Patient-specific quantification of cardiorespiratory motion for cardiac stereotactic radioablation treatment planning.

Background: Cardiac radioablation is a new treatment for patients with refractory ventricular tachycardia (VT). The target for cardiac radioablation is subject to cardiorespiratory motion (CRM), the heart's movement with breathing and cardiac contraction. Data regarding the magnitude of target CRM are limited but are highly important for treatment planning. Objectives: The study sought to assess CRM amplitude by using ablation catheter geometrical data. Methods: Electroanatomic mapping data of patients undergoing catheter ablation for VT at 3 academic centers were exported. The spatial position of the ablation catheter as a function of time while in contact with endocardium was analyzed and used to quantify CRM. Results: Forty-four patients with ischemic and nonischemic cardiomyopathy and VT contributed 1364 ablation lesions to the analysis. Average cardiac and respiratory excursion were 1.62 ± 1.21 mm and 12.12 ± 4.10 mm, respectively. The average ratio of respiratory to cardiac motion was approximately 11:1. CRM was greatest along the craniocaudal axis (9.66 ± 4.00 mm). Regional variations with respect to respiratory and cardiac motion were observed: basal segments had smaller displacements vs midventricular and apical segments. Patient characteristics (previous cardiac surgery, height, weight, body mass index, and left ventricular ejection fraction) had a statistically significant, albeit clinically moderate, impact on CRM. Conclusion: CRM is primarily determined by respiratory displacement and is modulated by the location of the target and the patient's biometric characteristics. The patient-specific quantification of CRM may allow to decrease treatment volume and reduce radiation exposure of surrounding organs at risk while delivering the therapeutic dose to the target.

Pulmonary Vein Isolation for Atrial Fibrillation: Comparison of a Very High-Power Very Short-Duration (vHPvSD) Ablation Protocol versus a Hybrid Ablation Approach-Procedural and Mid-Term Outcome Data.

Background: Pulmonary vein isolation (PVI) using radiofrequency ablation (RFA) is a standard-of-care treatment in the rhythm control strategy of symptomatic atrial fibrillation (AF). Ablation protocols, varying in the power and duration of energy delivery, have changed rapidly in recent years. Very high-power very short-duration ablation (vHPvSD) is expected to shorten procedural times compared to conventional ablation approaches. However, the existing data suggest that this might come at the cost of lower first-pass isolation rates, a predictor of poor ablation long-term outcomes. This study aims to compare a vHPvSD protocol to a hybrid strategy, in which the power and duration of the energy transfer are adapted depending on the anatomical location. Methods: We retrospectively analyzed procedural and outcome data from 93 patients (55 vHPvSD vs. 38 hybrid) scheduled for de novo pulmonary vein isolation. A vHPvSD ablation protocol (90 Watt (W), 4 s) was compared to a hybrid protocol using vHPvSD on the posterior wall and 50 W HPSD (high-power short-duration) ablation guided by the Ablation Index along the remaining spots. Results: Ablation times were significantly shorter in the vHPvSD cohort (5.4 min. vs. 14.2 min, p < 0.001), thus resulting in a significant reduction in the overall procedural duration (91 min vs. 106 min, p = 0.003). The non-significant slightly higher first-pass isolation rates in the vHPvSD cohort (85% vs. 76%, p = 0.262) did not affect freedom from AF 6 months after the procedure (83% vs. 87%, p = 0.622). Conclusions: vHPvSD helps in shortening the PVI procedural duration, thus neither affecting first-pass isolation rates nor freedom from atrial tachyarrhythmia recurrence at 6 months after the index procedure.

Impact of ventricular tachycardia ablation in subcutaneous implantable cardioverter defibrillator carriers: a multicentre, international analysis from the iSUSI project.

