Background:Patients with mitral valve prolapse (MVP) are at risk of ventricular arrhythmias (VAs), ranging from premature ventricular complexes (PVCs) to life-threatening VAs. The association between PVC burden and heart rate in patients with MVP is not known. We aimed to identify the association between PVC burden and heart rate in patients with MVP. Methods:In this this cross-sectional ambispective case control study we included MVP patients with available Holter monitorings. We defined PVC profiles as fast-heart-rate-dependent-PVC (F-HR-PVC) in case of positive correlation with heart rate, slow-heart-rate-dependent-PVC (S-HR-PVC) in case of negative correlation, and independent-heart-rate-PVC (I-HR-PVC) when no correlation was found. For comparison, we included a control group of age- and sex-matched patients with idiopathic PVCs. Results:We included 70 patients with MVP (48 years [interquartile range 35-58], 79% female) and 70 age- and sex-matched patients with idiopathic PVCs. A total of 153 Holter monitorings from patients with MVP were analysed and compared to 70 Holter monitorings from patients with idiopathic PVCs. In the MVP group, we found F-HR-PVC in 44 (63%) patients, I-HR-PVC in 24 (34%) and S-HR-PVC in 2 (3%). MVP patients had more frequently F-HR-PVC and less frequently S-HR-PVC than the control group (p < 0.05 for both). MVP patients with F-HR-PVC had higher rate of NSVTs (incidence rate ratio 2.9 [95% confidence interval 1.1-7.8], p = 0.03) compared to I-HR-PVC. Conclusion:Fast-heart-rate-dependent-PVC was the most common PVC profile in MVP patients, and slow-heart-rate-dependent-PVC was rare. These findings suggest a catecholamine-sensitive mechanism acting as trigger for ventricular arrhythmias in MVP patients.

BACKGROUND:Interleukin-6 receptor (IL-6R) inhibition by tocilizumab improves myocardial salvage index (MSI) in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect remain unclear. METHODS:This pre-defined exploratory sub-study of the ASSAIL-MI trial enumerated circulating monocytes and examined their transcriptome profile in relation to the MSI and peak troponin T (TnT) in STEMI patients randomiseded to tocilizumab (n = 101) or placebo (n = 98). RNA sequencing was performed on peripheral monocytes in 14 patients. To elaborate the in vivo findings, in vitro chemotaxis and apoptosis assays were performed on THP-1 monocytes and cardiomyocyte (HL-1) cell lines, respectively. FINDINGS:STEMI patients had increased monocyte counts at 24 h and 3-7 days after hospitalisation/PCI and this increase was attenuated by tocilizumab. Lower monocyte levels at 24 h were associated with lower TnT levels and higher MSI. Monocyte gene expression suggested that tocilizumab modulated cytokine signalling pathways related to myocardial remodelling, apoptosis, and chemotaxis, potentially through a decrease in suppressor of cytokine signalling 3 (SOCS3). In vitro, tocilizumab limited apoptosis of cardiomyocytes exposed to ischemia/reperfusion and reduced chemotaxis in monocytes exposed to IL-6. INTERPRETATION:These findings suggest that IL-6R inhibition by tocilizumab during STEMI is associated with reduced monocyte counts and cardioprotective alterations in monocyte signalling potentially linked to the downregulation of SOCS3. FUNDING:This work was supported by the South-Eastern Norway Regional Health Authority (no. 2019067) and The Research Council of Norway (no. 282867) The ASSAIL-MI main study was supported by an independent grant from ROCHE who also provided drugs/placebo for infusion.

