The SCN5A gene encodes for the INa channel implicated in long QT syndrome type-3 (LQTS-type-3). Clinical symptoms of this type are lethal as most patients had a sudden death during sleep. Screening of SCN5A in South Indian cohort by PCR-SSCP analyses revealed five polymorphisms — A29A (exon-2), H558R (exon-12), E1061E and S1074R (exon-17) and IVS25 + 65G > A (exon-25) respectively. In-silico and statistical analyses were performed on all the polymorphisms.
Exon-2 of SCN5A gene revealed A282G polymorphism (rs6599230), resulting in alanine for alanine (A29A) silent substitution in the N-terminus of SCN5A protein. Exon-12 showed A1868G polymorphism (H558R — rs1805124) and its ‘AA’ genotype and ‘A’ allele frequency were found to be higher in LQTS patients pointing towards its role in LQTS etiology.
Two polymorphisms A3378G (E1061E) and the novel C3417A (S1074R) were identified as compound heterozygotes/genetic compounds in exon-17 of SCN5A located in the DIIS6–DIIIS1 domain of the SCN5A transmembrane protein. IVS25 + 65G > A was identified in intron-25 of SCN5A. The ‘G’ allele was identified as the risk allele.
Variations were identified in in-silico analyses which revealed that these genetic compounds may lead to downstream signaling variations causing aberrations in sodium channel functions leading to prolonged QTc. The compound heterozygotes of SCN5A gene polymorphisms revealed a significant association which may be deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QTc.
•Screening of SCN5A in South Indian cohort showed 4 reported and 1 novel polymorphism.•Compound heterozygotes found to have a significant association with LQTS•Genetic compounds maybe deleterious leading to an aberrant sodium ion channel
LQTS, Long QT syndrome; cLQTS, Congenital long QT syndrome; FDRs, First degree relatives; LQT3, Long QT syndrome type-3; SCN5A, Sodium channel, voltage-gated, type V, alpha subunit; LQTS; SCN5A; Polymorphisms; Compound heterozygotes
Permanent cardiac pacing is the only effective treatment for symptomatic bradycardia, but complications associated with conventional transvenous pacing systems are commonly related to the pacing lead and pocket. We describe the early performance of a novel self-contained miniaturized pacemaker.
Methods and results
Patients having Class I or II indication for VVI pacing underwent implantation of a Micra transcatheter pacing system, from the femoral vein and fixated in the right ventricle using four protractible nitinol tines. Prespecified objectives were >85% freedom from unanticipated serious adverse device events (safety) and <2 V 3-month mean pacing capture threshold at 0.24 ms pulse width (efficacy). Patients were implanted (n = 140) from 23 centres in 11 countries (61% male, age 77.0 ± 10.2 years) for atrioventricular block (66%) or sinus node dysfunction (29%) indications. During mean follow-up of 1.9 ± 1.8 months, the safety endpoint was met with no unanticipated serious adverse device events. Thirty adverse events related to the system or procedure occurred, mostly due to transient dysrhythmias or femoral access complications. One pericardial effusion without tamponade occurred after 18 device deployments. In 60 patients followed to 3 months, mean pacing threshold was 0.51 ± 0.22 V, and no threshold was ≥2 V, meeting the efficacy endpoint (P < 0.001). Average R-wave was 16.1 ± 5.2 mV and impedance was 650.7 ± 130 ohms.
Early assessment shows the transcatheter pacemaker can safely and effectively be applied. Long-term safety and benefit of the pacemaker will further be evaluated in the trial.
Clinical Trial Registration
ClinicalTrials.gov ID NCT02004873.
Transcatheter pacing system; Leadless cardiac pacemaker; Miniaturization
Atrial synchronous left ventricular (LV) only pacing using two leads and VDD pacemaker could be a cost effective alternative to conventional cardiac resynchronization therapy (CRT).
We implanted right atrial (RA) and LV leads with VDD pulse generator (LV only pacing) in five carefully screened heart failure patients who could not afford conventional CRT. All had NYHA class III/IV symptoms despite maximal guideline directed medical therapy. The sensed atrioventricular delay was programmed to pre-excite the LV and achieve fusion beat. Response to treatment was assessed at 6 months.