AIMS: Catheter ablation (CA) of ventricular tachycardia (VT) has become an important tool to improve clinical outcomes in patients with appropriate transvenous implantable cardioverter defibrillator (ICD) shocks. The aim of our analysis was to test whether VT ablation (VTA) impacts long-term clinical outcomes even in subcutaneous ICD (S-ICD) carriers. METHODS AND RESULTS: International Subcutaneous Implantable Cardioverter Defibrillator (iSUSI) registry patients who experienced either an ICD shock or a hospitalization for monomorphic VT were included in this analysis. Based on an eventual VTA after the index event, patients were divided into VTA+ vs. VTA- cohorts. Primary outcome of the study was the occurrence of a combination of device-related appropriate shocks, monomorphic VTs, and cardiovascular mortality. Secondary outcomes were addressed individually. Among n = 1661 iSUSI patients, n = 211 were included: n = 177 experiencing ICD shocks and n = 34 hospitalized for VT. No significant differences in baseline characteristics were observed. Both the crude and the yearly event rate of the primary outcome (5/59 and 3.8% yearly event rate VTA+ vs. 41/152 and 16.4% yearly event rate in the VTA-; log-rank: P value = 0.0013) and the cardiovascular mortality (1/59 and 0.7% yearly event rate VTA+ vs. 13/152 and 4.7% yearly event rate VTA-; log-rank P = 0.043) were significantly lower in the VTA + cohort. At multivariate analysis, VTA was the only variable remaining associated with a lower incidence of the primary outcome [adjusted hazard ratio 0.262 (0.100-0.681), P = 0.006]. CONCLUSION: In a real-world registry of S-ICD carriers, the combined study endpoint of arrhythmic events and cardiovascular mortality was lower in the patient cohort undergoing VTA at long-term follow-up. CLINICALTRIALS.GOV IDENTIFIER: NCT0473876.

Identification of a Phage Display-Derived Peptide Interacting with the N-Terminal Region of Factor VII Activating Protease (FSAP) Enables Characterization of Zymogen Activation.

Factor VII Activating protease (FSAP) has a protective effect in diverse disease conditions as inferred from studies in FSAP-/- mice and humans deficient in FSAP activity due to single-nucleotide polymorphism. The zymogen form of FSAP in plasma is activated by extracellular histones that are released during tissue injury or inflammation or by positively charged surfaces. However, it is not clear whether this activation mechanism is specific and amenable to manipulation. Using a phage display approach, we have identified a Cys-constrained 11 amino acid peptide, NNKC9/41, that activates pro-FSAP in plasma. The synthetic linear peptide has a propensity to cyclize through the terminal Cys groups, of which the antiparallel cyclic dimer, but not the monocyclic peptide, is the active component. Other commonly found zymogens in the plasma, related to the hemostasis system, were not activated. Binding studies with FSAP domain deletion mutants indicate that the N-terminus of FSAP is the key interaction site of this peptide. In a monoclonal antibody screen, we identified MA-FSAP-38C7 that prevented the activation of pro-FSAP by the peptide. This antibody bound to the LESLDP sequence (amino acids 30-35) in an intrinsically disordered stretch in the N-terminus of FSAP. The plasma clotting time was shortened by NNKC9/41, and this was reversed by MA-FSAP-38C7, demonstrating the utility of this peptide. Peptide NNKC9/41 will be useful as a tool to delineate the molecular mechanism of activation of pro-FSAP, elucidate its biological role, and provide a starting point for the pharmacological manipulation of FSAP activity.

Very High-Power Short-Duration (HPSD) Ablation for Pulmonary Vein Isolation: Short and Long-Term Outcome Data.

