Amiodarone and pulmonary toxicity in atrial fibrillation: a nationwide Israeli study.

BACKGROUND AND AIMS: Amiodarone-related interstitial lung disease (ILD) is the most severe adverse effect of amiodarone treatment. Most data on amiodarone-related ILD are derived from periods when amiodarone was given at higher doses than currently used. METHODS: A nationwide population-based study was conducted among patients with incident atrial fibrillation (AF) between 1 December 1999 and 31 December 31 2021. Amiodarone-exposed patients were matched 1:1 with controls unexposed to amiodarone based on age, sex, ethnicity, and AF diagnosis duration. The final patient cohort included only matched pairs where amiodarone therapy was consistent throughout follow-up. Directed acyclic graphs and inverse probability treatment weighting (IPTW) modelling were used. Patients with either prior ILD or primary lung cancer (PLC) were excluded. The primary outcome was the incidence of any ILD. Secondary endpoints were death and PLC. RESULTS: The final cohort included 6039 amiodarone-exposed patients who were matched with unexposed controls. The median age was 73.3 years, and 51.6% were women. After a mean follow-up of 4.2 years, ILD occurred in 242 (2.0%) patients. After IPTW, amiodarone exposure was not significantly associated with ILD [hazard ratio (HR): 1.45, 95% confidence interval (CI): 0.97, 2.44, P = 0.09]. There was a trivial higher relative risk of ILD among amiodarone-exposed patients between Years 2 and 8 of follow-up [maximal risk ratio (RR): 1.019]. Primary lung cancer occurred in 97 (0.8%) patients. After IPTW, amiodarone was not associated with PLC (HR: 1.18, 95% CI: 0.76, 2.08, P = 0.53). All-cause death occurred in 2185 (18.1%) patients. After IPTW, amiodarone was associated with reduced mortality risk (HR: 0.65, 95% CI: 0.60, 0.72, P < 0.001). The results were consistent across a variety of sensitivity analyses. CONCLUSION: In a contemporary AF population, low-dose amiodarone was associated with a trend towards increased risk of ILD (15%-45%) but a clinically negligible change in absolute risk (maximum of 1.8%), no increased risk of PLC, and a lower risk of all-cause mortality.

Clinical Outcomes of Patients with COVID-19 Infection and Cardiac Implantable Electronic Devices.

BACKGROUND: Existing cardiac disease contributes to poor outcome in patients with coronavirus disease 2019 (COVID-19). Little information exists regarding COVID-19 infection in patients with a cardiac implantable electronic device (CIED). OBJECTIVES: To assess the association between CIEDs and severity of COVID-19 infection. METHODS: We performed a retrospective analysis including 13,000 patients > 18 years old with COVID-19 infection between January and December 2020. Patients with COVID-19 who had a permanent pacemaker or defibrillator were matched 1:4 based on age and sex followed by univariate and multivariate analyses. Baseline characteristics and clinical outcomes were assessed. RESULTS: Forty patients with CIED and 160 patients without CIED were included in the current analysis. Mean age was 72.6 ± 13 years, and approximately 50% were females. Majority of the patients in the study arm had a pacemaker (63%), whereas only 15 patients (37%) had a defibrillator. Patients with COVID-19 and CIED presented more often with atrial fibrillation, coronary artery disease, heart failure, hypertension, diabetes, and chronic kidney disease. They were more likely to be hospitalized in the intensive care unit (ICU) and required more ventilatory support (35% vs. 18.3%). Thirty-day mortality (22.5% vs. 13.8%) and 1-year mortality (25% vs. 15%) were higher among patients with COVID-19 and CIED. CONCLUSIONS: Patients with COVID-19 and CIED had a significantly higher prevalence of co-morbidities that were associated with increased mortality. Although, CIED by itself was not found as an independent risk factor for morbidity and mortality, it may serve as a warning for severe illness with COVID-19.

Developing a risk score to predict mortality in the first year after implantable cardioverter defibrillator implantation: Data from the Israeli ICD Registry.