Prevalence and response to treatment of arrhythmias are different for women and men. We characterized patients admitted for catheter ablation (CA) of premature ventricular complexes (PVC) according to sex, and compared mapping strategy and procedural outcome in the two groups. Clinical characteristics and outcomes from the CA procedures were retrospectively collected from health journals from patients undergoing CA for PVCs from 2011-2020 in our tertiary referral center. We included 332 patients referred for CA of PVCs, of whom 208 (63%) were women. The women were younger than the men (46±14 vs 54±14 years, p<0.001), and fewer had coronary artery disease (1 vs 17%, p<0.001), hypertension (13 vs 23%, p=0.001), diabetes (1 vs 10%, p<0.001) and heart failure (2 vs 7%, p<0.001). In line with this, more women had a normal echocardiogram (79 vs 64%, p=0.004) and EF>50% (94 vs 85%, p=0.012). Despite less cardiac disease, more women were reported more symptoms in general (97 vs 87%, p<0.001), and palpitations specifically (80 vs 64%, p<0.001). The women in our cohort had a numerically slightly lower PVC burden in the last 24h ECG prior to CA, although this did not reach statistical significance (17±12 vs 20±13%, p=0.110). More women than men had PVCs with origin in the outflow tracts (88 vs 79%, p=0.043). Woman and men did not differ with regard to acute success rate or complications. Activation mapping was less often used as the sole mapping strategy in women (52 vs 68%, p=0.012) but in a linear regression model that controlled for age, symptoms, number of PVCs and coupling interval, number of PVCs on last 24h ECG was the only parameter independently associated with mapping strategy (p=0.016). In a subgroup analysis, we compared 154 women and 65 men without structural heart disease (no heart failure, coronary disease or valvular disease, and normal echocardiography with EF >50%). Even for this population, women were younger than men (46±13 vs 52±13 years, p=0.002). However, in these patients no statistical differences were found with regard to symptoms (97 vs 92%, p=0.080), outflow tract origin (89 vs 84%, p=0.4) or acute success rate (82 vs 78 %, p=0.6). Complications occurred in four patients (three pericardial effusions/tamponade and one unintended puncture of an artery), all in women (3 vs 0%, p=0.2). The women admitted for CA of PVCs in our center were younger than the men, had a lower prevalence of structural heart disease, and more often outflow tract PVCs. For the subgroup without structural heart disease, no differences were found between the sexes, apart from referred women being younger. Acute outcomes and complications did not differ between the sexes in either analysis. Further studies are needed to clarify whether women develop idiopathic PVCs at a younger age than men, and the potential mechanism behind this phenomenon, or if they are referred to CA at an earlier time point of the disease.

Abstract Introduction Neutrophil extracellular traps (NETs) are associated with impaired fibrinolysis in ischemic stroke, while NETs degradation enhances lysis of coronary thrombi in ex vivo experiments. Whether circulating NET markers are associated with local fibrinolytic activity in patients with ST-elevation myocardial infarction (STEMI) has not been reported. Purpose We investigated associations between circulating NET markers and gene expression of fibrinolytic markers in aspirated coronary thrombi from patients with STEMI. Furthermore, we explored whether local upregulation of NET formation by peptidylarginine deiminase 4 (PAD4) was reflected in the circulation. Methods Coronary thrombi from 35 STEMI patients undergoing primary percutaneous coronary intervention (PCI) were aspirated and promptly snap-frozen to -80°C. Peripheral blood samples were collected simultaneously. Median time from start of symptoms to PCI was 152 min. Thrombus gene expression of tissue Plasminogen Activator (tPA), urinary-type Plasminogen Activator (uPA), plasminogen-activation inhibitor type 1 (PAI-1) and PAD4 were quantified with RT-PCR. Gene expression of PAD4 was also measured in circulating leukocytes. Circulating NET markers were measured by a fluorescent nucleic acid stain using fluorometry (dsDNA), an in-house ELISA technique (MPO-DNA) and commercial ELISA (H3Cit). Correlations were tested using Spearman’s rho. Results There were no correlations between any of the circulating NET markers and gene expression of the fibrinolytic markers tPA, uPA and PAI-1 in the thrombus. Of the circulating NET markers, dsDNA correlated with thrombus gene expression of PAD4 (rs=0.491 p=0.006), whereas none of the NET markers correlated with gene expression of PAD4 in circulating leukocytes. Conclusion Circulating NET markers were not associated with gene expression of fibrinolytic activity in thrombi from patients with STEMI. Local NET formation in the thrombi, measured as PAD4 expression, was associated with the circulating NET marker dsDNA. These findings suggest that circulating NET markers have limited utility for assessing local fibrinolytic activity, but might reflect PAD4-dependent NET formation in coronary thrombi.

