Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM. METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 (RPS6KB1 or S6K1) gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect. CONCLUSIONS: Our study demonstrates for the first time that the variants in the S6K1 gene are associated with HCM, and early detection of the S6K1 variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of S6K1 gene variants.

Outcomes in congenital and childhood complete atrioventricular block: A meta-analysis.

BACKGROUND: The long-term outcomes of patients with congenital and childhood complete atrioventricular block (CCAVB/CAVB) after pacemaker implantation are unclear. METHODS: We performed a meta-analysis of all the studies of CCAVB. A systematic search of PubMed and CENTRAL databases from January 1, 1967 to January 31, 2020 was performed. The quality of studies included was critically appraised using the Newcastle-Ottawa scale, and outcome data were analyzed using the restricted maximum likelihood function. RESULTS: Twenty-nine studies were eligible for analysis, with a total of 1553 patients. The all-cause-mortality was 5.7% (95% confidence interval [CI]: 2.5%-9.9%), while pacing-induced cardiomyopathy (PICM) was seen in 3.8% (95% CI: 1.2-7.2). Diagnosis at birth (effect size [ES] [95%CI]: -2.23 [-0.36 to -0.10]; p < .001), presence of congenital heart disease (ES [95%CI]: -0.67 [0.41-0.93]; p < .001), younger age at pacemaker implantation (ES [95%CI]: -0.01 [-0.02 to -0.001]; p = .02), and duration of pacing (ES [95%CI]: -0.03 [-0.05 to -0.003]; p = .03), were associated with an higher mortality on binominal logistic regression. None of the parameters were significant on multivariate analysis. CONCLUSION: Pooled proportional mortality in patients with CCAVB and CAVB is 5.7% with an infrequent incidence of PICM (3.8%) in the paced patients with AVB suggesting that pacing in these patients is an effective management strategy with a low incidence of long-term side effects. Registry and randomized data can throw additional light regarding the natural history and appropriate management strategy in these patients.

A histological study of the atria in patients with isolated rheumatic mitral regurgitation with and without atrial fibrillation.

BACKGROUND: There is a high incidence of atrial fibrillation (AF) in patients with isolated rheumatic mitral regurgitation (MR). The histopathologic changes in the atria of patients with isolated rheumatic MR with and without AF are unknown. OBJECTIVES: We aimed to determine the histological findings in patients with isolated severe rheumatic MR with and without AF. METHODS: Patients with severe isolated rheumatic MR undergoing valve replacement surgeries underwent endocardial biopsies from right atrial appendage, left atrial appendage, right free wall, left free wall, left posterior wall, and mitral valve. Group I consisted of patients in sinus rhythm (SR), and Group II included patients with AF. We analyzed and compared these 10 histological features in the biopsies of patients in Groups I and II. RESULTS: Of the 25 patients, 12 were in Group I and 13 in Group II. In Group I, patients had severe myocyte hypertrophy (60% vs. 18%, p = .04) that was significantly more in the right atrium (22.7% vs. 11.4%, p = .059). Interstitial adipose tissue deposition was more common in Group I (30% vs. 25%, p = .06). Interstitial fibrosis was evenly distributed at all sites without significant difference between the two groups. Group II patients had a higher prevalence and severity of vacuolar degeneration (91% vs. 60%, p = .09). CONCLUSIONS: Patients with isolated severe rheumatic MR and AF have more vacuolar degeneration in the atrial tissue. Patients with SR have myocyte hypertrophy and interstitial adipose tissue deposition. Interstitial fibrosis is uniformly distributed in patients in SR and AF.

A randomized study of yoga therapy for the prevention of recurrent reflex vasovagal syncope.