INTRODUCTION: Life expectancy of less than 1 year is usually a contraindication for implantable cardioverter defibrillator (ICD) implantation. The aim was to identify patients at risk of death during the first year after implantation. METHODS AND RESULTS: Data were derived from a prospective Israeli ICD Registry. Two groups of patients were compared, those who died and those who were alive 1 year after ICD implantation. Factors associated with 1-year mortality were identified on a derivation cohort. A risk score was established and validated. A total of 2617 patients have completed 1 year of follow-up after ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation. Age greater than 75 years (hazard ratio [HR], 2.7; 95% confidence interval [95% CI], 1.6 to 4.4), atrial fibrillation (AF; HR, 1.9; 95% CI, 1.12 to 3.17), chronic lung disease (HR, 2.0; 95% CI, 1.1 to 3.76), anemia (HR, 2.3; 95% CI, 1.3 to 3.93) and chronic renal failure (CRF; HR, 3.4; 95% CI, 1.74 to 6.6) were independent risk factors for 1-year mortality. We propose a simple AAACC ("triple A double C") score for prediction of 1-year mortality after ICD implantation: Age greater than 75 years (3 points(pts)), anemia (2 pts), AF (1 pt), CRF (3 pts) and chronic lung disease (1 pt). Mortality risk increased with rising number of points (from 1% with 0 pts to 12.5% with >4 pts). The risk score was evaluated with receiver operating characteristic curve and the area under the curve of the validation curve is 0.71 (95% CI, 0.66 to 0.76). CONCLUSIONS: Age greater than 75, AF, chronic lung disease, anemia, and CRF were independent risk factors for 1-year mortality. AAACC risk score identifies patients at high risk of death during 1 year after ICD implantation.

Arrhythmic Events in Brugada Syndrome: A Nationwide Israeli Survey of the Clinical Characteristics, Treatment; and Long-Term Follow-up (ISRABRU-VF).

BACKGROUND: Limited information exists about detailed clinical characteristics and management of the small subset of Brugada syndrome (BrS) patients who had an arrhythmic event (AE). OBJECTIVES: To conduct the first nationwide survey focused on BrS patients with documented AE. METHODS: Israeli electrophysiology units participated if they had treated BrS patients who had cardiac arrest (CA) (lethal/aborted; group 1) or experienced appropriate therapy for tachyarrhythmias after prophylactic implantable cardioverter defibrillator (ICD) implantation (group 2). RESULTS: The cohort comprised 31 patients: 25 in group 1, 6 in group 2. Group 1: 96% male, mean CA age 38 years (range 13-84). Nine patients (36%) presented with arrhythmic storm and three had a lethal outcome; 17 (68%) had spontaneous type 1 Brugada electrocardiography (ECG). An electrophysiology study (EPS) was performed on 11 patients with inducible ventricular fibrillation (VF) in 10, which was prevented by quinidine in 9/10 patients. During follow-up (143 ± 119 months) eight patients experienced appropriate shocks, none while on quinidine. Group 2: all male, age 30-53 years; 4/6 patients had familial history of sudden death age < 50 years. Five patients had spontaneous type 1 Brugada ECG and four were asymptomatic at ICD implantation. EPS was performed in four patients with inducible VF in three. During long-term follow-up, five patients received ≥ 1 appropriate shocks, one had ATP for sustained VT (none taking quinidine). No AE recurred in patients subsequently treated with quinidine. CONCLUSIONS: CA from BrS is apparently a rare occurrence on a national scale and no AE occurred in any patient treated with quinidine.

Contemporary rates and outcomes of single- vs. dual-coil implantable cardioverter defibrillator lead implantation: data from the Israeli ICD Registry.

AIMS: Dual-coil leads were traditionally considered standard of care due to lower defibrillation thresholds (DFT). Higher complication rates during extraction with parallel progression in implantable cardioverter defibrillator (ICD) technology raised questions on dual coil necessity. Prior substudies found no significant outcome difference between dual and single coils, although using higher rates of DFT testing then currently practiced. We evaluated the temporal trends in implantation rates of single- vs. dual-coil leads and determined the associated adverse clinical outcomes, using a contemporary nation-wide ICD registry. METHODS AND RESULTS: Between July 2010 and March 2015, 6343 consecutive ICD (n = 3998) or CRT-D (n = 2345) implantation patients were prospectively enrolled in the Israeli ICD Registry. A follow-up of at least 1 year of 2285 patients was available for outcome analysis. The primary endpoint was all-cause mortality. Single-coil leads were implanted in 32% of our cohort, 36% among ICD recipients, and 26% among CRT-D recipients. Secondary prevention indication was associated with an increased rate of dual-coil implantation. A significant decline in dual-coil leads with reciprocal incline of single coils was observed, despite low rates of DFT testing (11.6%) during implantation, which also declined from 31 to 2%. In the multivariate Cox model analysis, dual- vs. single-coil lead implantation was not associated with an increased risk of mortality [hazard ratio (HR) = 1.23; P= 0.33], heart failure hospitalization (HR = 1.34; P=0.13), appropriate (HR = 1.25; P= 0.33), or inappropriate ICD therapy (HR = 2.07; P= 0.12). CONCLUSION: Real-life rates of single-coil lead implantation are rising while adding no additional risk. These results of single-coil safety are reassuring and obtained, despite low and contemporary rates of DFT testing.

