Occurrence Of Arrhythmic Events Research Articles

The relative importance of ischaemia and scar in the genesis of ventricular arrhythmia in ischaemic cardiomyopathy

Abstract Background Ventricular arrhythmias are a leading cause of death in patients with ischaemic cardiomyopathy (ICM). Ischaemia and scar are thought to contribute to arrhythmogenesis; as scar is considered fixed, strategies to reduce ischaemia such as revascularisation are undertaken to attempt to reduce risk, despite limited evidence behind this practice. Purpose The study rationale was to understand the relative contributions of ischaemia and scar on the genesis of arrhythmia in an ICM population, by undertaking a detailed assessment of arrhythmic substrate in a highly characterised population and secondly by validating these findings in a large cohort. Methods We assessed the relationship between scar, ischaemic burden and impact of ischaemia modulation via revascularisation on the arrhythmic substrate (study 1) and major arrhythmic events (study 2). S1: Patients were eligible for enrolment if they had an LVEF≤40%, extensive coronary disease (BCIS Jeopardy Score (JS) ≥6) and were due to undergo CABG or PCI. Arrhythmic substrate was characterised by the LV activation recovery interval (ARI) dispersion recorded by electrocardiographic imaging (ECGi). Scar and ischaemic burden were assessed via stress perfusion cardiac magnetic resonance (pCMR) imaging, calculated as a percentage of total LV myocardial volume. ECGi and pCMR were repeated 3 months post revasc. S2: Arrhythmia data were collected from device interrogation reports and blinded core lab analyses performed of CMR scans and angiograms of patients enrolled in the REVIVED-BCIS2 trial. Extent of revasc (quantified by change in JS/baseline JS) was used to estimate change in ischaemic burden. The primary outcome was death or aborted sudden death. Results S1: 30 patients were recruited; age 67±10 years, 87% male, BMI 28±5. Baseline LV ARI dispersion at rest was correlated with scar burden (r=0.37, p=0.04) but not ischaemic burden (r=0.25,p=0.21). Changes in metrics are shown(Table 1). Ischaemic burden reduced after revascularisation. Delta ischaemic burden was correlated with delta LV ARI dispersion (r=0.51, p=0.007 unadjusted). S2: Data was collected on 479 patients from REVIVED-BCI2 who underwent CMR; age 69±9 yrs, 88% male, BMI 28±6, LVEF 26±8%. 237 were randomised to PCI and 242 to OMT; no difference in rates of all-cause death, CV death, aborted sudden death, appropriate device therapy or arrhythmia was identified between the groups. Scar burden was associated with death or aborted sudden death, extent of revascularisation was not(Figure 1). Conclusion In our studies, the volume of scar was strongly related to both the arrhythmic substrate and occurrence of arrhythmic events. Whilst ischaemia reduction affected the arrhythmic substrate, this did not translate to a reduction in clinical events. These findings suggest that scar burden, rather than ischaemia reduction by revascularisation, should be the focus of risk stratification and therapeutic decision making in patients with ICM.Table 1Figure 1

Estrogen-induced phenotype in hiPSC-derived cardiomyocytes of a woman affected by both Long QT Syndrome Type 2 and Polycystic Ovary Syndrome

Abstract Introduction Long QT Syndrome (LQTS) is an arrhythmogenic disorder caused either by genetic alteration or by exogenous factors. Polycystic Ovary Syndrome (PCOS) is a disease associated with high levels of testosterone and low levels of estrogen (E2). It has been suggested that hormones can influence the occurrence of malignant cardiac events in LQTS type 2 (LQT2) women, carriers of mutations on the potassium channel (hERG). However, the precise mechanisms governing this process still need to be clarified. Purpose We studied a patient affected by both LQT2 and PCOS who started experiencing cardiac symptoms after initiation of hormonal replacement therapy. We observed a correlation with the occurrence of arrhythmic events and the irregular assumption of the hormonal replacement therapy, thus we aim to dissect the underlying mechanism in patient-in-a-dish cardiac cellular model. Methods Induced Pluripotent Stem Cells (hiPSC) were generated from a woman affected by both LQT2 and PCOS and from a healthy donor, and then differentiated into cardiomyocytes (hiPSC-CMs). hiPSC-CMs were stimulated with E2 10nM for five time points (1, 5, 10, 15 and 30 minutes). The expression of potassium channel hERG, and of the G-coupled estrogen receptor (GPER) regulating the fast non-genomic pathway, were quantified after E2 stimulation at different time points by In Cell Western (ICW). The Unstimulated sample were used to normalize GPER and hERG expression to 100%. Electrophysiological experiments were performed using the whole-cell patch-clamp technique in current-clamp mode to record spontaneous action potentials (APs). AP duration at 30%, 50% and 90% repolarization (APD30, APD50 and APD90) was quantified. During spontaneous activity, AP duration values were rate-corrected with Bazett’s formula, thus obtaining cAPD. Results LQT2 hiPSC-CMs express higher levels of GPER (p<0.05) and hERG (p<0.01) than healthy hiPSC-CMs. A significant decrease in GPER expression was detected during 10nM E2 stimulation in healthy cardiomyocytes at the five time points (p<0.0001), while any difference was detected in hERG expression levels. E2 stimulation at different time points did not affect neither GPER nor hERG expression in LQT2 hiPSC-CMs. In LQT2 hiPSC-CMs, APDC values were significantly increased (p<0.0001) compared to healthy cells; pre-incubation with E2 for 10 minutes significantly shortened cAPD50 and increased spontaneous firing rate. In healthy hiPSC-CMs, E2 had no effect. Conclusions The hiPSC-CM model reproduces the LQT2 clinical phenotype. cAPD50 shortening by E2 was unexpected based on the proarrhythmic effect in the patient. The mechanism of LQT2-specific effects of E2 are under investigation.