AIMS: Vasovagal syncope (VVS) is a common cardiovascular dysautonomic disorder that significantly impacts health and quality of life (QoL). Yoga has been shown to have a positive influence on cardiovascular autonomics. This study assessed the effectiveness of yoga therapy on the recurrence of VVS and QoL. METHODS AND RESULTS: We randomized subjects with recurrent reflex VVS (>3 episodes in the past 1 year) and positive head-up tilt test to guideline-directed therapy (Group 1) or yoga therapy (Group 2). Patients in Group 1 were advised guideline-directed treatment and Group 2 was taught yoga by a certified instructor. The primary endpoint was VVS recurrences and QoL. Between June 2015 and February 2017, 97 highly symptomatic VVS patients were randomized (Group 1: 47 and Group 2: 50). The mean age was 33.1 ± 16.6 years, male:female of 40:57, symptom duration of 17.1 ± 20.7 months, with a mean of 6.4 ± 6.1 syncope episodes. Over a follow-up of 14.3 ± 2.1 months Group 2 had significantly lower syncope burden compared with Group 1 at 3 (0.8 ± 0.9 vs. 1.8 ± 1.4, P < 0.001), 6 (1.0 ± 1.2 vs. 3.4 ± 3.0, P < 0.001), and at 12 months (1.1 ± 0.8 vs. 3.8 ± 3.2, P < 0.001). The Syncope functional score questionnaire was significantly lower in Group 2 compared with Group 1 at 3 (31.4 ± 7.2 vs. 64.1 ± 11.5, P < 0.001), 6 (26.4 ± 6.3 vs. 61.4 ± 10.7, P < 0.001), and 12 months (22.2 ± 4.7 vs. 68.3 ± 11.4, P < 0.001). CONCLUSION: For patients with recurrent VVS, guided yoga therapy is superior to conventional therapy in reducing symptom burden and improving QoL.

Safety and Efficacy of Ibutilide for Acute Pharmacological Cardioversion of Rheumatic Atrial Fibrillation.

INTRODUCTION: Ibutilide is indicated for acute cardioversion of nonvalvular atrial fibrillation (AF). However, its efficacy and safety in the pharmacological cardioversion of rheumatic AF are unknown. METHODS: Patients with mild-to-moderate rheumatic mitral valve (MV) disease with symptomatic, paroxysmal, or persistent AF were included in the analysis. Intravenous ibutilide was administered at doses tailored to body weight (0.5-2.0 mg) for over 10 min. The primary end point was efficacy, assessed as the rate of conversion of AF to sinus rhythm. The secondary end point was safety, including arrhythmic events and death within 24 h of drug initiation. RESULTS: From June 2016 to October 2018, 165 patients (94 with mitral stenosis, 23 with mitral regurgitation, 11 with mixed MV disease, and 37 with MV replacement) received ibutilide (mean dose 0.90 ± 0.54 mg). Ibutilide successfully converted AF to sinus rhythm in 127/165 (76.9%) patients, with a conversion time of 7.9 ± 4.1 min. The QTc increased from 419.9 ± 15.8 to 487.5 ± 34 ms after ibutilide administration (p < 0.001). The mean change in QTc after ibutilide administration (∆QTc) was 72.01 ± 36.03. There were no deaths, but 3 patients (1.8%) developed torsades de pointes (TdP) requiring defibrillation 55 ± 37 min after infusion. CONCLUSION: Ibutilide cardioverted 77% of rheumatic AF to sinus rhythm, indicating its potential as a clinically useful option for pharmacological cardioversion of rheumatic AF. TdP is a potentially serious adverse event that requires careful monitoring.

Effects of permanent cardiac pacing on ventricular repolarization when compared to cardioneuroablation.

INTRODUCTION: The impact of cardioneuroablation (CNA) on ventricular repolarization by using corrected QT interval (QTc) measurements has been recently demonstrated. The effects of cardiac pacing (CP) on ventricular repolarization have not been studied in patients with vasovagal syncope (VVS). We sought to compare ventricular repolarization effects of CNA (group 1) with CP (group 2) in patients with VVS. METHODS: We enrolled 69 patients with age 38 ± 13 years (53.6% male), n = 47 in group 1 and n = 22 in group 2. Clinical diagnosis of cardioinhibitory type was supported by cardiac monitoring or tilt testing. QTc was calculated at baseline (time-1), at 24 h after ablation (time-2), and at 9-12 months (time-3) in the follow-up. RESULTS: In the group 1, from time-1 to time-2, a significant shortening in QTcFredericia (from 403 ± 27 to 382 ± 27 ms, p < 0.0001), QTcFramingham (from 402 ± 27 to 384 ± 27 ms, p < 0.0001), and QTcHodges (from 405 ± 26 to 388 ± 24 ms, p < 0.0001) was observed which remained lower than baseline in time-3 (373 ± 29, 376 ± 27, and 378 ± 27 ms, respectively). Although the difference between measurements in time-1 and time-2 was not statistically significant for QTcBazett, a significant shortening was detected between time-1 and time-3 (from 408 ± 30 to 394 ± 33, p = 0.005). In the group 2, there was no time-based changes on QTc measurements. In the linear mixed model analysis, the longitudinal reduction tendency in the QTcFredericia and QTcFramingham was more pronounced in group 1. CONCLUSIONS: Our results demonstrate that CNA reduces QTc levels through neuromodulation effect whereas CP has no effect on ventricular repolarization in patients with VVS.

