Study to establish genetic association of cardiac conduction defect in Indian patients undergoing pacemaker implantation

Background: The aim was to study the genetic association of cardiac conduction defects (CCDs) by evaluating single nucleotide polymorphism (SNP) in genes of SCN1B and KCNJ2 and to evaluate baseline characteristics between cases and controls.Methods: Case group consisted of 81 individuals with diagnosis of conduction disturbances who underwent permanent pacemaker implantation. The control group consisted of 79 unrelated individuals above 18 years of age of the local population not having a present or past personal or family history (first degree relatives) of any cardiac ailment especially CCDs. Isolation of genomic deoxyribonucleic acid (DNA) from all samples was done, genomic DNA was checked to ensure the presence of intact DNA.Results: SCN1B: SNP rs55742440 had no bearing on the protein except in producing a splice variant. SNP rs67701503 does not lie in the splice-site region, thus not having any significance in the regulation of the gene as well. NetGene2 analysis of SNP rs67486287 negates its presence in the splice site. KCNJ2:SNP rs199473653 leads to a missense amino acid change, resulting in homozygous GG variant found in almost equal frequency in both groups. SNP rs199473653 gene has not been reported as a disease causing mutation.Conclusions: The alteration of nucleotide in SCN1B intron (SNP rs55742440, rs67701503, rs67486287) between cases and controls was found to have no odds of affecting the outcome of CCD. There was no variation or alteration in nucleotide bases of KCNJ2 (SNP rs786205813, rs199473653) between the groups.

Cardiac Emerinopathy

Background: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. Methods: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). Results: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. Conclusions: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.

Complete atrioventricular block due to timolol eye drops: a case report and literature review

Background Timolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block. Case presentation A 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (− 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup. Conclusion We conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.