Four patients were males. The mean age was 58 ± 12 years. At follow up, there was improvement in electrocardiographic, and echocardiographic parameters: Mean QRS duration decreased from 174 ± 17 msec to 128 ± 10.9 msec (p = 0.009), LV end-diastolic diameter decreased from 73.2 ± 12 mm to 65.8 ± 9.6 mm (p = 0.026), LV end-systolic diameter decreased from 65 ± 12 mm to 54 ± 10 mm (p = 0.020). There was a trend towards reduction of LV end-systolic and end-diastolic volumes. LV ejection fraction improved from 25 ± 6% to 34 ± 6% (p = 0.013) and left atrial dimension reduced from 44 ± 4 mm to 39 ± 5 mm (p = 0.045). All patients improved clinically.
RA-LV pacing using VDD pacemaker is a safe and effective technique of CRT. This may be a cost effective alternative to conventional CRT for patients in developing countries.
Atrial synchronous pacing; Cardiac resynchronization therapy; Biventricular pacing; Univentricular pacing; LV only pacing; BiV, Biventricular pacing; CRT, Cardiac resynchronization therapy; GDMT, guideline directed medical therapy
Electrical storm (ES) due to drug refractory ventricular tachycardia (VT) occurring within first few weeks of acute myocardial infarction (MI) has poor prognosis. Catheter ablation has been proposed for treating VT occurring late after MI, but there is limited data on catheter ablation in VT within first few weeks of MI.
Methods and Results
Five patients (4 males, mean age 54.2±12.11 years) between June 2008 to July 2012, referred for VT presenting as ES refractory to antiarrhythmic drugs in the early post infarction period (six weeks following MI) despite revascularization. Three patients had anterior wall MI and two inferior wall MI with left ventricular ejection fraction ranging from 26 to 35%.All underwent catheter ablation within 48 hours of being in VT except one who presented late. Clinical VT was induced in all five patients. Total number of VTs induced were 11 (2.2±1.09 per patient). Two patients needed epicardial ablation via pericardial puncture. Though acute success was 100%, one patient had recurrence of clinical VT the next day of procedure.One patient succumbed to sepsis with multiple organ failure. The remaining four patients are doing well without further clinical recurrence of VT over a period of 3.7 years of follow-up.
Catheter ablation can be a useful adjunctive therapy for patients with recurrent VT in the early post infarction period. This procedure appears to be safe with acceptable success rate.
Electrical storm; Myocardial Infarction; Catheter Ablation
This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA - C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP ‘C’ allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population.
atrial natriuretic peptide; long QT syndrome; cardiogenesis; biomarker; polymorphisms
Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study.
We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India.
Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing.
Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.
TNNI3-Troponin I; Cardiomyopathy; SNPs; HCM; Indians; Mutations
Radiofrequency ablation is a therapeutic option for recurrent ventricular tachycardia (VT) in both ischaemic and non-ischaemic subsets. Usually this is attempted by mapping endocardially; however, in some situations epicardial approach may be needed to access the VT circuit. We report two cases in which epicardial approach was used to successfully ablate the VT, when endocardial ablation was ineffective.
Electroanatomic mapping; Epicardial approach; Substrate based mapping; Ventricular tachycardia (VT)
Reducing sympathetic output to the heart from the neuraxis can protect against ventricular arrhythmias. The purpose of this study was to assess the value of thoracic epidural anesthesia (TEA) and left cardiac sympathetic denervation (LCSD) in the management of ventricular arrhythmias in patients with structural heart disease (SHD).
