Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis. CASE PRESENTATION: The male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby's parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child. CONCLUSIONS: CPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia: a landmark study.

AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

Management of patients with an electrical storm or clustered ventricular arrhythmias: a clinical consensus statement of the European Heart Rhythm Association of the ESC-endorsed by the Asia-Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin-American Heart Rhythm Society.

Electrical storm (ES) is a state of electrical instability, manifesting as recurrent ventricular arrhythmias (VAs) over a short period of time (three or more episodes of sustained VA within 24 h, separated by at least 5 min, requiring termination by an intervention). The clinical presentation can vary, but ES is usually a cardiac emergency. Electrical storm mainly affects patients with structural or primary electrical heart disease, often with an implantable cardioverter-defibrillator (ICD). Management of ES requires a multi-faceted approach and the involvement of multi-disciplinary teams, but despite advanced treatment and often invasive procedures, it is associated with high morbidity and mortality. With an ageing population, longer survival of heart failure patients, and an increasing number of patients with ICD, the incidence of ES is expected to increase. This European Heart Rhythm Association clinical consensus statement focuses on pathophysiology, clinical presentation, diagnostic evaluation, and acute and long-term management of patients presenting with ES or clustered VA.

First implantable cardiac defibrillator insertions in New South Wales, 2005-2020: an analysis of linked administrative data.

OBJECTIVES: To determine the annual numbers of first ICD insertions in New South Wales during 2005-2020; to examine health outcomes for people who first received ICDs during this period. STUDY DESIGN: Retrospective cohort study; analysis of linked administrative health data. SETTING, PARTICIPANTS: All first insertions of ICDs in NSW, 2005-2020. MAIN OUTCOME MEASURES: Annual numbers of first ICD insertions, and of emergency department presentations and hospital re-admissions 30 days, 90 days, 365 days after first ICD insertions; all-cause and disease-specific mortality (to ten years after ICD insertion). RESULTS: During 2005-2020, ICDs were first inserted into 16 867 people (18.5 per 100 000 population); their mean age was 65.7 years (standard deviation, 13.5 years; 7376 aged 70 years or older, 43.7%), 13 214 were men (78.3%). The annual number of insertions increased from 791 in 2005 to 1256 in 2016; the first ICD insertion rate increased from 15.5 in 2005 to 18.9 per 100 000 population in 2010, after which the rate was stable until 2019 (19.8 per 100 000 population). Of the 16 778 people discharged alive from hospital after first ICD insertions, 54.4% presented to emergency departments within twelve months, including 1236 with cardiac arrhythmias (7.4%) and 434 with device-related problems (2.6%); 56% were re-admitted to hospital, including 1944 with cardiac arrhythmias (11.5%) and 2045 with device-related problems (12.1%). A total of 5624 people who received first ICDs during 2005-2020 (33.3%) died during follow-up (6.7 deaths per 100 person-years); the survival rate was 94.4% at one year, 76.5% at five years, and 54.2% at ten years. CONCLUSIONS: The annual number of new ICDs inserted in NSW has increased since 2005. A substantial proportion of recipients experience device-related problems that require re-admission to hospital. The potential harms of ICD insertion should be considered when assessing the likelihood of preventing fatal ventricular arrhythmia.

Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia.

AIMS: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. METHODS AND RESULTS: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). CONCLUSION: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.

Leadless pacemakers at 5-year follow-up: the Micra transcatheter pacing system post-approval registry.