Effects of low-to-moderate doses of X-rays on the cardiac rhythm via the sympathetic nervous system in female mice

Radiotherapy is one of the common therapeutic approaches in the treatment of breast cancer, with the heart inevitably being exposed to ionizing radiation which may cause late cardiac pathologies. Our recent study revealed that right atrium irradiation of right-sided breast cancer patients is associated with the development of cardiac diseases such as heart failure, arrhythmias, and conduction disorders. The aim of this project is to examine the effect of low to moderate doses of X-rays on the development of late cardiac pathologies. We specifically studied the alterations in the cardiac sympathetic nervous system which is located in potentially arrhythmogenic structures of the sinoatrial and atrioventricular nodes. Female C57Bl/6J mice were exposed to X-rays irradiation targeted to top, bottom or whole heart, such that different cardiac nodes were exposed. To examine the presence of a threshold in a dose-response for cardiac rhythm pathology, as assessed by ultrasound examinations, mice were exposed to doses ranging from 0.25 to 2 Gy. Molecular and cellular mechanisms involved in these cardiac disorders at early (24-hours) and late (60-weeks) time points post-irradiation were studied. At the functional level, our Doppler echography data show the presence of an alteration of cardiac function with the occurrence of arrhythmic events at 60-weeks post-irradiation in all irradiated animals, specifically in top heart irradiation. To confirm these results, we will also use transesophageal atrial stimulation (10 Hz during 3 sec) to assess supraventricular arrhythmias. At the molecular level, we focused on proteins involved in cardiac conduction system and in sympathetic innervation patterning 24-hours post-irradiation. Our Western Blot results show a significant increase of Connexin 40 (P = 0.02), Connexin 43 (P = 0.02), Tyrosine Hydroxylase (P = 0.04), and b3-Tubulin (P = 0.03) protein levels in whole heart irradiated animals. Altogether, our preliminary results showed modifications of cardiac function 60-weeks post-irradiation with the development of cardiac rhythm disorders and molecular alterations of cardiac conduction and sympathetic nervous system already present 24-hours post-irradiation.

Characterization and long-term follow-up of children with brugada syndrome: experience from a tertiary paediatric referral centre

Abstract Introduction Brugada syndrome (BrS) is an autosomal dominant channelopathy, which typically presents in young adults. It can also be diagnosed in children, but data in this age group is scarce. Purpose To describe the clinical features, management and long-term follow-up of children with BrS history followed-up in a tertiary paediatric referral centre. Methods Single centre retrospective study of consecutive patients with history of BrS, defined as having a BrS positive phenotype (BrS(+)), or a negative phenotype-positive genotype (BrS(−)). They were all followed up in a paediatric heart rhythm clinic. Clinical and demographical data were collected and analysed according to the phenotype. Results 30 patients were included, with a median age at diagnosis of 7 years (IQR 1–13) and a mean follow-up time of 7±3 years. Sixteen patients were BrS(+), predominantly male (n=13, 81%). 88% (n=14) performed a genetic test, which was positive in 57% (n=8); the most frequent mutation was SCN5A (n=5). Family history of BrS was present in 56% (n=9) and almost one third had family history of sudden cardiac death (SCD). Most of the patients had a type 1 Brugada ECG pattern (n=14) and 2 patients presented a fever and drug induced pattern, respectively. Fourteen patients were BrS(−), mostly female (n=11, 79%) with a loss-of-function mutation in the SCN5A gene (n=10). They all had family members with BrS, mainly from the paternal side, and 43% (n=6) mentioned SCD history. Although most of the patients were asymptomatic, the prevalence of rhythm or conduction disturbances was not infrequent, particularly in BrS(+) patients (n=12, 75%). Also, in this group and during follow-up, 3 patients had documented supraventricular tachyarrhythmias, and 2 patients had syncope episodes, one of which required an implantable cardioverter-defibrillator. No events were reported in the BrS(−) patients. Nine patients (n=9/30, 30%) were hospitalized, 3 due to an arrhythmic event (all in the BrS(+) group). Overall, no sudden cardiac death event was reported during follow-up. Conclusion In our study, although the majority of the patients were asymptomatic, the occurrence of arrhythmic events was not negligible, especially in the BrS(+) patients. Despite the significant family history, patients with BrS(−) had no events reported during follow-up. Nevertheless, the management of these patients is not clear cut, and a personalized therapeutic strategy with close follow-up is essential. Funding Acknowledgement Type of funding sources: None.

ShRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.

Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G/A) in KCNQ1, with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs.

Abstract 12119: Silencing of Notch Signaling Tempers the Occurrence of Arrhythmic Events in the Post-Infarcted Heart

Notch1 receptor signaling is active during cardiac development and is upregulated in the adult myocardium following ischemic damage. We previously documented that Notch1 signaling modulates the electrical activity of myocytes, but whether activation of the Notch receptor system contributes to the functional properties of the injured heart remains to be clarified. In the current study, we assessed the consequences of silencing of Notch1 signaling on electrical activity and arrhythmogenic behavior of the mouse heart, in physiological condition and following myocardial infarction (MI). For this purpose, mice with cardiac-restricted, inducible deletion of Notch1 gene (conditional knock-out, cKO) and corresponding control (Ctrl) mice were studied at baseline and up to one month after permanent coronary artery ligation. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were comparable in both male and female naïve cKO and Ctrl mice. At ~2 and ~4 weeks after MI, chamber dilation occurred and ejection fraction was equally reduced in cKO and Ctrl animals. By electrocardiographic recordings in the conscious state over a period of 10 minutes, no arrhythmic events were observed in naïve Ctrl and cKO mice. In contrast, at one day after MI, a large fraction of Ctrl mice developed premature ventricular complexes (PVCs, 72%, n=18) and ventricular tachycardia (VT, 28%), but the fraction of cKO mice with PVCs was substantially reduced (31%, n=32) and VT was not observed. From 3-~30 days after MI, arrhythmic events occurred sporadically and no major differences were detected between the two groups of mice. Following euthanasia at 30 days after MI, infarcted hearts were perfused in a Langendorff system and monophasic action potential and pseudo-ECGs collected. Spontaneous VT were found in both Ctrl (18%, n=11) and cKO (7% n=14) hearts in sinus rhythm. Importantly, programmed electrical stimulation (S1-S2 protocol) induced PVCs and/or VT in 55% of Ctrl infarcted hearts (n=11), but only in 23% of cKO organs (n=13). Collectively, these findings support the possibility that Notch1 signaling modulates the electrical activity of the injured heart and its propensity to develop arrhythmias.

Non-sustained ventricular tachycardia on remote patient monitoring in heart failure patients

Abstract Background Non-sustained ventricular tachycardia (NSVT) is commonly found in patients with structural heart disease and was historically obtained from registers of external ambulatory monitoring. The advent of remote patient monitoring (RPM) in Cardiac implantable electronic devices (CIEDs) has made it possible to detect asymptomatic NSVT in Heart Failure (HF) patients more frequently, but its impact in real world is uncertain. Purpose To determine the clinical impact of NSVT detection in RPM in ischemic and non-ischemic chronic heart failure patients with reduced ejection fraction (HFrEF) and CIEDs. Methods We retrospectively enrolled 121 consecutive patients with HFrEF, CIEDs and RPM. Patients were evaluated through routine episodic CIEDs interrogation, routine clinical evaluations and continuous monitoring data obtained from CIEDs and transmitted remotely to the care team and divided into NSVT positive (Group 1) and negative groups (Group 2). Primary endpoint was admissions to the emergency department by HF decompensation and secondary endpoint was the occurrence of arrhythmic events. A sub-analysis of non-ischemic HF was also performed. Results NSVT was detected in 78 (72,2%) patients. The mean number of episodes of NSVT was 611,68±3271,25 during the follow-up period or 2,445±16,688 in 24 hours. Mean age was 62,40±13,218 years, 71,9% were males and mean follow-up period was 56,30±39,37 months. Fifty-eight patients (47,9%) had transvenous implantable cardioverter defibrillator (ICD), 48 (39,7%) implantable cardiac resynchronization therapy (CRT) defibrillator (CRT-D), 14 (11,6%) subcutaneous ICD (S-ICD) and 1 (0,8%) CRT pacemaker (CRT-P). Medium left ventricular ejection fraction (LVEF) was 34,70±12,53%, 25 (23,14%) were in NYHA III-IV and 46 (39,0%) were ischemic (29 (37,7%) in Group 1 and 11 (37,9%) in Group 2). NSVT was associated with the occurrence of sustained ventricular tachycardia (VT) (1,88±0,186episodes of VT in group 1 and 0,03±0,186 in group 2, p=0,012), ventricular fibrillation (VF) (1,44±5,325 episodes of VT in group 1 and 0,03±0,186 in group 2, p=0,011) and admissions to the emergency department by HF decompensation at 5 years (r=0,310, p=0,011). A sub-analysis in non-ischemic HF patients also showed correlation between NSVT and VT (r=0,602, p<0,05) and admissions to the emergency department by HF decompensation at 5 years (r=0,382, p=0,014). Conclusions On remote patient monitoring with CIEDs, NSVT in HF patients was associated with arrhythmic events and may serve as a predictor for HF decompensations. Funding Acknowledgement Type of funding sources: None.

