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Circulation Journal : Official Journal... Nov 2023Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely...
BACKGROUND
Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like).
CONCLUSIONS
Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.
Topics: Child; Child, Preschool; Humans; Infant; Infant, Newborn; Arrhythmias, Cardiac; Calmodulin; East Asian People; Long QT Syndrome; Phenotype; Tachycardia, Ventricular; Death, Sudden, Cardiac
PubMed: 37380439
DOI: 10.1253/circj.CJ-23-0195 -
Journal of Cardiovascular... Mar 2024Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC... (Review)
Review
INTRODUCTION
Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC burden may lead to the development of PVC-induced cardiomyopathy (PVC-CM) even in patients without structural heart disease. Treatment for effective suppression of PVCs, can reverse PVC-CM. Both antiarrhythmic drugs (AADs) and catheter ablation (CA) are recognized treatment modalities for any cardiac arrhythmias. However, with increasing preference of CA, the role of AADs needs further defining regarding their efficacy, safety, indications and patient selection to treat PVC-CM.
METHODS
To ascertain the role of AADs to treat PVC-CM; whether they are indicated to treat PVC-CM, and if so, when, we interrogated PubMed and other search engines for English language publications with key words premature ventricular complexes (PVCs), cardiomyopathy, anti-arrhythmic drugs, catheter ablation, and pharmacological agents. All publications were carefully reviewed and scrutinized by the authors for their inclusion in the review paper. For illustration of cases, ethical standard was observed as per the 1975 Declaration of Helsinki, and the patient was treated as per the prevailing standard of care. Informed consent was obtained from the patient for conducting the ablation procedure.
RESULTS
Our literature search specifically the pharmacological treatment of PVC-CM with AADs revealed significant paradigm shift in treatment approach for PVCs and PVC-induced cardiomyopathy. No major large, randomized control trials of AADs versus CA for PVC-CM were found. We found that beta-blockers and calcium channel blockers are particularly effective in the treatment of PVCs originating from right ventricular outflow tract. For Class Ic AADs - flecainide and propafenone, small clinical studies showed Class Ic AADs to be effective in PVC suppression, but their usage was not recommended in patients with significant coronary artery disease. Mexiletine was found to have modest effect on PVC suppression. Studies showed sotalol to significantly reduce PVCs frequency in patients receiving both low and high doses. Studies also showed amiodarone to have higher successful PVC suppression, but not recommended as a first-line treatment for patients with idiopathic PVCs in the absence of symptoms and left ventricular dysfunction. For dronedarone, no major clinical data were available.
CONCLUSIONS
Based on the available data in the literature, we conclude that AADs play important role in the treatment of PVC-induced cardiomyopathy. However, appropriate patient selection criteria are vitally important, and in general terms AADs are indicated or polymorphic PVCs, epicardial PVCs; and when CA procedure is contraindicated, or not feasible or failed.
Topics: Humans; Anti-Arrhythmia Agents; Ventricular Premature Complexes; Stroke Volume; Ventricular Dysfunction, Left; Cardiomyopathies; Catheter Ablation
PubMed: 37676022
DOI: 10.1111/jce.16055 -
International Journal of Molecular... Oct 2023Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in...
Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
Topics: Humans; Brugada Syndrome; NAV1.5 Voltage-Gated Sodium Channel; Arrhythmias, Cardiac; Mutation
PubMed: 37894777
DOI: 10.3390/ijms242015089 -
Dermatology Practical & Conceptual Jul 2023Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent erythema, burning pain and warmth of the extremities. The symptoms greatly compromise...
INTRODUCTION
Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent erythema, burning pain and warmth of the extremities. The symptoms greatly compromise the patients' quality of life leading to severe disability. SCN9A mutations can be the cause of the disease. Dermatologists are often the specialists these patients turn to for assistance.
OBJECTIVES
To describe the demographic and clinical characteristics of patients with primary EM, to assess the presence and mutation types in the SCN9A gene, to evaluate the effectiveness of several therapeutic approaches, and to propose a diagnostic algorithm with therapeutic implications.
METHODS
A monocentric retrospective study using the database of patients with a discharge diagnosis of primary EM of our Center. Demographic, clinical, instrumental and laboratory data of patients were reviewed.
RESULTS
Eleven female patients (age range 16 to 57) were selected. All patients were affected in both the lower and upper extremities. Follow-up ranged from 2 to 9 years. Four patients had four different heterozygous variants of the SCN9A gene. Two patients, although genetically negative, had a suggestive family history. A variety of medications were tried in all our patients to alleviate symptoms, but their efficacy was variable, partial and/or transitory. The most effective therapies were antihistamines, venlafaxine, and mexiletine.
CONCLUSIONS
The diagnosis and treatment of EM remain challenging. Patients with this condition display a wide spectrum of clinical manifestations and severity, as well as a paucity of resources and structures to support them. Mutations in the SCN9A gene are not always detected.
PubMed: 37557164
DOI: 10.5826/dpc.1303a191 -
Circulation Jun 2024Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium...
Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, Transgenic Rabbits, and Patients.
BACKGROUND
Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.
METHODS
Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model.
RESULTS
After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD (∆APD shortening 113 ms), indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (= -0.8; <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate (=0.01).
CONCLUSIONS
Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.
PubMed: 38939955
DOI: 10.1161/CIRCULATIONAHA.124.068959 -
Biomedicines Aug 2023The present study was designed to test the hypothesis that the selectivity of blocking the late Na current (I) over the peak Na current (I) is related to the fast offset...
