BACKGROUND:Filamin-C (FLNC) gene variants are associated with cardiac and skeletal muscle diseases including a clear role of loss-of-function variants in dilated cardiomyopathy. OBJECTIVE:This study aimed to assess the contribution of rare FLNC variants to hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM). METHODS:Family-based studies in 2 specialist services and statistical modeling of rare FLNC missense variants were conducted, using a cohort of 3289 sarcomere-negative HCM cases and 122,348 genome aggregation database controls. RESULTS:Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197). FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype. Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group, and musculoskeletal abnormalities were present in 4 families (33%). 5 of 12 variants (41.7%) in the "ECG-positive" group cosegregated, and 2 were apparently de novo. 11 variants were missense, and 1 splice site. Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99). CONCLUSION:Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities.

BACKGROUND:Many patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) have devices capable of right ventricular pacing (RVP). Although pacing can reduce left ventricular outflow tract gradient (LVOTg), it can also reduce cardiac output, so its net effect is variable. OBJECTIVES:We tested whether electromechanical optimization of the programmed atrio-ventricular delay (AVD) allows RVP to achieve a net benefit on symptoms. METHODS:EMORI-HCM (Electromechanically Optimized Right Ventricular Pacing in Obstructive Hypertrophic Cardiomyopathy) is a multicenter, blinded, randomized, crossover trial of AVD-optimized RVP in patients with symptomatic oHCM with resting or provoked gradient of at least 30 mm Hg. Patients with existing dual-chamber devices were randomized to either 3 months of continuous AVD-optimized RVP (intervention) followed by 3 months of backup-only RVP (control), or vice versa. AVD was optimized using a high-precision multiple-alternation protocol assessing acute change in beat-by-beat blood pressure while varying AVD. The primary outcome was symptoms measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. Secondary outcomes include patient-reported daily symptom data collected using a dedicated smartphone application (ORBITA-app), dichotomous patient preference, EQ-5D, exercise capacity, and LVOTg. Patients were blinded to treatment allocation. Symptom assessments were self-administered. Outcome measures were recorded at baseline, crossover, and completion. Analysis was by Bayesian ordinal mixed modeling. RESULTS:Between October 2021 and October 2024, 117 screened patients met the inclusion criteria, of whom 60 were randomized. AVD-optimized RVP improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+4.5; 95% credible interval [CrI]: 1.3-8.1; probability of benefit [Prbenefit] = 0.997) and daily symptom scores (OR: 1.29; 95% CrI: 0.98-1.68; Prbenefit: 0.969) compared with backup-only pacing. AVD-optimized RVP improved exercise capacity (+1.0 mL/kg/min; 95% CrI: 0.1-2.0; Prbenefit: 0.984) and LVOTg (-7.3 mm Hg; 95% CrI: -13.5 to -1.1; Prbenefit: 0.010). It had no effect on B-type natriuretic peptide (Prbenefit: 0.893) and ejection fraction was preserved (Prbenefit: 0.409). CONCLUSIONS:In patients with oHCM, RVP delivered at electromechanically optimized AVD improves symptoms and exercise capacity. (Electromechanically Optimized Right Ventricular Pacing in Obstructive Hypertrophic Cardiomyopathy [EMORI-HCM], NCT05257772).

AbstractAimsThe trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium‐glucose co‐transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT.Methods and resultsWe compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy‐four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non‐ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end‐diastolic inner‐dimension (LVIDd) and diastolic function (E/A and e/e′). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049).ConclusionsWe observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.