BACKGROUND AND AIMS: Prior reports have demonstrated a favourable safety and efficacy profile of the Micra leadless pacemaker over mid-term follow-up; however, long-term outcomes in real-world clinical practice remain unknown. Updated performance of the Micra VR leadless pacemaker through five years from the worldwide post-approval registry (PAR) was assessed. METHODS: All Micra PAR patients undergoing implant attempts were included. Endpoints included system- or procedure-related major complications and system revision rate for any cause through 60 months post-implant. Rates were compared through 36 months post-implant to a reference dataset of 2667 transvenous pacemaker patients using Fine-Gray competing risk models. RESULTS: 1809 patients were enrolled between July 2015 and March 2018 and underwent implant attempts from 179 centres in 23 countries with a median follow-up period of 51.1 months (IQR: 21.6-64.2). The major complication rate at 60 months was 4.5% [95% confidence interval (CI): 3.6%-5.5%] and was 4.1% at 36 months, which was significantly lower than the 8.5% rate observed for transvenous systems (HR: .47, 95% CI: .36-.61; P < .001). The all-cause system revision rate at 60 months was 4.9% (95% CI: 3.9%-6.1%). System revisions among Micra patients were mostly for device upgrades (41.2%) or elevated thresholds (30.6%). There were no Micra removals due to infection noted over the duration of follow-up. At 36 months, the system revision rate was significantly lower with Micra vs. transvenous systems (3.2% vs. 6.6%, P < .001). CONCLUSIONS: Long-term outcomes with the Micra leadless pacemaker continue to demonstrate low rates of major complications and system revisions and an extremely low incidence of infection.

An Overview of Arrhythmias in Pregnancy.

Cardiovascular disease significantly jeopardizes pregnancies in the United States, impacting 1% to 4% of pregnancies annually. Among complications, cardiac arrhythmias are prevalent, posing concerns for maternal and fetal health. The incidence of arrhythmias during pregnancy is rising, partly due to advances in congenital heart surgery and a growing population of women with structural heart disease. While most arrhythmias are benign, the increasing prevalence of more serious arrhythmias warrants a proactive approach. Guidance and reassurance suffice in many cases, but persistent symptoms require cautious use of antiarrhythmic drugs or other therapies for a safe outcome. Managing more serious arrhythmias requires a comprehensive, multidisciplinary approach involving specialists, including maternal-fetal medicine physicians, cardiologists, electrophysiologists, and anesthesiologists.

Efficient termination of cardiac arrhythmias using optogenetic resonant feedback pacing.

Malignant cardiac tachyarrhythmias are associated with complex spatiotemporal excitation of the heart. The termination of these life-threatening arrhythmias requires high-energy electrical shocks that have significant side effects, including tissue damage, excruciating pain, and worsening prognosis. This significant medical need has motivated the search for alternative approaches that mitigate the side effects, based on a comprehensive understanding of the nonlinear dynamics of the heart. Cardiac optogenetics enables the manipulation of cellular function using light, enhancing our understanding of nonlinear cardiac function and control. Here, we investigate the efficacy of optically resonant feedback pacing (ORFP) to terminate ventricular tachyarrhythmias using numerical simulations and experiments in transgenic Langendorff-perfused mouse hearts. We show that ORFP outperforms the termination efficacy of the optical single-pulse (OSP) approach. When using ORFP, the total energy required for arrhythmia termination, i.e., the energy summed over all pulses in the sequence, is 1 mJ. With a success rate of 50%, the energy per pulse is 40 times lower than with OSP with a pulse duration of 10 ms. We demonstrate that even at light intensities below the excitation threshold, ORFP enables the termination of arrhythmias by spatiotemporal modulation of excitability inducing spiral wave drift.

Arrhythmias in Adult Congenital Heart Disease Heart Failure.

Heart failure and arrhythmias represent 2 major causes of mortality and morbidity in adults with congenital heart disease. Arrhythmias and heart failure are interdependent, and one may exacerbate the other. Treatment of one also has a positive impact on the other. Management approaches need to be multifaceted, including pharmacotherapy, optimization of hemodynamic status with catheter-based or surgical interventions, and specific management of arrhythmia with device or catheter ablation therapy.

Pacemaker remote monitoring challenges in pediatric population: Single center long term experience.

