Discriminating factors excluding patients from a catheter-based left atrial appendage closure and an outcome analysis of non-intervened and intervened patients.

Introduction: The catheter-based left atrial appendage closure (LAAC) has evolved as an alternative to oral anticoagulation (OAC) among non-valvular atrial fibrillation (AF) patients in whom long-term OAC is contraindicated. In daily practice, however, a sizeable number of patients who have been referred for an LAAC do not receive this intervention. This study aimed primarily to investigate the factors deterring the practice of an LAAC in referred AF patients, and secondarily to compare the complication rates of intervened patients with those who had refused the intervention within 1 year. Material and methods: This retrospective single-centre study includes 200 patients. After a thoroughly conducted clinical selection process, 161 of these patients (80.5%) were excluded from receiving an LAAC intervention. Results: An analysis comparing these patients to those receiving an LAAC reveales that a higher proportion of intervened patients had suffered a prior gastrointestinal bleeding (48.7 vs. 28.0%; p = 0.013) as well as a haemorrhagic stroke (12.8 vs. 2.5%; p = 0.015), and was not anticoagulated at the time of presentation (35.9 vs. 14.9%; p = 0.006). The main reason for not conducting the procedure was patient refusal (62.1%) followed by multimorbidity (16.8%). The annual rate of ischaemic strokes and bleedings among patients refusing the intervention was 2.1% and 29.5%, respectively, and this was not statistically different from the intervened patients (each p > 0.05). Conclusions: The reasons why patients did not undergo the catheter-based LAAC were mainly reluctance for the procedure and multimorbidity. Furthermore, it could be assumed that the potential benefit of the LAAC may not be realised within the first year.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there are limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic patients with CPVT with and without ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with ICD (31.1%) and 162 without ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in the no ICD group and in those not on optimal medical therapy. Patients with ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

[Historical developments in the diagnosis and treatment of pre-excitation syndromes (WPW)]. / Historische Entwicklung in Diagnostik und Therapie bei Präexzitationssyndromen (WPW).

In 1930, Wolff, Parkinson and White described the syndrome that bears their names. The mechanisms of supraventricular tachycardias were analyzed by brilliant electrocardiography interpretation by Pick and Langendorf. Wellens and Durrer using electrophysiologic studies analyzed the tachycardia mechanism invasively. In Germany the group by Seipel and Breithardt as well as Neuss and Schlepper studied the tachycardia mechanisms and response to antiarrhythmic drugs invasively by electrophysiological studies. Following the first successful interruption of an accessory pathway by Sealy in 1967, surgeons and electrophysiologists cooperated in Germany. Two centers, Hannover and Düsseldorf were established. Direct current (DC) ablation of accessory pathways was introduced by Morady and Scheinman. Because of side effects induced by barotrauma of DC, alternative strategies were studied. In 1987, radiofrequency ablation was introduced and thereafter established as curative therapy of accessory pathways in all locations.

Generalized anxiety is a predictor of impaired quality of life in patients with atrial fibrillation: Findings from the prospective observational ARENA study.

OBJECTIVE: Atrial fibrillation (AF) is associated with impaired health-related quality of life (HRQoL), an increased risk of morbidity, and mortality. Traditional AF-related outcomes (e.g., AF recurrence) primarily demonstrate the physiological benefits of AF management but do not focus on the benefits experienced subjectively by the patient (i.e., patient-reported outcomes), which have been suggested as optimal endpoints in AF intervention studies. The aim of this study is to identify medical and psychological factors associated with impaired HRQoL at 1-year follow-up. METHODS: Using data from the prospective observational multicenter ARENA study in patients with AF, we analyzed associations between medical factors, anxiety, and HRQoL at 1-year follow-up assessed using 5-level EuroQoL-5D. RESULTS: In 1353 AF patients (mean age 71.4 ± 10.3 years, 33.8% female), none of the medical predictors (e.g., heart disease) or history of cardioversion were associated with HRQoL at the 1-year follow-up. Higher generalized anxiety (ß = -0.114, p < .001) but not cardiac anxiety (ß = -0.006, p = .809) at baseline predicted decreased HRQoL, independent of confounding variables and patients' medical status. Furthermore, the worsening of patients' generalized anxiety was associated with decreased HRQoL (ß = -0.091, p < .001). In contrast, the improvement of generalized anxiety over time predicted higher HRQoL (ß = 0.097, p < .001). Finally, the worsening of patients' cardiac anxiety over time was associated with decreased HRQoL (ß = -0.081, p < .001). CONCLUSION: Our results highlight the importance of anxiety as a predictor of future HRQoL in patients with AF. Additional studies to examine the impact of anxiety treatment on HRQoL in this population are needed. CLINICAL TRIAL REGISTRATION: The investigators registered on ClinicalTrials.gov (NCT02978248) on November 30, 2016 https://clinicaltrials.gov/ct2/show/NCT02978248.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome.

