Predictors of symptom improvement in patients with chronic coronary syndrome after percutaneous coronary intervention.

BACKGROUND: Decreases in symptom load and improvements in quality of life are important goals in the invasive treatment of symptomatic chronic coronary syndrome (CCS). To date, it is not known which patients profit most from the invasive treatment. METHODS: This sub-analysis of the prospective, multi-centre PLA-pCi-EBO trial includes 145 patients with symptomatic CCS and successful PCI. The prespecified endpoints angina pectoris and quality of life (Seattle Angina Questionnaire-SAQ) were assessed 1 and 6 months after PCI. Predictors of symptom improvement were analyzed by logistic regression analysis. RESULTS: Quality of life, physical limitation, and angina frequency markedly improved 6 months after PCI. Worse baseline health status (i.e., low SAQ subscales) was the best predictor of highly clinically relevant improvements (≥ 20 points in SAQ subscales) in symptom load and quality of life. Demographic factors (age, sex, body-mass index) and cardiovascular disease severity (number of involved vessels, ejection fraction) did not predict relevant improvements after PCI. The influence of psychologic traits has not previously been assessed. We found that neither optimism nor pessimism had a relevant effect on symptomatic outcome. However, patients who exercised more after PCI had a much larger improvement in quality of life despite no differences in physical limitation or angina frequency. CONCLUSION: PCI effectively reduces symptom load and improves quality of life in patients with symptomatic CCS. Reduced baseline health status (symptom load, quality of life) are the only relevant predictors for improvements after PCI. Physical activity after PCI is associated with greater benefits for quality of life. TRIAL REGISTRY: The German Clinical Trials Register registration number is DRKS0001752.

Effects of atrial fibrillation ablation on arrhythmia burden and ventricular function in end-stage heart failure: Lessons from CASTLE-HTx.

AIMS: The CASTLE-HTx trial showed the benefit of atrial fibrillation (AF) ablation compared to medical therapy in decreasing mortality, need for left ventricular assist device implantation or heart transplantation (HTx) in patients with end-stage heart failure (HF). Herein we describe the effects of catheter ablation on AF burden, arrhythmia recurrences, and ventricular function in end-stage HF. METHODS AND RESULTS: The CASTLE-HTx protocol randomized 194 patients in end-stage HF with AF to catheter ablation and medical therapy or medical therapy alone. AF burden, left ventricular ejection fraction (LVEF), and type of AF were assessed at baseline and at each follow-up visit. Overall, 97 patients received ablation; 66 patients (68%) underwent pulmonary vein isolation (PVI) and 31 patients (32%) were treated with PVI and additional ablation. Electroanatomic mapping showed the extent of left atrial low voltage (cardiomyopathy) >10% in 31 (31.9%) patients. At 12 months post-ablation, persistent AF was present in 31/89 patients (34.8%), which was significantly less frequent compared to baseline (p = 0.0001). Median AF burden reduction was 36.3 (interquartile range 13.6-63.3) percentage points at 12 months and LVEF improved from 29.2 ± 6.2% to 39.1 ± 8.3% (p < 0.001) following ablation. AF burden reduction <50% was significantly associated with LVEF improvement ≥5% at 12 months after ablation (p = 0.017). CONCLUSION: Atrial fibrillation ablation in end-stage HF leads to a substantial decrease in AF burden, a regression from persistent to paroxysmal AF and notably improved LVEF. Favourable ablation outcomes were observed in patients regardless of the presence or absence of signs indicating left atrial cardiomyopathy.

Prognostic utility of mid-regional pro-adrenomedullin and growth differentiation factor 15 in patients undergoing transfemoral transcatheter aortic valve implantation.