Two to one CRTD pacing: When the T wave and the P wave interact.

We presented a unique phenomenon of 2:1 cardiac resynchronization therapy pacing due to T wave oversensing. Ultimately, by utilizing a unique feature of integrated bipolar sensing, we succeeded to eliminate the T wave oversensing signals, and restore 1:1 CRTD pacing. Importantly, this feature enabled us to overcome the T wave oversensing issue, without the need to decrease the ventricular sensitivity, which could potentially interfere with ventricular arrhythmia detection and appropriate shock delivery when required.

Swallow-induced syncope and carotid sinus hypersensitivity: Coincident or associated conditions?

Swallow induced syncope is a rare clinical condition which is thought to result from an abnormal vagal reflex leading to bradycardia and cerebral hypoperfusion. It mostly occurs in patients with organic or functional disorders of the esophagus, and often requires permanent pacemaker implantation, along with treatment of the underlying esophageal pathology. In the following case, we report of a 71-year-old male with achalasia post per oral endoscopic myectomy, who presented with syncope and documented AV-block while eating solid food. In addition, long sinus pauses were noted during carotid sinus massage, suggesting that the two distinct entities may be associated, and further supporting the mechanism of neurally mediated syncope in the pathophysiology of swallow-induced syncope.

Successful treatment of ventricular fibrillation storm triggered by short-long-short sequence; time to avoid managed ventricular pacing.

Sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) is caused by ventricular tachyarrhythmia that can be effectively treated by implantable cardioverter defibrillator (ICD) therapy. We report of a 28-year-old man with HCM and a dual chamber ICD, originally implanted for primary prevention of SCD, (programmed to AAI(R)-DDD(R); managed ventricular pacing (MVP) mode, Medtronic Inc. St Paul, MN USA). He presented with recurrent ICD shocks due to ventricular fibrillation (VF) despite antiarrhythmic therapy. Careful assessment of the stored electrograms demonstrated a repetitive pattern of VF initiation following short-long-short sequences. Initially, activation of ventricular rate stabilization (VRS) algorithm failed to prevent recurrent VF. Ultimately, deactivation of MVP and reprogramming the device to DDD mode with VRS on, resulted in arrhythmia suppression and avoidance of ICD shocks. Physicians should be aware that although VRS function is available in MVP mode, it does not function in the AAI mode during MVP; in order to effectively treat short-long-short sequence induced ventricular arrhythmia by device programming.

Clinical Outcomes of Single- versus Dual-Chamber Implantable Cardioverter Defibrillators: Lessons from the Israeli ICD Registry.

OBJECTIVE: To compare the clinical outcomes of a single- versus dual-chamber ICD for primary prevention of sudden cardiac death in a large, national ICD registry. METHODS: Data were collected from the prospective Israeli ICD Registry. Baseline characteristics and clinical outcomes including mortality, admissions for heart failure (HF), and ICD therapy were compared between the two groups. RESULTS: A total of 1,125 subjects, 37% with a single-chamber and 63% with a dual-chamber ICD, constructed the baseline cohort. Approximately 80% had ischemic heart disease (IHD). Mean follow-up was 22 months, mean ejection fraction was 30%, and mean QRS width was 103 milliseconds in both groups. During follow-up, there were no significant differences in the rate of mortality, admissions for HF, appropriate or inappropriate therapy, or in time to any of the clinical outcomes. Using multivariate analysis, single-chamber ICD was not associated with increased risk of death or admission for HF. In a subgroup of patients with IHD, single-chamber ICD was associated with a higher rate of inappropriate therapy. CONCLUSIONS: In this large retrospective population-based cohort, dual-chamber ICD showed no benefit in reducing the incidence of death or HF admissions, whereas in a subgroup of patients with IHD, single-chamber ICD was associated with increased inappropriate therapy. Further prospective studies are necessary to assess the benefit of dual-chamber ICD in reducing the rate of inappropriate therapy.