BACKGROUND: A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death remains unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients using gene panels including SLC4A3. METHODS: In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was validated in a zebrafish embryo heart model. RESULTS: Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in SLC4A3: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes. CONCLUSION: In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.

Sparse 3D contrast-enhanced whole-heart imaging for coronary artery evaluation.

BACKGROUND: We investigated the feasibility of evaluating coronary arteries with a contrast-enhanced (CE) self-navigated sparse isotropic 3D whole heart T1-weighted magnetic resonance imaging (MRI) study sequence. METHODS: A total of 22 consecutive patients underwent coronary angiography and/or cardiac computed tomography (CT) including cardiac MRI. The image quality was evaluated on a 3-point Likert scale. Inter-reader variability for image quality was analyzed with Cohen's kappa for the main coronary segments (left circumflex [LCX], left anterior descending [LAD], right coronary artery [RCA]) and the left main trunk (LMT). RESULTS: Inter-reader agreement for image quality of the coronary tree ranged from substantial to perfect, with a Cohen's kappa of 0.722 (RCAmid) to 1 (LCXprox). The LMT had the best image quality. Image quality of the proximal vessel segments differed significantly from the mid- and distal segments (RCAprox vs. RCAdist, p < 0.05). The LCX segments showed no significant difference in image quality along the vessel length (LCXprox vs. LCXdist, p = n.s.). The mean acquisition time for the study sequence was 553 s (±46 s). CONCLUSION: Coronary imaging with a sparse 3D whole-heart sequence is feasible in a reasonable amount of time producing good-quality imaging. Image quality was poorer in distal coronary segments and along the entire course of the LCX.

Septal myocardial scar burden predicts the response to cardiac contractility modulation in patients with heart failure.

We hypothesized that myocardial septal scarring, assessed by cardiac magnetic resonance (CMR) using late gadolinium enhancement (LGE), at the site of cardiac contractility modulation (CCM) lead placement may predict treatment response. Eligible heart failure (HF) patients underwent LGE CMR imaging before CCM device implantation. The response to CCM therapy at follow-up was determined by a change in NYHA class and echocardiographic left ventricular ejection fraction (LVEF) assessment. Patients were classified as responders, if they showed an improvement in either NYHA class or improvement of LVEF by ≥ 5%. 58 patients were included. 67% of patients were classified as responders according to improved NYHA; 55% according to LVEF improvement. 74% of patients were responders if either NYHA class or LVEF improvement was observed. 90% of responders (according to NYHA class) showed septal LGE < 25% at septal position of the leads, while 44% of non-responders showed septal LGE > 25% (p < 0.01). In patients treated with CCM, an improvement of NYHA class was observed when leads were placed at myocardial segments with a CMR- LGE burden less than 25%.

Patient Selection for Protected Percutaneous Coronary Intervention: Who Benefits the Most?

The evolution of percutaneous coronary intervention (PCI) enables a complete revascularization of complex coronary lesions. However, simultaneously, patients are presenting nowadays with higher rates of comorbidities, which may lead to a lower physiologic tolerance for complex PCI. To avoid hemodynamic instability during PCI and achieve safe complete revascularization, protected PCI using mechanical circulatory support devices has been developed. However, which patients would benefit from the protected PCI is still in debate. Hence, this review provides practical approaches for the selection of patients by outlining current clinical data assessing utility of protected PCI in high-risk patients.