New York Heart Association class change on heart failure patients with implantable devices: does it matters?

Abstract Background Chronic heart failure (CHF) is a pathology with high prevalence and an important cause of morbidity and mortality. Benefits of implantable devices have been demonstrated in selected groups of patients with benefits on symptoms and heart failure hospitalization. Purpose To determine the clinical impact of New York Heart Association class change (NYHA) in patients with CHF and Cardiac Implantable Electric Devices (CIEDs). Methods We retrospectively enrolled 178 consecutive patients with CHF and CIEDs between November 2003 and January 2021, during a follow-up period of 51±43,9 months. Patients demographic characteristic and NYHA class change impact on occurrence of arrhythmic events, heart failure hospitalization (HFH) or long-term admission in an emergency department were assessed. Patients with NYHA class change were considered responders to therapy. Results Out of 178 patients enrolled in this study, sixty-seven (37,6%) had a reduction ≥1 in NYHA functional class and in this group, 61 patients (91,0%) had a cardiac resynchronization therapy (CRT) and 9% had an implantable cardioverter defibrillator. Mean age 68±11,3 years, 44 (65,7%) patients were male, 33 (49,2%) were in NYHA class II, 30 (44,8%) NYHA class III and 4 (6%) NYHA class IV. Mean QRS width 129,9±63,1 ms before CIEDs. Fifty-eight patients (86,6%) had an improvement in one NYHA functional class and 9 patients (13,4%) in two NYHA functional class. Fourty NYHA responders patients (59,7%) had paroxistic or permanent atrial fibrillation and 31,9% had an epicardial coronary artery disease, that was a negative predictor of NYHA response (p=0,012). A total of 35 (19,7%) enrolled patients experience non-sustained ventricular tachycardia (NSVT) and 74,3% were non-responders (p=0,019). There was fifteen and twenty HFH at 2 and 5 years of follow-up, respectively, and we observed that an improvement in NYHA class was associated with a reduction in HFH at 2 years of follow-up (p=0,043; OR 0,029, 95% CI 0,050–1,06) and 5 years of follow-up (p 0,027, OR 0,252; 95% CI 0,069 – 0,915). Emergency department (ED) admission related to HF decompensations was significantly reduced at 2 years of follow-up (p=0,035, OR 0,22, 95% CI 0,048 – 1,0) and at 5 years of follow-up (p=0,001, OR 0,15, 95% CI 0,044 – 0,55). There was no difference on cardiovascular or all-cause mortality. Conclusion CHF patients with CIEDs and improving on NYHA class have less NSVT episodes, HFH and HF decompensations with ED admission, both at 2 and 5 years of follow-up. Funding Acknowledgement Type of funding sources: None.

Mitral annular disjunction and cardiovascular outcome in Marfan syndrome

Abstract Background Mitral annular disjunction (MAD) has received growing interest in patients with mitral valve prolapse (MVP), ventricular tachycardia (VT) and sudden cardiac death (SCD). The clinical significance of MAD in Marfan syndrome (MFS) remains largely unexplored. Purpose To define the prevalence of MAD and examine the relation with cardiovascular outcomes and arrhythmia in patients with MFS. Methods The presence of MAD was assessed by echocardiography and the extent of MAD was categorized in tertiles. Patients also underwent resting ECG and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (VT/SCD) and mitral valve surgery. Results A total of 142 patients (median age 25 years [range 2–64], 51% women) were evaluated. Forty-eight (34%) patients had MAD. Patients with MAD had larger aortic root Z-scores (4.1 [2.8–5.7] vs. 3.0 [1.8–4.0], p<0.001) and more often showed MVP (71% vs. 15%, p<0.001), ventricular ectopy (42% vs. 21%, p=0.027) and non-sustained ventricular tachycardia (39% vs. 17%, p=0.014) than patients without MAD. During follow-up, aortic events occurred at similar rates in patients with vs. without MAD (35% vs. 25%, p=0.103), but patients in the upper MAD tertile (>10mm) showed a higher occurrence of aortic events (60% vs. 21%, p=0.011) compared to patients with MAD(+) ≤10mm. Arrhythmic events and a need for mitral valve surgery were observed exclusively in patients with MAD (p=0.004 and p<0.001, respectively). Conclusions MAD is associated with a higher need for mitral valve intervention, occurrence of arrhythmic events and, in patients with extensive MAD, more aortic events. Cardiac imaging in MFS should consider the assessment of MAD as a potential marker for adverse outcome. Funding Acknowledgement Type of funding sources: None. Cardiovascular outcome and arrhythmia

Autophagy-related gene 5 (Atg5) is required for maintaining subcellular calcium homeostasis during acute cardiac stress