BACKGROUND: Remote monitoring (RM) of cardiac implantable electronic devices for adults offers improved treatment efficacy and, consequently, better patient clinical outcomes. There is scant data on the value and prognosis of RM in the pediatric population. AIMS: The goal of this study was to determine the efficacy of RM by analyzing the connectivity of bedside transmitters, adherence to planned automatic follow-ups, and occurrence of alert-based events. METHODS: We evaluated the pediatric population with implanted pacemakers for congenital AV block or after surgically corrected congenital heart diseases. RESULTS: A total of 69 patients were included in our study. The median (Q1-Q3) patient age was 6.0 (2.0-11.0) years. All patients received bedside transmitters and were enrolled in the RM system. Among them, 95.7% of patients had their first scheduled follow-up successfully sent. Patients were followed up remotely over a median time of 33.0 (13-45) months. Only 42% of patients were continuously monitored, and all scheduled transmissions were delivered on time. Further analysis revealed that 34.8% of patients missed transmissions between June and September (holiday season). Alert-based events were observed in 40.6% patients, mainly related to epicardial lead malfunction and arrhythmic events. Overall compliance was also compromised by socioeconomic factors. CONCLUSIONS: Our findings are in concordance with recently published results by PACES regarding a high level of compliance in patient enrollment to RM and time to initial transmission. However, a lower level of adherence was observed during the holiday season due to interrupted connectivity of bedside transmitters. Importantly, a relatively low occurrence of alert transmissions was observed, mainly related to epicardial lead malfunction and arrhythmic events.

Transvenous Pacemaker Placement: A Review for Emergency Clinicians.

BACKGROUND: Transvenous pacemaker placement is an integral component of therapy for severe dysrhythmias and a core skill in emergency medicine. OBJECTIVE: This narrative review provides a focused evaluation of transvenous pacemaker placement in the emergency department setting. DISCUSSION: Temporary cardiac pacing can be a life-saving procedure. Indications for pacemaker placement include hemodynamic instability with symptomatic bradycardia secondary to atrioventricular block and sinus node dysfunction; overdrive pacing in unstable tachydysrhythmias, such as torsades de pointes; and failure of transcutaneous pacing. Optimal placement sites include the right internal jugular vein and left subclavian vein. Insertion first includes placement of a central venous catheter. The pacing wire with balloon is then advanced until electromechanical capture is obtained with the pacer in the right ventricle. Ultrasound can be used to guide and confirm lead placement using the subxiphoid or modified subxiphoid approach. The QRS segment will demonstrate ST segment elevation once the pacing wire tip contacts the endocardial wall. If mechanical capture is not achieved with initial placement of the transvenous pacer, the clinician must consider several potential issues and use an approach to evaluating the equipment and correcting any malfunction. Although life-saving in the appropriate patient, complications may occur from central venous access, right heart catheterization, and the pacing wire. CONCLUSIONS: An understanding of transvenous pacemaker placement is essential for emergency clinicians.

Strategies to improve atrioventricular synchrony in patients with a Micra AV leadless pacemaker.

The second generation of transcatheter pacing systems, called Micra AV, can provide atrioventricular (AV) synchronous pacing via a new pacing algorithm relying on sensing mechanical atrial contraction. Several novel programming parameters were introduced to enable AV synchronous pacing, including an A3 window and A4 window as well as a conduction mode switch and an activity mode switch. In addition to several automated features, manual programming optimization of some of the novel parameters is key to improving AV synchrony. A solid knowledge of the features and their programming is essential for electrophysiologists implanting or following patients with Micra AV devices. Differences in programming optimization might partially explain the high variability of AV synchrony published in real-world data reports. This article reviews the key programming parameters of Micra AV. Subsequently, optimal programming recommendations for defined patient profiles are presented. Those were established by consensus within an expert panel comprised of 11 European electrophysiologists from high-volume Micra AV centres. The patient profiles were (1) high degree AV block and slow sinus rhythm; (2) high degree AV block and fast sinus rhythm; and (3) intermittent AV block. The panel recommended to evaluate the mechanical atrial activity on transthoracic echocardiography prior to implant. It was also agreed that Auto A3 Threshold and Tracking Check should be turned off in all patients, AV conduction mode switch should be turned off in all patients with high degree AV block, and the lower rate should be programmed to 50 bpm with exceptions based on individual clinical assessment. Future studies will be useful to evaluate the strength of those recommendations to improve the AV synchrony.

Ventricular Arrhythmias in Left Ventricular Assist Device Patients-Current Diagnostic and Therapeutic Considerations.