BACKGROUND: Risk prediction in patients with severe, symptomatic aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) remains an unsolved issue. In addition to classical risk scoring systems, novel circulating biomarkers like mid-regional pro-adrenomedullin (MR-proADM) and growth differentiation factor 15 (GDF-15) may be of value in assessing risk. METHODS: Consecutive patients undergoing elective transfemoral TAVI were included in this prospective observational study. Baseline information, imaging findings, blood samples, and clinical outcomes were collected. Blood levels of the classical biomarkers interleukin-6 (IL-6) and high-sensitivity C-reactive peptide (hsCRP) and of the novel biomarkers MR-proADM and GDF-15 were measured and their predictive utility for mortality assessed. RESULTS: The study cohort consisted of 92 patients undergoing TAVI. The median age was 80.7 years [IQR 77.2;83.3], and 48 (52.2%) were male. Analysis of the area under the curve (AUC) of the receiver-operating characteristics showed that the hsCRP levels discriminated poorly (AUC 0.66, 95% CI [0.52;0.8], p = 0.027), whereas all other biomarkers reached a higher level of discrimination (IL-6: AUC 0.76, 95% CI [0.66;0.86], p < 0.001; MR-proADM: AUC 0.73, 95% CI [0.61;0.85], p = 0.002; GDF-15: AUC 0.73, 95% CI [0.61;0.85], p = 0.002). Kaplan-Meier analysis in conjunction with Youden J-statistics yielded the optimal cutoff points for each biomarker to predict survival: IL-6 4.65 pg/mL, hsCRP 12.9 mg/L, MR-proADM 1.02 nmol/L, and GDF-15 2400.1 pg/mL. CONCLUSION: Novel circulating biomarkers like MR-proADM and GDF-15 may provide additional value in predicting survival after TAVI.

Simulation of cardiac arrhythmias in human induced pluripotent stem cell-derived cardiomyocytes.

The effects and mechanisms of cardiac arrhythmias are still incompletely understood and an important subject of cardiovascular research. A major difficulty for investigating arrhythmias is the lack of appropriate human models. Here, we present a protocol for a translational simulation of different types of arrhythmias using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and electric cell culture pacing. The protocol comprises the handling of ventricular and atrial hiPSC-CM before and during in vitro arrhythmia simulation and possible arrhythmia simulation protocols mimicking clinical arrhythmias like atrial fibrillation. Isolated or confluent hiPSC-CM can be used for the simulation. In vitro arrhythmia simulation did not impair cell viability of hiPSC-CM and could reproduce arrhythmia associated phenotypes of patients. The use of hiPSC-CM enables patient-specific studies of arrhythmias, genetic interventions, or drug-screening. Thus, the in vitro arrhythmia simulation protocol may offer a versatile tool for translational studies on the mechanisms and treatment options of cardiac arrhythmias.

The association between gout and subsequent cardiovascular events: a retrospective cohort study with 132,000 using propensity score matching in primary care outpatients in Germany.

BACKGROUND: Both the risk of developing heart disease and the course of the disease are determined in particular by comorbidities. In this context, gout has recently been identified as an important factor in influencing the development of cardiovascular events such as heart failure or coronary artery disease. METHODS: This retrospective cohort study compared the incidence of angina pectoris (AP) (ICD-10: I20), myocardial infarction (MI) (ICD-10: I21, I22), chronic coronary heart disease (CHD) (ICD-10: I25), atrial fibrillation (AF), and heart failure (HF) as a function of gout in Germany in a large collective of 66,000 gout patients in comparison to 66,000 individuals without gout between using propensity score matching (1:1) from January 2005 to December 2020. RESULTS: Within 10 years after the index date, AP was diagnosed in 5.2% of gout and 2.9% of non-gout patients (p < 0.001), MI in 3.1% of gout and 2.2% of non-gout patients (p < 0.001), CHD in 16.5% of gout and 11.8% of non-gout patients, AF in 12.6% of gout and 8.4% of non-gout patients (p < 0.001), and HF in 14.7% of gout and 8.5% of non-gout patients (p < 0.001). For all diagnoses except CHD, the association was stronger in male than in female patients. CONCLUSION: The relationship shown between gout and cardiovascular disease indicates that gout could be one of a series of inflammatory conditions that increase the risk of cardiac disease. The association we have shown between gout and all major cardiac diseases suggests that there is a risk modifier, the treatment of which could help prevent these diseases. Further research is needed to determine whether treating gout can effectively reduce this risk.

Impact of Accidental High or Low Implantation Depth on Peri-Procedural Outcomes after Implantation with the Self-Expanding ACURATE neo2.