What are the atrioventricular delays in right ventricular apical and septal pacing for optimal hemodynamics in patients with normal left ventricular function?

INTRODUCTION: There is a surge of interest in alternate site pacing to prevent pacing-induced left ventricular dysfunction. However, little is known regarding the appropriate atrioventricular (AV) delay between right ventricular (RV) septal and RV apical pacing for optimal hemodynamic benefit. OBJECTIVES: To determine the programmed values of atrial sensed and atrial paced AV delays in basal RV septal and apical RV pacing that results in the maximum delivered stroke volume (SV). METHODS: We calculated the Doppler-derived SV at various sensed and paced AV delays in 50 patients with complete AV block implanted with a dual-chamber pacemaker (group A: 25 RV apical pacing; group B: 25 RV septal pacing). The hemodynamic difference in terms of the SV between sensed and paced AV delay, corresponding to the site of RV pacing was then compared for statistical significance. RESULTS: In group A, maximal SV was derived at a sensed AV delay of 123.2 ± 11 ms and paced AV delay of 129.2 ± 10 ms, and in group B, at a sensed AV delay of 123.6 ± 8 ms and paced AV delay of and 132.8 ± 7 ms. At these intervals, there was no difference in the SV between septal and apical RV pacing (P = .28 and .22, respectively). CONCLUSION: The atrial sensed and atrial paced AV delays for septal and apical RV pacing for optimal hemodynamics are similar. For optimal hemodynamics, the atrial paced AV delay is longer than the atrial sensed AV delay.

Transvenous pacing in complex post-operative congenital heart disease guided by angiography: A case report.

Transvenous pacing in patients with postoperative complex congenital heart disease (CHD) can be challenging and pose technical challenges to lead placement because of the complex anatomy, distortions produced by the surgical procedures, and the altered relationship of cardiac chambers. We describe the utility of angiography for transvenous dual chamber pacemaker implantation in a post-operative complex congenital heart disease.

Electrocardiographic characteristics and mapping approach of ventricular arrhythmias originating from the left ventricular summit.

The left ventricular summit is the most common site of idiopathic epicardial ventricular tachycardia (VT). We report a case of a 48-yr-old lady who presented with VT of RBBB configuration, inferior axis and delayed initial activation. During electrophysiological study, local activation in the distal great cardiac vein (GCV) preceded surface QRS by 56 ms whereas mapping in the aortic sinuses and left ventricular outflow tract endocardially revealed late activation. Ablation in the distal GCV with an irrigated catheter successfully terminated the tachycardia. The 12­lead electrocardiogram is an invaluable tool for predicting the VT focus and planning the mapping strategy.

An unusual case of complete atrioventricular block causing Takotsubo syndrome.

Complete atrioventricular (AV) block in association with Takotsubo syndrome (TS) has been well recognized, but the cause and effect relationship has not been elucidated. We describe a 78-year-old female who presented with complete AV block but one week later developed new-onset, diffuse T-wave inversions, QT prolongation, and acceleration of junctional escape rate. Left ventriculogram revealed features typical of TS. One year after permanent pacemaker implantation, complete AV block persisted despite the reversal of wall motion defects implying that conduction abnormality was the trigger of TS rather than its consequence.

