A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy.

The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.

Characteristics of Left Atrial Deformation Parameters and Their Prognostic Impact in Patients with Pathological Left Ventricular Hypertrophy: Analysis by Speckle Tracking Echocardiography.

BACKGROUND: The pathological process of left ventricular (LV) hypertrophy is associated with left atrial (LA) remodeling. This study was aimed to evaluate the prognostic value of LA strain parameters in patients with pathological LV hypertrophy. METHODS: This study included 95 patients with hypertensive heart disease (HHD: n = 24), hypertrophic cardiomyopathy (HCM: n = 56), cardiac amyloidosis (CA: n = 15), and control subjects (n = 20). We used two-dimensional speckle tracking echocardiography (STE) to analyze LA global strain. LA electromechanical conduction time (EMT) at the septal (EMT-septal) and lateral wall (EMT-lateral), and their time difference (EMT-diff) were calculated. The incidence of cardiac death and heart failure hospitalization was defined as major cardiac events and that of atrial fibrillation as secondary outcome. RESULTS: Left atrial volume index was increased and LA booster strain was decreased in the HCM and CA groups compared with the HHD group. EMT-lateral was increased in the diseased groups compared with the control. EMT-diff was prolonged in the CA group compared with the HCM group. During the follow-up period (mean 3.4 years), major cardiac events and atrial fibrillation occurred in 17 and 13 patients, respectively. The occurrence of atrial fibrillation was associated with CA etiology, E/e', LA volume index, LAa, and EMT-lateral. The incidence of major cardiac events was independently correlated with LA volume index and EMT-diff in multivariate analysis. CONCLUSION: This study suggested that the EMT-diff could discriminate patients with a high risk of cardiac events among patients with pathological LV hypertrophy.

Association Between Genetic Variation in the SCN10A Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy.

Arrhythmias are associated with reduced quality of life and poor prognosis in patients with hypertrophic cardiomyopathy (HCM). Recent genome-wide association studies revealed that a nonsynonymous single nucleotide polymorphism, rs6795970, in the SCN10A gene was associated with the PR interval. We examined whether the PR prolonging allele (A allele) in the SCN10A gene may be associated with cardiac conduction abnormalities in HCM patients.We genotyped the polymorphism in 149 HCM patients. Conduction abnormalities were defined as first-degree heart block, bundle-branch block, and bifascicular heart block. Patients were divided into two groups: group A consisted of 122 patients (82%) without a conduction abnormality; and group B consisted of 27 patients (18%) with one or more cardiac conduction abnormalities. The frequency distribution of the SCN10A genotypes (G/G, G/A, and A/A) among the patients with HCM was 71%, 26%, and 3%, respectively. A cardiac conduction abnormality was documented in 9% with G/G and 40% with G/A or A/A. There was a significant difference in the genotype distribution between the two groups (P = 0.0002). In the dominant A allele model, there was a significant difference in genotypes between the two groups (P < 0.0001). In addition, the A allele remained significant after adjusting for other covariates in a multivariate model (odds ratio = 6.30 [95% confidence interval: 2.24 to 19.09], P = 0.0005).The rs6795970 in the SCN10A gene, which is reported to carry a high risk of heart block, might be associated with cardiac conduction abnormalities in HCM patients.

Features and clinical impact of extra-cardiac lesions with 18F-fluorodeoxyglucose positron emission tomography in patients with suspected cardiac sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic inflammatory disorder and can often affect any other organs beyond the heart. Whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is used to detect not only cardiac but also extra-cardiac involvement of sarcoidosis. However, the features and clinical impact of extra-cardiac lesions have not yet been fully elucidated. Therefore, this study aimed to clarify these using FDG-PET. METHODS AND RESULTS: We enrolled 120 consecutive patients with abnormal findings clinically suggesting cardiac sarcoidosis who underwent whole-body FDG-PET. In this study, a patient with suspected cardiac sarcoidosis was defined as one having both clinically suspected findings and FDG-PET positive cardiac uptake. Subsequently, a total of 36 patients with suspected cardiac sarcoidosis were found and analyzed. Extra-cardiac involvement was detected in 35 lesions of 14 patients (39% per patient). In particular, the extra-cardiac lesions were widely distributed throughout the body, and mediastinal/hilar lymph node involvement was most commonly observed. In most of the patients (93% per patient, 13/14), the extra-cardiac lesions were localized in the regions that were considered more accessible with less risk of complication compared with endomyocardial biopsy (EMB). Based on the FDG-PET findings, 8 patients underwent extra-cardiac biopsy without complication, and its diagnostic sensitivity for histological sarcoidosis was high (75%, 6/8). Moreover, FDG-PET-guided extra-cardiac biopsy could confirm histological sarcoidosis in 4 lesions that EMB failed to prove. CONCLUSIONS: Extra-cardiac involvement in patients with suspected cardiac sarcoidosis was relatively high. FDG-PET-guided extra-cardiac biopsy may be safe and useful for the imaging based diagnosis of cardiac sarcoidosis.

Correlation Between Quantitative Angiography-Derived Translesional Pressure and Fractional Flow Reserve.

Fractional flow reserve (FFR) is widely used for the assessment of myocardial ischemia. However, it has the disadvantage of cost and invasive complication risks. We investigated the usefulness of quantitative coronary angiography-derived translesional pressure (QCA-TP) for predicting functional myocardial ischemia, using FFR as the gold standard. We retrospectively analyzed 152 coronary narrowings (98 left anterior descending arteries, 28 left circumflex arteries, and 26 right) in 132 patients with mild-severe coronary stenosis who underwent coronary angiography and FFR measurements simultaneously. QCA-TP was calculated using software implemented in the QCA software. Coronary morphology was calculated using both densitometry and lumen edges. Functional myocardial ischemia was defined as an FFR of 0.8 or less. The mean values of diameter stenosis by QCA and FFR were 48.9% ± 14.9 and 0.76 ± 0.14, respectively. QCA-TP was significantly correlated with FFR (r = 0.76, p <0.01). The cut-off values of QCA-TP for predicting functional myocardial ischemia based on FFR were 72.8 mm Hg for the left anterior descending arteries (accuracy, 86.7%; area under the curve [AUC], 0.93), 60.5 mm Hg for the left circumflex arteries (accuracy, 89.3%; AUC, 0.88), and 64.4 mm Hg for the right (accuracy, 88.5%; AUC, 0.94). Therefore, our data suggest that QCA-TP can predict myocardial ischemia with high diagnostic accuracy.

Systolic left ventricular apical bulging after biventricular pacing mimicking takotsubo cardiomyopathy.

Resolution of the issue of nonresponsiveness to cardiac resynchronization therapy (CRT) remains crucial to the successful treatment of conduction disturbances in heart failure. In this study, a patient with refractory heart failure including left bundle branch block was treated via surgical CRT. The epicardial left ventricular (LV) lead, implanted using thoracoscopic guidance, was unexpectedly located on the apical side. Echocardiographic findings of the LV motion mimicked takotsubo cardiomyopathy. The LV lead was successfully re-implanted along a lateral branch of the cardiac vein using an endovascular approach, resulting in restored contractility and reversal of the LV remodeling.