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Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript ( cis -eQTL) and protein ( cis -pQTL) abundance. We further establish a novel targeted trans -QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans -eQTLs and five trans -pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans -acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization. Numerous disease-associated variants have been described in GWAS for atrial fibrillation. Here the authors integrate omics data to investigate the consequences of genetic variants for transcript and protein levels in the atrium of the human heart. With this multi-omics approach, authors reveal the regulatory network underlying atrial fibrillation and provide a resource for cardiac gene prioritization.

Cardiac ischemia reperfusion (I/R) injury is a serious consequence of reperfusion therapy for myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the citrullination of proteins. In previous studies, PAD4 inhibition protected distinct organs from I/R injury by preventing the formation of neutrophil extracellular traps (NETs) and attenuating inflammatory responses. Here, we hypothesized that cardiomyocyte PAD4 expression may play a role in acute I/R injury. Infarct size was determined in isolated pressure constant-perfused hearts from WT and PAD4-deficient (PAD4-/-) mice. Additionally, extracellular reactive oxygen species (ROS) and cell viability were quantified in freshly isolated adult cardiomyocytes exposed to hypoxia followed by reoxygenation (H/R). Resistance to oxidative stress was proven in both genotypes by treatment of neonatal cardiomyocytes with hydrogen peroxide. Moreover, intracellular ROS formation, ATP production, mitochondrial membrane polarisation, caspase-3 activation, and cell viability were quantified after hypoxia followed by 4 h and 20 h of reoxygenation, respectively. The PAD4-specific inhibitor GSK484 was added before H/R or at reperfusion in certain experiments. Infarct size was smaller in PAD4-/- hearts following I/R when compared to the WT. Similarly, the viability of adult and neonatal PAD4-/- cardiomyocytes was better preserved after H/R, accompanied by reduced ROS formation. PAD4 deficiency maintained mitochondrial integrity and protected neonatal cardiomyocytes against apoptosis. However, these cells did not exhibit resistance to hydrogen peroxide-induced cell death, indicating an unaltered antioxidative state. Whereas pharmacological PAD4 inhibition by GSK484 before H/R sustained intracellular ATP levels in WT cardiomyocytes, administration of GSK484 at reoxygenation did not. However, GSK484 significantly improved cardiomyocyte metabolic activity, regardless of the time of administration. Our study is the first to demonstrate that PAD4 expression in cardiomyocytes contributes to H/R injury independent of systemic immune responses and NETs. Consequently, PAD4 may serve as a therapeutic target to alleviate I/R injury.

Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research.

BackgroundHeyde syndrome (HS) is known as the association of severe aortic stenosis (AS) and recurrent gastrointestinal bleeding (GIB) from angiodysplasia. Data on the prevalence of HS and results after TAVI remain scarce.Methods2548 consecutive patients who underwent TAVI for the treatment of AS from 2008 to 2017 were evaluated for a history of GIB and the presence of HS. The diagnosis of HS was defined as a clinical triad of severe AS, a history of recurrent GIB, and an endoscopic diagnosis of angiodysplasia. These patients (Heyde) were followed to investigate clinical outcomes, bleeding complications and the recurrence of GIB and were compared to patients with GIB unrelated to HS (Non-Heyde).ResultsA history of GIB prior to TAVI was detected in 190 patients (7.5%). Among them, 47 patients were diagnosed with HS (1.8%). Heyde patients required blood transfusions more frequently compared to Non-Heyde patients during index hospitalization (50.0% vs. 31.9%, p = 0.03). Recurrent GIB was detected in 39.8% of Heyde compared to 21.2% of Non-Heyde patients one year after TAVI (p = 0.03). In patients diagnosed with HS and recurrent GIB after TAVI, the rate of residual ≥ mild paravalvular leakage (PVL) was higher compared to those without recurrent bleeding (73.3% vs. 38.1%, p = 0.05).ConclusionA relevant number of patients undergoing TAVI were diagnosed with HS. Recurrent GIB was detected in a significant number of Heyde patients during follow-up. A possible association with residual PVL requires further investigation to improve treatment options and outcomes in patients with HS.Graphic abstract