Importance:Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective:To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants:An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention:Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures:Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results:Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance:There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Introduction: Patients with hypertrophic cardiomyopathy (HCM) are at risk for lethal ventricular arrhythmia, but the electrophysiological substrate behind this is not well-understood. We used non-invasive electrocardiographic imaging to characterize patients with HCM, including cardiac arrest survivors.Methods: HCM patients surviving ventricular fibrillation or hemodynamically unstable ventricular tachycardia (n = 17) were compared to HCM patients without a personal history of potentially lethal arrhythmia (n = 20) and a pooled control group with structurally normal hearts. Subjects underwent exercise testing by non-invasive electrocardiographic imaging to estimate epicardial electrophysiology.Results: Visual inspection of reconstructed epicardial HCM maps revealed isolated patches of late activation time (AT), prolonged activation-recovery intervals (ARIs), as well as reversal of apico-basal trends in T-wave inversion and ARI compared to controls (p < 0.005 for all). AT and ARI were compared between groups. The pooled HCM group had longer mean AT (60.1 ms vs. 52.2 ms, p < 0.001), activation dispersion (55.2 ms vs. 48.6 ms, p = 0.026), and mean ARI (227 ms vs. 217 ms, p = 0.016) than structurally normal heart controls. HCM ventricular arrhythmia survivors could be differentiated from HCM patients without a personal history of life-threatening arrhythmia by longer mean AT (63.2 ms vs. 57.4 ms, p = 0.007), steeper activation gradients (0.45 ms/mm vs. 0.36 ms/mm, p = 0.011), and longer mean ARI (234.0 ms vs. 221.4 ms, p = 0.026). A logistic regression model including whole heart mean activation time and activation recovery interval could identify ventricular arrhythmia survivors from the HCM cohort, producing a C statistic of 0.76 (95% confidence interval 0.72–0.81), with an optimal sensitivity of 78.6% and a specificity of 79.8%.Discussion: The HCM epicardial electrotype is characterized by delayed, dispersed conduction and prolonged, dispersed activation-recovery intervals. Combination of electrophysiologic measures with logistic regression can improve differentiation over single variables. Future studies could test such models prospectively for risk stratification of sudden death due to HCM.

AbstractIntroductionThe novel Confirm Rx™ implantable cardiac monitor (ICM) with SharpSense™ technology incorporates a new P‐wave discriminator designed to improve AF detection. This study aimed to evaluate the diagnostic performance of the Confirm Rx™ ICM in detecting AF episodes of varying durations.MethodsWe conducted a multicenter retrospective analysis of consecutive patients implanted with a Confirm Rx™ ICM (v1.2) across nine UK hospitals, all with documented AF lasting at least 6 min. Electrocardiograms (ECGs) were manually adjudicated by cardiologists. To account for intra‐ and inter‐reviewer variability, a random sample of 10% of ECGs underwent additional review. Disagreements were resolved by a third reviewer. Diagnostic performance was determined by calculating the gross and patient‐averaged positive predictive value (PPV) for AF episodes of different duration. The source of false positive (FP) detection was also categorized.ResultsOverall, 16,230 individual ECGs from 232 patients were included. The median AF episode duration was 14 min. R‐wave amplitude remained stable during follow‐up (0.52 ± 0.27 mV [initial] vs. 0.54 ± 0.29 mV [end of follow‐up], p = .10). The gross and patient‐averaged PPV were 75.0% and 67.0%, respectively. Diagnostic performance (gross) increased with progressively longer AF episodes: 88.0% for ≥1 h, 97.3% for 6 h, and 100% for 24 h. The main source of FP during tachycardia was T‐wave oversensing (54.2%), while in non‐tachycardic episodes it was predominantly ectopy (71.2%). The AF burden precision was excellent (93.3%).ConclusionThe Confirm Rx™ ICM diagnostic performance was modest for all AF episodes (75%), with accuracy increasing for longer AF episodes.

Cardiac arrhythmias are associated with significant morbidity, mortality and poor quality of life. Cardiovascular magnetic resonance (CMR) imaging, with its unsurpassed capability of non-invasive tissue characterisation, high accuracy, and reproducibility of measurements, plays an integral role in determining the underlying aetiology of cardiac arrhytmias. CMR can reliably diagnose previous myocardial infarction, non-ischemic cardiomyopathy, characterise congenital heart disease and valvular pathologies, and also detect the underlying substrate concealed on conventional investigations in a significant proportion of patients with arrhythmias. Determining the underlying substrate of arrhythmia is of paramount importance for treatment planning and prognosis. However, CMR imaging in patients with irregular heart rates can be problematic. Understanding the different ways to overcome the limitations of CMR in arrhythmia is essential for providing high-quality imaging, comprehensive information, and definitive answers in this diverse group of patients.

