The study consisted of 79 consecutive patients with ischemic cardiomyopathy (age 65 +/- 9 years; 81% men; ejection fraction 30% +/- 6%) and logistic European system for cardiac operative risk evaluation > 10% having coronary artery bypass surgery. Myocardial viability was assessed by delayed contrast-enhanced magnetic resonance imaging. Left ventricular dyssynchrony was calculated using tissue Doppler from measurements of regional electromechanical coupling times in left ventricular basal segments before coronary artery bypass surgery. RESULTS Twenty (25.3%) patients died within 30 days following coronary artery bypass surgery. Survivors (n = 59) showed a larger extent of viable myocardium (6.9 +/- 3.6 viable segments vs 3.4 +/- 3.3 viable segments, P < .001) and smaller left ventricular dyssynchrony (75 +/- 5 ms vs 179 +/- 83 ms, P < .001) than nonsurvivors. The presence of significant dyssynchrony (>or=105 ms) and absence of myocardial viability (<5 viable segments) independently predicted 30-day mortality with hazard ratio 3.26, 95% confidence interval 1.61 to 8.33 (P < .01) and hazard ratio 1.72, 95% confidence interval 1.59 to 1.89 (P < .01), respectively. All but 2 patients (94.1%) with viable myocardium and without left ventricular dyssynchrony survived coronary artery bypass surgery as compared with only 12 (52.2%) patients with nonviable myocardium and severe dyssynchrony (P < .001). CONCLUSIONS In high-risk patients with ischemic left ventricular dysfunction having coronary artery bypass surgery, both myocardial viability and left ventricular dyssynchrony are important predictors of perioperative outcome. Assessment of myocardial viability and left ventricular dyssynchrony should be a routine part of the preoperative evaluation of these patients.

Electrocardiographic changes can precede the development of myocardial hypertrophy in the setting of hypertrophic cardiomyopathy

A comparison was made of electrocardiographic findings in 107 first-degree relatives of patients with hypertrophic cardiomyopathy without any clinical and echocardiographic signs of the disease and 188 healthy persons with a negative family history. A significantly larger number of electrocardiographic signs of left ventricular hypertrophy (P less than 0.05) and abnormal Q wave (P less than 0.005) was shown in the group of the relatives. Abnormalities of the R wave in V1-3 and of the ST-T segment were also more frequent in this group, but the difference is not statistically significant. In all, electrocardiographic abnormalities were found in 13 of 107 asymptomatic relatives of the patients with hypertrophic cardiomyopathy. These relatives had normal clinical and echocardiographic findings. These 13 patients underwent long-term follow-up (4.5-8 years). Typical hypertrophic cardiomyopathy developed in two patients (an increase in the myocardial thickness from 6 to 15 m in six years and from 8 to 13 mm in 4.5 years, respectively) which was accompanied by progression of the electrocardiographic findings. Electrocardiography is the only commonly available method which may reveal the latent forms of hypertrophic cardiomyopathy at the stage when neither myocardial hypertrophy nor other signs of the disease are expressed. Longitudinal follow-up is necessary for all the relatives of the patients with hypertrophic cardiomyopathy who have abnormal or borderline electrocardiographic findings. A normal echocardiogram cannot exclude the disease at this stage.

Low Prevalence and Variable Clinical Presentation of Troponin I and Troponin T Gene Mutations in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in cardiac sarcomeric proteins. Troponin I (TNNI3) and troponin T (TNNT2) are important parts of the sarcomere in heart muscle, and mutations in their genes are responsible for development of HCM. The prevalence of mutations in these two genes is low; hence, the data on clinical outcome are scarce. Yet, some of these mutations were shown to be malignant with a high incidence of sudden death. Here, we describe the disease course in three families affected with TNNI3 and one family with TNNT2 gene mutations. In TNNI3-HCM, the phenotypic manifestation ranged from clinically silent to sudden cardiac death with the worst prognosis observed in carriers of Ala157Val mutation in exon 7. In contrast, TNNT2-HCM was associated with favorable prognosis. Thus, the findings of the present study add evidence on the phenotypic presentation of this genetic disease.

