Publications by authors named "Michael J Ackerman"

681 Publications

Role of Chronic, Long Term Intravenous Lidocaine in the Clinical Management of Patients with Malignant Type 3 Long QT Syndrome.

Heart Rhythm 2021 Sep 16. Epub 2021 Sep 16.

Department of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, Minnesota; Department of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, Minnesota; Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Type 3 long QT syndrome (LQT3) is caused by pathogenic, gain-of-function variants in SCN5A leading to a prolonged action potential, ventricular ectopy, and torsades de pointes. Treatment options include pharmacotherapy, cardiac denervation, and/or device therapy. Rarely, patients with malignant LQT3 require cardiac transplantation.

Objective: To evaluate the role of chronic, continuous intravenous (IV) lidocaine as a therapeutic option for select patients with LQT3 refractory to standard therapy.

Methods: We performed a retrospective review of patients evaluated and treated at Mayo Clinic and identified 4/161 (2.5%) LQT3 patients who were refractory to standard therapies and therefore treated with IV lidocaine.

Results: There were 4 patients (2/4 female). The median age at first IV lidocaine infusion was 2 months (IQR=1.5-4.8 months) and median cumulative duration on IV lidocaine was 11.5 months (IQR=8.7-17.8 months). The main indication for IV lidocaine in all patients was persistent ventricular arrhythmias. Prior to IV lidocaine, all patients received an implantable cardioverter-defibrillator and while on intermittent IV lidocaine, all patients underwent bilateral cardiac sympathetic denervation. Additionally, 2 patients had cardiac ablation for premature ventricular complexes. In all patients, lidocaine infusion resulted in a significant reduction of LQT3-triggered cardiac events. The main side effects of IV lidocaine observed were dizziness (n=2) and seizures (n=2). During follow-up, 3/4 patients underwent an orthotopic cardiac transplant. The remaining patient continues to receive IV lidocaine bolus for rescue as needed.

Conclusion: For patients with LQT3 who are refractory to standard treatment, chronic IV lidocaine infusion can be used as a potential 'bridge-to-transplant'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hrthm.2021.09.016DOI Listing
September 2021

Changes in ion channel expression and function associated with cardiac arrhythmogenic remodeling by Sorbs2.

Biochim Biophys Acta Mol Basis Dis 2021 Sep 4;1867(12):166247. Epub 2021 Sep 4.

The Departments of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA. Electronic address:

The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is an important component of cardiomyocyte sarcomere. It has been recently reported that loss of Sorbs2 is causally associated with arrhythmogenic cardiomyopathy in human. However, the ionic mechanisms leading to cardiac arrhythmogenesis by Sorbs2 deficiency are unknown. In this study, we hypothesized that Sorbs2 plays an important role in regulating cardiac ion channel expression and function. Using electrophysiological and molecular biological approaches, we found that the Sorbs2 knockout (KO) mice progressively developed cardiac structural and electrical remodeling as early as 1 to 2 months of age and died prematurely at 5 to 7 months of age. Electrocardiographic recordings showed that Sorbs2 KO mice had conduction delays, spontaneous ventricular extrasystoles and polymorphic ventricular tachyarrhythmia. Intracellular recordings revealed abnormal action potentials with depolarized resting potential, reduced upstroke velocity, prolonged repolarization, and effective refractory period in the ventricular preparations of Sorbs2 KO mice. Patch clamp experiments demonstrated that Sorbs2 KO mice displayed distinct abnormalities in the expression and function of cardiac ion channels, including those of the voltage-gated Na channels, L-type Ca channels, the voltage-gated K channels and the inward-rectifier K channels. Moreover, Sorbs2 physically interacted with the RNAs and/or proteins of important cardiac ion channels and directly regulated their expression in vitro. Our results indicate that Sorbs2 plays a pivotal role in the regulation of cardiac channel physiology. Loss of Sorbs2 promotes cardiac ion channelopathies and life-threatening arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2021.166247DOI Listing
September 2021

Detection of hypertrophic cardiomyopathy by an artificial intelligence electrocardiogram in children and adolescents.