Abstract Background Autophagy exerts protective effects during cardiac stress inflicted by β-adrenergic stimulation and pressure overload. Contrarily, deletion of the cardiac-specific Atg5 gene contributes to left ventricular hypertrophy and contractile dysfunction, resulting in dilated cardiomyopathy. Heart failure is characterized by perturbations of excitation-contraction coupling (ECC) underlying alterations in intracellular calcium signaling. Purpose In this study, we aimed to understand whether loss of basal autophagy due to Atg5 deletion specifically in cardiomyocytes contributes directly to disturbances in subcellular calcium cycling. Methods Cardiac-specific Atg5−/− and Atg5+/+ mice were used to isolate ventricular cardiomyocytes, which were loaded with 8 μM Ca2+ indicator Fluo4/AM. Isolated cells were electrically stimulated and subjected to elevated workload by increasing pacing frequencies from 1 to 4 Hz. Cytosolic and nuclear calcium transients (CaTs) were recorded in line-scan mode using a laser scanning confocal microscope. Pharmacological inhibition of autophagic flux was performed by an intraperitoneal injection of 40 mg/kg leupeptin to Atg5+/+ mice. Results At baseline (1 Hz) stimulation the amplitude and kinetics of calcium transients were comparable between Atg5−/− and Atg5+/+ cells. However, after progressive increase of the pacing rate from 1 Hz to 4 Hz, Atg5−/− cardiomyocytes displayed reduced cytoplasmic and nuclear CaT amplitude, but increased nuclear time-averaged CaTs compared to controls. Such increase in nuclear calcium load stimulates Ca2+-dependent transcriptional activity, and likely involves CaMKII-mediated pro-hypertrophic gene program thus contributing to cardiac remodelling. In addition, we observed increased occurrence of arrhythmic events in Atg5−/− hearts at high pacing frequency, indicative of intracellular calcium overload and disturbed ECC. Acute pharmacological autophagy inhibition failed to elicit direct changes in time-averaged CaTs in the cytoplasm and nucleoplasm, suggesting that loss of Atg5-dependent autophagy seems to induce adverse cardiac remodelling that involves increased CaMKII activity due to the imbalances in nuclear Ca2+ levels. Conclusion Specific loss of ATG5 protein impairs calcium cycling during acute stress exposure by reducing CaT amplitudes, promoting arrhythmia, and increasing nuclear calcium load, which may induce hypertrophic gene expression. Further work is needed to identify key components mediating autophagy-related cardioprotection to develop strategies against cardiac remodeling and its progression to heart failure. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund (FWF)

Clinical characteristics and risk of arrhythmic events in patients younger than 12 years diagnosed with Brugada syndrome.

Brugada syndrome (BrS) is an inheritable disease with an increased risk of sudden cardiac death. Although several score systems have been proposed, the management of children with BrS has been inconsistently described. The purpose of this study was to identify the characteristics, outcome, and risk factors associated with cardiovascular and arrhythmic events (AEs) in children younger than 12 years with BrS. In this single-center case series, all children with spontaneous or drug/fever-induced type 1 Brugada electrocardiographic (ECG) pattern and younger than 12 years at the time of diagnosis were enrolled. Forty-three patients younger than 12 years at the time of diagnosis were included. The median follow-up was 3.97 years (interquartile range 2-12 years). In terms of first-degree atrioventricular block, premature beats, nonmalignant AEs, malignant AEs, and episodes of syncope, no significant differences were observed either between patients with spontaneous and drug/fever-induced type 1 Brugada ECG pattern or between female and male patients (except a significant difference between female and male patients for first-degree atrioventricular block). A higher incidence of malignant AEs was observed in patients with syncope (3 of 8 [37.5%] vs 0 of 35 [0%]; P = .005) than in patients without syncope. SCN5A mutations were associated with a higher occurrence of malignant AEs (3 of 14 [21.4%] vs 0 of 25 [0%]; P = .04) compared with no SCN5A mutations. A spontaneous type 1 Brugada ECG pattern is not associated with a higher incidence of syncope, first-degree atrioventricular block, premature beats, nonmalignant AEs, and malignant AEs than the drug/fever-induced type 1 Brugada ECG pattern. Syncope events are correlated with an increased incidence of malignant AEs. Moreover, SCN5A mutations are associated with a higher occurrence of malignant AEs.

