Identification of Novel Mutations in RBM20 in Patients with Dilated Cardiomyopathy

The genetic basis of most of dilated cardiomyopathy (DCM) cases remains unknown. A recent study indicated that mutations in a highly localized five amino acid hotspot in exon 9 of RBM20, a gene encoding a ribonucleic acid‐binding protein, caused aggressive DCM. We undertook this study to confi rm and extend the nature of RBM20 mutations in another DCM cohort. Clinical cardiovascular data, family histories, and blood samples were collected from patients with idiopathic DCM. DNA from 312 DCM probands was sequenced for nucleotide alterations in exons 6 through 9 of RBM20, and additional family members as possible. We found six unique RBM20 rare variants in six unrelated probands (1.9%). Four mutations, two of which were novel (R634W and R636C) and two previously identified (R634Q and R636H), were identified in a five amino acid hotspot in exon 6. Two other novel variants (V535I in exon 6 and R716Q in exon 9) were outside of this hotspot. Age of onset and severity of heart failure were variable, as were arrhythmias and conduction system defects, but many subjects suffered severe heart failure resulting in early death or cardiac transplantation. This article concludes that DCM in patients with RBM20 mutations is associated with advanced disease. Clin Trans Sci 2010; Volume 3: 90–97     

Heart Rate Variability and Major Arrhythmic Events in Patients with Idiopathic Dilated Cardiomyopathy

This prospective study of 71 patients with idiopathic dilated cardiomyopathy (IDC) and preserved sinus rhythm was designed to evaluate the relation between heart rate variability (HRV) and subsequent major arrhythmic events. Standard time- and frequency-domain HRV parameters were obtained from analysis of 24-hour Holter ECG recordings. During a mean follow-up of 15 ± 5 months, major arrhythmic events including sustained ventricular tachycardia, ventricular fibrillation, and sudden cardiac death occurred in 10 of the 71 study patients (14%). Neither time- nor frequency-domain indices of HRV differed significantly between patients with and patients without subsequent major arrhythmic events. However, there was a trend toward a lower standard deviation of the average normal RR interval for all 5-minute segments of the 24-hour recording (68 ± 17 ms vs 80 ± 31 ms; P = 0.06) in patients with major arrhythmic events. In addition, the percentage of adjacent normal RR intervals differing > 50 ms over the recording period tended to be lower in patients with major arrhythmic events (6%± 3% vs 9%± 6%; P = 0.08). Our results indicate a tendency toward attenuated parasympathetic activity in IDC patients with subsequent major arrhythmic events compared to arrhythmia-free patients. Larger studies with longer follow-up periods are necessary to clarify the role of HRV measurements for arrhythmia risk prediction in patients with IDC.     

Predictive Value of High-Sensitivity C-Reactive Protein in Patients with Idiopathic Dilated Cardiomyopathy

We analyzed the serum concentrations of high-sensitivity C-reactive protein (hsCRP) at the time of diagnostic cardiac catheterization in 198 patients with idiopathic dilated cardiomyopathy (IDC) to evaluate its prognostic value. Patients were dichotomized according to a median value of hsCRP of 2 mg/dL. Predefined study endpoints over 69 ± 33 months of follow-up included major arrhythmic events and transplant-free survival. Major arrhythmic events during follow-up occurred in 20 of 98 patients (20%) with low, compared to 22 of 100 patients (22%) with high hsCRP (ns). By multivariate analysis, a depressed left ventricular ejection fraction (LVEF) was the only significant predictor of arrhythmic risk. Death or cardiac transplantation was observed in 36% of patients with high, versus 22% of patients with low hsCRP (P < 0.05). By multivariate analysis, hsCRP and LVEF were independent predictors of transplant-free survival. Thus, in this patient population with IDC, hsCRP had independent prognostic value with regard to transplant-free survival, but did not contribute in the stratification with regard to arrhythmic risk.     

How Many Patients with Dilated Cardiomyopathy May Potentially Benefit from Cardiac Resynchronization Therapy?