Abstract Background The majority of patients with hypertrophic cardiomyopathy present with dynamic left ventricular (LV) outflow tract obstruction (LVOTO), referred to as hypertrophic obstructive cardiomyopathy (HOCM). Symptomatic treatment aims at reducing LVOTO with either medical therapy, invasive septal reducing therapies, or pacemaker therapy. There is conflicting evidence regarding the efficacy of pacemaker therapy. The effect of pacing strategies at physical exertion has not been investigated in HOCM. Purpose To identify the optimal pacing strategy for reducing LVOTO without compromising cardiac output at rest and exercise in HOCM. Methods In this ongoing project, we have so far included eight patients with symptomatic HOCM referred to our hospital for alcohol septal ablation (ASA). The day before ASA, we placed temporary pacing leads in the right atrium, the right ventricular (RV) apex and on the LV lateral wall. We also inserted a pulmonary artery catheter and performed per operative echocardiography. All patients had sinus rhythm. Intrinsic rhythm served as baseline and was followed by atrial sensed RV pacing, LV pacing and biventricular (BiV) pacing at rest and during supine cycling. We assessed LVOTO by echocardiography, and cardiac output by the thermodilution method under intrinsic rhythm and all pacing modalities. Results The mean age was 52±15 years, and two of eight patients were female. The mean maximal LV wall thickness was 16±1 mm. The resting LVOTO was 50±23 mmHg. Due to difficulties in placing the LV lead within a reasonable time frame, complete study protocol was not performed in all patients. All eight patients performed RV pace at rest, but only five patients (63 %) were LV and BiV paced at rest. Five patients performed supine cycling but only four patients completed with RV and BiV pacing. The graphs display LVOTO and CO in sinus rhythm and the different pacing maneuvers at rest and during supine cycling. At rest, 6 out of 8 patients (75%) had LVOTO reduction during RV pace, and CO was unchanged. Four of five patients (80%) had LVOTO reduction during BiV and LV pace compared to sinus rhythm, also with unchanged CO. During supine cycling four of five patients (80%) had a reduction of the LVOTO gradient during RV and BiV pacing, without significant CO change. No complications occurred during the interventions. Conclusion In this ongoing study on cardiac pacing in HOCM, RV, LV, and BiV pacing reduced LVOTO while CO remained unchanged at rest and during exercise.

Abstract Introduction Successful catheter ablation (CA) of premature ventricular complexes (PVCs) depends on identification of the site of origin (SOO), but no parameter suggested for prediction of success from CA have been sufficiently validated in previous studies. Activation mapping and pace-mapping are invasive methods for the identification of SOO, and the burden of PVCs is critical for activation mapping to identify SOO. The number of PVCs in 24h ambulatory ECGs is claimed to predict occurrence of PVCs during the procedure, and hence procedural success, but the predictive value remains unknown. Purpose The primary objective of this study was to quantify the predictive value of pre-procedural of 24h ambulatory ECG with regard to sufficient number of PVCs during the CA procedure. Methods Patients admitted for CA of PVCs at our hospital from 2011-2020 were included. Data were retrospectivity collected from electronic health records. Clinical characteristics, results from clinical pre-procedural examinations, including 24h ambulatory ECG, exercise testing and echocardiogram, as well as acute outcomes were recorded. Results A total of 332 patients were included, CA was performed in 285 (86 %) patients, while 47 (14 %) patients had insufficient number of PVCs to allow adequate identification of SOO. Neither clinical characteristics nor results of cardiac imaging separated patients with sufficient and insufficient number of PVCs for CA, respectively. Patients with sufficient number of PVCs had nominally more PVCs in the preceding 24h ambulatory ECG, although the difference was not statistically significant (16007 (6509-26205) vs. 8332 (3066-20974), p = 0.055). A receiver operating characteristics (ROC) curve analysis of sufficient number of PVCs during CA and number of PVCs in the preceding 24h ambulatory ECG had an area under curve (AUC) of 0.610 (0.95% CI 0.498-0.722, p = 0.055). The commonly clinically used cut-off of >10 000 PVCs/24h had a positive predictive value of 67 % and a negative predictive value of 57 % for sufficient number of PVCs during CA. The median period from the 24h ambulatory ECGs to CA was 183 days (6 months). The positive and negative predicative values for >10 000 PVCs in 24h ambulatory ECG performed >6 months prior to the procedure were 67 % and 71 %, respectively, compared to 53 % and 61 % for 24h ECGs performed <6 months prior to the procedure. The ROC curve for sufficient number of PVCs during the procedure and number of PVCs in a 24h ambulatory ECG performed >6 months and <6 months prior to the procedure did not differ, with had AUC values of 0.665 and 0.584, respectively (p = 0.4). Conclusion In this retrospective analysis of a large cohort of patients admitted for CA of PVCs, number of PVCs in 24h ambulatory ECGs recorded prior to the procedure had a low predictive value for presence of PVCs during CA. Others parameters need to be evaluated to improve prediction.