A simplified wall-based model for regional innervation/perfusion mismatch assessed by cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT to predict arrhythmic events in ischaemic heart failure

AimsCardiac 123iodine-meta-iodobenzylguanidine (123I-mIBG) single-photon emission computed tomography (SPECT) imaging provides information on regional myocardial innervation. However, the value of the commonly used 17-segment summed defect score (SDS) as a prognostic marker is uncertain. The present study examined whether a simpler regional scoring approach for evaluation of 123I-mIBG SPECT combined with rest 99mTc-tetrofosmin SPECT myocardial perfusion imaging could improve prediction of arrhythmic events (AEs) in patients with ischaemic heart failure (HF).Methods and ResultsFive hundred and two ischaemic HF subjects of the ADMIRE-HF study with complete cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT studies were included. Both SPECT image sets were read together by two experienced nuclear imagers and scored by consensus. In addition to standard 17-segment scoring, the readers classified walls (i.e. anterior, lateral, inferior, septum and apex) as normal, matched defect, mismatched (innervation defect > perfusion defect), or reverse mismatched (perfusion defect > innervation defect). Cox proportional hazards ratios (HRs) were used to determine if age, body mass index, functional class, left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), norepinephrine, 123I-mIBG SDS, 99mTc-tetrofosmin SDS, innervation/perfusion mismatch SDS, and our simplified visual innervation/perfusion wall classification were associated with occurrence of AEs (i.e. sudden cardiac death, sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate implantable cardioverter-defibrillator therapy). At 2-year median follow-up, 52 subjects (10.4%) had AEs. Subjects with 1 or 2 mismatched walls were twice as likely to have AEs compared with subjects with either 0 or 3–5 mismatched walls (16.3% vs. 8.3%, P = 0.010). Cox regression analyses showed that patients with a visual mismatch in 1-2 walls had an almost two times higher risk of AEs [HR 2.084 (1.109–3.914), P = 0.001]. None of the other innervation, perfusion and mismatch scores using standard 17 segments were associated with AEs. BNP (ng/L) was the only non-imaging parameter associated with AEs.ConclusionA visual left ventricular wall-level based scoring method identified highest AE risk in ischaemic HF subjects with intermediate levels of innervation/perfusion mismatches. This simple technique for the evaluation of SPECT studies, which are often challenging in HF subjects, seems to be superior to the 17-segment scoring method.

Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome

Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored. To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS. This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019. The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery. A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD. This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.

Late gadolinium enhancement as a predictor of arrhythmias in patients with hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of arrhythmias and sudden cardiac death (SCD). The Late gadolinium enhancement (LGE) in cardiovascular magnetic resonance (CMR) has been associated with the occurrence of arrhythmic events. Purpose The aim was to analyze the association between LGE burden and location and arrhythmic events in HCM patients (P). Methods Retrospective analysis of P with HCM in a single tertiary center. Baseline clinical, echocardiographic and CMR characteristics were collected. On follow up arrhythmias (ventricular fibrillation (VF), sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT), paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF) and atrial flutter (AFL)) were identified. LGE on CMR was compared between patients with and without arrhythmias. Results 61P (59% male) were included, with a mean age of 58 ± 2 years. The HCM risk-SCD score was 3.35 ± 0.28%. On echocardiography mean left ventricle ejection fraction was 62.16 ± 1.36% and maximum wall thickness 20.59 ± 0.596mm. 31.1% had systolic anterior movement of mitral valve and 26.7% had left ventricle outflow tract obstruction. LGE was present in 88.5% P with a median number of 5 ± 7 segments involved. Interventricular septum (IVS) was involved in 78.7% P, anterior wall in 57.4%, inferior wall in 54.1%, lateral wall in 52.5%, posterior wall in 9.8%, basal segments in 62.3%, median segments in 68.9% and apical segments in 63.9%. On follow up 3.3%P died, 45.8% had hospitalizations (22,2% because of an arrhythmia) and 75% had arrhythmias (1.6% VF, 6.6% SVT, 50% NSVT, 9.8% PSVT, 37.7% AF and 6.6% AFL). The number of segments with LGE correlated with arrhythmias (p = 0.05 for arrhythmias, p = 0.03 for SVT, p = 0.008 for NSVT and p = 0.042 for PSVT). A cut off of 5 segments involved was a good predictor of arrhythmias (p = 0.002), NSVT (p= 0.006), PSVT (p = 0.024) and AF (p = 0.0029). For SVT the best cut off was 9 (p = 0.003). Considering the LGE location, we found an association between the segments involved and the occurrence of different arrhythmias (table 1). Conclusion Supraventricular and ventricular Arrhythmias are frequent in patients with HCM, with the most frequents being NSVT and AF. The LGE burden (&amp;gt;5 segments) and location (median inferior IVS, median anterior IVS, median anterior wall, basal anterior IVS, apical anterior wall, median inferior wall, apical anterior wall and basal inferior IVS) were correlated with arrhythmic events. Abstract Figure.

Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions.

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs. Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca2+ transient duration (CTD90) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na+ (INa), L-type Ca2+ (ICaL), and rapid delayed rectifying K+ (IKr) currents was quantified. Finally, we compared the drug-induced effects on CTD90 against the corresponding in vitro experiments. Results: The observed CTD90 changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD90 prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting IKr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na+ blockers and by drugs with similar effects on ICaL and IKr in Koivumäki2018 and Paci2020, while only by strong ICaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis. Conclusion: To conclude, The CTD90 changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.