Int J Cardiol 2021 Oct 19;340:42-47. Epub 2021 Aug 19.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, United States of America; Department of Molecular Pharmacology & Experimental Therapeutics; Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Background: There is no established screening approach for hypertrophic cardiomyopathy (HCM). We recently developed an artificial intelligence (AI) model for the detection of HCM based on the 12‑lead electrocardiogram (AI-ECG) in adults. Here, we aimed to validate this approach of ECG-based HCM detection in pediatric patients (age ≤ 18 years).

Methods: We identified a cohort of 300 children and adolescents with HCM (mean age 12.5 ± 4.6 years, male 68%) who had an ECG and echocardiogram at our institution. Patients were age- and sex-matched to 18,439 non-HCM controls. Diagnostic performance of the AI-ECG model for the detection of HCM was estimated using the previously identified optimal diagnostic threshold of 11% (the probability output derived by the model above which an ECG is considered to belong to an HCM patient).

Results: Mean AI-ECG probabilities of HCM were 92% and 5% in the case and control groups, respectively. The area under the receiver operating characteristic curve (AUC) of the AI-ECG model for HCM detection was 0.98 (95% CI 0.98-0.99) with corresponding sensitivity 92% and specificity 95%. The positive and negative predictive values were 22% and 99%, respectively. The model performed similarly in males and females and in genotype-positive and genotype-negative HCM patients. Performance tended to be superior with increasing age. In the age subgroup <5 years, the test's AUC was 0.93. In comparison, the AUC was 0.99 in the age subgroup 15-18 years.

Conclusions: A deep-learning, AI model can detect pediatric HCM with high accuracy from the standard 12‑lead ECG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2021.08.026DOI Listing
October 2021

Mapping human calreticulin regions important for structural stability.

Biochim Biophys Acta Proteins Proteom 2021 Nov 4;1869(11):140710. Epub 2021 Aug 4.

Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania. Electronic address:

Calreticulin (CALR) is a highly conserved multifunctional chaperone protein primarily present in the endoplasmic reticulum, where it regulates Ca homeostasis. Recently, CALR has gained special interest for its diverse functions outside the endoplasmic reticulum, including the cell surface and extracellular space. Although high-resolution structures of CALR exist, it has not yet been established how different regions and individual amino acid residues contribute to structural stability of the protein. In the present study, we have identified key residues determining the structural stability of CALR. We used a Saccharomyces cerevisiae expression system to express and purify 50 human CALR mutants, which were analysed for several parameters including secretion titer, melting temperature (T), stability and oligomeric state. Our results revealed the importance of a previously identified small patch of conserved surface residues, amino acids 166-187 ("cluster 2") for structural stability of the human CALR protein. Two residues, Tyr172 and Asp187, were critical for maintaining the native structure of the protein. Mutant D187A revealed a severe drop in secretion titer, it was thermally unstable, prone to degradation, and oligomer formation. Tyr172 was critical for thermal stability of CALR and interacted with the third free Cys163 residue. This illustrates an unusual thermal stability of CALR dominated by Asp187, Tyr172 and Cys163, which may interact as part of a conserved structural unit. Besides structural clusters, we found a correlation of some measured parameter values in groups of CALR mutants that cause myeloproliferative neoplasms (MPN) and in mutants that may be associated with sudden unexpected death (SUD).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbapap.2021.140710DOI Listing
November 2021

Return-to-Play for Athletes With Long QT Syndrome or Genetic Heart Diseases Predisposing to Sudden Death.

J Am Coll Cardiol 2021 Aug;78(6):594-604

Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA; Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota, USA; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Background: Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete's return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe.

Objectives: This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play.

Methods: A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020.

Results: There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up.

Conclusions: This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.04.026DOI Listing
August 2021

Comparison of electrocardiograms (ECG) waveforms and centralized ECG measurements between a simple 6-lead mobile ECG device and a standard 12-lead ECG.

Ann Noninvasive Electrocardiol 2021 Jul 19:e12872. Epub 2021 Jul 19.