Should HFrEF patients with NYHA class II expect benefit from CCM therapy? Results from the MAINTAINED observational study.

BACKGROUND: Cardiac contractility modulation (CCM) is an FDA-approved device therapy for patients with refractory systolic heart failure and normal QRS width. Randomized trials demonstrated benefits of CCM primarily for patients with severe heart failure (> NYHA class II). PURPOSE: To better understand individualized indication in clinical practice, we compared the effect of CCM in patients with baseline NYHA class II vs. NYHA class III or ambulatory IV over the 5-year period in our large clinical registry (MAINTAINED Observational Study). METHODS: Changes in NYHA class, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), NT-proBNP level, and KDIGO chronic kidney disease stage were compared as functional parameters. In addition, mortality within 3 years was compared with the prediction of the Meta-Analysis Global Group in Chronic heart failure risk score. RESULTS: A total of 172 patients were included in the analyses (10% with NYHA class II). Only patients with NYHA class III/IV showed a significant improvement in NYHA class over 5 years of CCM (II: 0.1 ± 0.6; p = 0.96 vs. III/IV: - 0.6 ± 0.6; p < 0.0001). In both groups, LVEF improved significantly (II: 4.7 ± 8.3; p = 0.0072 vs. III/IV: 7.0 ± 10.7%; p < 0.0001), while TAPSE improved significantly only in NYHA class III/IV patients (II: 2.2 ± 1.6; p = 0.20 vs. III/IV: 1.8 ± 5.2 mm; p = 0.0397). LVEF improvement was comparable in both groups over 5 years of CCM (p = 0.83). NYHA class II patients had significantly lower NT-proBNP levels at baseline (858 [175/6887] vs. 2632 [17/28830] ng/L; p = 0.0044), which was offset under therapy (399 [323/1497] vs. 901 [13/18155] ng/L; p = 0.61). Actual 3-year mortality was 17 and 26% vs. a predicted mortality of 31 and 42%, respectively (p = 0.0038 for NYHA class III/IV patients). CONCLUSIONS: NYHA class III/IV patients experienced more direct and extensive functional improvements with CCM and a survival benefit compared with the predicted risk. However, our data suggest that NYHA class II patients may also benefit from the sustained positive effects of LVEF improvement.

Epigenetic mechanism of L-type calcium channel ß-subunit downregulation in short QT human induced pluripotent stem cell-derived cardiomyocytes with CACNB2 mutation.

AIMS: A loss-of-function mutation in L-type calcium (Ca2+) channel subunit gene CACNB2 has been reported to cause short QT syndrome subtype 5 (SQT5). However, the mechanism underlying the loss-of-function of the Ca2+ channel has not been clarified. In the present study, we aim to explore the DNA methylation mechanism of L-type Ca2+ channel downregulation in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of SQT5. METHODS AND RESULTS: The hiPSC-CMs were generated from a healthy donor and a SQT5 patient carrying the CACNB2 variant c.1439C > T/p.S480L. The variant was genetically corrected using ribonucleoprotein-based CRISPR/Cas9 technique to obtain an isogenic control cell line. The action potential (AP) and Ca2+ current were measured by patch clamp. Protein expression levels were determined by western blotting. Dot blotting and bisulfite sequence were performed for epigenetic study. Our results showed that AP durations at 10% repolarization (APD10) and 50% repolarization (APD50) were significantly shortened in SQT5 cells and both the expression level of the ß-subunit and channel current of L-type Ca2+ channel were reduced. Besides, an increased level of whole-genome DNA methylation and DNA methylation of CpG island in the promoter region of CACNB2 gene was detected. Overexpression of demethylation enzyme could rescue the decreased expression of CACNB2 and the L-type Ca2+ current. CONCLUSION: In SQT5 hiPSC-CMs carrying the CACNB2-S480L variant, the decreased L-type Ca2+ current resulting from decreased CACNB2 protein expression was caused by enhanced methylation in the promoter region of the CACNB2 gene and upregulation of DNA methyltransferases might be one of the mechanisms.