Background: Precise implantation could play a crucial role in the technical success of transcatheter aortic valve replacement (TAVR) for some prostheses. The impact of an accidental implantation depth (ID) outside the recommended range has not been assessed for the ACURATE neo2 (NEO2). Methods: Data from 1839 patients with severe native aortic stenosis treated with the NEO2 prosthesis were evaluated. We compared the results of prostheses implanted in an ID both inside and outside the recommendations. The outcome assessment followed the Valve Academic Research Consortium-3 criteria. Results: Patients were retrospectively divided into high (<3 mm; n = 412), optimal (3-7 mm; n = 1236), and low (>7 mm; n = 169) implantations. Technical success (94.7% vs. 94.7% vs. 91.7%, p = 0.296) and device success were high (90.1% vs. 89.3% vs. 84.6%, p = 0.112) without differences between groups. Rates of relevant paravalvular regurgitation (PVL; >mild or VinV due to PVL) were comparable (1.2% vs. 1.8% vs. 1.2%, p = 0.759). Even when hemodynamics were superior in the high-implantation group, with greater iEOA (1.01 cm2/m2 vs. 0.95 cm2/m2 vs. 0.92 cm2/m2, p < 0.001), spontaneous embolization or after post-dilatation was more common. Low implantation was associated with a higher rate of associated pacemaker implantation (PPI) (6.1% vs. 8.8% vs. 14.8%, p = 0.001). Conclusions: Implantation with the ACURATE neo2 showed excellent hemodynamic results, including low gradients and a small number of relevant PVL, in line with a high technical success rate that was irrespective of the ID. A favorable outcome can also be achieved in accidental low or high positions. Low implantation was associated with a higher rate of associated pacemaker implantation. Deliberately high implantation should be avoided due to the risk of embolization.

Rates and predictors for sustained ventricular tachycardia in patients with cardiac sarcoidosis and AV block as first cardiac presentation: Implications for device implantation.

BACKGROUND: Atrioventricular block (AVB) is a frequent initial presentation of cardiac sarcoidosis (CS), but dangerous ventricular arrhythmias (VA) can occur. Despite the scarcity of data, guidelines recommend implantable cardioverter-defibrillator (ICD) rather than a pacemaker implantation whenever a device is needed. OBJECTIVE: In this study, we aimed to establish predictors for sustained VA in patients with CS presenting with pacing indication because of an AVB. METHODS: We prospectively enrolled 112 patients with CS. Excluding those with VA, 82 patients remained and were divided into 2 groups: 34 individuals with AVB as initial presentation and 48 with other symptoms as first presentation (OSF). Both groups were compared for clinical characteristics, rates of VA, left ventricular assist device (LVAD) implantation, heart transplantation, and mortality. RESULTS: During follow-up, VA was detected in 50% in the AVB and 10.4% in the OSF group (P = .001). Death, LVAD implantation, and heart transplantation occurred in 11.8% in AVB group vs 10.4% in the OSF group (P = .847). Late gadolinium enhancement (LGE) was equally observed in both groups: 70% vs 70.5% (P = .966), whereas more patients in the AVB group exhibited abnormal positron emission tomography (PET) uptake: 86.2% vs 54.3% (P = .007). In multivariate analysis, AVB (hazard ratio [HR], 25.15), right ventricular (RV) LGE in cardiovascular magnetic resonance (CMR) (HR, 7.39) were predictors for VA occurrence, whereas the use of immunosuppressive therapy was associated with less VA (HR, 0.26). CONCLUSIONS: Patients with CS presenting with AVB have a high risk of sustained VA. Although immunosuppressive drugs may reduce the occurrence of VA, ICD implantation is reasonable, especially in case of RV LGE.

Cellular calcium handling and electrophysiology are modulated by chronic physiological pacing in human induced pluripotent stem cell-derived cardiomyocytes.

Electric pacing of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) has been increasingly used to simulate cardiac arrhythmias in vitro and to enhance cardiomyocyte maturity. However, the impact of electric pacing on cellular electrophysiology and Ca2+ handling in differentiated hiPSC-CM is less characterized. Here we studied the effects of electric pacing for 24 h or 7 days at a physiological rate of 60 beats/min on cellular electrophysiology and Ca2+ cycling in late-stage, differentiated hiPSC-CM (>90% troponin+, >60 days postdifferentiation). Electric culture pacing for 7 days did not influence cardiomyocyte cell size, apoptosis, or generation of reactive oxygen species in differentiated hiPSC-CM compared with 24-h pacing. However, epifluorescence measurements revealed that electric pacing for 7 days improved systolic Ca2+ transient amplitude and Ca2+ transient upstroke, which could be explained by elevated sarcoplasmic reticulum Ca2+ load and SERCA activity. Diastolic Ca2+ leak was not changed in line-scanning confocal microscopy, suggesting that the improvement in systolic Ca2+ release was not associated with a higher open probability of ryanodine receptor (RyR)2 during diastole. Whereas bulk cytosolic Na+ concentration and Na+/Ca2+ exchanger (NCX) activity were not changed, patch-clamp studies revealed that chronic pacing caused a slight abbreviation of the action potential duration (APD) in hiPSC-CM. We found in whole cell voltage-clamp measurements that chronic pacing for 7 days led to a decrease in late Na+ current, which might explain the changes in APD. In conclusion, our results show that chronic pacing improves systolic Ca2+ handling and modulates the electrophysiology of late-stage, differentiated hiPSC-CM. This study might help to understand the effects of electric pacing and its numerous applications in stem cell research including arrhythmia simulation.NEW & NOTEWORTHY Electric pacing is increasingly used in research with human induced pluripotent stem cell cardiomyocytes (hiPSC-CM), for example to simulate arrhythmias but also to enhance maturity. Therefore, it is mandatory to understand the effects of pacing itself on cellular electrophysiology in late-stage, matured hiPSC-CM. This study provides an electrophysiological characterization of the effects of chronic electric pacing at a physiological rate on differentiated hiPSC-CM.