Windland Smith Rice Comprehensive Sudden Cardiac Death Program, Divisions of Heart Rhythm Services and Pediatric Cardiology, Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Background: Interval duration measurements (IDMs) were compared between standard 12-lead electrocardiograms (ECGs) and 6-lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand-held mobile device designed for use by patients at home.

Methods: Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12-lead and 6-lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi-automated technique.

Results: Despite differences in patient position (supine for 12-lead ECGs and sitting for 6-lead ECGs), mean IDMs were comparable, with mean values for the 12-lead and 6-lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, -5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities.

Conclusions: The 6-lead hand-held device is potentially useful for a clinical follow-up of remote patients, and for a safety follow-up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12-lead ECG recordings during the current COVID-19 pandemic as remote patient monitoring becomes more common in virtual or hybrid-design clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/anec.12872DOI Listing
July 2021

Risk Prediction in Women With Congenital Long QT Syndrome.

J Am Heart Assoc 2021 Jul 9;10(14):e021088. Epub 2021 Jul 9.

Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life-threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome-related sudden cardiac death), and was applied with the end point of life-threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow-up duration among the 767 enrolled women was 22 243 patient-years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype-phenotype data, we identified 3 risk groups with 10-year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10-year projected rates of life-threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65-0.71) and 0.71 (95% CI 0.66-0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60-0.70) and 0.77 (95% CI 0.70-0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life-threatening events in women with type 1 or type 2 long QT based on personalized genotype-phenotype data. The projected risk estimates can be used to guide female-specific management in long QT syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.121.021088DOI Listing
July 2021

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

Circ Arrhythm Electrophysiol 2021 Jul 9;14(7):e009726. Epub 2021 Jul 9.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (W.Z.).

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.009726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301722PMC
July 2021

A call for training programmes in cardiovascular genomics.

Nat Rev Cardiol 2021 Aug;18(8):539-540

Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41569-021-00586-5DOI Listing
August 2021

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

J Arrhythm 2021 Jun 8;37(3):481-534. Epub 2021 Apr 8.

The First Affiliated Hospital of Nanjing Medical University Nanjing China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/joa3.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207384PMC
June 2021

Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death.

Nat Rev Cardiol 2021 May 24. Epub 2021 May 24.

Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's University of London and St George's University Hospitals NHS Foundation Trust, London, UK.

A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41569-021-00555-yDOI Listing
May 2021

Precision Medicine Approaches to Cardiac Arrhythmias: JACC Focus Seminar 4/5.

J Am Coll Cardiol 2021 May;77(20):2573-2591

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Sydney, New South Wales, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.03.325DOI Listing
May 2021

Development of a Patient-Specific p.D85N-Potassium Voltage-Gated Channel Subfamily E Member 1-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for Drug-Induced Long QT Syndrome.

Circ Genom Precis Med 2021 Jun 18;14(3):e003234. Epub 2021 May 18.

Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (M.K., D.Y., C.S.J.K., W.Z., D.J.T., J.R.G., M.J.A.).

Background: Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (KCNE1) common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM).

Methods: p.D85N-KCNE1 iPSCs were generated from a 23-year-old female with an exaggerated heart rate-corrected QT interval response to metoclopramide (ΔQTc of 160 ms). Clustered regularly interspaced short palindromic repeats-associated 9 technology was used to generate gene-corrected isogenic iPSCs. Field potential duration and action potential duration (APD) were measured from iPSC-CMs.

Results: At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer field potential duration (281±15 ms, n=13 versus 223±8.6 ms, n=14, <0.01) and action potential duration at 90% repolarization (APD90; 579±22 ms, n=24 versus 465±33 ms, n=26, <0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2 nM increased significantly field potential duration (379±20 ms, n=13, <0.01) and APD90 (666±11 ms, n=46, <0.01) in p.D85N-KCNE1 iPSC-CMs but not in isogenic-control. The effect of dofetilide on APD90 (616±54 ms, n=7 versus 526±54 ms, n=10, <0.05) was confirmed by Patch-clamp. Interestingly, treatment of p.D85N-KCNE1 iPSC-CMs with estrogen at a concentration of 1 nM exaggerated further dofetilide-induced APD90 prolongation (696±9 ms, n=81, <0.01) and caused more early afterdepolarizations (11.7%) compared with isogenic control (APD90: 618±8 ms, n=115 and early afterdepolarizations: 2.6%, <0.05).