BACKGROUND: Circumferential pulmonary vein isolation (PVI) using radiofrequency ablation (RFA) is a standard of care intervention for patients with symptomatic atrial fibrillation (AF). During follow-up, a substantial number of patients need a redo procedure due to reconnections on the basis of insufficient non-transmural ablation lesions. High-power short-duration ablation (HPSD) is expected to create efficient lesions while causing fewer complications than in conventional RFA settings. The aim of this study was to compare one-year outcome data of very HPSD (90 Watt, 4 s) to a strategy using 50 Watt HPSD ablation guided by the CLOSE protocol using the Ablation Index (AI), an arbitrary unit composed of power, contact force and ablation time. METHODS: We retrospectively analyzed short and long-term (median follow-up 23.2 ± 9.9 months) outcome data from 52 patients that were scheduled for first-do-symptomatic PVI. A very HPSD ablation protocol with 90 Watt and a 4 s duration cut-off was compared to an HPSD CLOSE approach (50 Watts; AI 550 at the anterior LA wall; AI 400 at the posterior LA wall, the roof and the floor) in terms of freedom from AF recurrence in a long-term electrocardiogram (ECG) over a five days surveillance period. To gain an impression of the subjective sense of wellbeing, the Atrial Fibrillation Effects on QualiTy-of-Life (AFEQT) score was recorded. RESULTS: Overall freedom from AF was found in 81% (90 W 4 s) vs. 87.5% (50 W), (p = 0.52). There were 3 AF recurrences during the blanking period (90 W 4 s) vs. 1 (50 W). Within each population, one patient was scheduled for a redo-PVI-procedure. The AFEQT score was in favor of the 90 Watt 4 s approach (86.1 vs. 77.5; p = 0.37). CONCLUSION: Within our relatively small studied population, we found hints that in addition to shortening ablation times and radiation exposure without significantly increasing the rate of relevant intraprocedural complications, very high power short-duration ablation (90 W 4 s) provides comparable efficacy rates after one year.

Ertugliflozin to reduce arrhythmic burden in ICD/CRT patients (ERASe-trial) - A phase III study.

Sodium glucose cotransporter 2 (SGLT2) have proven profound positive effects in heart failure with reduced ejection fraction (HFrEF). These effects are independent from the presence of diabetes. Metabolic effects, antiinflammatory, and antifibrotic properties are discussed as underlying mechanisms. Despite a strong correlation of ventricular arrhythmias with HFrEF, the impact of ertugliflozin on the ventricular arrhythmic burden has not been investigated, yet. Therefore, the Ertugliflozin to Reduce Arrhythmic burden in ICD ± CRT patientS (ERASe) trial was designed to investigate the efficacy and safety of ertugliflozin in patients with reduced and midrange ejection fraction (EF) with or without diabetes. METHODS: Within a multicentre, national, randomized, double-blind, placebo-controlled, phase 3b trial we aim to enrol a total of 402 patients across Austria. Patients with reduced or midrange EF and ICD ± CRT therapy >3 months and previous ventricular tachycardia (at least 10 documented VT episodes within the last 12 months) are randomized in a 1:1 ratio to ertugliflozin (5 mg once daily orally administered) or matching placebo. The primary endpoint of the ERASe trial is to investigate the impact of ertugliflozin on total burden of ventricular arrhythmias. Further objectives will include number of therapeutic interventions of implanted devices, atrial fibrillation and heart failure biomarkers. CONCLUSION: The ERASe trial will be the first trial to test ertugliflozin in heart failure patients with nonpreserved ejection fraction and ongoing ICD ± CRT therapy regardless of their diabetic status. The ERASe trial may therefore extend the concept of SGLT2 inhibition to improve cardiac remodelling, including reduced arrhythmic burden. Trial registration Identifier EudraCT Nr. 2020-002581-14 / ClinicalTrials.gov Identifier: NCT04600921.

Long-term follow-up of medically treated patients with spontaneous coronary artery dissection: a prospective, Swiss single-centre cohort study.