Comparison of Efficacy, Pattern of Response, Occurrence of Arrhythmias, and the Tolerability of Nitroglycerine and Isoprenaline as Provocative Drugs During Head-Up Tilt Test.

BACKGROUND: Various protocols exist for performing head-up tilt test (HUTT). Serious ventricular arrhythmias have been reported during HUTT using Isoprenaline (ISO) provocation and their incidence with sublingual Nitroglycerine provocation is unknown. This study aims to assess the efficacy, pattern of response, tolerability, and frequency of arrhythmias during head-up tilt test with sublingual Nitroglycerine (NTG) provocation compared to ISO) provocation. METHODS: This is a retrospective observational study. RESULT: From 2007 to 2015, a total of 816 patients (68% men, median age 49 IQR 25.75-65 years) underwent head-up tilt testing using sublingual NTG provocation whereas ISO was used in 189 patients (66.1% men, median age 48 IQR 36-60 years). A positive response was more frequently observed in the NTG group than the ISO group (48.4% vs 35.9%, p=0.002), with more frequent type II b (cardio-inhibition with >3sec asystole) and type III (vasodepressor) responses ([15. 9% vs 4.1%, p=0.001] and 0% vs 29.4%, p=0.004) respectively. Bradyarrhythmias occurring always as a part of a positive HUTT response were the commonest arrhythmias (29% in NTG group vs 25.4% in ISO group, p=0.31). Tachyarrhythmias (or premature beats) were more frequent in the ISO group (12.7% vs 7.9%, p=<0.005). The use of NTG was significantly associated with a positive response (OR 1.775, 95% CI 1.269-2.483, p=0.001), whereas the use of ISO predicted the occurrence of premature beats/tachyarrhythmias (OR 3.06, 95% CI 2.195-4.267, p<0.005). Intolerance needing termination of the test was significantly more frequent in the ISO group than NTG group (1.6% vs 0.12%, p= 0.02). CONCLUSION: Head-up tilt test with NTG provocation has a higher yield of a positive response, lower incidence of unwanted arrhythmias and better tolerability compared to ISO. The occurrence of VASIS type II b and type III response was more with Nitroglycerine than Isoprenaline.

Evaluation of baseline ECG in patients undergoing Oral Flecainide Challenge test for suspected Brugada Syndrome: An analysis of lead II.

BACKGROUND AND OBJECTIVES: We analyzed Lead II in patients undergoing an Oral Flecainide Challenge test (FCT), to identify any pointers that could predict a positive FCT and thereby help in recognition of latent BS. METHODS: The following parameters in lead II were retrospectively analyzed from the pre-test ECG in 62 patients undergoing FCT for suspected BS: The presence or absence of S waves, S wave amplitude, duration and upslope duration; J point parameters- Early repolarization, QRS notch, and QRS Slur; ST segment parameters-lack of isoelectric ST segment, ST duration and QT interval. RESULTS: 48 had positive FCT (Group-1) while 14 were negative for FCT(Group-2). Lack of an isoelectric ST segment (50% vs 14.29%, p = 0.018) and slurring of QRS (33.33% vs 0%, p = 0.014) was more common in Group-1 than Group-2. Group-1 had shorter ST segment duration (median 81.5 (IQR 64-103.5) vs 110 (IQR 90-132), p = 0.002) and shorter ST: QT ratio (median 0.28 (IQR 0.22-0.35) vs 0.23 (0.18-0.27), p = 0.007). QRS notch/depressed J point (87.5%), QRS slur (100%), and lack of isoelectric ST segment (92.31%) had high sensitivity for predicting an inducible Type 1 Brugada pattern. Combining two parameters- ST: QT ratio<0.24 and lack of isoelectric ST segment-considerably improved the specificity (73.3%), and the positive predictive value of the test to 76%. The results remained accurate when validated in a small prospective cohort. CONCLUSION: Shortened ST segment in Lead II, lack of isoelectric ST segment, slurred QRS and ST/QT ratio <0.24 are predictive of underlying Brugada pattern in baseline ECG.

Histopathological Study of Left and Right Atria in Isolated Rheumatic Mitral Stenosis With and Without Atrial Fibrillation.