Conclusions: This iPSC-CM study provides further evidence that the p.D85N-KCNE1 common variant in combination with environmental factors such as QT prolonging drugs and female sex is proarrhythmic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003234DOI Listing
June 2021

Myocardial Histopathology in Patients With Obstructive Hypertrophic Cardiomyopathy.

J Am Coll Cardiol 2021 May;77(17):2159-2170

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological features including myocyte hypertrophy, myocyte disarray, and interstitial fibrosis.

Objectives: This study sought to correlate myocardial histopathology with clinical characteristics of patients with obstructive HCM and post-operative outcomes following septal myectomy.

Methods: The authors reviewed the pathological findings of the myocardial specimens from 1,836 patients with obstructive HCM who underwent septal myectomy from 2000 to 2016. Myocyte hypertrophy, myocyte disarray, interstitial fibrosis, and endocardial thickening were graded and analyzed.

Results: The median age at operation was 54.2 years (43.5 to 64.3 years), and 1,067 (58.1%) were men. A weak negative correlation between myocyte disarray and age at surgery was identified (ρ = -0.22; p < 0.001). Myocyte hypertrophy (p < 0.001), myocyte disarray (p < 0.001), and interstitial fibrosis (p < 0.001) were positively associated with implantable cardioverter-defibrillator implantation. Interstitial fibrosis (p < 0.001) and endocardial thickening (p < 0.001) were associated with atrial fibrillation pre-operatively. In the Cox survival model, older age (p < 0.001), lower degree of myocyte hypertrophy (severe vs. mild hazard ratio: 0.41; 95% confidence interval: 0.19 to 0.86; p = 0.040), and lower degree of endocardial thickening (moderate vs. mild hazard ratio: 0.75; 95% confidence interval: 0.58 to 0.97; p = 0.019) were independently associated with worse post-myectomy survival. Among 256 patients who had genotype analysis, patients with pathogenic or likely pathogenic variants (n = 62) had a greater degree of myocyte disarray (42% vs. 15% vs. 20%; p = 0.022). Notably, 13 patients with pathogenic or likely pathogenic genetic variants of HCM had no myocyte disarray.

Conclusions: Histopathology was associated with clinical manifestations including the age of disease onset and arrhythmias. Myocyte hypertrophy and endocardial thickening were negatively associated with post-myectomy mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.03.008DOI Listing
May 2021

Clinical Impact of Secondary Risk Factors in -Mediated Dilated Cardiomyopathy.

Circ Genom Precis Med 2021 04 19;14(2):e003240. Epub 2021 Apr 19.

Department of Cardiovascular Medicine, Division of Circulatory Failure (S.S., N.L.P.), Mayo Clinic, Rochester, MN.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284363PMC
April 2021

Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.

EClinicalMedicine 2021 Mar 27;33:100773. Epub 2021 Feb 27.

Division of Allergy and Infectious Diseases, University of Washington, United States.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.

Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.

Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60,  = 0.047) but not HCQ/AZ (HR=1.25,  = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63-1.64,  = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57-1.45,  = 0.70).

Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.

Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. ClinicalTrials.gov number NCT04354428.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912360PMC
March 2021

Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.

EClinicalMedicine 2021 Mar 27;33:100773. Epub 2021 Feb 27.

Division of Allergy and Infectious Diseases, University of Washington, United States.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.

Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.

Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60,  = 0.047) but not HCQ/AZ (HR=1.25,  = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63-1.64,  = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57-1.45,  = 0.70).

Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.

Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. ClinicalTrials.gov number NCT04354428.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912360PMC
March 2021

Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features.

Circ Genom Precis Med 2021 04 10;14(2):e003097. Epub 2021 Feb 10.

Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.

Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of -positive probands, and clinical evaluation was performed.

Results: Genetic screening of led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).

Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284361PMC
April 2021

Use of Artificial Intelligence and Deep Neural Networks in Evaluation of Patients With Electrocardiographically Concealed Long QT Syndrome From the Surface 12-Lead Electrocardiogram.