BackgroundA small aortic annulus is associated with increased risk of prosthesis–patient mismatch (PPM) after transcatheter aortic valve implantation (TAVI). Whether specific transcatheter heart valve (THV) designs yield superior hemodynamic performance in these small anatomies remains unclear.MethodsData from 8411 consecutive patients treated with TAVI from May 2012 to April 2019 at four German centers were retrospectively evaluated. A small aortic annulus was defined as multidetector computed tomography-derived annulus area < 400 mm2. TAVI was performed with a balloon-expanding intra-annular (Sapien-3, n = 288), self-expanding intra-annular (Portico, n = 110), self-expanding supra-annular (Evolut, n = 179 and Acurate-Neo, n = 428) and mechanically expanding infra-annular (Lotus, n = 64) THV according to local practice. PPM was defined as indexed effective orifice area ≤ 0.85cm2/m2.ResultsA small annulus was found in 1069 (12.7%) patients. PPM was detected in 38.3% overall with a higher prevalence after implantation of a balloon-expanding intra-annular or mechanically expanding infra-annular THV compared to self-expanding intra- and supra-annular THV. Multivariable analysis linked self-expanding THV (Evolut: Odds ratio [OR] 0.341, Acurate-Neo: OR 0.436, Portico: OR 0.291), postdilatation (OR 0.648) and age (OR 0.968) to lower rates of PPM, while aortic valve calcification was associated with an increased risk (OR 1.001). Paravalvular regurgitation > mild was more frequent after TAVI with self-expanding THV (p = 0.04).ConclusionIn this large contemporary multicenter patient population, a substantial number of patients with a small aortic anatomy were left with PPM after TAVI. Self-expanding supra- and intra-annular THV demonstrated superior hemodynamics in these patients at risk, however at the cost of higher rates of residual paravalvular regurgitation.Graphic abstract

ObjectivesThis study aimed to assess the clinical outcome of the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary obstruction (BASILICA) technique in a single-center patient cohort considered at high or prohibitive risk of transcatheter aortic valve implantation (TAVI)-induced coronary obstruction.MethodsBetween October 2019 and January 2021, a total of 15 consecutive patients (age 81.0 [78.1, 84.4] years; 53.3% female; EuroSCORE II 10.6 [6.3, 14.8] %) underwent BASILICA procedure prior to TAVI at our institution. Indications for TAVI were degeneration of stented (n = 12, 80.0%) or stentless (n = 1, 6.7%) bioprosthetic aortic valves, or calcific stenosis of native aortic valves (n = 2, 13.3%), respectively. Individual risk of TAVI-induced coronary obstruction was assessed by pre-procedural computed tomography analysis. Procedural and 30-day outcomes were documented in accordance with Valve Academic Research Consortium (VARC)-2 criteria.ResultsBASILICA was attempted for single left coronary cusp in 12 patients (80.0%), for single right coronary cusp in 2 patients (13.3%), and for both cusps in 1 patient (6.7%), respectively. The procedure was feasible in 13 patients (86.7%) resulting in effective prevention of coronary obstruction, whilst TAVI was performed without prior successful bioprosthetic leaflet laceration in two patients (13.3%). In one of these patients (6.7%), additional chimney stenting immediately after TAVI was performed. No all-cause deaths or strokes were documented after 30 days.ConclusionThe BASILICA technique appears to be a feasible, safe and effective concept to avoid iatrogenic coronary artery obstruction during TAVI in both native and bioprosthetic valves of patients at high or prohibitive risk.ClinicalTrials.gov Identifier: NCT04227002 (Hamburg AoRtic Valve cOhoRt).

Both, the decreased L-type Ca2+ current (ICa,L) density and increased spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is linked to these compartment-specific changes (up- or down-regulation) in Ca2+-handling. Perforated patch-clamp experiments were performed in atrial myocytes from 53 patients with AF and 104 patients in sinus rhythm (Ctl). A significantly higher frequency of transient inward currents (ITI) activated by spontaneous Ca2+ release was confirmed in myocytes from AF patients. Next, inhibition of PKA by H-89 promoted a stronger effect on the ITI frequency in these myocytes compared to myocytes from Ctl patients (7.6-fold vs. 2.5-fold reduction), while the β-agonist isoproterenol (ISO) caused a greater increase in Ctl patients (5.5-fold vs. 2.1-fold). ICa,L density was larger in myocytes from Ctl patients at baseline (p < 0.05). However, the effect of ISO on ICa,L density was only slightly stronger in AF than in Ctl myocytes (3.6-fold vs. 2.7-fold). Interestingly, a significant reduction of ICa,L and Ca2+ sparks was observed upon Ca2+/Calmodulin-dependent protein kinase II inhibition by KN-93, but this inhibition had no effect on ITI. Fluorescence resonance energy transfer (FRET) experiments showed that although AF promoted cytosolic desensitization to β-adrenergic stimulation, ISO increased cAMP to similar levels in both groups of patients in the L-type Ca2+ channel and ryanodine receptor compartments. Basal cAMP signaling also showed compartment-specific regulation by phosphodiesterases in atrial myocytes from 44 Ctl and 43 AF patients. Our results suggest that AF is associated with opposite changes in compartmentalized PKA/cAMP-dependent regulation of ICa,L (down-regulation) and ITI (up-regulation).