A wall based regional innervation/perfusion mismatch assessed by cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT to predict arrhythmic events in ischemic heart failure patients

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiac 123I-mIBG SPECT imaging provides information on regional myocardial innervation. However, there is no consensus on how to use a, 17-segment based score to assess prognosis. The present study examined whether a simpler regional scoring approach for evaluation of 123I-mIBG SPECT combined with rest 99mTc-tetrofosmin SPECT myocardial perfusion imaging could be used for the prediction of arrhythmic events (AEs) in ischemic heart failure (HF). Methods 261 ischemic HF subjects (NYHA II/III, LVEF ≤35% on gated SPECT) of the ADMIRE-HF study cohort with complete cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT studies were enrolled. Both SPECT image sets were read together by 2 experienced nuclear imagers and scored by consensus. In addition to standard 17 segments scoring, the readers classified walls (i.e. anterior, lateral, inferior, septum and apex) as normal, matched defect of innervation and perfusion, mismatched (i.e., innervation defect lager than perfusion defect) or reverse mismatched (i.e., innervation defect smaller than perfusion defect). Cox proportional hazards ratios (HR) were used to determine if the visual segmental wall classification innervation/perfusion mismatch score, 123I-mIBG summed defect scores (SDS), 99mTc-tetrofosmin SDS and innervation/perfusion mismatch SDS, age, LVEF, NYHA class, B-type natriuretic peptide (BNP) and norepinephrine (NE) plasma levels were associated with occurrence of AEs (i.e. sudden cardiac death, sustained VT, resuscitated cardiac arrest, appropriate ICD therapy). Results At 2-year median follow-up, 38 subjects (14.6%) had AEs. Subjects with 1 or 2 mismatched walls were more than twice as likely to have AEs compared with subjects with either 0 or 3-5 mismatched walls (24.0% vs 10.8%, p = 0.006). Cox regression analyses showed that the combination of the presence of visual mismatch in 1-2 walls and BNP and were the only independent predictors of AEs (HR 2.583 [1.261-5.107],p = 0.001) However, compared to the visual mismatch, the contribution of BNP is relatively small (i.e., HR 1.001 [1.000-1.001]). Conclusion In ischemic HF with LVEF ≤35 the highest risk of AEs occurs in subjects with intermediate levels of visual wall-level innervation/perfusion mismatches. Therefore, a simple visual wall-level based assessment of combined cardiac 123I-mIBG and rest 99mTc-tetrofosmin SPECT can be used to differentiate those HF patients at higher AE risk from those with relatively low AE risk. Table 1. Cox regression analysis Variable HR (95% CI) X2 change X2 p-value AE’s 1-2 mismatched segments 2.412 (1.204-4.830) 6.581 5.880 0.010 BNP 1-2 mismatched segments 1.001 (1.000-1.001) 2.538 (1.261-5.107) 13.434 4.129 0.001 Abstract Figure. Kaplan Meier curves for AEs

Nucleoside Diphosphate Kinase B Contributes to Arrhythmogenesis in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare, inheritable cardiac disorder characterized by ventricular tachyarrhythmias, progressive loss of cardiomyocytes with fibrofatty replacement and sudden cardiac death. The exact underlying mechanisms are unclear. Methods: This study investigated the possible roles of nucleoside diphosphate kinase B (NDPK-B) and SK4 channels in the arrhythmogenesis of ARVC by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results: In hiPSC-CMs from a patient with ARVC, the expression levels of NDPK-B and SK4 channels were upregulated, the cell automaticity was increased and the occurrence rate of arrhythmic events was enhanced. Recombinant NDPK-B applied into hiPSC-CMs from either healthy donors or the patient enhanced SK4 channel current (ISK4), cell automaticity and the occurrence of arrhythmic events, whereas protein histidine phosphatase 1 (PHP-1), a counter actor of NDPK-B, prevented the NDPK-B effect. Application of PHP-1 alone or a SK4 channel blocker also reduced cell automaticity and arrhythmic events. Conclusion: This study demonstrated that the elevated NDPK-B expression, via activating SK4 channels, contributes to arrhythmogenesis in ARVC, and hence, NDPK-B may be a potential therapeutic target for treating arrhythmias in patients with ARVC.