JAMA Cardiol 2021 May;6(5):532-538

Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: Long QT syndrome (LQTS) is characterized by prolongation of the QT interval and is associated with an increased risk of sudden cardiac death. However, although QT interval prolongation is the hallmark feature of LQTS, approximately 40% of patients with genetically confirmed LQTS have a normal corrected QT (QTc) at rest. Distinguishing patients with LQTS from those with a normal QTc is important to correctly diagnose disease, implement simple LQTS preventive measures, and initiate prophylactic therapy if necessary.

Objective: To determine whether artificial intelligence (AI) using deep neural networks is better than the QTc alone in distinguishing patients with concealed LQTS from those with a normal QTc using a 12-lead electrocardiogram (ECG).

Design, Setting, And Participants: A diagnostic case-control study was performed using all available 12-lead ECGs from 2059 patients presenting to a specialized genetic heart rhythm clinic. Patients were included if they had a definitive clinical and/or genetic diagnosis of type 1, 2, or 3 LQTS (LQT1, 2, or 3) or were seen because of an initial suspicion for LQTS but were discharged without this diagnosis. A multilayer convolutional neural network was used to classify patients based on a 10-second, 12-lead ECG, AI-enhanced ECG (AI-ECG). The convolutional neural network was trained using 60% of the patients, validated in 10% of the patients, and tested on the remaining patients (30%). The study was conducted from January 1, 1999, to December 31, 2018.

Main Outcomes And Measures: The goal of the study was to test the ability of the convolutional neural network to distinguish patients with LQTS from those who were evaluated for LQTS but discharged without this diagnosis, especially among patients with genetically confirmed LQTS but a normal QTc value at rest (referred to as genotype positive/phenotype negative LQTS, normal QT interval LQTS, or concealed LQTS).

Results: Of the 2059 patients included, 1180 were men (57%); mean (SD) age at first ECG was 21.6 (15.6) years. All 12-lead ECGs from 967 patients with LQTS and 1092 who were evaluated for LQTS but discharged without this diagnosis were included for AI-ECG analysis. Based on the ECG-derived QTc alone, patients were classified with an area under the curve (AUC) value of 0.824 (95% CI, 0.79-0.858); using AI-ECG, the AUC was 0.900 (95% CI, 0.876-0.925). Furthermore, in the subset of patients who had a normal resting QTc (<450 milliseconds), the QTc alone distinguished those with LQTS from those without LQTS with an AUC of 0.741 (95% CI, 0.689-0.794), whereas the AI-ECG increased this discrimination to an AUC of 0.863 (95% CI, 0.824-0.903). In addition, the AI-ECG was able to distinguish the 3 main genotypic subgroups (LQT1, LQT2, and LQT3) with an AUC of 0.921 (95% CI, 0.890-0.951) for LQT1 compared with LQT2 and 3, 0.944 (95% CI, 0.918-0.970) for LQT2 compared with LQT1 and 3, and 0.863 (95% CI, 0.792-0.934) for LQT3 compared with LQT1 and 2.

Conclusions And Relevance: In this study, the AI-ECG was found to distinguish patients with electrocardiographically concealed LQTS from those discharged without a diagnosis of LQTS and provide a nearly 80% accurate pregenetic test anticipation of LQTS genotype status. This model may aid in the detection of LQTS in patients presenting to an arrhythmia clinic and, with validation, may be the stepping stone to similar tools to be developed for use in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2020.7422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876623PMC
May 2021

Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R.

Channels (Austin) 2021 12;15(1):253-261

Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin , Madison, WI, USA.

: Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current ( ) amplitude of the mutant channel by increasing the cell surface expression of SCN5A. : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19336950.2021.1875645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872018PMC
December 2021

Artificial Intelligence-Enabled Assessment of the Heart Rate Corrected QT Interval Using a Mobile Electrocardiogram Device.

Circulation 2021 03 1;143(13):1274-1286. Epub 2021 Feb 1.

Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic (L.W.D., Z.I.A., P.A.N., P.A.F., M.J.A.), Mayo Clinic, Rochester, MN.