The present study was designed to test the hypothesis that the selectivity of blocking the late Na current (I) over the peak Na current (I) is related to the fast offset kinetics of the Na channel inhibitor. Therefore, the effects of 1 µM GS967 (I inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on I and I were compared in canine ventricular myocardium. I was estimated as the maximum velocity of action potential upstroke (V). Equal amounts of I were dissected by the applied drug concentrations under APVC conditions. The inhibition of I by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of I over I inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of I over I is related to the fast offset kinetics of the Na channel inhibitor.
PubMed: 37760824
DOI: 10.3390/biomedicines11092383 -
European Heart Journal May 2024Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether...
BACKGROUND AND AIMS
Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate.
METHODS
LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years.
RESULTS
Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (βB) therapy in 94% of them reduced the rate of those with a QTc ≥500 ms from 18% to 12% (P < .001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received βBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had CEs. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3.
CONCLUSIONS
Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events.
PubMed: 38751064
DOI: 10.1093/eurheartj/ehae289 -
Heart Rhythm Mar 2024Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A, which...
BACKGROUND
Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A, which encodes the cardiac sodium channel alpha subunit (Na1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families.
OBJECTIVE
The purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of Na1.5_p.V1525M.
METHODS
We studied sodium currents from patient-specific human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and heterologously transfected human embryonic kidney (HEK) tsA201 cells using the whole-cell patch-clamp technique. We determined gene and protein expression by quantitative polymerase chain reaction, RNA sequencing, and western blot and performed a genetic panel for arrhythmogenic diseases.
RESULTS
Our results showed a large reduction in I density in hiPSC-CM derived from 2 V1525M single nucleotide variant (SNV) carriers compared with hiPSC-CM derived from a noncarrier, suggesting a dominant-negative effect of the Na1.5_p.V1525M channel. I was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the Na1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of I function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued I function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses Na1.5_p.H558R.
CONCLUSION
Our results in patient-specific hiPSC-CM point to a dominant-negative effect of Na1.5_p.V1525M, which can be reverted by the presence of Na1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS.
Topics: Humans; Brugada Syndrome; Sodium; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel
PubMed: 38008367
DOI: 10.1016/j.hrthm.2023.11.019 -
Revue Neurologique May 2024Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as...
Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as lifestyle adaptation and avoiding key triggers. To understand how myotonia affects patients' lives, the IMPACT survey, an online questionnaire on patient-reported outcomes, was developed based on international IMPACT questionnaire. The French IMPACT 2022 survey was completed by 47 NDM French patients. Besides muscle stiffness (98%), patients reported muscle pain (83%), falls (70%) and anxiety (77%). These issues negatively impacted abilities to work/study (49%), daily life at home (49%) and overall mobility outside (49%). Most patients (96%) reported ongoing pharmacological treatment (mexiletine, 91%) associated with improvement in muscle stiffness (100%) and reduction in falls (94%), muscle pain (87%) and anxiety (80%). Patients were moderately satisfied (19.1%), satisfied (42.6%) and very satisfied (29.8%) with the current management; 32% rated their quality of life positively (≥ 8 on 10-point scale). In conclusion, this French survey confirms the impact of myotonia on daily life and quality of life. The improvement in patient-reported outcomes in treated participants highlights the importance of managing myotonia with effective treatments. More work should be initiated to assess the importance of NDM symptom management and patients' adherence and compliance to treatment.
PubMed: 38811249
DOI: 10.1016/j.neurol.2024.04.007 -
Clinics (Sao Paulo, Brazil) 2023Long QT Syndrome (LQTS) is an inherited disease with an abnormal electrical conduction system in the heart that can cause sudden death as a result of QT prolongation....
INTRODUCTION
Long QT Syndrome (LQTS) is an inherited disease with an abnormal electrical conduction system in the heart that can cause sudden death as a result of QT prolongation. LQT2 is the second most common subtype of LQTS caused by loss of function mutations in the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene. Although more than 900 mutations are associated with the LQTS, many of these mutations are not validated or characterized.
METHODS AND RESULTS
Sequencing analyses of genomic DNA of a family with LQT2 identified a putative mutation. i.e., KCNH2(NM_000238.3): c.3099_3112del, in KCNH2 gene which appeared to be a definite pathogenic mutation. The family pedigree information showed a gender difference in clinical features and T-wave morphology between male and female patients. The female with mutation exhibited recurring ventricular arrhythmia and syncope, while two male carriers did not show any symptoms. In addition, T-wave in females was much flatter than in males. The female proband showed a positive reaction to the lidocaine test. Lidocaine injection almost completely blocked ventricular arrhythmia and shortened the QT interval by ≥30 ms. Treatment with propranolol, mexiletine, and implantation of cardioverter-defibrillators prevented the sustained ventricular tachycardia, ventricular fibrillation, and syncope, as assessed by a 3-year follow-up evaluation.
CONCLUSIONS
A putative mutation c.3099_3112del in the KCNH2 gene causes LQT2 syndrome, and the pathogenic mutation mainly causes symptoms in female progeny.
Topics: Humans; Male; Female; Ether-A-Go-Go Potassium Channels; ERG1 Potassium Channel; Sex Factors; Mutation; Long QT Syndrome; Syncope; Lidocaine
PubMed: 37783170
DOI: 10.1016/j.clinsp.2023.100285