GRIMM, W., et al .: How Many Patients with Dilated Cardiomyopathy May Potentially Benefit from Cardiac Resynchronization Therapy? The clinical and electrocardiographic Marburg Cardiomyopathy database was analyzed to identify potential candidates for cardiac resynchronization therapy (CRT) with biventricular or left ventricular pacing among 566 patients with dilated cardiomyopathy (DCM). All of the following restrictive selection criteria were fulfilled by 38 patients (7%): NYHA functional class ≥ 3 (   n = 193   , 34%), left ventricular ejection fraction (LVEF) <30% (n = 238, 42%), sinus rhythm (   n = 437   , 77%), left bundle branch block (LBBB,   n = 142   , 25%), and QRS duration ≥ 150 ms (   n = 136   , 24%). In 78 of the 566 patients (14%) all of the following less restrictive selection criteria were fulfilled: NYHA functional class ≥3 (   n = 193   , 34%), LVEF < 35% in presence of any underlying rhythm (n = 326, 58%), QRS duration ≥ 120 ms with right or left bundle branch block (   n = 223   , 39%). Thus, between 7% and 14% of patients with DCM were candidates for CRT depending on the application of strict versus less restrictive selection criteria.(PACE 2003; 26[Pt. II]:155–157)     

SCN5A Rare Variants in Familial Dilated Cardiomyopathy Decrease Peak Sodium Current Depending on the Common Polymorphism H558R and Common Splice Variant Q1077del

Obtaining functional data with newly identified rare variants increases certainty that the variant identified is relevant for dilated cardiomyopathy (DCM) causation. Two novel SCN5A rare variants, R222Q and I1835T, segregated with DCM in two families with affected individuals homozygous or heterozygous for the common SCN5A polymorphism H558R. cDNAs with each rare variant were constructed in the common Q1077del or Q1077 splice variant backgrounds with and without the H558R polymorphism and expressed in HEK293 cells. Sodium current (I_Na) was studied for each using whole‐cell voltage clamp. In the Q1077del background I_Na densities of R222Q and I1835T were not different from wild type, but the combined variants of R222Q/H558R, I1835T/H558R caused approximately 35% and approximately 30% reduction, respectively, and each showed slower recovery from inactivation. In the Q1077del background R222Q and R222Q/H558R also exhibited a significant negative shift in both activation and inactivation while I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak I_Na densities, decay, or recovery from inactivation for R222Q/H558R and I1835T/H558R. We conclude that the biophysical findings, dependent upon common SCN5A variants, provide further evidence that these novel SCN5A rare variants are relevant for DCM. Clin Trans Sci 2010; Volume 3: 287–294     

Long Runs of Non-Sustained Ventricular Tachycardia on 24-Hour Ambulatory Electrocardiogram Predict Major Arrhythmic Events in Patients with Idiopathic Dilated Cardiomyopathy

This study examined the prognostic significance of the rate and length of non-sustained (NS) ventricular tachycardia (VT) on 24-hour ambulatory electrocardiograms (ECG) recorded in 343 patients with idiopathic dilated cardiomyopathy (IDC) in the prospective Marburg Cardiomyopathy study. NSVT was defined as ≥3 consecutive ventricular premature beats at >120 bpm. During 52 ± 21 months of follow-up, major arrhythmic events defined as sustained VT, VF, or sudden cardiac death occurred in 46 of 343 patients (13%). Patients with 3–4 beat runs of NSVT had a similar arrhythmia-free survival as patients without NSVT on baseline 24-hour ambulatory ECG. The incidence of major arrhythmic events during follow-up increased significantly from 2% per year in patients without NSVT, to 5% per year in patients with 5–9 beat runs of NSVT, to 10% per year in patients with ≥10 beat runs of NSVT (P < 0.05). Unlike the length, the rate of NSVT was similar in patients with versus without subsequent major arrhythmic events (163 ± 23 vs 160 ± 24 bpm). Thus, the length but not the rate of NSVT on 24-hour ambulatory ECG was a predictor of major arrhythmic events in patients with IDC. The presence of NSVT with ≥10 beat runs on ambulatory ECG was associated with a particularly high risk of major arrhythmic events.     