Apical versus Non-Apical Lead: Is ICD Lead Position Important for Successful Defibrillation?

INTRODUCTION: We aim to compare the acute and long-term success of defibrillation between non-apical and apical ICD lead position. METHODS AND RESULTS: The position of the ventricular lead was recorded by the implanting physician for 2,475 of 2,500 subjects in the Shockless IMPLant Evaluation (SIMPLE) trial, and subjects were grouped accordingly as non-apical or apical. The success of intra-operative defibrillation testing and of subsequent clinical shocks were compared. Propensity scoring was used to adjust for the impact of differences in baseline variables between these groups. There were 541 leads that were implanted at a non-apical position (21.9%). Patients implanted with a non-apical lead had a higher rate of secondary prevention indication. Non-apical location resulted in a lower mean R-wave amplitude (14.0 vs. 15.2, P < 0.001), lower mean pacing impedance (662 ohm vs. 728 ohm, P < 0.001), and higher mean pacing threshold (0.70 V vs. 0.66 V, P = 0.01). Single-coil leads and cardiac resynchronization devices were used more often in non-apical implants. The success of intra-operative defibrillation was similar between propensity score matched groups (89%). Over a mean follow-up of 3 years, there were no significant differences in the yearly rates of appropriate shock (5.5% vs. 5.4%, P = 0.98), failed appropriate first shock (0.9% vs. 1.0%, P = 0.66), or the composite of failed shock or arrhythmic death (2.8% vs. 2.3% P = 0.35) according to lead location. CONCLUSION: We did not detect any reduction in the ICD efficacy at the time of implant or during follow-up in patients receiving a non-apical RV lead.

Postoperative Atrial Fibrillation Following Coronary Artery Bypass Graft Surgery Predicts Long-Term Atrial Fibrillation and Stroke.

BACKGROUND: Atrial fibrillation (AF) is a common complication of coronary artery bypass graft (CABG) surgery, occurring in 20%-40% of patients, mostly during the first week after surgery. It is associated with increased morbidity and mortality, but data are limited. OBJECTIVES: To assess the correlation between new-onset in-hospital AF following CABG and long-term AF, cerebrovascular accident (CVA), or death. METHODS: We conducted an analysis of 161 consecutive patients who underwent isolated CABG surgery in a tertiary center during the period 2002-2003. RESULTS: Patients' mean age was 72 years, and the majority were males (77%). Approximately half of the patients experienced prior myocardial infarction, and 14% had left ventricular ejection fraction < 40%. Postoperative AF (POAF) occurred in 27% of the patients. Patients were older and had larger left atrium diameter. POAF was strongly correlated with late AF (OR 4.34, 95%CI 1.44-13.1, P = 0.01) during a mean follow-up of 8.5 years. It was also correlated with long-term stroke but was not associated with long-term mortality. CONCLUSIONS: POAF is a common complication of CABG surgery, which is correlated with late AF and stroke. Patients with POAF should be closely monitored to facilitate early administration of anticoagulant therapy in a high risk population upon recurrence of AF.

Incidence of Implantable Cardioverter Defibrillator Therapy and Mortality in Primary and Secondary Prevention of Sudden Cardiac Death.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce mortality in patients implanted for primary and secondary prevention of sudden cardiac death. Data on the incidence of appropriate ICD therapies in primary vs. secondary prevention are limited. OBJECTIVES: To compare ICD therapies and mortality in primary vs. secondary prevention of sudden cardiac death. METHODS: We conducted a retrospective analysis of 581 consecutive patients receiving an ICD for primary (66%) or secondary (34%) prevention indications. RESULTS: During long-term follow-up, 29% of patients implanted for secondary prevention received appropriate ICD therapy vs. 18% implanted for primary prevention. However, the overall 7 year mortality rate was not significantly different between the two groups (26.9%, P = 0.292). Multivariate analysis showed that patients implanted for primary prevention had a significantly lower risk of appropriate ICD therapy even after adjustment for age, left ventricular ejection fraction < 0.35 and chronic renal failure (HR 1.63, 95% CI 1.10-2.41, P = 0.015). CONCLUSIONS: Patients implanted for secondary prevention were more likely to receive appropriate ICD therapy, with a significantly shorter time period from ICD implant to the first therapy. However, all-cause mortality was comparable between primary and secondary prevention groups.

