Citations

Introduction: The main goal of Clinical Decision Support (CDS) is to provide timely and useful information for providers to deliver high-quality and safe care. Issues, like alert fatigue and provider burnout are commonly cited as unintended consequences of the CDS systems. Herein, we describe leveraging electronic health record (EHR) self-service reporting tools to gain insights on a CDS rule designed to avoid providers from ordering QT-prolonging medication in patients with history of QT-prolongation. Methods: Our EHR (Epic) SlicerDicer reporting tool was used to identify the frequency of QT-prolongation Best Practice Advisory (BPA) triggerings from 1/1/2020 to 12/31/2020 across Mayo Clinic sites. Additionally, associated patient encounter and BPA-specific data were queried. Text from acknowledgement comments to the BPA were reviewed and central themes and comments were categorized. Epic Clarity Data Warehouse was queried to identify the BPA-triggering medications and frequencies. Comparisons of percent action taken on the BPA were compared internally to Mayo Clinic’s BPA benchmark, and with national benchmarks using Epic BestPractice Pulse dashboard. Results: A total of 17,538 BPAs of interest were triggered across the Mayo Clinic sites in 2020, of which 3,696 (20.1%) were acted upon through either monitoring or medication discontinuation. This is below Mayo Clinic’s median of 29.2% for inpatient BPAs and 45.6% BPAs for outpatient, but above the national median of 10% (IQR 6.1-13.1%) for inpatient and 10% (IQR 4.3-19.5%) for outpatient BPAs actioned upon. A total of 30 different medications triggered the BPA, with the most common being ondansetron (41.5%), amiodarone (11.3%), and haloperidol (10.1%). User comments were left on 2,382 orders (13.5%) that acknowledged the BPA, but provided argument to prescribe drug. Three most common themes identified from comments on overridden BPAs: patient previously tolerated medication (19.0%), QT interval not prolonged on recent ECG (14.2%), and patient on hospice care (5.2%). Conclusion: Analysis of free text comments of CDS can be and should be performed to reveal opportunities for further improvement of CDS. Providers should be encouraged to provide comments when encountering CDS interventions.

Background: Multifocal ectopic Purkinje-related premature contractions (MEPPC), the most recent addition to the spectrum of SCN5A -mediated cardiac channelopathies, is characterized by frequent premature ventricular complexes (PVCs) originating from the Purkinje system, atrial arrhythmias, and a predilection for PVC-mediated dilated cardiomyopathy. MEPPC-causative variants tend to cluster within the voltage sensing domain (VSD) of Na v 1.5. Objective: To describe the clinical and cellular electrophysiological phenotype associated with a novel, putative MEPPC-causative SCN5A variant (p.Gln419Pro-SCN5A) that resides outside the VSD of Na v 1.5. Methods: p.Gln419Pro-SCN5A was identified in a 21-year-old male with a history of frequent, multifocal PVCs and atrial tachycardia. Subsequently, three p.Gln419Pro-SCN5A-positive relatives, each with early onset atrial arrhythmias and/or frequent, multifocal PVCs, were identified. All individuals had structurally normal hearts by echocardiography and/or cardiac magnetic resonance imaging. p.Gln419Pro-SCN5A was engineered by site directed mutagenesis and heterologously expressed in TSA201 cells. The standard whole-cell patch clamp technique was used to measure SCN5A wild-type (WT) and p.Gln419Pro-SCN5A sodium currents. Results: Analysis of the current-voltage relationship revealed that neither peak sodium current densities nor late inward sodium current were impacted by p.Gln419Pro-SCN5A. However, p.Gln419Pro-SCN5A significantly shifted V 1/2 in inactivation by -4.6 mV from -84.5±0.7 mV (WT, n=10) to -89.1±0.4 mV (Gln419Pro, n=12, p<0.05 vs. WT) and V 1/2 in activation by -11.6 mV from -30.9±1.3 mV (WT, n=10) to -42.5±1.0 mV (Gln419Pro, n=12, p<0.05 vs. WT) leading to a larger hyperpolarized window current. Flecainide dramatically reduced PVC burden in p.Gln419Pro-SCN5A-positive patients. Conclusions: p.Gln419Pro-SCN5A represents only the fifth MEPPC-causative variant described to date and the first associated with a classic MEPPC phenotype localizing outside Na v 1.5’s VSD. As class I antiarrhythmic drugs are highly efficacious in MEPPC, this clinical entity merits consideration in all young patients found to have a high burden of Purkinje-related PVCs.