Methods and Results
Clinical data of 14 patients (age 25-75 years, 54.2±16.6 yrs,(mean±SD) 13 males) who underwent TEA, LCSD, or both, to control ventricular tachycardia (VT) refractory to medical therapy and catheter ablation were reviewed.12 patients were in VT storm and 2 patients experienced recurrent VT despite maximal medical therapy and catheter ablation procedures. Total number of therapies per patient prior to either procedure ranged from 5 to 202 (median of 24, 25th and 75th percentile of 5 and 56). Eight patients underwent TEA and 9 patients underwent LCSD (3 patients had both procedures). No major procedural complications occurred. After initiation of TEA, 6 patients had a large (≥80%) decrease in VT burden. Post LCSD, 3 patients had no further VT, 2 patients had recurrent VT which either resolved within 24 hours or responded to catheter ablation, and 4 patients continued to have recurrent VT. Nine out of 14 patients survived to hospital discharge (1 TEA alone, 3 TEA/LCSD combined, 4 LCSD alone), one of whom underwent an urgent cardiac transplantation (TEA alone).
Initiation of TEA and LCSD in patients with refractory VT was associated with a subsequent decrease in arrhythmia burden in 6 out of 8 (75%- CI 51% to 91%) and 5 out of 9 (56%- CI 34% to 75%) patients, respectively. These data suggest that TEA and LCSD may be effective additions to the management of refractory ventricular arrhythmias in SHD when other treatment modalities have failed and/or may serve as a bridge to more definitive therapy.
ventricular tachyarrhythmias; nervous system; sympathetic
Familial hypertrophic cardiomyopathy (FHC) is a Mendelian disorder usually caused by mutations in any one of more than 12 genes, most of which encode sarcomere proteins. The disease exhibits extensive genetic heterogeneity, and it is important to identify mutations that result in adverse symptoms and/or lethality in affected individuals. An analysis of disease-causing mutations has been initiated in the Indian population to determine prevalent mutations.
FHC was detected using echocardiography and by analysis of clinical symptoms and family history. The disease-causing mutation was identified using polymerase chain reaction DNA sequencing.
The p.R787H mutation was identified in the MYH7 gene in two FHC families. Sequence and structure analysis suggested impaired binding of the mutant protein to the myosin essential light chain.
Although the mutation results in variable clinical symptoms in the affected individuals, probably owing to the effect of modifier genes and/or environmental factors, it does not appear to be a lethal mutation.
Beta-cardiac myosin heavy chain 7 gene; Familial hypertrophic cardiomyopathy; Hypertrophy; Mutation
Ventricular tachycardia (VT) occurring late after myocardial infarction is often due to reentry circuit in the peri-infarct zone. The circuit is usually located in the sub-endocardium, though subepicardial substrates are known. Activation mapping during VT to identify target regions for ablation can be difficult if VT is non inducible or poorly tolerated. In the latter, a substrate based approach of mapping during sinus rhythm in conjunction with pace mapping helps to define the reentry circuit and select target sites for ablation in majority of patients with hemodynamically unstable VT. Percutaneous epicardial catheter ablation has been attempted as an approach where ablation by a conventional endocardial access has been unsuccessful. We report a case of post myocardial infarction scar VT which could be successfully ablated with a substrate based approach from the epicardial aspect.
ventricular tachycardia; substrate based mapping; epicardial approach; electroanatomic mapping
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (~4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.
Drug refractory ventricular tachycardia (VT) occurring as a storm after acute myocardial infarction has grave prognosis. We report a case of a middle-aged lady who presented with drug refractory VT that lead to persistent electrical storm two weeks after an anterior wall myocardial infarction. She underwent a successful catheter ablation of VT followed a few days later by implantation of an AICD. Catheter ablation of the VT could control the persistent electrical storm and the patient was free from a recurrence of VT at three month follow up.
Electrical storm; Catheter ablation; Purkinje arborization triggers
Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disorder characterized mainly by left ventricular hypertrophy and myocyte disarray; it is the most common cause of sudden death in otherwise healthy individuals. More than 270 mutations in genes encoding the cardiac sarcomere have been identified. Attempts to establish a genotype-phenotype correlation for each of the mutations have not been highly successful. It has been suggested that additional genetic loci, as well as nongenetic factors such as lifestyle, gender and age, may play a role in modulating the clinical presentation of the disease. The p.R870H mutation has been identified as the cause of familial hypertrophic cardiomyopathy in an Indian family. The results indicate that the disease phenotype varied among various affected members of the family, and the variation may be attributed to factors, such as gender and gene dosage.
Angiotensin; Cardiomyopathy; Hypertrophy