AIMS OF THE STUDY: Spontaneous coronary artery dissection (SCAD) is an increasingly diagnosed cause of acute myocardial infarction. However, there is still a limited number of larger cohorts with long-term follow-up. We report on the largest Swiss single-centre cohort to date, with follow-up of up to 22 years. METHODS: We prospectively collected SCAD cases from June 1998 until December 2020. A strategy of systematic follow-up angiography was applied. Information on long-term follow-up was collected up to the end of 2020. Major cardiovascular events (MACE) were defined as all-cause death, non-fatal MI, and non-fatal cardiac arrest. RESULTS: We identified 105 SCAD patients (mean age 53 ± 11 years, 98 female, 5 peripartum). Presentation was myocardial infarction in all patients. In 102 patients, there was one contiguous dissection. Three patients had two (n = 2) or three (n = 1) non-contiguous dissections. In the majority of patients (n = 97), the primary treatment approach was conservative (dual antiplatelet therapy for 12 months in 90% of patients, statins in 91%). Seven patients were treated with percutaneous coronary intervention (PCI) and one patient underwent bypass surgery. Elective follow-up angiograms were performed in 73 asymptomatic patients after a median follow-up of 6.0 months (interquartile range [IQR] 5.5-6.5). These showed healing of the dissection (n = 65) or a good result after PCI (n = 5) in 70 patients. Three patients had a persistent dissection but conservative treatment was continued. After a median follow-up of 7.5 years (IQR 3.6-12.5) (longest follow-up: 22.5 years) there were 15 MACE. Five MACE occurred within 30 days of the index event: death following catastrophic peripartum left main SCAD (n = 1), out-of-hospital cardiac arrest with successful resuscitation 16 days after SCAD (n = 1), ST-segment elevation myocardial infarction due to occlusion of the dissected artery 10 hours after the index angiogram with subsequent PCI (n = 1), SCAD of a second vessel 8 days after the index SCAD (n = 1), and non-ST-segment elevation myocardial infarction with persistent, multisite SCAD 10 days after the index event (n = 1). There were 10 late MACE, including myocardial infarction and recurrent SCAD (different vessel/lesion) a median of 7.6 years (IQR 3.9-9.6) after the index event in eight patients and death with unclear cause in two patients. CONCLUSION: This SCAD series highlights its highly variable clinical course during the acute phase and in the long term. Although most SCAD patients can be treated conservatively with subsequent healing of the dissection and good clinical outcome, there are also patients with dramatic acute presentation or MACE several years after the initial presentation.

Wedge Pressure vs Left Ventricular End-Diastolic Pressure for Pulmonary Hypertension Classification and Prognostication in Severe Aortic Stenosis.

BACKGROUND: Differentiation between precapillary and postcapillary pulmonary hypertension (PH) classically relies on mean pulmonary artery wedge pressure (mPAWP). The left ventricular end-diastolic pressure (LVEDP) is proposed as an equivalent alternative. However, mPAWP and LVEDP may differ substantially. We compared the impact of the choice of using the mPAWP vs the LVEDP on PH classification and mortality prediction in patients with severe aortic stenosis (AS) undergoing valve replacement. METHODS: In 335 patients with severe AS , both mPAWP and LVEDP were measured. A mean pulmonary artery pressure ≥ 25 mm Hg was used to define PH, and either mPAWP or LVEDP was used to differentiate between precapillary and postcapillary PH (≤ 15 vs > 15 mm Hg). Mortality after a median follow-up of 1484 days after aortic valve replacement was assessed. RESULTS: Overall, mPAWP was lower than LVEDP (16 ± 8 mm Hg vs 21 ± 8 mm Hg; P < 0.001). Among 140 patients (42%) with PH, the PAWP-based classification revealed 76 (54% of those with PH) with isolated postcapillary PH, 48 (34%) with combined pre- and postcapillary PH, and 16 (12%) with precapillary PH. When the LVEDP was used, 59 patients (42%) were differently classified. These patients had higher mortality than those who were not differently classified [hazard ratio 2.79 (95% confidence interval, 1.17-6.65); P = 0.02]. Higher mPAWP was associated with increased mortality [hazard ratio 1.07 (95% confidence interval, 1.03-1.11) per 1 mm Hg; P = 0.001], whereas higher LVEDP was not. CONCLUSIONS: Use of LVEDP rather than mPAWP results in a divergent PH classification in nearly every second patient with severe AS. These patients have higher mortality after aortic valve replacement. The mPAWP, but not the LVEDP, predicts mortality.