Nocturnal Cardiac Arrhythmias in Heart Failure With Obstructive and Central Sleep Apnea.

BACKGROUND: Both OSA and central sleep apnea (CSA) may contribute to nocturnal cardiac arrhythmias (NCAs). Data are scarce regarding the prevalence of clinically important nocturnal atrial and ventricular arrythmias in patients with heart failure with reduced ejection fraction (HFrEF) and OSA or CSA. RESEARCH QUESTION: In a cohort of patients with HFrEF, how does the prevalence of NCA compare among those with OSA, CSA, and those with no to mild sleep apnea? Is the severity of OSA or CSA associated with atrial and ventricular NCAs? STUDY DESIGN AND METHODS: This cross-sectional analysis is an ancillary study of the Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure (ADVENT-HF) trial. We compared the prevalence of NCAs (excessive supraventricular ectopic activity [ESVEA], defined as premature atrial complexes ≥30/h or supraventricular tachycardia ≥ 20 beats); atrial fibrillation/flutter [AF]; and > 10 premature ventricular complexes [PVC/h]) on ECGs from polysomnograms of patients with HFrEF between those with OSA (apnea-hypopnea index [AHI ≥ 15 events/h]), those with CSA (AHI ≥ 15 events/h), and those with no to mild sleep apnea (AHI < 15 events/h [control]). RESULTS: The prevalence of ESVEA was higher in patients with OSA (n = 430) and CSA (n = 150) compared with control participants (n = 76): 0%, 9%, and 12%, respectively. The prevalence of AF in the control, OSA, and CSA groups was 9%, 17%, and 27%; the prevalence of > 10 PVC/h was 45%, 59%, and 63%. In multivariable regression analyses, premature atrial complexes/h was associated with OSA severity (obstructive AHI: 22.4% increase per 10 events/h [95% CI, 5.2-42.3; P = .009), although neither obstructive nor central AHI was associated with AF or > 10 PVC/h. INTERPRETATION: In patients with HFrEF, the prevalences of nocturnal ESVEA, AF, and PVC > 10/h were higher in those with OSA or CSA than in those without OSA or CSA, and OSA severity was related to the burden of nocturnal atrial ectopy. Severity of OSA or CSA was not significantly related to AF or > 10 PVC/h. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01128816; URL: www. CLINICALTRIALS: gov.

Microembolizations in the arterial cerebral circulation during atrial fibrillation ablation: cryoballoon technique advantages and neurocognitive safety-results of a prospective observational study.

AIMS: The significance of micro-embolic signals (MESs) during atrial fibrillation (AF) ablation is unclear. Previous studies had limitations, and cryoballoon (CB) ablation patients were under-represented. Minimizing MESs is recommended due to their uncertain neurocognitive impact. METHODS AND RESULTS: This prospective observational study included AF patients from a German centre between February 2021 and August 2022. Patients were equally divided into paroxysmal (Group A) and persistent (Group B) AF. Group A received cryoballoon-pulmonary vein isolation only, while Group B also had left atrial roof ablation. MESs were detected using transcranial Doppler ultrasonography during ablation. Neurocognitive status was assessed pre- and post-procedure and at 3 months using the CERAD Plus battery. The study analyzed 100 patients with a median age of 65.5 years. A total of 19 698 MESs were observed, with 80% being gaseous and 20% solid in origin, primarily occurring during pulmonary vein angiography and the balloon freeze and thawing phase. The median MES per patient was 130 (IQR: 92-256) in total, 298 (IQR: 177-413) in bilateral (36%), and 110 (IQR: 71-130) in unilateral (64%) recordings. No significant difference in total MES counts was found between the groups. None of the 11 neuropsychological tests showed cognitive decline post-procedure or at 3 months. CONCLUSION: Our observations confirm that neurocognitive abilities are not affected either 24 h or 3 months after AF ablation using the CB technique. However, despite the low MES burden associated with the CB, more work is needed to reduce small embolic events during AF ablation.