Background: Heart rate-corrected QT interval (QTc) prolongation, whether secondary to drugs, genetics including congenital long QT syndrome, and/or systemic diseases including SARS-CoV-2-mediated coronavirus disease 2019 (COVID-19), can predispose to ventricular arrhythmias and sudden cardiac death. Currently, QTc assessment and monitoring relies largely on 12-lead electrocardiography. As such, we sought to train and validate an artificial intelligence (AI)-enabled 12-lead ECG algorithm to determine the QTc, and then prospectively test this algorithm on tracings acquired from a mobile ECG (mECG) device in a population enriched for repolarization abnormalities.

Methods: Using >1.6 million 12-lead ECGs from 538 200 patients, a deep neural network (DNN) was derived (patients for training, n = 250 767; patients for testing, n = 107 920) and validated (n = 179 513 patients) to predict the QTc using cardiologist-overread QTc values as the "gold standard". The ability of this DNN to detect clinically-relevant QTc prolongation (eg, QTc ≥500 ms) was then tested prospectively on 686 patients with genetic heart disease (50% with long QT syndrome) with QTc values obtained from both a 12-lead ECG and a prototype mECG device equivalent to the commercially-available AliveCor KardiaMobile 6L.

Results: In the validation sample, strong agreement was observed between human over-read and DNN-predicted QTc values (-1.76±23.14 ms). Similarly, within the prospective, genetic heart disease-enriched dataset, the difference between DNN-predicted QTc values derived from mECG tracings and those annotated from 12-lead ECGs by a QT expert (-0.45±24.73 ms) and a commercial core ECG laboratory [10.52±25.64 ms] was nominal. When applied to mECG tracings, the DNN's ability to detect a QTc value ≥500 ms yielded an area under the curve, sensitivity, and specificity of 0.97, 80.0%, and 94.4%, respectively.

Conclusions: Using smartphone-enabled electrodes, an AI DNN can predict accurately the QTc of a standard 12-lead ECG. QTc estimation from an AI-enabled mECG device may provide a cost-effective means of screening for both acquired and congenital long QT syndrome in a variety of clinical settings where standard 12-lead electrocardiography is not accessible or cost-effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050231DOI Listing
March 2021

Efficacy of intentional permanent atrial pacing in the long-term management of congenital long QT syndrome.

J Cardiovasc Electrophysiol 2021 03 10;32(3):782-789. Epub 2021 Feb 10.

Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota, USA.

Background: Unfortunately, some patients with long QT syndrome (LQTS) experience breakthrough cardiac events (BCEs) despite maximal therapy. Small studies have shown that refractory LQTS cases may benefit from intentional permanent atrial pacing (IPAP). As such, we sought to determine the genotype-specific utilization and efficacy of IPAP in a single-center LQTS registry.

Methods And Results: In this retrospective study, electronic medical records from 1065 patients diagnosed with LQTS were used to identify individuals that received IPAP. Pre- and post-IPAP heart rate, heart rate-corrected QT (QTc) values, annual BCE rate, and IPAP-related complications were compared between genotypes. BCEs were defined as LQTS-associated syncope/seizures, sustained ventricular arrhythmia (VA)-terminating ICD therapies, and sudden cardiac arrest/death. Overall, 52 out of 1065 LQTS patients received adjunctive IPAP therapy (77% female; median age 18.5 [interquartile range, 1-35.5] years; 73% with prior VA). Over an average IPAP follow-up of 121 ± 82 months, the average heart rate increased from 65.8 ± 20.4 bpm to 78.9 ± 17.1 bpm; (p < .01) and the average QTc decreased from 533.4 ± 66.6 to 488.3 ± 52.4 ms; (p < .01). The mean BCE rate dropped from 0.88 to 0.19 per patient-year (p = .01), driven by a marked decrease in the LQT2 cohort (1.01 BCE/year to 0.02 BCE/year; p = .003). No serious IPAP-related complications were observed.