Serial Changes in Coronary Plaque Formation Using CT Angiography in Patients Undergoing PCSK9-Inhibitor Therapy With 1-year Follow-up.

PURPOSE: Previous studies have shown positive effects of intensive low-density lipoprotein (LDL)-lowering therapy on atheroma volume using invasive intravascular ultrasound. This study describes the changes in coronary plaque composition on coronary computed tomography angiography in patients treated with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. MATERIALS AND METHODS: In this prospective study, coronary plaques were analyzed using third-generation dual-source computed tomography before and after 1 year of PCSK9-inhibitor treatment. Plaque markers included total plaque volume (TPV), calcified plaque volume (CPV), noncalcified plaque volume (NCPV), lumen volume and vessel volume (VV), minimal luminal area (MLA), minimal lumen diameter (MLD), corrected coronary opacification, eccentricity, remodeling index, and functional plaque parameters. Primary endpoint was defined as change in TPV; the secondary endpoint was TPV or CPV regression or nominal change in plaque parameters. RESULTS: We analyzed 74 coronary plaques in 23 patients (60±9 y, 65% male). After 1 year of PCSK9-inhibitor treatment, LDL was reduced from 148 to 66 mg/dL ( P <0.0001). Significant changes were found for VV (196 to 215 mm 3 , P =0.0340), MLA (3.1 to 2.6 mm 2 , P =0.0413), and MLD (1.7 to 1.4 mm, P =0.0048). TPV, CPV, NCPV, lumen volume, and functional plaque parameters did not change significantly ( P >0.05). CONCLUSIONS: Coronary artery plaque analysis by coronary computed tomography angiography highlights that LDL lowering therapy affects plaque composition. The primary endpoint of TPV change was not reached; however, VV, MLA, and MLD changed significantly.

Regulation of Ion Channel Function in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Cancer Cell Secretion Through DNA Methylation.

Background: Cardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Experimental studies investigating the effects of cancer cell secretion without chemotherapy on ion channel function in human cardiomyocytes are still lacking. Methods: The human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from three healthy donors were treated with gastrointestinal (GI) cancer (AGS and SW480 cells) medium for 48 h. The qPCR, patch-clamp, western blotting, immunostaining, dot blotting, bisulfite sequence, and overexpression of the ten-eleven translocation (TET) enzyme were performed for the study. Results: After treated with cancer cell secretion, the maximum depolarization velocity and the action potential amplitude were reduced, the action potential duration prolonged, peak Na+ current, and the transient outward current were decreased, late Na+ and the slowly activating delayed rectifier K+ current were increased. Changes of mRNA and protein level of respective channels were detected along with altered DNA methylation level in CpG island in the promoter regions of ion channel genes and increased protein levels of DNA methyltransferases. Phosphoinositide 3-kinase (PI3K) inhibitor attenuated and transforming growth factor-ß (TGF-ß) mimicked the effects of cancer cell secretion. Conclusions: GI cancer cell secretion could induce ion channel dysfunction, which may contribute to occurrence of arrhythmias in cancer patients. The ion channel dysfunction could result from DNA methylation of ion channel genes via activation of TGF-ß/PI3K signaling. This study may provide new insights into pathogenesis of arrhythmia in cancer patients.

Local dose rate effects in implantable cardioverter-defibrillators with flattening filter free and flattened photon radiation.