INTRODUCTION: La différentiation entre l'hypertension pulmonaire (HP) précapillaire et postcapillaire repose traditionnellement sur la pression artérielle pulmonaire d'occlusion moyenne (PAPOm). La pression télédiastolique du ventricule gauche (PTDVG) est proposée comme alternative équivalente. Toutefois, la PAPOm et la PTDVG peuvent largement différer. Nous avons comparé les répercussions du choix entre l'utilisation de la PAPOm vs l'utilisation de la PTDVG sur la classification de l'HP et la prédiction de la mortalité des patients atteints d'une sténose aortique (SA) grave qui subissaient un remplacement valvulaire. MÉTHODES: Nous avons mesuré la PAPOm et la PTDVG de 335 patients atteints de SA grave. Nous avons utilisé une pression artérielle pulmonaire moyenne ≥ 25 mmHg pour définir l'HP, et utilisé la PAPOm ou la PTVDG pour différencier entre l'HP précapillaire et postcapillaire (≤ 15 mmHg vs > 15 mmHg). Nous avons évalué la mortalité après un suivi médian de 1 484 jours après le remplacement valvulaire aortique. RÉSULTATS: Dans l'ensemble, la PAPOm était plus faible que la PTVDG (16 ± 8 mmHg vs 21 ±8 mmHg; P < 0,001). Parmi les 140 patients (42 %) atteints d'HP, la classification en fonction de la PAPO a révélé 76 (54 % des patients atteints d'HP) patients atteints d'HP postcapillaire isolée, 48 (34 %) patients atteints d'HP précapillaire et postcapillaire combinée et 16 (12 %) patients atteints d'HP précapillaire. Lorsque nous avons utilisé la PTVDG, 59 patients (42 %) étaient classifiés différemment. La mortalité chez ces patients était plus élevée que chez les patients qui n'étaient pas classifiés différemment (rapport de risque 2,79 [intervalle de confiance à 95 %, 1,17-6,65]; P = 0,02). La PAPOm plus élevée était associée à une mortalité accrue (rapport de risque 1,07 [intervalle de confiance à 95 %, 1,03-1,11] par 1 mmHg; P = 0,001), tandis que la PTVDG plus élevée ne l'était pas. CONCLUSIONS: Le fait d'utiliser la PTVDG plutôt que la PAPOm entraîne une classification divergente de l'HP chez presque tous les deux patients atteints de SA grave. La mortalité après le remplacement valvulaire aortique de ces patients est plus élevée. La PAPOm, mais non la PTVDG, prédit la mortalité.

Corrected QT Interval in Severe Aortic Stenosis: Clinical and Hemodynamic Correlates and Prognostic Impact.

BACKGROUND: The role of the electrocardiogram for risk stratification in patients with severe aortic stenosis is not established. We assessed the hemodynamic correlates and the prognostic value of the corrected QT interval (QTc) in patients with severe aortic stenosis undergoing aortic valve replacement. METHODS: The QT interval was measured in a 12-lead electrocardiogram in 485 patients (age 74 ± 10 years, 57% male) with severe aortic stenosis (indexed aortic valve area 0.41 ± 0.13 cm2/m2, left ventricular ejection fraction 58 ± 12%) the day prior to cardiac catheterization. Prolonged QTc was defined as QTc >450 ms in men and QTc >470 ms in women. The outcome parameter was all-cause mortality. RESULTS: Patients with prolonged QTc (n = 100; 77 men, 23 women) had similar indexed aortic valve area but larger left ventricular and left atrial size, lower left ventricular ejection fraction, more severe mitral regurgitation, lower cardiac index, and higher mean pulmonary artery pressure, mean pulmonary artery wedge pressure, and pulmonary vascular resistance, as compared with patients with normal QTc (n = 385). After a median follow-up of 3.7 years (interquartile range, 2.6-5.2) after surgical (n = 349) or transcatheter (n = 136) aortic valve replacement, patients with prolonged QTc had higher mortality than those with normal QTc (hazard ratio 2.81 [95% confidence interval, 1.51-5.20]; P < .001). Prolonged QTc was an independent predictor of death along with more severe mitral regurgitation and higher pulmonary vascular resistance. CONCLUSIONS: In patients with severe aortic stenosis, prolonged QTc is a marker of an advanced disease stage associated with an adverse hemodynamic profile and increased long-term mortality after aortic valve replacement.

Transforming Growth Factor-ß (TGF-ß) Inhibits the Expression of Factor VII-activating Protease (FSAP) in Hepatocytes.