The co-ordinated electrical activity of ∼2 billion cardiac cells ensures stability of the heartbeat. Indeed, the remarkably low incidence (<1%) of ventricular arrhythmias in the healthy heart is only possible when the electrical event across this syncytium is closely controlled. In contrast, the diseased myocardium is associated with increased electrophysiological heterogeneity, unstable rhythm, and increased incidence of lethal arrhythmias. But what is the link between cellular and tissue level heterogeneity? Recent research has shown the existence of considerable cellular heterogeneity even in the healthy heart, suggesting that cell-to-cell variability in electrical (e.g. action potential duration) and mechanical performance (e.g. twitch amplitude) is a normal property. This observation has been previously unappreciated because the aggregated function in the form of QT-interval and cardiac output varies <1% on a beat-to-beat basis. This article describes the underlying cellular variability that is tolerated-and perhaps needed-by different regions of the heart for normal function and indicates why this variability is not apparent in function at the chamber and organ level. Thus, in contrast to the current dominant view, this article postulates that heterogeneity is normal and potentially endows various functional benefits. This new view of how the component parts of the heart come together to function also suggests novel mechanisms for cardiac pathologies, namely that dysfunction may emerge from changes in the extent and/or nature of heterogeneity. Once understood, restoring normal forms of heterogeneity could be a novel approach to treatment.

Abstract Background One third of patients with hypertrophic cardiomyopathy present with dynamic left ventricular outflow tract obstruction (LVOTO), referred to as hypertrophic obstructive cardiomyopathy (HOCM). Symptomatic treatment aims at reducing LVOTO with either medications, invasive septal reduction, or pacing. The importance of pacing site is unclear, and effects of pacing during physical activity have not been investigated. Purpose To determine the effect of right ventricular (RV) and biventricular (BiV) pacing, respectively, on LVOTO and cardiac output (CO) during exercise in patients with HOCM. Methods Patients with symptomatic HOCM, sinus rhythm, and no bundle branch block, scheduled for alcohol septal ablation (ASA), were eligible for inclusion. The day before ASA, we placed temporary pacing leads in the right atrium, the RV apex, and on the left ventricle’s lateral wall via the coronary sinus. LVOTO was assessed by echocardiography, and CO was measured by thermodilution with a pulmonary artery catheter. Patients performed supine cycling for 2 minutes until heart rate (HR) increased ≥20 bpm. We measured LVOTO and CO in sinus rhythm, and during cycling with atrial sensed RV pacing, and atrial sensed BiV pacing. The order of pacing sites was randomized, and the personnel performing echocardiography and CO measurements were blinded to the order of pacing. Results We included six patients (54±15 years) with a mean maximal left ventricular wall thickness of 16.7±1.8 mm. Resting LVOTO was 55.7±30.9 mmHg. The figures show LVOTO and CO in sinus rhythm (HR 85±10 bpm), RV pacing (HR 90±10 bpm), and BiV pacing (HR 91±9 bpm) during supine cycling. The LVOTO declined from 56±34 mmHg in sinus rhythm to 27±12 mmHg and 25±5 mmHg respectively for atrial sensed RV and BiV pacing. CO remained unchanged during sinus rhythm (9.0±1.2 L/min), atrial sensed RV pacing (9.0±1.7 L/min), and BiV pacing (8.9±1.5 L/min). Conclusion In this ongoing study evaluating cardiac pacing in HOCM, preliminary data indicate that both RV and BiV pacing are effective in reducing LVOTO during exercise, without compromising CO.