Case report of persistent atrial fibrillation with durably isolated pulmonary veins: what's next?

Background: Pulmonary vein isolation (PVI) has emerged as a safe and effective treatment for patients with paroxysmal and persistent atrial fibrillation. Nevertheless, in some patients, a relapse of atrial fibrillation occurs although pulmonary veins are durably isolated. For those patients, the underlying mechanisms of atrial fibrillation perpetuation are manifold and optimal treatment options are not yet defined. Case summary: We describe a case of a 55-year-old man with a history of atrial fibrillation and previous PVI presenting with persistent AF and arrhythmia induced cardiomyopathy. During the redo procedure, electro-anatomical mapping revealed durably isolated PV. Bipolar mapping showed large low-voltage areas at the posterior wall and the septum. As the patient was refractory to electrical cardioversion, it was decided to modify the large low-voltage areas as potential arrhythmic substrate. After performing additional ablation with isolation of the posterior wall and two anterior/septal lines, the patient spontaneously converted to sinus rhythm. Discussion: Ablation in patients with persistent AF despite durable PVI remains a challenge for the treating team. Individualized ablation approaches addressing additional arrhythmic substrates or extra-PV triggers can be considered to treat patients with persistent AF and durable PVI.

Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation.

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing Spp1 in TREM2+ cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

[Oral anticoagulation in supraventricular arrhythmia]. / Orale Antikoagulation bei supraventrikulären Rhythmusstörungen.

Atrial fibrillation represents the most frequent persistent cardiac arrhythmia and is associated with an increased morbidity and mortality. An important component of the holistic treatment of atrial fibrillation is oral anticoagulation (OAC) for the prevention of stroke. The CHA2DS2-VASc score as a risk score is recommended for estimation of the individual stroke risk and the concomitant need of OAC in these patients. In the majority of patients the OAC is nowadays carried out with direct oral anticoagulants (DOAC), which have proved to be effective with a moderate side effect profile and have replaced vitamin K antagonists as the standard substance. In the meantime, these principles have become established as the usual practice but some issues regarding OAC in patients with atrial fibrillation are still insufficiently answered. Furthermore, it is unclear whether OACs need to be continued after successful treatment of atrial fibrillation with pulmonary vein ablation or in some cases can even be discontinued. Unanswered questions also remain regarding the treatment of subclinical atrial fibrillation and atrial high-frequency episodes detected by implanted heart rhythm devices. Especially the duration of atrial high-frequency episodes that should trigger the initiation of OAC treatment is still under debate. Therefore, currently the benefits of stroke prevention must be carefully weighed up against the risk of bleeding complications.

Cryoballoon-Assisted Pulmonary Vein Isolation and Left Atrial Roof Ablation Using a Simplified Sedation Strategy without Esophageal Temperature Monitoring: No Notable Thermal Esophageal Lesions and Low Arrhythmia Recurrence Rates after 2 Years.

BACKGROUND: Atrial fibrillation (AF) ablation is increasingly effective for managing heart rhythm but poses risks like esophageal fistulas. Minimizing esophageal thermal lesions while simplifying procedures is crucial. METHODS: This prospective study involved 100 consecutive AF patients undergoing cryoballoon ablation with simplified sedation, without esophageal temperature monitoring. Patients with paroxysmal AF (Group A) received pulmonary vein isolation only, while those with persistent AF (Group B) also had left atrial roof ablation. Gastroesophageal endoscopy was performed post-procedure to detect lesions, and cardiological follow-ups were conducted at 3, 12, and 24 months. RESULTS: The cohort included 69% men, with a median age of 65.5 years. Post-ablation endoscopy was performed in 92 patients; esophageal lesions were found in 1.1% of Group A and none of Group B. GERD was diagnosed in 14% of patients, evenly distributed between groups and not linked to lesion occurrence. Gastric hypomotility was observed in 16% of patients, with no significant difference between groups. At 24 months, arrhythmia-free survival was 88% in Group A and 74% in Group B. CONCLUSION: Cryoballoon-assisted pulmonary vein isolation, with or without additional left atrial roof ablation and without esophageal temperature monitoring during a simplified sedation strategy, shows low risk of esophageal thermal injury and effective ablation outcomes.