Comparison of Long-Term Effect of Dual-Chamber Pacing and Alcohol Septal Ablation in Patients with Hypertrophic Obstructive Cardiomyopathy

Introduction. Nonpharmacological treatment of patients with hypertrophic obstructive cardiomyopathy (HOCM) comprises surgical myectomy (SME), alcohol septal ablation (ASA), and dual-chamber (DDD) pacing. The aim of the study was to compare the long-term effect of DDD pacing and ASA in symptomatic HOCM patients. Patients and Methods. We evaluated retrospective data from three cardiocenters; there were 24 patients treated with DDD pacing included and 52 treated with ASA followed for 101 ± 49 and 87 ± 23 months, respectively. Results. In the group treated with DDD pacing, the left ventricle outflow tract gradient (LVOTG) decreased from 82 ± 44 mmHg to 21 ± 21 mmHg, and NYHA class improved from 2.7 ± 0.5 to 2.1 ± 0.6 (both P < 0.001). In the ASA-treated group, a decline in LVOTG from 73 ± 38 mmHg to 24 ± 26 mmHg and reduction in NYHA class from 2.8 ± 0.5 to 1.7 ± 0.8 were observed (both P < 0.001). The LVOTG change was similar in both groups (P = 0.264), and symptoms were more affected by ASA (P = 0.001). Conclusion. ASA and DDD pacing were similarly effective in reducing LVOTG. The symptoms improvement was more expressed in patients treated with ASA.

Variants in miRNA Regulating Cardiac Growth Are Not a Common Cause of Hypertrophic Cardiomyopathy

Objectives: A substantial proportion of patients with hypertrophic cardiomyopathy (HCM) do not have causative mutations in the genes for heart sarcomere. The purpose of this study was to evaluate the association between microRNA (miRNA) sequence variants and HCM. Methods: We performed genetic testing on 56 HCM patients who had previously been found to be negative for mutations in the 4 major genes for sarcomeric proteins. The coding and adjacent regions (120-220 nt) of selected miRNAs were analyzed for the presence of sequence variants. The testing was based on PCR amplification of DNA-encoding miRNAs and subsequent denaturing capillary electrophoresis. Results: A total of 3 different variants were detected in the 11 selected miRNAs. These included polymorphisms rs45489294 in miRNA 208b, rs13136737 in miRNA 367 and rs9989532 in miRNA 1-2. In the patient group, the most frequent polymorphism was in miRNA 208b (10 times) followed by miRNA 367 (7 times). Both polymorphisms were found to occur with similar frequencies in the group of healthy controls. The remaining detected variant was not present in the control group, but was not connected with the HCM phenotype in the children of the probands. Conclusion: Sequence variants in miRNAs of patients with HCM are not frequent and the contribution of these variants to the development of this disease was not demonstrated.

Anti-calreticulin antibodies and calreticulin in sera of patients diagnosed with dilated or hypertrophic cardiomyopathy

Abstract Distinct cellular level of the Ca2+-binding chaperone calreticulin (CRT) is essential for correct embryonal cardiac development and postnatal function. However, CRT is also a potential autoantigen eliciting formation of antibodies (Ab), whose role is not yet clarified. Immunization with CRT leads to cardiac injury, while overexpression of CRT in cardiomyocytes induces dilated cardiomyopathy (DCM) in animals. Hence, we analysed levels of anti-CRT Ab and calreticulin in the sera of patients with idiopatic DCM and hypertrophic cardiomyopathy (HCM). ELISA and immunoblot using human recombinant CRT and Pepscan with synthetic, overlapping decapeptides of CRT were used to detect anti-CRT Ab. Serum CRT concentration was tested by ELISA. Significantly increased levels of anti-CRT Ab of isotypes IgA (p < 0.001) and IgG (p < 0.05) were found in patients with both DCM (12/34 seropositive for IgA, 7/34 for IgG) and HCM (13/38 seropositive for IgA, 11/38 for IgG) against healthy controls (2/79 for IgA, 1/79 for IgG). Titration analysis in seropositive DCM and HCM patients documented anti-CRT Ab detected at 1/1600 dilution for IgG and 1/800 for IgA (and IgA1) and at least at 1/200 dilution for IgA2, IgG1, IgG2 and IgG3. Pepscan identified immunogenic CRT epitopes recognized by IgA and IgG Ab of these patients. Significantly increased levels of CRT relative to healthy controls were found in sera of patients with HCM (p < 0.01, 5/19). These data extend the knowledge of seroprevalence of anti-CRT Ab and CRT, and suggest possible involvement of autoimmune mechanisms directed to CRT in some forms of cardiomyopathies, which are clinically heterogeneous.