Journal of Magnetic Resonance ImagingEarly View Editorial Editorial for "MRI Assessment of Myocardial Deformation for Risk Stratification of Major Arrhythmic Events in Patients with Non-Ischemic Cardiomyopathy Eligible for Primary Prevention Implantable Cardioverter Defibrillators" Emil Espe PhD, Corresponding Author Emil Espe PhD [email protected] orcid.org/0000-0001-8500-4921 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway Address reprint requests to: E.E., Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo; KG Jebsen Center for Cardiac Research, Oslo, Norway. E-mail: [email protected]Search for more papers by this authorMathis Korseberg Stokke MD, PhD, Mathis Korseberg Stokke MD, PhD orcid.org/0000-0002-8869-8153 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, NorwaySearch for more papers by this author Emil Espe PhD, Corresponding Author Emil Espe PhD [email protected] orcid.org/0000-0001-8500-4921 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway Address reprint requests to: E.E., Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo; KG Jebsen Center for Cardiac Research, Oslo, Norway. E-mail: [email protected]Search for more papers by this authorMathis Korseberg Stokke MD, PhD, Mathis Korseberg Stokke MD, PhD orcid.org/0000-0002-8869-8153 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, NorwaySearch for more papers by this author First published: 15 February 2024 https://doi.org/10.1002/jmri.29300 Level of Evidence: 5 Technical Efficacy: Stage 3 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022; 43(40): 3997-4126. 10.1093/eurheartj/ehac262 PubMedWeb of Science®Google Scholar 2Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator:Randomized trial in patients with nonischemicdilated cardiomyopathy and asymptomaticnonsustained ventricular tachycardia—AMIOVIRT. J Am Coll Cardiol 2003; 41(10): 1707-1712. 10.1016/S0735-1097(03)00297-3 PubMedWeb of Science®Google Scholar 3Reant P, Mirabel M, Lloyd G, et al. Global longitudinal strain is associated with heart failure outcomes in hypertrophic cardiomyopathy. Heart 2016; 102(10): 741-747. 10.1136/heartjnl-2015-308576 CASPubMedWeb of Science®Google Scholar 4Heermann P, Hedderich DM, Paul M, et al. Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking. J Cardiovasc Magn Reson 2014; 16: 75. 10.1186/s12968-014-0075-z PubMedWeb of Science®Google Scholar 5Morner S, Lindqvist P, Waldenstrom A, Kazzam E. Right ventricular dysfunction in hypertrophic cardiomyopathy as evidenced by the myocardial performance index. Int J Cardiol 2008; 124(1): 57-63. 10.1016/j.ijcard.2006.12.022 PubMedWeb of Science®Google Scholar 6La Vecchia L, Varotto L, Zanolla L, Spadaro GL, Fontanelli A. Right ventricular function predicts transplant-free survival in idiopathic dilated cardiomyopathy. J Cardiovasc Med (Hagerstown) 2006; 7(9): 706-710. 10.2459/01.JCM.0000243006.90170.ce PubMedWeb of Science®Google Scholar 7Elming MB, Jensen DH, Winslow UC, et al. Right ventricular Free Wall strain and effect of defibrillator implantation in patients with nonischemic systolic heart failure. J Card Fail 2023; 29(6): 883-892. 10.1016/j.cardfail.2022.12.018 PubMedWeb of Science®Google Scholar 8Ghanbari F, Cirillo J, Rodriguez J, et al. MRI assessment of myocardial deformation for risk stratification of major arrhythmic events in patients with non-ischemic cardiomyopathy eligible for primary prevention implantable cardioverter defibrillators. J Magn Reson Imaging 2024. https://doi.org/10.1002/jmri.29238. 10.1002/jmri.29238 PubMedWeb of Science®Google Scholar 9Kind T, Mauritz GJ, Marcus JT, van de Veerdonk M, Westerhof N, Vonk-Noordegraaf A. Right ventricular ejection fraction is better reflected by transverse rather than longitudinal wall motion in pulmonary hypertension. J Cardiovasc Magn Reson 2010; 12(1): 35. 10.1186/1532-429X-12-35 PubMedWeb of Science®Google Scholar 10Russell K, Eriksen M, Aaberge L, et al. A novel clinical method for quantification of regional left ventricular pressure-strain loop area: A non-invasive index of myocardial work. Eur Heart J 2012; 33(6): 724-733. 10.1093/eurheartj/ehs016 PubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case–control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4