PURPOSE: In the beam penumbra of stereotactic body radiotherapy volumes, dose rate effects in implantable cardioverter-defibrillators (ICDs) may be the predominant cause for failures in the absence of neutron-generating photon energies. We investigate such dose rate effects in ICDs and provide evidence for safe use of lung tumor stereotactic radioablation with flattening filter free (FFF) and flattened 6 Megavolt (MV) beams in ICD-bearing patients. METHODS: Sixty-two ICDs were subjected to scatter radiation in 1.0, 2.5, and 7.0 cm distance to 100 Gy within a 5â€¯× 5 cm2 radiation field. Radiation was applied with 6 MV FFF beams (constant dose rate of 1400 cGy/min) and flattened (FLAT) 6 MV beams (430 cGy/min). Local dose rates (LDR) at the position of all ICDs were measured. All ICDs were monitored continuously. RESULTS: With 6 MV FFF beams, ICD errors occurred at distances of 1.0 cm (LDR 46.8 cGy/min; maximum ICD dose 3.4 Gy) and 2.5 cm (LDR 15.6 cGy/min; 1.1 Gy). With 6 MV FLAT beams, ICD errors occurred only at 1 cm distance (LDR 16.8 cGy/min; 3.9 Gy). No errors occurred at an LDR below 7 cGy/min, translating to a safe distance of 2.5 cm (1.5 Gy) in flattened and 7 cm (0.4 Gy) in 6 MV FFF beams. CONCLUSION: A LDR in ICDs larger than 7 cGy/min may cause ICD malfunction. At identical LDR, differences between 6 MV FFF and 6 MV FLAT beams do not yield different rates of malfunction. The dominant reason for ICD failures could be the LDR and not the total dose to the ICD. For most stereotactic treatments, it is recommended to generate a planning risk volume around the ICD in which LDR larger than 7 cGy/min are avoided.

Impact of baseline left ventricular ejection fraction on long-term outcomes in cardiac contractility modulation therapy.

BACKGROUND: Cardiac contractility modulation (CCM), being reserved for patients with symptomatic chronic heart failure (HF) and narrow QRS complex under guideline directed medical therapy, can recover initially reduced left ventricular ejection fraction (LVEF); however, the influence of pre-implantation LVEF on long-term outcomes is not fully understood. This study aimed to compare the effects of lower and higher preimplantation LVEF on long-term outcomes in CCM-therapy. METHODS: One-hundred seventy-two patients from our single-centre registry were retrospectively included (2002-2019). Follow-up data were collected up to 5 years after implantation. Patients were divided into Group 1 (baseline LVEF≤ 30%) and Group 2 (≥ 31%). Both groups were compared based on differences in survival, echocardiographic- and clinical parameters including LVEF, tricuspid annular plane systolic excursion (TAPSE), NYHA class or Minnesota living with heart failure questionnaire-score (MLWHFQ). RESULTS: 11% of the patients did have a LVEF ≥31%. Mean LVEF ± SD for both groups were 21.98 ± 5.4 versus 35.2 ± 3.7%, respectively. MLWHFQ (47 ± 21.2 vs. 42±21.4) and mean peak oxygen consumption (VO2, 13.6 ± 4.1 vs. 12.7 ± 2.8 ml/kg/min) were comparable between both groups. LVEF-grouping did not influence survival. Lower baseline LVEF resulted in significantly better recovery of echocardiographic parameters such as LVEF and TAPSE. Irrespective from baseline LVEF, both groups showed nearly comparable improvements for clinical parameters like NYHA-class and MLWHFQ. CONCLUSION: Long-term biventricular systolic recovery potential in CCM-therapy might be better for preimplantation LVEF values ≤30%, whereas clinical parameters such as NYHA-class can improve irrespective from baseline LVEF.

Symptom Severity and Health-Related Quality of Life in Patients with Atrial Fibrillation: Findings from the Observational ARENA Study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with impaired health-related quality of life (HRQoL), high symptom severity, and poor cardiovascular outcomes. Both clinical and psychological factors may contribute to symptom severity and HRQoL in AF. METHODS: Using data from the observational Atrial Fibrillation Rhine-Neckar Region (ARENA) trial, we identified medical and psychosocial factors associated with AF-related symptom severity using European Heart Rhythm Association symptom classification and HRQoL using 5-level EuroQoL- 5D. RESULTS: In 1218 AF patients (mean age 71.1 ± 10.5 years, 34.5% female), female sex (OR 3.7, p < 0.001), preexisting coronary artery disease (CAD) (OR 1.7, p = 0.020), a history of cardioversion (OR 1.4, p = 0.041), cardiac anxiety (OR 1.2; p < 0.001), stress from noise (OR 1.4, p = 0.005), work-related stress (OR 1.3, p = 0.026), and sleep disturbance (OR 1.2, p = 0.016) were associated with higher AF-related symptom severity. CAD (ß = -0.23, p = 0.001), diabetes mellitus (ß = -0.25, p < 0.001), generalized anxiety (ß = -0.30, p < 0.001), cardiac anxiety (ß = -0.16, p < 0.001), financial stress (ß = -0.11, p < 0.001), and sleep disturbance (ß = 0.11, p < 0.001) were associated with impaired HRQoL. CONCLUSIONS: Psychological characteristics, preexisting CAD, and diabetes may play an important role in the identification of individuals at highest risk for impaired HRQoL and high symptom severity in patients with AF.