Conclusion: In high-risk LQTS patients, namely those with recalcitrant LQT2, IPAP appears to be a safe and efficacious adjunct therapy. The beneficial effects of IPAP may stem from attenuating the QTc and circumventing a pause-dependent trigger. Whether IPAP might obviate the need for an ICD in some instances warrants further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.14920DOI Listing
March 2021

Suppression-Replacement Gene Therapy for Type 1 Long QT Syndrome.

Circulation 2021 Apr 28;143(14):1411-1425. Epub 2021 Jan 28.

Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the -encoded K7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1.

Methods: A dual-component suppression-and-replacement (SupRep) gene therapy was created by cloning a short hairpin RNA and a short hairpin RNA-immune cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep.

Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls.

Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051836DOI Listing
April 2021

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Eur Heart J 2021 03;42(11):1073-1081

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart (ERN GUARDHEART http://guardheart.ern-net.eu).

Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of 'reduced RVOT conduction reserve'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa1051DOI Listing
March 2021

Conversion of left atrial volume to diameter for automated estimation of sudden cardiac death risk in hypertrophic cardiomyopathy.

Echocardiography 2021 02 16;38(2):183-188. Epub 2020 Dec 16.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Background: A subset of patients with hypertrophic cardiomyopathy (HCM) is at high risk of sudden cardiac death (SCD). Practice guidelines endorse use of a risk calculator, which requires entry of left atrial (LA) diameter. However, American Society of Echocardiography (ASE) guidelines recommend the use of LA volume index (LAVI) for routine quantification of LA size. The aims of this study were to (a) develop a model to estimate LA diameter from LAVI and (b) evaluate whether substitution of measured LA diameter by estimated LA diameter derived from LAVI reclassifies HCM-SCD risk.

Methods: The study cohort was comprised of 500 randomly selected HCM patients who underwent transthoracic echocardiography (TTE). LA diameter and LAVI were measured offline using digital clips from TTE. Linear regression models were developed to estimate LA diameter from LAVI. A European Society of Cardiology endorsed equation estimated SCD risk, which was measured using LA diameter and estimated LA diameter derived from LAVI.

Results: The mean LAVI was 48.5 ± 18.8 mL/m . The derived LA diameter was 45.1 mm (SD: 5.5 mm), similar to the measured LA diameter (45.1 mm, SD: 7.1 mm). Median SCD risk at 5 years estimated by measured LA diameter was 2.22% (interquartile range (IQR): 1.39, 3.56), while median risk calculated by estimated LA diameter was 2.18% (IQR: 1.44, 3.52). 476/500 (95%) patients maintained the same risk classification regardless of whether the measured or estimated LA diameter was used.

Conclusions: Substitution of measured LA diameter by estimated LA diameter in the HCM-SCD calculator did not reclassify risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/echo.14943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986336PMC
February 2021

Echocardiography-Guided Risk Stratification for Long QT Syndrome.

J Am Coll Cardiol 2020 12;76(24):2834-2843

Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Background: The ability to identify those patients at the highest phenotypic risk for long QT syndrome (LQTS)-associated life-threatening cardiac events remains suboptimal.

Objectives: This study sought to validate the association between electromechanical window (EMW) negativity, as derived from echocardiography, and symptomatic versus asymptomatic status in patients with LQTS.

Methods: We analyzed a cohort of 651 patients with LQTS (age 26 ± 17 years; 60% females; 158 symptomatic; 51% LQTS type 1; 33% LQTS type 2; 11% LQTS type 3; 5% multiple mutations) and 50 healthy controls. EMW was calculated as the difference between the interval from QRS onset to aortic valve closure midline, as derived for continuous-wave Doppler, and the electrocardiogram-derived QT interval for the same beat.

Results: A negative EMW was found among nearly all patients with LQTS compared to controls, with more profound EMW negativity in patients with symptomatic LQTS compared to those with asymptomatic LQTS (-52 ± 38 ms vs. -18 ± 29 ms; p < 0.0001). Logistic regression identified EMW, heart rate-corrected QT interval (QTc), female sex, and LQTS genotype as univariate predictors of symptomatic status. After multivariate analysis, EMW remained an independent predictor of symptomatic status (odds ratio for each 10-ms decrease in EMW: 1.37; 95% confidence interval: 1.27 to 1.48; p < 0.0001). EMW outperformed QTc in predicting symptomatic patients (area under the curve: 0.78 vs. 0.70; p = 0.01). After training and implementation, EMW correlation from echocardiographic sonographers showed excellent reliability (intraclass correlation coefficient: 0.93; 95% confidence interval: 0.89 to 0.96).