Background: Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy Syndrome (TS) with severe QT prolongation, cardiac hypertrophy, syndactyly, facial dysmorphisms, developmental delay, and sudden death by impaired channel inactivation and increase peak current. Recently, a small number of patients with CACNA1C mutations with only long QT syndrome (LQTS) have been described. Objective: To explore whether CACNA1C mutations associated with TS were mechanistically and clinically distinct from CACNA1C-mediated LQTS. Methods/Results: Illumina HiSeq 2000 platform-based whole exome sequencing with variant alignment using HGSC Mercury analysis and Atlas2 revealed a novel variant CACNA1C-L762F that co-segregated with affected patients of a large, multi-generational family with LQTS and sudden death. The proband presented at 3 years of age with out-of-hospital cardiac arrest and demonstrated QTc of 530. The mutation localized to the DII/DIII intracellular linker domain of the channel in a highly conserved region in close proximity to the 6th DI transmembrane domain. Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased late current indicating its gain-of-function cellular electrophysiological phenotype. Comprehensive review and topological mapping of all described CACNA1C mutations associated with TS or LQTS revealed disease-specific hotspots. TS-associated mutations localized to cytoplasmic aspects of transmembrane domains while LQTS-associated mutations localized to cytoplasmic N- and C-terminal domains and linker regions. Probands hosting TS mutations demonstrated markedly prolonged QTc values compared to LQTS (618 vs 486 ms, p<0.001) and were younger at presentation (2.7 vs 20.1 years, p<0.002). Supporting these associations, the L762F mutation localized closer to the CACNA1C transmembrane domain than any other LQTS mutation and are associated with a QTc and age of diagnosis reflective of TS-associated mutations. Conclusions: The CACNA1C-L762F mutation is associated with biochemical and clinical features which highlight a molecular and clinical distinction between TS- and LQTS-associated CACNA1C mutations.

Introduction: Although most patients with mitral valve prolapse (MVP) have a benign prognosis, there is a subgroup with bileaflet MVP syndrome (biMVPS) at increased risk of idiopathic ventricular fibrillation (VF). The phenotypic features of this syndrome include myxomatous bileaflet prolapse, complex ventricular ectopy (VE), T-wave inversion in inferolateral ECG leads, and female predominance. The mechanism of ventricular arrhythmia in these patients is unknown. Methods: We reviewed our center’s ablation experience of 14 consecutive patients with biMVPS patients between February 2007 and October 2013 (n=13 female, median [range] age at index ablation 33.8 [21.0 - 58.7] years, left ventricular ejection fraction [EF] 60 [45-67] %, all ≤ moderate mitral regurgitation [MR]). We compared findings from 6 with prior sudden cardiac arrest (SCA) and recurrent ICD shocks for drug refractory VF with 8 who had symptomatic drug-refractory complex VE but without prior SCA. Results: All patients with prior SCA had a predominant VE trigger for the VF. There was no difference between the two groups in EF, MR severity, VE burden, and number of different VE morphologies or foci ablated. Sites of successful VE ablation at index procedure were the LV papillary muscles (PM, n=6 anterior, 6 posterior), fascicular system (n=5 anterior, 4 posterior), mitral annulus (n=2), outflow tracts (3 RVOT, 1 LVOT), and coronary sinus (n=1). All patients had at least one LV papillary or fascicular VE focus. Purkinje origin VE was identified as the VF trigger in 6/6 SCA patients (3 from PM, 3 from LV fascicles) and only 4/8 (none from PM) non-SCA patients (p=0.04). Acute success was seen in 17/19 procedures with no complications. VF storm occurred within 24 hours of ablation in a single patient. At 310 (39 - 2099) days follow-up, 1 SCA patient received a single shock (p=0.031 compared to pre-ablation), and symptoms from VE were reduced in 12/14. Conclusions: BiMVPS is characterized by VE from the LV fascicles and papillary muscles that trigger VF. The VE is invariably multifocal and may also involve the outflow tracts and mitral annulus. Ablation of clinically dominant VE foci alleviates symptoms and reduces the number of VF-terminating ICD shocks.

Introduction: Congenital long QT syndrome (LQTS) is a sudden cardiac death-predisposing genetic disorder that has a characteristic electrocardiographic signature. Specific LQTS genotypes have been associated classically with different qualitative electrocardiographic ST - T wave patterns; however, clinical recognition of these patterns could be improved by an automated and quantitative method. We therefore aimed to use a novel, quantitative T wave morphological analysis technique from 12-lead surface ECGs to identify genotype specific LQTS ECG patterns. Methods: We analyzed a genotyped cohort of 420 patients (22 ± 15.7years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using a custom T wave program to automatically detect subtle changes in T wave morphology across all 12 Leads. Classification was performed using the top three T wave features in a linear discriminant classifier by 10x10 cross-validation. Results: The top three discriminant features were (1) a steeper T wave left slope for LQT1 in lead II (2950 vs 1700 mV/ms, p < 0.0001), (2) a greater center of gravity in 1st segment of T wave in lead aVR in LQT1 (0.248 vs 0.209, p<0.0001) and (3) a smaller Tpeak - Tend/QT ratio in lead aVR in LQT1 (0.20 vs 0.24, p<0.0001). Using these top three features, we were able to successfully differentiate LQT1 and LQT2 in 79% of cases (figure 1). Conclusions: An automated morphological T wave analysis was able to discriminate between the two most common LQTS genotypes. This novel method enhances phenotypic characterization of LQT and could have a significant clinical impact on the diagnosis and management of patients with suspected LQTS.

Abstract Background Pathogenic variants in the lamin A/C gene (LMNA) can lead to a wide range of phenotypes from dilated and arrhythmogenic cardiomyopathies and conduction abnormalities to partial lipodystrophies. This case highlights a coincidental pathogenic LMNA variant identified in a patient with sudden cardiac arrest (SCA). We demonstrate the need for careful interpretation of pathogenic variants identified in cardiomyopathy genes by highlighting a case in which a coincidental pathogenic LMNA variant was found in a patient with premature ventricular complex (PVC)-induced ventricular fibrillation (VF). Case summary We present the case of a 16-year-old male with SCA secondary to VF. Genetic testing identified a maternally inherited pathogenic variant in LMNA annotated c.1961dup; p.T655Nfs*49. The patient received an implantable cardiac defibrillator and was discharged on nadolol. The patient’s two brothers were also variant-positive. However, the patient and both brothers had normal chamber dimensions on echocardiogram and no late gadolinium enhancement on cardiac magnetic resonance imaging. The family members with the variant were recommended to have prophylactic implantable cardiac defibrillators and thus sought a second opinion. The patient received an appropriate shock and device interrogation identified PVCs. Electrophysiology study identified PVC-induced VF which was ablated with no recurrent ventricular arrhythmias/implantable cardioverter defibrillator therapies over 8 months of follow-up. Although the variant in LMNA could lead to cardiac arrest, the clinical phenotype was consistent with a non-genetic aetiology. The family members were told to have periodic cardiac evaluation. Discussion This case demonstrates the identification of a coincidental pathogenic variant in a cardiomyopathy gene in a patient with cardiac arrest. Although this variant could lead to cardiomyopathy, it appears the cardiac arrest was not due to the pathogenic variant. This highlights the need to consider the clinical phenotype when interpreting genetic test results for cardiomyopathies even in the presence of a positive genetic test result.

Abstract Proper management of patients affected by genetic disorders causing life-threatening arrhythmias is important for several reasons, including even societal ones, given the predominantly young age of those affected. Incorrect management often has dire consequences, ranging from unnecessary psychologic damage for the patients whose life becomes too limited by the fear of sudden death to equally avoidable tragedies when the entire armamentarium of effective therapies is not fully utilized. In this review, we focus primarily on long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of the most commonly used cardiac sympathetic denervation (CSD), namely left cardiac sympathetic denervation (LCSD). The two of us have used LCSD in the management of our patients with either LQTS or CPVT for a very long time and have been involved in ∼500 such interventions. It is on the basis of this personal and direct experience that we wish to share our views with clinical cardiologists and electrophysiologists, adult and paediatric, and with genetic cardiologists. We will begin by reviewing the history and rationale underlying sympathetic denervation therapy and will continue with a disease-specific intensification of therapy, and then with a discussion on how the impressive efficacy of LCSD should translate into guideline-directed therapy in both current and future guidelines, in order to upgrade the quality of care in the era of precision medicine.

Abstract An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation–contraction coupling. However, the mutual influencing of excitation–contraction and mechano-electrical feedback in the beating heart, here designated ‘electromechanical reciprocity’, remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed—by volume loading during the rapid filling phase—when repolarization is still ongoing. This creates a ‘sensitized’ electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management.

AbstractStudy ObjectiveThe primary objective of this retrospective safety study was to determine the incidence of torsades de pointes (TdP) or death following perioperative administration of low‐dose, 4 mg, ondansetron for postoperative nausea and vomiting.Design and SettingThis is a single‐center retrospective clinical trial.PatientsThe authors identified 32,737 patients who received 37,589 doses of ondansetron during a 2‐year time frame between March 2009 and February 2011 for surgical nausea prophylaxis or treatment of nausea.Measurements and Main ResultsPatients were cross‐matched with an electrocardiogram and adverse outcome database; this identified 4759 patients with documentation of a QTc >450 milliseconds (ms), all ventricular tachycardias including TdP within 48 hours of receiving ondansetron, or death within 7 days of receiving ondansetron. No patients developed TdP or died as a direct result of ondansetron administration (n = 0; event rate = 0.0 per 10,000, 95% CI 0.0 to 1.1 per 10,000). Forty‐six of 32,737 surgical patients had documented monomorphic ventricular tachycardia (VT) (n = 14; event rate = 4.3 per 10,000, 95% CI 2.3 to 7.2 per 10,000) or died (n = 32; event rate = 9.8 per 10,000, 95% CI 6.7 to 13.8 per 10,000) within 48 h of ondansetron administration. All monomorphic VT episodes were precipitated by existing cardiovascular disease; and 7 of 14 patients had documented monomorphic VT prior to receiving ondansetron. Of the 32 surgical patients who died, all deaths were precipitated by pre‐existing disease.ConclusionNo episodes of TdP were identified in patients receiving ondansetron perioperatively. This suggests that low‐dose ondansetron does not contribute to the development of TdP.

Background: Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. Methods: Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. Results: Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P =0.05) SCA survivors and 8 out of 68 (11.8%; P =0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P <0.02) SUD cases without ventricular fibrosis. Conclusions: Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.