BackgroundPatients with chronic hemodialysis due to end-stage renal disease (ESRD) or severely impaired kidney function (CKD) constitute a relevant share of patients undergoing trans-catheter aortic valve implantation (TAVI). However, data on specific challenges and outcomes remain limited.AimWe aimed to characterize this patient population, evaluate clinical results and assess the significance of calcification patterns.MethodsThis retrospective single-center analysis evaluated 2,712 TAVI procedures (2012–2019) according to baseline renal function: GFR < 30 ml/min/1.73m2 (CKD; n = 210), chronic hemodialysis (ESRD; n = 119) and control (CTRL; n = 2383). Valvular and vascular calcification patterns were assessed from contrast-enhanced multi-detector computed tomography. Outcomes were evaluated in accordance with the VARC-2 definitions.ResultsOperative risk was higher in ESRD and CKD vs. CTRL (STS-score 8.4% and 7.6% vs. 3.9%, p < 0.001) and patients with ESRD had more severe vascular calcifications (49.1% vs. 33.9% and 29.0%, p < 0.01). Immediate procedural results were similar but non-procedure-related major/life-threatening bleeding was higher in ESRD and CKD (5.0% and 5.3% vs. 1.6%, p < 0.01). 3-year survival was impaired in patients with ESRD and CKD (33.3% and 35.3% vs. 65.4%, p < 0.001). Multivariable analysis identified ESRD (HR 1.60), CKD (HR 1.79) and vascular calcifications (HR 1.29) as predictors for 3-year and vascular calcifications (HR 1.51) for 30-day mortality.ConclusionPatients with ESRD and CKD constitute a vulnerable patient group with extensive vascular calcifications. Immediate procedural results were largely unaffected by renal impairment, yielding TAVI a particularly valuable treatment option in these high-risk operative patients. Mid-term survival was determined by underlying renal disease, cardiovascular comorbidities, and vascular calcifications as a novel risk marker.

Background Blunt chest injury may induce several cardiovascular traumata, requiring immediate care. Right coronary artery dissection (RCA) is an extremely rare sequela in this setting and is associated with high mortality, if it remains undiagnosed. Case presentation We present the case of an RCA dissection after blunt chest trauma in a 16-year-old patient, who initially presented with a second-degree atrioventricular block as solitary manifestation on admission. Typical electrocardiographic findings, such as ST segmental changes or pathological Q waves were absent. Serial echocardiograms excluded segmental motion abnormalities, pericardial effusion or right ventricular strain. Nevertheless, a complementary computed tomography coronary angiography revealed this potentially lethal condition several hours later. The patient underwent an emergency surgical myocardial revascularization under the circulatory support of veno-arterial extracorporeal membrane oxygenation and suffered a prolonged right ventricular insufficiency with severe late-onset cardiogenic shock, due to an extensive myocardial infarction of the inferoseptal ventricular wall. Conclusion Right coronary artery dissection after high-speed blunt chest injury constitutes a diagnostic challenge, especially in the absence of typical electrocardiographic and echocardiographic findings in young patients. This condition may dramatically deteriorate in time, leading to severe cardiogenic shock and life-threatening arrhythmias.

Objectives: Several conditions associated with type A aortic dissection may require preoperative invasive mechanical ventilation (IMV). The current literature lacks data on this subset of patients’ prevalence and postoperative outcomes. This study aims to investigate this unexplored issue in a multicenter European registry. Methods: Data from 3735 patients included in the European Registry of Type A Aortic Dissection (ERTAAD) were the subject of this analysis. Bootstrapped Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression was performed for variable selection to identify key predictors of hospital death. In the second step, a multilevel multivariable logistic regression (MMLR) was carried out, given the clustered structure of the data. Results: A total of 346 (9.3%) out of 3735 patients required preoperative IMV. Compared to the non-IMV patients, patients requiring IMV had a significantly higher rate of organ malperfusion (52% vs. 35%, p < 0.001) and a higher proportion of tears in the aortic root (p = 0.048). The in-hospital mortality rate among IMV patients was 38% vs. 15% in non-IMV patients (p < 0.001), without a difference in post-discharge survival (p = 0.84). At the MMLR, patients who required IMV had 135% higher odds of in-hospital death compared to the remaining patients. IMV yielded the second highest odds in the prediction model for in-hospital mortality (OR 2.13, CI 1.60 to 2.85, p < 0.001). Among IMV patients, the extension of surgery to the aortic arch was significantly associated with increased in-hospital mortality (p < 0.001, OR 2.98). In multivariable analysis, preoperative IMV was independently associated with increased odds of in-hospital mortality. Conclusions: The need for invasive mechanical ventilation before surgical repair for type A aortic dissection is not infrequent. In this subpopulation, the in-hospital mortality rate was twofold compared to patients who did not require IMV. The awareness of the preoperative risk profile and outcomes of this subset of patients should urge surgeons to tailor the surgical strategy more appropriately to improve the immediate postoperative results.