Conclusions: In this validation study, patients with a history of LQTS-associated life-threatening cardiac events had a more profoundly negative EMW. EMW outperformed heart rate-corrected QT interval as a predictor of symptomatic status. EMW is now a clinically validated risk factor. In December 2019, our institution's echocardiography clinical practice committee approved use of EMW for patients with LQTS, making it a routinely reported echocardiographic finding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2020.10.024DOI Listing
December 2020

Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

PLoS One 2020 24;15(11):e0242747. Epub 2020 Nov 24.

Lankenau Institute for Medical Research, Wynnewood, PA, United States of America.

Background: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin.

Methods: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF.

Results: Acacetin (5-10 μM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF.

Conclusions: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242747PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685455PMC
January 2021

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.

JACC Clin Electrophysiol 2020 11 26;6(12):1561-1570. Epub 2020 Aug 26.

Joe DiMaggio Children's Hospital Heart Institute, Memorial Healthcare System, Hollywood, Florida, USA.

Objectives: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).

Background: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.

Methods: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.

Results: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).

Conclusions: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679474PMC
November 2020

Left Cardiac Sympathetic Denervation Monotherapy in Patients With Congenital Long QT Syndrome.

Circ Arrhythm Electrophysiol 2020 12 16;13(12):e008830. Epub 2020 Nov 16.

Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (T.N., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN.

Background: Videoscopic left cardiac sympathetic denervation (LCSD) is an effective antifibrillatory, minimally invasive therapy for patients with potentially life-threatening arrhythmia syndromes like long QT syndrome (LQTS). Although initially used primarily for treatment intensification following documented LQTS-associated breakthrough cardiac events while on beta-blockers, LCSD as 1-time monotherapy for certain patients with LQTS requires further evaluation. We are presenting our early experience with LCSD monotherapy for carefully selected patients with LQTS.

Methods: Among the 1400 patients evaluated and treated for LQTS, a retrospective review was performed on the 204 patients with LQTS who underwent LCSD at our institution since 2005 to identify the patients where the LCSD served as stand-alone, monotherapy. Clinical data on symptomatic status before diagnosis, clinical, and genetic diagnosis, and breakthrough cardiac events after diagnosis were analyzed to determine efficacy of LCSD monotherapy.

Result: Overall, 64 of 204 patients (31%) were treated with LCSD alone (37 [58%] female, mean QTc 466±30 ms, 16 [25%] patients were symptomatic before diagnosis with a mean age at diagnosis 17.3±11.8 years, 5 had [8%] ≥1 breakthrough cardiac event after diagnosis, and mean age at LCSD was 21.1±11.4 years). The primary motivation for LCSD monotherapy was an unacceptable quality of life stemming from beta-blocker related side effects (ie, beta-blocker intolerance) in 56/64 patients (88%). The underlying LQTS genotype was LQT1 in 36 (56%) and LQT2 in 20 (31%). There were no significant LCSD-related surgical complications. With a mean follow-up of 2.7±2.4 years so far, only 3 patients have experienced a nonlethal, post-LCSD breakthrough cardiac event in 180 patient-years.

Conclusions: LCSD may be a safe and effective stand-alone therapy for select patients who do not tolerate beta-blockers. However, LCSD is not curative and patient selection will be critical when potentially considering LCSD as monotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.120.008830DOI Listing
December 2020

Prevalence and Phenotypic Correlations of Calmodulinopathy-Causative Variants Detected in a Multicenter Molecular Autopsy Cohort of Sudden Unexplained Death Victims.

Circ Genom Precis Med 2020 12 15;13(6):e003032. Epub 2020 Nov 15.

Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics (D.J.C., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003032DOI Listing
December 2020
-->