Deletion of the Habp2 gene encoding Factor VII-activating protease (FSAP) increases liver fibrosis in mice. A single nucleotide polymorphism (G534E) in HABP2 leads to lower enzymatic activity and is associated with enhanced liver fibrosis in humans. Liver fibrosis is associated with a decrease in FSAP expression but, to date, nothing is known about how this might be regulated. Primary mouse hepatocytes or the hepatocyte cell line, AML12, were treated with different factors, and expression of FSAP was determined. Of the various regulatory factors tested, only transforming growth factor-ß (TGF-ß) demonstrated a concentration- and time-dependent inhibition of FSAP expression at the mRNA and protein level. The TGF-ß-Type I receptor (ALK-5) antagonist SB431542 and Smad2 siRNA, but neither SIS3, which inhibits SMAD3, nor siRNA against Smad3 could block this effect. Various regions of the HABP2 promoter region were cloned into reporter constructs, and the promoter activity was determined. Accordingly, the promoter activity, which could phenocopy changes in Habp2 mRNA in response to TGF-ß, was found to be located in the 177-bp region upstream of the transcription start site, and this region did not contain any SMAD binding sites. Mutation analysis of the promoter and chromatin immunoprecipitation assays were performed to identify an important role for the ATF3 binding element. Thus, TGF-ß is the most likely mediator responsible for the decrease in FSAP expression in liver fibrosis.

Phenotypical analysis of atypical PKCs in vivo function display a compensatory system at mouse embryonic day 7.5.

BACKGROUND: The atypical protein kinases C (PKC) isoforms ι/λ and ζ play crucial roles in many cellular processes including development, cell proliferation, differentiation and cell survival. Possible redundancy between the two isoforms has always been an issue since most biochemical tools do not differentiate between the two proteins. Thus, much effort has been made during the last decades to characterize the functions of aPKCs using gene targeting approaches and depletion studies. However, little is known about the specific roles of each isoform in mouse development. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the importance of PKCι in mouse development we designed PKCι deletion mutants using the gene targeting approach. We show that the deletion of PKCι, results in a reduced size of the amniotic cavity at E7.5 and impaired growth of the embryo at E8.5 with subsequent absorption of the embryo. Our data also indicate an impaired localization of ZO-1 and disorganized structure of the epithelial tissue in the embryo. Importantly, using electron microscopy, embryoid body formation and immunofluorescence analysis, we found, that in the absence of PKCι, tight junctions and apico-basal polarity were still established. Finally, our study points to a non-redundant PKCι function at E9.5, since expression of PKCζ is able to rescue the E7.5 phenotype, but could not prevent embryonic lethality at a later time-point (E9.5). CONCLUSION: Our data show that PKCι is crucial for mouse embryogenesis but is dispensable for the establishment of polarity and tight junction formation. We present a compensatory function of PKCζ at E7.5, rescuing the phenotype. Furthermore, this study indicates at least one specific, yet unknown, PKCι function that cannot be compensated by the overexpression of PKCζ at E9.5.

Functional comparison of protein domains within aPKCs involved in nucleocytoplasmic shuttling.

The atypical protein kinases C (PKC) isoforms ι and ζ play crucial roles in regulation of signaling pathways related to proliferation, differentiation and cell survival. Over the years several interaction partners and phosphorylation targets have been identified. However, little is known about the regulation of atypical aPKC isoforms. To address this question, we performed a comparative analysis of atypical aPKCι/λ and ζ in MDCK cells. By using green fluorescence protein (GFP) fusion proteins containing the full-length or truncated proteins, we were able to recognize differences in subcellular localization and nucleocytoplasmic shuttling of both isoforms. We show, that an earlier described nuclear localization sequence (NLS), plays a role in the regulation of atypical aPKCζ but not in aPKCι, despite the fact that it is present in both isoforms. Leptomycin B treatment induces accumulation of GFP-fusion protein of both isoforms in the nucleus. Regardless, the loss of the NLS only decreases shuttling of aPKCζ, while aPKCι remains unaffected. In addition, we identified the hinge region as a potential regulator of localization of atypical PKCs. With a set of chimeric proteins we show that the hinge region of aPKCι mediates nuclear localization. In contrast, the hinge region of aPKCζ causes exclusion from the nucleus, indicating two different mechanisms leading to isoform specific regulation. Taken together, we show for the first time, that the atypical isoforms aPKCι and ζ underly different mechanisms regarding their regulation of subcellular localization and translocation into the nucleus in MDCK cells.