BACKGROUND: Mitral stenosis (MS) has the highest incidence of atrial fibrillation (AF) in chronic rheumatic valvular disease. There are very few studies in isolated MS comparing histopathological changes in patients with sinus rhythm (SR) and AF. OBJECTIVES: To analyze the histological changes associated with isolated MS and compare between changes in AF and SR. METHODS: This was a prospective study in patients undergoing valve replacement surgery for symptomatic isolated MS who were divided into 2 groups, Group I AF (n = 13) and Group II SR (n = 10). Intra-operative biopsies performed from 5 different sites from both atria were analyzed for 10 histopathologic changes commonly associated with AF. RESULTS: On multivariate analysis, myocytolysis (odds ratio [OR]: 1.48, P = 0.05) was found to be associated with AF, whereas myocyte hypertrophy (OR: 0.21, P = 0.003), and glycogen deposition (OR: 0.43, P = 0.002) was associated with SR. Interstitial fibrosis the commonest change was uniformly distributed across both atria irrespective of the rhythm. CONCLUSION: In rheumatic MS, SR is associated with myocyte hypertrophy whereas AF is associated with myocytolysis. Endocardial inflammation is more common in left atrial appendage irrespective of rhythm. Interstitial fibrosis is seen in >90% of patients distributed in both the atria and is independent of the rhythm. Amyloid and Aschoff bodies are uncommon and the rest of the changes are uniformly distributed across both the atria.

Suicidal Zinc Phosphide Poisoning Unmasking Brugada Syndrome and Triggering Near Fatal Ventricular Arrhythmia.

Brugada syndrome (BrS) is an inherited channelopathy associated with increased incidence of ventricular arrhythmias and has many acquired triggers. Zinc phosphide (ZnP) is a rodenticide and is commonly implicated in suicidal poison ingestion. ZnP poisoning can cause myocardial toxicity and death. We report a case of ZnP poisoning that triggered a type I Brugada pattern and ventricular fibrillation in a 67-year-old male. He had no other features of toxicity and recovered later. As metal phosphide is the commonest toxin involved in suicidal poisoning in India and BrS being endemic here, this case highlights an important clinical problem.

Diagnostic dilemma with a narrow QRS regular rhythm at normal rates in a patient with corrected transposition of great arteries.

A 35 year old male, known case of corrected transposition of great arteries presented with exertional dyspnea and recurrent pre-syncope. 12 lead electrocardiogram revealed a regular rhythm at 75 beats per minute, P waves occurring on the upstroke of T waves and apparent 1:1 P-QRS relationship. The possibilities to be considered - complete AV block with junctional escape, junctional rhythm with 1:1 retrograde conduction, junctional rhythm with isorhythmic AV dissociation and prolonged PR interval have been discussed.

Genotype-phenotype correlation in long QT syndrome families.

Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1-4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of "anticipation" in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.

Transvenous permanent pacemaker implantation in dextrocardia: technique, challenges, outcome, and a brief review of literature.

AIMS: Dextrocardia is a rare congenital anomaly. Pacemaker implantation in dextrocardia can be challenging because of the distorted anatomy and associated anomalies. The literature regarding implantation of pacemaker in dextrocardia is scarce. METHODS AND RESULTS: The study involved retrospective analysis of records of patients with dextrocardia who had undergone pacemaker implantation between January 2006 and July 2013 from a single centre. Six patients with dextrocardia (five males and one female) underwent permanent pacemaker implantation (PPI) between January 2006 and July 2013. Of them, three had situs solitus dextrocardia and three situs inversus dextrocardia. All three patients with situs solitus dextrocardia had associated corrected transposition of great arteries. The indication for pacemaker implantation was symptomatic complete atrioventricular (AV) block in four, high-grade AV block in one, and sinus node dysfunction in one patient. A favourable outcome was noted during a mean follow-up of 3.9 years (4 months to 7 years) with one patient needing a pulse generator replacement. CONCLUSION: Permanent pacemaker implantation in dextrocardia can be challenging because of the distorted anatomy. Use of a technique employing angiography to delineate chamber anatomy and relationship can assist the operator during such difficult PPIs. The medium- and long-term survival after a successful pacemaker implantation in dextrocardia is favourable.