Background Idiopathic ventricular fibrillation (VF) is a diagnosis of exclusion following normal cardiac investigations. We sought to determine if exercise‐induced changes in electrical substrate could distinguish patient groups with various ventricular arrhythmic pathophysiological conditions and identify patients susceptible to VF. Methods and Results Computed tomography and exercise testing in patients wearing a 252‐electrode vest were combined to determine ventricular conduction stability between rest and peak exercise, as previously described. Using ventricular conduction stability, conduction heterogeneity in idiopathic VF survivors (n=14) was compared with those surviving VF during acute ischemia with preserved ventricular function following full revascularization (n=10), patients with benign ventricular ectopy (n=11), and patients with normal hearts, no arrhythmic history, and negative Ajmaline challenge during Brugada family screening (Brugada syndrome relatives; n=11). Activation patterns in normal subjects (Brugada syndrome relatives) are preserved following exercise, with mean ventricular conduction stability of 99.2±0.9%. Increased heterogeneity of activation occurred in the idiopathic VF survivors (ventricular conduction stability: 96.9±2.3%) compared with the other groups combined (versus 98.8±1.6%; P =0.001). All groups demonstrated periodic variation in activation heterogeneity (frequency, 0.3–1 Hz), but magnitude was greater in idiopathic VF survivors than Brugada syndrome relatives or patients with ventricular ectopy (7.6±4.1%, 2.9±2.9%, and 2.8±1.2%, respectively). The cause of this periodicity is unknown and was not replicable by introducing exercise‐induced noise at comparable frequencies. Conclusions In normal subjects, ventricular activation patterns change little with exercise. In contrast, patients with susceptibility to VF experience activation heterogeneity following exercise that requires further investigation as a testable manifestation of underlying myocardial abnormalities otherwise silent during routine testing.

A 36-year-old man presented to our hospital with a 2-week history of palpitations in the context of 3 months of a dry cough, weight loss, and night sweats.

BACKGROUND:The rate of left ventricular (LV) lead displacement after cardiac resynchronization therapy (CRT) remains high despite improvements in lead technology. In 2017, a novel quadripolar lead with active fixation technology became available in the UK. METHODS:This was a retrospective, observational study analyzing device complications in 476 consecutive patients undergoing successful first-time implantation of a CRT device at a tertiary center from 2017 to 2020. RESULTS:Both active (n = 135) and passive fixation (n = 341) quadripolar leads had similar success rates for implantation (99.3% vs. 98.8%, p = 1.00), although the pacing threshold (0.89 [0.60-1.25] vs. 1.00 [0.70-1.60] V, p = .01) and lead impedance (632 [552-794] vs. 730 [636-862] Ohms, p < .0001) were significantly lower for the active fixation lead. Patients receiving an active fixation lead had a reduced incidence of lead displacement at 6 months (0.74% vs. 4.69%, p = .036). There was no significant difference in the rate of right atrial (RA) and right ventricular (RV) lead displacement between the two groups (RA: 1.48% vs. 1.17%, p = .68; RV: 2.22% vs. 1.76%, p = .72). Reprogramming the LV lead after displacement was unsuccessful in most cases (successful reprogramming: Active fix = 0/1, Passive fix = 1/16) therefore nearly all patients required a repeat procedure. As a result, the rate of intervention within 6 months for lead displacement was significantly lower when patients were implanted with the active fixation lead (0.74% vs. 4.40%, p = .049). CONCLUSION:The novel active fixation lead in our study has a lower incidence of lead displacement and re-intervention compared to conventional quadripolar leads for CRT.

This chapter assesses myocardial energetics. The heart requires very large amounts of energy, cycling many times its own weight in ATP daily, and uses a variable combination of carbohydrates, lipids, lactate, and amino acids as fuel. A key feature of the healthy heart is ‘metabolic flexibility’, i.e. the ability to use different substrates according to circumstances. As the syndrome of heart failure progresses, a steady downregulation of all aspects of cardiac metabolism may be seen. In extreme disease states, a fundamental deficiency in ATP can be demonstrated, but more subtle metabolic abnormalities are detectable at an earlier stage. Additionally, there are multiple downstream disturbances in mitochondrial function, in the high-energy phosphate pool and in excitation–contraction coupling. Ultimately, the detection of abnormalities of myocardial metabolism and energetics has spurred an interest in therapeutic modulation of metabolism in heart failure. This is attractive, as potentially such modulation would improve myocardial efficiency without the need for increased fuel delivery. Such therapies could have an additive effect to current heart failure management which generally relies on correction of the maladaptive neurohumoral consequences of the heart failure syndrome.

Implantable cardiac monitors (ICMs) have excellent sensitivity for atrial fibrillation (AF) detection, ranging between 94-99%, but have a high number of false-positive (FP) detections. The Confirm Rx™ (Abbott, Chicago, IL, USA) with SharpSense™ (C-Rx) technology added a P-wave discriminator to its algorithm with the aim of reducing FP episodes.