Distribution and prognostic impact of coronary artery disease and nonischemic cardiomyopathies in patients with electrical storm.

BACKGROUND: he distribution and prognostic impact of coronary artery disease (CAD) in ES are still under debate. METHODS: Consecutive ES patients with implantable cardioverter-defibrillator (ICD) were included retrospectively from 2002 to 2016. Three analyses were applied to characterize ES patients: (a) ES patients without CAD (non-CAD), (b) ES patients with CAD (CAD), and (c) diagnostic findings assessed by coronary angiography (CA) at the time of ES (immediate CA). CAD was compared with non-CAD ES patients, and progressive CAD was compared with stable CAD ES patients. The primary endpoint was all-cause mortality at 2.5 years. Secondary endpoints were the composite endpoint of first recurrent ventricular tachyarrhythmias and appropriate ICD therapies, and recurrence of ES (ES-R) at 2.5 years. RESULTS: Within a total of 87 consecutive ES patients. CAD was present in more than two-thirds (67%). However, only 52% patients underwent immediate CA at the time of ES. Here, 84% had CAD, of which 39% revealed progressive CAD with the need of target vessel revascularization (TVR) or cardiac transplantation ( n = 1). At long-term follow-up, neither the presence (or absence) of CAD (41% vs. 34%; log rank P = 0.708) nor of progressive CAD (33% vs. 26%; log rank P = 0.372) was associated with all-cause mortality at 2.5 years, and further secondary endpoints including the composite of recurrent ventricular tachyarrhythmias plus appropriate ICD therapies, or ES-R. CONCLUSION: In ES patients, CAD was more common than non-CAD-related cardiac diseases, accompanied by an underinvestigated rate of CA despite increasing rates of progressive CAD. CAD had no prognostic impact in ES.

J wave syndromes in patients with spinal and bulbar muscular atrophy.

BACKGROUND: Males with X-linked recessive spinobulbar muscular atrophy (SBMA) are reported to die suddenly and a Brugada electrocardiography (ECG) pattern may be present. A hallmark of this pattern is the presence of ST segment elevations in right precordial leads associated with an increased risk of sudden cardiac death. OBJECTIVE: We aimed to detect subtle myocardial abnormalities using ECG and cardiovascular magnetic resonance imaging (CMR) in patients with SBMA. METHODS: 30 SBMA patients (55.7 ± 11.9 years) and 11 healthy male controls underwent 12-lead ECGs were recorded using conventional and modified chest leads. CMR included feature-tracking strain analysis, late gadolinium enhancement and native T1 and T2 mapping. RESULTS: Testosterone levels were increased in 6/29 patients. Abnormal ECGs were recorded in 70%, consisting of a Brugada ECG pattern, early repolarization or fragmented QRS. Despite normal left ventricular ejection fraction (66 ± 5%), SBMA patients exhibited more often left ventricular hypertrophy as compared to controls (34.5% vs 20%). End-diastolic volumes were smaller in SBMA patients (left ventricular volume index 61.7 ± 14.7 ml/m2 vs. 79.1 ± 15.5 ml/m2; right ventricular volume index 64.4 ± 16.4 ml/m2 vs. 75.3 ± 17.5 ml/m2). Tissue characterization with T1-mapping revealed diffuse myocardial fibrosis in SBMA patients (73.9% vs. 9.1%, device-specific threshold for T1: 1030 ms). CONCLUSION: SBMA patients show abnormal ECGs and structural abnormalities, which may explain an increased risk of sudden death. These findings underline the importance of ECG screening, measurement of testosterone levels and potentially CMR imaging to assess cardiac risk factors.

MicroRNA-365 regulates human cardiac action potential duration.

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.