Comparative Analysis of Mitochondria Surrounding the Intercalated Discs in Heart Diseases-An Ultrastructural Pilot Study.

BACKGROUND: Mitochondria play a crucial role in adapting to fluctuating energy demands, particularly in various heart diseases. This study investigates mitochondrial morphology near intercalated discs in left ventricular (LV) heart tissues, comparing samples from patients with sinus rhythm (SR), atrial fibrillation (AF), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). METHODS: Transmission electron microscopy was used to analyze mitochondria within 0-3.5 µm and 3.5-7 µm of intercalated discs in 9 SR, 10 AF, 9 DCM, and 8 ICM patient samples. Parameters included mean size in µm2 and elongation, count, percental mitochondrial area in the measuring frame, and a conglomeration score. RESULTS: AF patients exhibited higher counts of small mitochondria in the LV myocardium, resembling SR. DCM and ICM groups had fewer, larger, and often hydropic mitochondria. Accumulation rates and percental mitochondrial area were similar across groups. Significant positive correlations existed between other defects/size and hydropic mitochondria and between count/area and conglomeration score, while negative correlations between count and size/other defects and between hydropic mitochondria and count could be seen as well. CONCLUSION: Mitochondrial parameters in the LV myocardium of AF patients were similar to those of SR patients, while DCM and ICM displayed distinct changes, including a decrease in number, an increase in size, and compromised mitochondrial morphology. Further research is needed to fully elucidate the pathophysiological role of mitochondrial morphology in different heart diseases, providing deeper insights into potential therapeutic targets and interventions.

Outcomes of transfemoral TAVR using two new-generation devices in patients with horizontal aorta.

BACKGROUND: Challenging anatomies and comorbidities have impact on success in transcatheter aortic valve replacement (TAVR). There is controversy whether the extent of the aortic angle (AA) has an impact on procedural outcomes. Matched comparative outcome data of new generation transcatheter heart valves (THVs) in horizontal aorta (HA) are scarce. METHODS: A total of 1582 patients with severe native aortic stenosis (AS) treated with the SAPIEN3 Ultra (Ultra; n = 526) or ACURATE Neo2 (Neo2; n = 1056) THVs from January 2017 to January 2023 were analyzed. Patients with non-horizontal aortas (AA < 51.7°, n = 841) were excluded. The population was matched by 1-to-1 nearest-neighbor matching (Ultra, n = 246; Neo2, n = 246). Clinical and procedural outcome were evaluated according to VARC-3 recommendations. RESULTS: Technical success (93.1% vs. 94.7%, p = 0.572) was high after Ultra and Neo2. Device success (80.5% vs. 89.8%, p = 0.05) was inferior with Ultra. Neo2 reveals superior hemodynamic properties with lower rate of severe prosthesis patient mismatch (12.0% vs. 3.7%, p = 0.001) and elevated gradients ( ≥ $\ge $ 20 mmHg: 11.9% vs. 1.7%, p < 0.001). Ultra showed a lower rate of relevant paravalvular regurgitation ( > $\gt $ mild paravalvular regurgitation or Valve-in-Valve due to paravalvular regurgitation: 0.0% vs. 3.7%, p = 0.004). The rate of procedural bailout maneuvers (0.8% vs. 0.4%, p = 1.000) and thirty-day all-cause mortality (1.3% vs. 2.2%, p = 0.496) was similar. CONCLUSION: Transfemoral TAVR in patients with severe aortic stenosis and HA, using the balloon expandable Sapien3 Ultra and self-expanding ACURATE Neo2 prosthesis, is feasible and safe. Therefore, valve selection between these platforms should be made irrespective of the aortic angle by a team experienced with both valves based on their specific advantages. Large, randomized trials in this sub-group of patients would be necessary to compare long term outcomes.

NaV1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

The sodium channel NaV1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that NaV1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, INaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of NaV1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that INaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of NaV1.8. In contrast, we did not find any effects on ventricular APD90. The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of NaV1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of NaV1.8 in control cells. In conclusion, we show that NaV1.8-induced INaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of NaV1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms NaV1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.

Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

BACKGROUND: Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. METHODS: Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. RESULTS: Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. CONCLUSIONS: Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.