Background: A novel familial arrhythmia syndrome, cardiac ryanodine receptor (RyR2) calcium release deficiency syndrome (CRDS), has recently been described. We evaluated a large and well characterized family to assess provocation testing, risk factor stratification and response to therapy in CRDS. Methods: We present a family with multiple unheralded sudden cardiac deaths and aborted cardiac arrests, primarily in children and young adults, with no clear phenotype on standard clinical testing. Results: Genetic analysis, including whole genome sequencing, firmly established that a missense mutation in RYR2, Ala4142Thr, was the underlying cause of disease in the family. Functional study of the variant in a cell model showed RyR2 loss-of-function, indicating that the family was affected by CRDS. EPS (Electrophysiological Study) was undertaken in 9 subjects known to carry the mutation, including a survivor of aborted sudden cardiac death, and the effects of flecainide alone and in combination with metoprolol were tested. There was a clear gradation in inducibility of nonsustained and sustained ventricular arrhythmia between subjects at EPS, with the survivor of aborted sudden cardiac death being the most inducible subject. Administration of flecainide substantially reduced arrhythmia inducibility in this subject and abolished arrhythmia in all others. Finally, the effects of additional metoprolol were tested; it increased inducibility in 4/9 subjects. Conclusions: The Ala4142Thr mutation of RYR2 causes the novel heritable arrhythmia syndrome CRDS, which is characterized by familial sudden death in the absence of prior symptoms or a recognizable phenotype on ambulatory monitoring or exercise stress testing. We increase the experience of a specific EPS protocol in human subjects and show that it is helpful in establishing the clinical status of gene carriers, with potential utility for risk stratification. Our data provide evidence that flecainide is protective in human subjects with CRDS, consistent with the effect previously shown in a mouse model.

Implantable cardiac monitors (ICMs) are commonly used for AF detection. The SJM Confirm has a positive predictive value (PPV) for AF of 64.0%. The novel Confirm Rx™ (Abbott, Chicago, IL, USA) with SharpSense™ technology incorporates a new P-wave discriminator aimed at improving AF detection. There are, however, limited ‘real-world data’ on its diagnostic performance.

Inherited arrhythmia syndromes are rare, but collectively they are a major cause of loss of life in otherwise healthy young people. Several syndromes are described, and the pathogenic mechanisms and molecular genetics are increasingly well understood. Most of them affect ion currents and are termed "channelopathies."

With the growing popularity of water-based sports, cases of swimming-induced pulmonary edema (SIPE) are becoming increasingly recognized. SIPE, a potentially life-threatening condition, is an acute cause of breathlessness in athletes. It has been described frequently in scuba divers, swimmers, and triathletes and is characterized by symptoms and signs of pulmonary edema following water immersion. It is important to recognize that athletes' symptoms can present with a spectrum of severity from mild breathlessness to severe dyspnea, hemoptysis, and hypoxia. In most cases, there is rapid resolution of symptoms within 48 hours of exiting the water. Recent advances in the understanding of the pathophysiology of SIPE, particularly regarding exaggerated pulmonary vascular pressures, have begun to explain this elusive condition more clearly and to distinguish its predisposing factors. It is essential that event organizers and athletes are aware of SIPE. Prompt recognition is required not only to prevent drowning, but also to implement appropriate medical management and subsequent advice regarding return to swimming and the risk of recurrence. This manuscript provides a current perspective on SIPE regarding the incidence rate, the current understanding of the pathophysiology, clinical presentation, medical management, recurrence rates, and advice on return to sport.

We read with interest the study from van der Harst et al. [(1)][1]. The authors show an association between 52 genetic loci and various features of the resting 12-lead electrocardiograph (ECG). ECG-based criteria are notably poor in estimating myocardial mass. The Sokolow-Lyon criteria remain

Pre-conditioning is an exciting physiological phenomenon that, despite great efforts, has so far resisted translation to mainstream clinical medicine. Many potential triggers (e.g., ischemia of the organ in question or a remote organ, many different drugs) have been investigated, but recent work has implicated activation of mitochondrial aldehyde dehydrogenase (ALDH2) as central to the process. A genetic polymorphism, known as ALDH2*2, is common worldwide (present in up to 40% of Han Chinese people) and produces a functionally different enzyme. The authors used a variety of protocols in the human ischemic forearm model, in participants with both enzyme types, to assess cytoprotection with low-dose sodium nitrite and attempt to further elucidate the role of ALDH2.

We read with interest the study from van der Harst et al. [(1)][1]. The authors show an association between 52 genetic loci and various features of the resting 12-lead electrocardiograph (ECG). ECG-based criteria are notably poor in estimating myocardial mass. The Sokolow-Lyon criteria remain

Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' - a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed.