Troponin T Assessment Allows for Identification of Mutation Carriers among Young Relatives of Patients with LMNA-Related Dilated Cardiomyopathy.

Background:LMNA-related dilated cardiomyopathy (LMNA-DCM) caused by mutations in the lamin A/C gene (LMNA) is one of the most common forms of hereditary DCM. Due to the high risk of mutation transmission to offspring and the high incidence of ventricular arrhythmia and sudden death even before the onset of heart failure symptoms, it is very important to identify LMNA-mutation carriers. However, many relatives of LMNA-DCM patients do not report to specialized centers for clinical or genetic screening. Therefore, an easily available tool to identify at-risk subjects is needed. Methods: We compared two cohorts of young, asymptomatic relatives of DCM patients who reported for screening: 29 LMNA mutation carriers and 43 individuals from the control group. Receiver operating characteristic (ROC) curves for potential indicators of mutation carriership status were analyzed. Results: PR interval, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hscTnT) serum levels were higher in the LMNA mutation carrier cohort. Neither group differed significantly with regard to creatinine concentration or left ventricular ejection fraction. The best mutation carriership discriminator was hscTnT level with an optimal cut-off value at 5.5 ng/L, for which sensitivity and specificity were 86% and 93%, respectively. The median hscTnT level was 11.0 ng/L in LMNA mutation carriers vs. <3.0 ng/L in the control group, p < 0.001. Conclusions: Wherever access to genetic testing is limited, LMNA mutation carriership status can be assessed reliably using the hscTnT assay. Among young symptomless relatives of LMNA-DCM patients, a hscTnT level >5.5 ng/L strongly suggests mutation carriers.

Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment.

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

Assessment of the inflammatory process by endomyocardial biopsy in patients with dilated cardiomyopathy based on pathological and immunohistochemical methods.

INTRODUCTION: Myocarditis may lead to dilated cardiomyopathy (DCM) in immunogenetically predisposed individuals. The diagnosis of myocardial inflammation is currently based on histopathological and immunohistochemical methods. Previous studies indicate that inflammatory cardiomyopathy occurs in approximately 50% of patients with DCM. AIM: The goal of the study was to assess the inflammatory process in patients with DCM by endomyocardial biopsy using histopathological and immunohistochemical methods. METHODS: Endomyocardial biopsy specimens was examined using routine histopathological methods and immunochemical staining for T lymphocytes (CD3(+), n=84), major histocompatibility complex I (HLA ABC, n=48) and II (HLA DPQR, n=84) antigens and the adhesion molecules ICAM-1 (n=51) and VCAM-1 (n=48) in 84 patients (69 male, 15 female; mean age 35.0+/-10.5 years) with angiographically-confirmed DCM. Familial disease occurrence was noted in 14 (16.7%) patients. Cardiac samples obtained from 18 patients who died of non-cardiovascular causes were used as a control group. RESULTS: Myocarditis was diagnosed, according to the Dallas criteria, in 8 (9.5%) patients. The frequency of inflammatory cardiomyopathy, defined as the presence of >2 CD3(+) T lymphocytes per high-power field (hpf) in myocardial biopsy, was 14.3%. When broader criteria were applied (presence of >2.0 CD3(+) lymphocytes/hpf and/or 1.5 CD3(+) lymphocytes/hpf in multiple foci and increased expression of class I/II HLA), inflammatory cardiomyopathy was diagnosed in 32.1% of patients. Inflammatory activation of the endothelium, indicated by increased expression of at least three adhesion molecules (class I and II HLA, ICAM-1, VCAM-1), was present in 22 (45.8%) patients. The expression of HLA DPQR, HLA ABC and ICAM-1 was observed on the endothelium of capillaries and larger vessels, interstitial cells, and the surface of activated lymphocytes; immunohistochemical reactions were diffuse. In patients with markedly elevated expression of the aforementioned adhesion molecules, the expression was also present on cardiomyocyte cell membranes. VCAM-1 was restricted to the endothelium of individual small veins. The control group did not demonstrate any signs of myocarditis, inflammatory cardiomyopathy or inflammatory endothelial activation. CONCLUSIONS: The application of immunohistochemical methods to myocardial biopsy in order to identify the inflammatory cell phenotype and the presence of adhesion molecules permits the diagnosis of inflammatory cardiomyopathy in 14% or 32% of patients, depending on the criteria used, while conventional pathology allows for this diagnosis in 9% of patients. The observed frequency of inflammatory cardiomyopathy, defined as the presence of >2 CD3(+) T lymphocytes/hpf in the myocardium, was lower (14%) than in previous studies, while the frequency of inflammatory endothelial activation was similar (45%).