CIRCADIAN-RELATED ECTOPIC RHYTHMS IN YOUNG PATIENTS: ETHIOPATHOLOGICAL FEATURES AND PRINCIPLES OF THERAPY

The autonomic nervous system plays a key role in the processes of adaptation, regulating the functioning of the whole organism. And a disturbance of the heart rhythm is typically one of the first manifestations of autonomic circadian maladaptation. The aim of this study was to assess the relationship between circadian rhythm disorders and autonomic misbalance with the occurrence of arrhythmic events in young patients with the further development of treatment strategy. Materials and methods: the study was performed at the Medical Centre «MEDION». 34 patients aged 18-35 years were enrolled to the study, divided into the test and control groups. Results: despite a significantly higher frequency of supraventricular arrhythmias in the test group compared to the control group, the supraventricular extrasystoles occurred in the control group predominantly at night time (with peak from 3 to 6 a.m.). In the test group, atrial ectopic beats were observed predominantly from 5 to 12 a. m. In the group of patients with the number of ventricular ectopic complexes over 500 / day, no time interval was found, during which the number of ventricular extrasystoles was statistically significantly predominant. The most important factors of ventricular ectopic events occurrence included: sleeping less than 6 hours, job lasting over 10 hours a day, and too little time spent outdoors. All individuals were recommended to modify their lifestyle and take when necessary autonomic normalization agents and antiarrhythmics. Conclusion: the modern lifestyle of the young generation leads to the disturbance of circadian biorhythms as a result of the unbalanced autonomic regulation and the subsequent occurrence of ectopic arrhythmic events. The most unfavourable factors in this case are sleeping less than 6 hours, a working day lasting over 10 hours, and outdoor-spent time lasting less than 2 hours a day.

GENECHOC study: A study designed to identify the genetic variants involved in appropriate shock in primary prevention. Clinical description of the patients

Arrhythmic risk stratification for primary prevention in patients with severe cardiomyopathy (CM) remains difficult. We established a large database of patients implanted for primary prevention with the aim to identify genetic modifiers involved in the occurrence of arrhythmic events. We described the clinical characteristics of patients included in the study. Patients were included in 22 French centers over a 9 year-period. Only patients implanted for primary prevention (no previous arrhythmias at the time of implantation in patients who had an EF less than 35%). Patients implanted with a resynchronization therapy were not included in the study. 1079 patients were enrolled (mean age 59 ± 11, 86.3% male). Ischemic CM was found in 77.1% and 20.5% had a non-ischemic CM. The mean EF was 27 ± 7%. The population was well treated with beta-blockers treatment in 89.9% and angiotensin converting enzyme inhibitors in 90.7%. VVI ICD was implanted in 721 patients (67%) and DDD ICD in 357 (33%). After a mean follow-up of 5.5 ± 2.5 years appropriate ICD therapy occurred in 388 (35.9%) patients. Predictive factors for appropriate therapy were male gender (38.2% in male vs. 21.6% in women, P = 9.10 −5 ). There was no significant difference for EF, 27.2 ± 5.3 in patients without ICD therapy vs. 26.8 ± 5 in patients with ICD therapy. The etiology of CM (ischemic vs. non ischemic) didn’t change the rate of appropriate therapy (respectively 34.9% vs. 37.7%, P = 0.4). 61 patients (5.6%) received inappropriate therapies mainly because of supraventricular tachycardia ( n = 24, 39.3%), T wave oversensing ( n = 11, 18%) and lead failure ( n = 14, 22.9%). Our population is similar in term of arrhythmic risk and clinical presentation to the usual population implanted for primary prevention. As for the first time this population is homogenous in term of geographic origin, it will allow using a GWAS analysis to identify genetic modifiers involved in SCD.

Abstract 16623: Can We Predict Ventricular Arrhythmias in Familial Left Ventricular Non Compaction?

Introduction: Left Ventricular Non Compaction (LVNC) is an unclassified cardiomyopathy characterized by left ventricular hypertrabeculation and deep intertrabecular recesses in communication with the ventricular cavity. LVNC is often associated with other cardiomyopathies or with genetical disorders, and is familial at least in 25% of cases. The diagnosis is based on echocardiographic criteria (Chin et al. 1990; Jenni et al.2001; Stollberger et al. 1987-2002). Hypothesis: The aim of this study was to assess the value of echocardiographic parameters in predicting the occurrence of arrhythmic events in patients with familial LVNC. Methods: we studied 26 subjects, aged 39.9 ± 16.2 years, 11 males and 15 females, at a single institution, representing 7 families with LVNC. None had concomitant hypertension, diabetes mellitus or other significant cardiovascular disorder. Patients were evaluated at 3-month interval either clinically or with 12-Lead ECG, echocardiography and 24-hour Holter monitoring. The average duration of follow up was 36 ± 9 months. Echocardiographic parameters, ejection fraction (EF) and end-diastolic diameter (EDD), were matched with ventricular arrhythmias (VA) to assess their predictive value. The Kaplan-Meier method was used to calculate the probability of ventricular events. Results: Left Ventricular (LV) systolic function was depressed in 10 of 26 patients (38.5%), with a mean EF of 44 ± 3.2% at the first visit. Nine of 26 patients (34.6%) had LV dilatation (EDD ≥ 60 mm): among them only 5 patients (55.5%) had EF &lt; 45%. Six of 26 patients (23.1%) underwent episodes of ventricular tachycardia (VT) during follow up. All 6 patients (100%) had LV dilatation, among them only 3 patients (50%) had depressed EF. By Chi square test and Kaplan Meier analysis, the only echocardiographic predictor of VA was LV dilatation (p &lt; 0.001). Conclusions: In families with isolated LVNC, LV dilatation was the only echocardiographic predictor associated with subsequent development of ventricular arrhythmias. This finding might be helpful to optimally target preventive therapies in patients with familial LVNC.