Left ventricular assist devices (LVAD) are used in the treatment of advanced left ventricular heart failure. LVAD can serve as a bridge to orthotopic heart transplantation or as a destination therapy in cases where orthotopic heart transplantation is contraindicated. Ventricular arrhythmias are frequently observed in patients with LVAD. This problem is further compounded as a result of diagnostic difficulties arising from presently available electrocardiographic methods. Due to artifacts from LVAD-generated electromagnetic fields, it can be challenging to assess the origin of arrhythmias in standard ECG tracings. In this article, we will review and discuss common mechanisms, diagnostics methods, and therapeutic strategies for ventricular arrhythmia treatment, as well as numerous problems we face in LVAD implant patients.

Gene and stem cell therapy for inherited cardiac arrhythmias.

Inherited cardiac arrhythmias are a group of genetic diseases predisposing to sudden cardiac arrest, mainly resulting from variants in genes encoding cardiac ion channels or proteins involved in their regulation. Currently available therapeutic options (pharmacotherapy, ablative therapy and device-based therapy) can not preclude the occurrence of arrhythmia events and/or provide complete protection. With growing understanding of the genetic background and molecular mechanisms of inherited cardiac arrhythmias, advancing insight of stem cell technology, and development of vectors and delivery strategies, gene therapy and stem cell therapy may be promising approaches for treatment of inherited cardiac arrhythmias. Recent years have witnessed impressive progress in the basic science aspects and there is a clear and urgent need to be translated into the clinical management of arrhythmic events. In this review, we present a succinct overview of gene and cell therapy strategies, and summarize the current status of gene and cell therapy. Finally, we discuss future directions for implementation of gene and cell therapy in the therapy of inherited cardiac arrhythmias.

Clinical Outcomes and Medical Burdens of Neonatal Arrhythmias in Children's Hospitals in China: A Protocol for Multi-Center Retrospective Cohort Study.

Neonatal arrhythmias are significant contributors to infant mortality. Timely diagnosis and treatment are essential for neonates with non-benign arrhythmias to avoid severe complications, and ongoing treatment and follow-up are sometimes needed. The main objective of this study will be to understand the incidence and demographic characteristics of arrhythmias in hospitalized neonates in China and the related factors of outcomes. A secondary objective will be to establish the first follow-up system for neonatal arrhythmias in China. The medical burdens of neonatal arrhythmias in China will also be investigated. The data from the Futang Research Center of Pediatric Development (FRCPD) database between January 2016 and December 2021 were obtained. Newborns admitted to member hospitals with a discharge diagnosis of "neonatal arrhythmia" (ICD-10 code P29.151) or "arrhythmia" (ICD-10 code I49.904) were included. The medical record information was collected and classified into two groups: heart failure and non-heart failure. The differences between the two groups and independent risk factors for neonatal arrhythmias complicated with heart failure were analyzed. In addition, a follow-up study of patients discharged from Beijing Children's Hospital was conducted to evaluate their outcomes at the age of 3 years old. Factors influencing hospitalization costs were analyzed using rank-sum tests and multiple linear regression. It is anticipated that the study findings will provide new and comprehensive data on the health needs of neonatal arrhythmias in China. The study will establish the first follow-up system for neonatal arrhythmias in China. This study will help reduce the burden of patients and their families as well as the society.

Position paper on sustainability in cardiac pacing and electrophysiology from the Working Group of Cardiac Pacing and Electrophysiology of the French Society of Cardiology.

Sustainability in healthcare, particularly within the domain of cardiac electrophysiology, assumes paramount importance for the near future. The escalating environmental constraints encountered necessitate a proactive approach. This position paper aims to raise awareness among physicians, spark critical inquiry and identify potential solutions to enhance the sustainability of our practice. Reprocessing of single-use medical devices has emerged as a potential solution to mitigate the environmental impact of electrophysiology procedures, while also offering economic advantages. However, reprocessing remains unauthorized in certain countries. In regions where it is possible, stringent regulatory standards must be adhered to, to ensure patient safety. It is essential that healthcare professionals, policymakers and manufacturers collaborate to drive innovation, explore sustainable practices and ensure that patient care remains uncompromised in the face of environmental challenges. Ambitious national/international programmes of disease prevention should be the cornerstone of the strategy. It is equally vital to implement immediate actions, as delineated in this position paper, to bring about tangible change quickly.