Sex differences in implantable cardioverter-defibrillator implantation indications and outcomes: lessons from the Nationwide Israeli-ICD Registry.

AIMS: Implantable cardioverter-defibrillators (ICDs) improve survival in certain high arrhythmic risk populations. However, there are sex differences regarding both the utilization and the benefit of these devices. Using a prospective national ICD registry, we aim to compare the indications for ICD implantation as well as outcomes in implanted women vs. men. METHODS AND RESULTS: All subjects implanted with an ICD or cardiac resynchronization therapy with a defibrillator (CRTD) in Israel between July 2010 and February 2013 were included. A total of 3544 subjects constructed the baseline cohort, of whom 615 (17%) were women. Women had the same age (64 years) and rate of secondary prevention indication (26%) as men. However, women were more likely than men to have significant heart failure symptoms (52 vs. 45%), QRS > 120 ms (41 vs. 36%), and a higher rate of non-ischaemic cardiomyopathy (54 vs. 21%, all P values <0.05). Using multivariate analysis, women were more likely to undergo CRTD implantation (odds ratio = 1.8, P < 0.01). Follow-up data were available for 1518 subjects with a mean follow-up of 12 months. During follow-up, there were no significant differences among genders in the rate of any single or the combined outcomes of appropriate device therapies, heart failure admissions, or death. First-year re-intervention rate was double among women (5.6 vs. 3.0%, P < 0.01). CONCLUSION: In real-world setting, women implanted with an ICD differ significantly from men in their baseline characteristics and in the use of CRTD devices. These, however, did not translate into outcome differences.

The impact of peri-procedural imaging on safety and efficacy of atrial fibrillation ablation: insights from the Israeli AF Catheter Ablation Registry (ICAR).

BACKGROUND: Pulmonary vein isolation (PVI) is the most effective therapy to achieve rhythm control in atrial fibrillation (AF). Peri-procedural imaging is used in many but not all centers. However, the impact of imaging on safety and efficacy of PVI is not clear. The Israeli Catheter Ablation Registry (ICAR) is a great opportunity to explore this issue in real-world practice. AIM: To describe the real-world utilization of peri-procedural imaging technologies in a large cohort of patients undergoing ablation for AF. METHODS: A prospective-multicenter cohort of AF patients who underwent PVI during the years 2019-2021. Peri-procedural imaging (CT, ICE, TEE) was utilized based on the center and operator discretion. The study endpoints were peri-procedural complications and AF recurrence at 12 months follow-up among patients with and without peri-procedural imaging. RESULTS: Between January 2019 and December 2021, a total of 921 patients underwent PVI. Peri-procedural imaging (at least 1 modality of CT, TEE, and or ICE) was utilized in 753 (81.8%) and no imaging among 168 (18.2%) patients. Cryoablation was the dominant energy used for PVI in both groups (92.3% of the non-imaging group, and 95.3% among imaging group), while RF was used in the rest of the patients. Fluoroscopy time was not different between the 2 groups; however, procedure duration was longer among the imaging group (90 min) compared to the non-imaging group (74.5 min, p = 0.006). By 12 months, the incidence of AF recurrence and repeated ablation were not different between the groups. Complications and re-hospitalization for cardiocerebrovascular reasons were not different among the 2 groups. Cox regression model demonstrated no association between preprocedural imaging and the risk of AF recurrence after ablation. CONCLUSION: This real-world multicenter prospective registry study demonstrated that the rate of complications and the rate of recurrence of AF during 1 year follow-up were not different among patients who had PVI either with or without peri-procedural imaging.

Incidence and Predictors for Recurrence of Ventricular Arrhythmia Presenting During Acute Myocarditis: A Multicenter Study.

BACKGROUND: Management of acute myocarditis (AM) patients experiencing ventricular arrhythmia (VA) during acute illness is controversial, especially regarding early implantable cardioverter-defibrillator (ICD) implantation. OBJECTIVES: The purpose of this study was to evaluate the prevalence of and find predictors for long-term sustained VA recurrence and overall mortality among AM patients with VA. METHODS: This was a multicenter retrospective analysis of AM patients (verified by cardiac magnetic resonance imaging or myocardial biopsy) with documented VA during the acute illness ("initial VA"). Patients with history of myocardial infarction, heart failure, or VA were excluded. The study endpoint was a composite of sustained VA and overall mortality during follow-up. RESULTS: The study included 69 AM patients with initial VA: sustained monomorphic ventricular tachycardia (MMVT) (n = 25), sustained polymorphic ventricular tachycardia (VT)/ventricular fibrillation (n = 13), and nonsustained VT (n = 31). Age was 44 ± 13 years, and 23 of 69 (33.3%) were women. During median follow-up of 5.5 years, 27 of 69 (39%) patients reached the composite endpoint including sustained VA (n = 24) and death (n = 11). Initial MMVT, predischarge left ventricular dysfunction (left ventricular ejection fraction <50%), and anteroseptal delayed enhancement on cardiac magnetic resonance imaging were significantly associated with the composite endpoint. On multivariable analysis, initial MMVT (HR: 5.17; 95% CI: 1.81-14.6; P = 0.001) and predischarge LV dysfunction (HR: 4.57; 95% CI: 1.83-11.5; P = 0.005) were independently associated with the composite endpoint. Using these 2 predictors, we could delineate subgroups with low (∼4%), medium (∼42%), and high (∼82%) 10-year incidence of composite endpoint. CONCLUSIONS: AM patients presenting with VA have high incidence of sustained VA recurrence and mortality posthospitalization. Initial MMVT and predischarge LV dysfunction are independently associated with VA recurrence and mortality. Implantable cardioverter-defibrillator implantation may be considered in such high-risk patients.

Outcomes of in-hospital cardiac arrest managed with and without a specialized code team: A retrospective observational study.

BACKGROUND: In-hospital cardiac arrest (IHCA) still has a poor prognosis despite medical advancements in recent decades. Early and high-quality cardiopulmonary resuscitation (CPR), as well as good teamwork, are important prognostic factors. There are no clear guidelines regarding the composition of a dedicated hospital CPR team. We compared outcomes of IHCA treated by a dedicated hospital CPR team compared to ward medical staff with advanced cardiac life support (ACLS) training. METHODS: A single-center retrospective observational study based on the cardiopulmonary resuscitation database of Soroka University Medical Center from January 2016 until December 2019. We compared the results of resuscitations conducted by regular ward medical staff, certified in ACLS, versus those conducted by the dedicated hospital's CPR team. RESULTS: Of the 360 CPR events analyzed, 141 (39.1%) ended in return of spontaneous circulation, 70 (19.4%) patients were alive after 24 hours, 23 (6.4%) survived for 30 days, and 18 (5%) survived to discharge. Of those who survived to discharge, 11 (61.1%) had a cerebral performance category (CPC) score of 1-2, and 7 (38.9%) had a score of 3-4 (mean 2.09). Survival-to-discharge was significantly higher in the CPR-team group compared to the ward-team group (7.6% vs. 1.9%, p = 0.013). However, with propensity score analysis the difference in survival became insignificant (RR = 1.97, 95% CI: 0.40-9.63, p = 0.40). CONCLUSION: We found no difference in survival between IHCA treated by a dedicated hospital CPR team compared to a standard ward team, both trained with biennial ACLS training. Nevertheless, crude survival-to-discharge was significantly higher in the CPR-team group.

Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause Infantile Hypertrophic Cardiomyopathy.

Hypertrophic and dilated cardiomyopathy (HCM, DCM) are leading causes of cardiovascular morbidity and mortality in children. The pseudokinase alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization and cardiomyocyte differentiation. ALPK3 coding mutations are causative of recessively inherited pediatric-onset DCM and HCM with variable expression of facial dysmorphism and skeletal abnormalities and implicated in dominantly inherited adult-onset cardiomyopathy. We now report two variants in ALPK3-a coding variant and a novel intronic variant affecting splicing. We demonstrate that compound heterozygosity for both variants is highly suggestive to be causative of infantile-onset HCM with webbed neck, and heterozygosity for the coding variant presents with adult-onset HCM. Our data validate partial penetrance of heterozygous loss-of-function ALPK3 mutations in late-onset hypertrophic cardiomyopathy and expand the genotypic spectrum of autosomal recessive ALPK3-related cardiac disease with Noonan-like features.