[Echocardiographic assessment of left atrial volume and emptying in hypertrophic cardiomyopathy]. / Echokardiograficzna ocena objetosci i oprózniania lewego przedsionka w kardiomiopatii przerostowej.

UNLABELLED: Left ventricular diastolic dysfunction plays an important role in the pathogenesis of symptoms in patients with hypertrophic cardiomyopathy (HCM). Theoretically abnormal LV filling should lead to left atrium (LA) enlargement and abnormal emptying. Our study was performed in 27 pts with hypertrophic cardiomyopathy (mean ventricular septum thickness 2.4 +/- 0.73 cm, mean posterior wall thickness 1.23 +/- 0.42 cm and mean LV wall thickness measured at 10 segments 1.93 +/- 0.37 cm) and 38 healthy volunteers. Transmitral Doppler flow parameters (Emax, Amax, t decE, Emax/Amax) did not differ in both groups. We used 2D echocardiographic automatic borderline detection method to assess the following LA volumes during its emptying: maximal volume (LAVmax), volumes at the end of rapid emptying (LAV-RE), before atrial contraction--P wave on ECG (LAV-P) and minimal LA volume after atrial contraction (LAVmin). We also calculated total LA emptying fraction (%LAEF), absolute volume changes during LA early emptying (delta LAV-RE) and atrial contraction (delta LAV-AC) and their ratio (delta LAV-RE/delta LAV-AC). 11 pts had mitral regurgitation. The mitral regurgitation fraction was calculated as the ratio of the area of mitral regurgitation to LA area. RESULTS: Significantly larger LAVmax (75.8 +/- 28.0 vs 60.7 +/- 18.1 ml, p<0.01), LAV-RE (50.4 +/- 21.4 vs 35.3 +/- 13.8 ml, p<0.005), LAV-P (50.7 +/- 20.5 vs 38.4 +/- 13.8 ml, p<0.01) and LAVmin (33.0 +/- 15.1 vs 26.3 +/- 11.7 ml, p<0.05) were found in HCM compared to C. The total LA emptying fraction %LAEF (58.0 +/- 11.4 vs 57.4 +/- 12.1%, NS), DLAV-RE (27.3 +/- 12.6 vs 25.3 +/- 11.0 ml, NS), and ratio delta LAV-RE/DLAV-AC (1.94 +/- 1.22 vs 2.38 +/- 1.10, NS) were similar both groups and active emptying delta LAV-AC (17.6 +/- 9.7 vs 12.1 +/- 5.3 ml, p<0.005) was significantly larger in HCM. The regurgitation fraction observed in HCM was 2.7-31.1%. Statistically significant correlation between LA total emptying fraction (%LAEF) and mitral regurgitation fraction (r=-0.47, p<0.05) and no relations between LA size and function parameters and LV hypertrophy parameters were found in HCM. CONCLUSION: LV hypertrophy in hypertrophic cardiomyopathy leads to LA enlargement and changes in its emptying. We found larger the following LA volumes: maximal volume, volume after early emptying, before atrial contraction and minimal volume and greater LA volume change during active emptying. Total LA emptying fraction, volume change during early/passive emptying and passive/active emptying volumes ratio were similar in both groups. No correlation existed between the degree of LV hypertrophy and LA volume and emptying parameters. We observed negative relation between mitral regurgitation fraction and LA total emptying fraction, but because of small group of pts with mitral regurgitation, further studies are needed.