Much research on premature ventricular complexes (PVCs) have used inferior axis and left bundle block pattern (I-LBBB) as a unique category of PVCs, with the assumption that PVCs with this pattern originate in the outflow tract (OT) region and are idiopathic.1Krittayaphong R Sriratanasathavorn C Bhuripanyo K Raungratanaamporn O Soongsawang J Khaosa-ard B Kangkagate C One-year outcome after radiofrequency catheter ablation of symptomatic ventricular arrhythmia from right ventricular outflow tract.Am J Cardiol. 2002; 89: 1269-1274Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,2Niwano S Wakisaka Y Niwano H Fukaya H Kurokawa S Kiryu M Hatakeyama Y Izumi T Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function.Heart. 2009; 95: 1230-1237Crossref PubMed Scopus (218) Google Scholar However, it is well established that these assumptions are not true for all I-LBBB PVCs.3Yamada T Twelve-lead electrocardiographic localization of idiopathic premature ventricular contraction origins.J Cardiovasc Electrophysiol. 2019; 30: 2603-2617Crossref PubMed Scopus (21) Google Scholar The distinction between OT and non-OT PVCs is important because catheter ablation (CA) of non-OT PVCs have lower success rates and higher complication rates.4Latchamsetty R Yokokawa M Morady F Kim HM Mathew S Tilz R Kuck KH Nagashima K Tedrow U Stevenson WG Yu R Tung R Shivkumar K Sarrazin JF Arya A Hindricks G Vunnam R Dickfeld T Daoud EG Oza NM Bogun F Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes.JACC Clin Electrophysiol. 2015; 1: 116-123Crossref PubMed Scopus (219) Google Scholar Therefore, more precise algorithms to identify the site of origin (SOO) from the surface electrocardiogram (ECG) are recommended.5Cronin EM Bogun FM Maury P Peichl P Chen M Namboodiri N Aguinaga L Leite LR Al-Khatib SM Anter E Berruezo A Callans DJ Chung MK Cuculich P d'Avila A Deal BJ Bella PD Deneke T Dickfeld TM Hadid C Haqqani HM Kay GN Latchamsetty R Marchlinski F Miller JM Nogami A Patel AR Pathak RK Saenz Morales LC Santangeli P Sapp Jr, JL Sarkozy A Soejima K Stevenson WG Tedrow UB Tzou WS Varma N Zeppenfeld K 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias.J Interv Card Electrophysiol. 2020; 59: 145-298Crossref PubMed Scopus (7) Google Scholar Nevertheless, referring general cardiologists still often categorize patients as having I-LBBB or non-I-LBBB. Clarification of the clinical utility of this categorization is therefore needed to interpret existing data and advise referring cardiologists. We performed a pragmatic retrospective study from the perspective of the referring cardiologist outside of expert electrophysiology centers to test the association between the I-LBBB pattern in the regular surface ECG and probability of success from CA. A total of 453 CAs for PVCs were performed at Oslo University Hospital Rikshospitalet from 2011 to 2020, including 333 first-time procedures. Patients who underwent their first CA for PVCs had a median age of 49 ± 14 years, and 209 (63%) were women. Co-morbidities were present in 117 patients (35%), with hypertension being most frequent. Symptoms were noted in 311 patients (93%), most frequently palpitations (247 patients, 74%). The median number of PVCs recorded in the last 24 hour Holter recording before referral was 14,576 (interquartile range 5,597 to 25,801), and the median PVC burden was 16% (interquartile range 8 to 26). CA was attempted in 245 patients (74%), and acute success was achieved in 198 (81%). Of the 333 patients referred for a first-time procedure, 290 patients (87%) had I-LBBB PVCs. These patients were younger than patients with non–I-LBBB PVCs (48 ± 14 vs 56 ± 13 years, p <0.001) and fewer had coronary artery disease (5% vs 21%, p <0.001) or ejection fraction <50% by echocardiography (7% vs 29%, p <0.001). More patients in the I-LBBB group reported palpitations (76% vs 61%, p = 0.03), whereas fewer reported dyspnea (12% vs 26%, p = 0.02). The PVC burden before CA was similar (16% vs 19%, p = 0.5) between the I-LBBB and non–I-LBBB groups, and the acute success rates (82% vs 74%, p = 0.3) and complication rates (2% vs 2%, p = 1.0) were comparable. The SOO was established during the invasive electrophysiologic procedure in 273 patients (82%). The patients with SOO from the OTs were younger than patients with PVCs with other SOOs (48 ± 14 vs 54 ± 14, p = 0.013), and fewer had ejection fraction <50% (7% vs 26%, p <0.001). As might be expected, patients who had PVCs with confirmed SOO in the OTs underwent CA more often than patients with PVCs from other SOOs (90% vs 65%, p <0.001). In addition, the success rate of CA for PVCs with confirmed SOO in the OTs was higher than for non-OT PVCs (85% vs 62%, p = 0.003). Importantly, among patients for whom the SOO was determined, 224 of 290 patients (77%) with I-LBBB PVCs were treated for PVCs originating from the OT, whereas 13 (4%) were treated for PVCs with SOOs outside of the OTs, and for 53 patients (18%), the SOO was not established. In comparison, 8 of 43 patients with non–I-LBBB PVCs (19%) were treated for PVCs with SOO in the OT (p <0.001 compared with I-LBBB). In summary, the I-LBBB pattern in the surface ECG taken was not a useful criterion to separate patients regarding the acute clinical outcome of CA. In contrast, per-procedure invasively confirmed SOO in the OT was associated with a higher rate of acute success. Hence, the I-LBBB pattern of PVCs alone is not clinically useful to categorize patients before CA. Our real-world data are an important reminder to referring cardiologists about the incomplete overlap between the I-LBBB pattern in the surface ECG and the SOO in the OT, and the importance of this fact, which is well known to electrophysiologists. In addition, our data are a caution for the interpretation of studies that have used this pattern as the sole ECG inclusion criterion. Referring cardiologists and future studies on the noninvasive evaluation of PVCs should use more advanced algorithms for the assessments of the SOO from the ECG. The authors have no conflicts of interest to declare.