Right Ventricular Myocardial Function in Patients with Either Idiopathic or Ischemic Dilated Cardiomyopathy Without Clinical Sign of Right Heart Failure: Effects of Cardiac Resynchronization Therapy

Objective: In dilated cardiomyopathy (DCM), right ventricular (RV) dysfunction has been reported and attributed both to altered loading conditions and to RV involvement in the myopathic process. The aim of the study was to detect RV myocardial function in DCM using two‐dimensional (2D) strain echocardiography and to assess the effects of cardiac resynchronization therapy (CRT) on RV myocardial strain during a 6‐month follow‐up. Methods and Results: A total of 110 patients (mean age: 55.4 ± 11.2 years) with either idiopathic (n = 60) or ischemic (n = 50) DCM, without overt clinical signs of RV failure, underwent standard echo and 2D strain analysis of RV longitudinal strain in RV septal and lateral walls. The two groups were comparable for clinical variables (New York Heart Association class III in 81.8%). Left ventricular volumes, ejection fraction, stroke volume, and mitral valve effective regurgitant orifice were similar between the two groups. No significant differences were evidenced in Doppler mitral and tricuspid inflow measurements. RV diameters were mildly increased in patients with idiopathic DCM, while RV tricuspid annulus systolic excursion and Tei‐index were comparable between the two groups. RV global longitudinal strain and regional peak myocardial strain were significantly impaired in patients with idiopathic DCM compared with those having ischemic DCM (all P < 0.001). Using left ventricular end‐systolic volume as marker for response to CRT, 70 patients (63.3%) were long‐term responders. Ischemic DCM patient responders to CRT showed a significant improvement in RV peak systolic strain. Conversely, in patients with idiopathic DCM and in ischemic patients nonresponders to CRT, no improvement in RV function was evidenced. By multivariable analysis, in the overall population, ischemic etiology of DCM (P < 0.0001), positive response to CRT (P < 0.001), and longitudinal intraventricular dyssynchrony (P <0.01) emerged as the only independent determinants of RV global longitudinal strain after CRT. Conclusions: Two‐dimensional strain represents a promising noninvasive technique to assess RV myocardial function in patients with DCM. RV myocardial deformation at baseline and after CRT are more impaired in idiopathic compared with ischemic DCM patients. Future longitudinal studies are warranted to understand the natural history of RV myocardial function, the extent of reversibility of RV dysfunction with CRT, and the possible prognostic impact of such indexes in patients with congestive heart failure.     

Marked Improvement in Left Ventricular Function and Significant Reverse Left Ventricular Remodeling within 3 Months of Cardiac Resynchronization Therapy in Patients with Dilated Cardiomyopathy

We monitored reverse left ventricular (LV) remodeling and LV function during the first 6 months of cardiac resynchronization therapy (CRT) in 34 patients (mean age = 55.3 ± 13.6 years, 28 men) with dilated cardiomyopathy (DCM), left bundle branch block, in stable New York Heart Association class III, and on fixed drug regimen who underwent implantation of CRT systems with or without cardioverter defibrillator back-up. QRS-complex duration was reduced from 169.69 ± 19.6 ms (SD) to 144.1 ± 23.4 ms during CRT. Parasternal M-mode and apical 2D-echocardiography was performed before and 3 and 6 months after device implantation. LV enddiastolic (EDD) and endsystolic (ESD) diameters were measured, and biplane LV enddiastolic (EDV), and endsystolic (ESV) volumes and ejection fractions (EF) were calculated using a modified Simpson formula. Significant decreases in LVEDD (P = 0.0064 at 3 months and P = 0.021 at 6 months), LVESD (P = 0.023 at 3 months, and P = 0.003 at 6 months), and LVESV (P = 0.006 resp. P = 0.007), and increases in LVEF (P = 0.003 at 3 months and P < 0.001 at 6 months) were observed. Mean LVEF increased from 23% at baseline to 39% at 6 months. CRT induced prominent reverse LV remodeling and significantly increased LVEF within a few months in patients with DCM.     

Long QT Syndrome and Dilated Cardiomyopathy with SCN5A p.R1193Q Polymorphism: Cardioverter-Defibrillator Implantation at 27 Months

Cardiac sodium channel dysfunction associated with the SCN5A gene presents with mixed phenotypes, including long QT syndrome type 3, sinus node dysfunction, and dilated cardiomyopathy (DCM). We report a Korean case of an overlap syndrome of cardiac sodium channelopathy with SCN5A p.R1193Q polymorphism, treated by the placement of an intrapericardial implantable cardioverter-defibrillator (ICD) at the age of 27 months. Although the patient received two appropriate life-saving shocks for ventricular fibrillations, he eventually died of DCM progression. However, this case shows that intrapericardial ICD implantation is feasible in young children with a high risk for sudden cardiac death. (PACE 2012; 35:e243-e246).