Background: Available evidence suggest that Ca2+/calmodulin-dependent protein kinase type II8 (CaMKII8) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKII8 by oxidation of two methionines at positions 281/282, oxidized-CaMKII8 (Ox-CaMKII8) has been proposed to be important for IRA. However, direct evidence for this is missing.Methods: We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKII8 by using hearts and cardiomyocytes from mice with CaMKII8 resistant to oxidation of methionines 281 and 282 (MMVV).Results: Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca2+ waves and Ca2+ sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca2+-handling proteins in MMVV and WT hearts.Conclusions: Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.

Supplementary data for research article titled "Beneficial effects of exercise initiated prior to development of hypertrophic cardiomyopathy in genotype positive mice"

BackgroundArrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.MethodsMI was induced in 7 male and 7 female pigs (Norwegian landrace, 35–40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout.ResultsThe protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.ConclusionMyocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.

Background We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines. Case presentation A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an “aconitine score” was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features. Conclusion This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an “aconitine score” that may be useful in cases of suspected aconitine poisoning.

BACKGROUND:Available evidence suggest that Ca2+/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.METHODS:We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV).RESULTS:Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca2+ waves and Ca2+ sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca2+-handling proteins in MMVV and WT hearts.CONCLUSIONS:Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.

Supplementary data for research article titled "Exercise training prior to manifestation of hypertrophic cardiomyopathy in mice attenuates expression of pro-fibrotic genes"

Abstract Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in‐depth assessment of lumican in clinical and experimental HCM. Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild‐type littermates (n = 8–10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid‐ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy. Results Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R2 = 0.60, P < 0.01) and III (R2 = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R2 = 0.28, P = 0.05) and interstitial (R2 = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20‐fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co‐localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super‐resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to (−15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer (−8.9%, P < 0.001) collagen fibres. Conclusions The ECM proteoglycan lumican is increased in HCM and co‐localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.

Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure.