Search

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. Methods: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan ( Bgn ), Tlr3 , and IFN-α/β receptor alpha chain ( Ifnar1 )–deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. Results: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn −/− , Tlr3 −/− , and Ifnar1 −/− mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1–BGN–TLR3–interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. Conclusions: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) of 30-50% undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [

The field of totally endoscopic, robotic-assisted mitral valve surgery has progressively gained popularity over the last twenty-five years. In this narrative review, we sought to discuss this expanding field from a historical perspective, a technical perspective, and a training perspective.

The long-term outcomes of mitral valve repair by nonresection techniques, such as annuloplasty and chordal replacement, for degenerative mitral valve regurgitation were investigated.All consecutive patients with degenerative mitral regurgitation who received solely chordal replacement and annuloplasty for mitral valve repair between 2003 and 2010 at the German Heart Center Munich were reviewed. The endpoints of this retrospective study were survival, cumulative incidence of reoperation on the mitral valve, and cumulative incidence of significant recurrent mitral regurgitation.A total of 346 patients were evaluated. The median follow-up period was 10.86 (range, 0.01-15.86) years. The 30-day mortality rate was 0.58% (n = 2 of 346), whereas the 5-year survival was 92.97% ± 1.41%. At 5 years, cumulative incidence of recurrent mitral regurgitation was 6.87% ± 1.57% and cumulative incidence of reoperation on the mitral valve was 3.69% ± 1.05%. Survival at 10 years was 83.35% ± 2.15%. At 10 years, cumulative incidence of recurrent mitral regurgitation was 13.31% ± 2.22% and cumulative incidence of reoperation was 7.84% ± 1.55%. Cox regression analysis identified age, diabetes mellitus, and reduced left ventricular ejection fraction55% as independent risk factors for death. Left ventricular ejection fraction55% was revealed as independent risk factor for significant recurrent mitral regurgitation.This study demonstrated excellent long-term outcomes with low incidence of reoperation after mitral valve repair using chordal replacement in a highly selected patient cohort. Our findings emphasized the importance of early intervention in severe degenerative mitral regurgitation, especially in patients with reduced left ventricular ejection fraction.

AIMS: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies.METHODS AND RESULTS: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers.CONCLUSIONS: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies.TRANSLATIONAL PERSPECTIVE: Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Robotic surgery has gained popularity over the past two decades due to the benefits related to smaller surgical incisions, enhanced technical dexterity and better intraoperative visualization. We present the Yale experience of the first two hundred totally endoscopic, robotic-assisted mitral valve repair procedures for the treatment of degenerative mitral regurgitation.We performed a retrospective cohort study of patients undergoing totally endoscopic, robotic-assisted isolated or concomitant mitral valve repair for degenerative mitral regurgitation at Yale-New Haven Hospital from October 2018 to April 2022. Mitral valve repair procedures for rheumatic or secondary functional mitral regurgitation and planned robotic-assisted mitral valve replacement cases were excluded.Two hundred consecutive procedures were performed. The median age was 65 years (interquartile range, 58-73 years). Six patients (3.0%) had a history of mediastinal radiation, four patients (2.0%) had previous cardiac surgery, and one patient (0.5%) had cardiac dextroversion. Median cardiopulmonary bypass and aortic cross-clamp times were 122 and 79 minutes, respectively. Femoral vessel cannulation was performed percutaneously in 57 (28.5%) patients with no major access-site related complication. Aortic cross-clamping was performed with the endoaortic balloon occlusion device in 151 (75.5%) patients. No conversions to sternotomy occurred. Satisfactory repair was achieved in 100% of cases, with 184 (92.0%) and 16 (8.0%) of patients having trace/none or mild residual mitral regurgitation, respectively. Forty-two patients (21.0%) underwent concomitant Cox-maze procedure and 25 patients (12.5%) underwent concomitant tricuspid valve repair. Thirty-day mortality rate was 0.5%, with an observed-to-expected ratio of 0.53. Two patients (1.0%) underwent re-exploration for bleeding, one had early postoperative stroke (0.5%), five developed pneumothorax (2.5%) and two required dialysis for acute renal failure (1.0%). The median length of hospital stay was four days.Excellent short-term outcomes can be achieved in experienced centers for the treatment of degenerative mitral regurgitation with a totally endoscopic, robotic-assisted approach.

ObjectiveThere is uncertainty about surgical procedures for adult patients aged 18–60 years undergoing aortic valve replacement (AVR). Options include conventional AVR (mechanical, mAVR; tissue, tAVR), the pulmonary autograft (Ross) and aortic valve neocuspidisation (Ozaki). Transcatheter treatment may be an option for selected patients. We used formal consensus methodology to make recommendations about the suitability of each procedure.MethodsA working group, supported by a patient advisory group, developed a list of clinical scenarios across seven domains (anatomy, presentation, cardiac/non-cardiac comorbidities, concurrent treatments, lifestyle, preferences). A consensus group of 12 clinicians rated the appropriateness of each surgical procedure for each scenario on a 9-point Likert scale on two separate occasions (before and after a 1-day meeting).ResultsThere was a consensus that each procedure was appropriate (A) or inappropriate (I) for all clinical scenarios as follows: mAVR: total 76% (57% A, 19% I); tAVR: total 68% (68% A, 0% I); Ross: total 66% (39% A, 27% I); Ozaki: total 31% (3% A, 28% I). The remainder of percentages to 100% reflects the degree of uncertainty. There was a consensus that transcatheter aortic valve implantation is appropriate for 5 of 68 (7%) of all clinical scenarios (including frailty, prohibitive surgical risk and very limited life span).ConclusionsEvidence-based expert opinion emerging from a formal consensus process indicates that besides conventional AVR options, there is a high degree of certainty about the suitability of the Ross procedure in patients aged 18–60 years. Future clinical guidelines should include the option of the Ross procedure in aortic prosthetic valve selection.

Aortic valve neocuspidization (AVNeo) for trileaflet aortic valve reconstruction using autologous pericardium (Ozaki procedure) depicts an encouraging new technique for the surgical treatment of aortic valve pathologies. The current study analyzes the early hemodynamic outcome of AVneo compared with surgical aortic valve replacement (SAVR) using the Abbott/St. Jude Trifecta aortic valve biological prostheses.All patients who underwent either AVNeo or SAVR between March 2017 and April 2020 were included. Exclusion criteria were emergency cases, endocarditis, redo- or additional root procedures. Main endpoints were differences between the two groups in terms of the effective orifice area (EOA) and the effective orifice area index (EOAI) at discharge.During the study period, 105 AVNeo patients and 458 SAVR patients met the inclusion criteria. EOA was significantly higher in the AVNeo group (2.4 cmAVNeo shows significantly larger EOA and EOAI compared to SAVR using the Abbott/St. Jude Trifecta aortic valve biological prostheses.

Isolated tricuspid valve endocarditis (TVE) is a rare disease which is managed medically in most patients. Only in specific cases, surgical intervention becomes necessary. Hence, data about surgical outcomes are sparse. This study reports on the operative experience in patients with isolated TVE over a period of 20 years.We retrospectively analyzed 32 patients with isolated TVE who underwent surgery from February 2001 to June 2021 at the German Heart Centre Munich.Thirty-day mortality was 3.1%. Overall survival was 89.9± 5.5% at 1 year and 76.9 ± 8.5% at 5 years. Cumulative incidence for reoperation was 11.1 ± 6.0% at 5 years. Four patients (12.5%) were treated for recurrent endocarditis. Tricuspid valve repair (TVr) was achieved in 16 patients (50%). If the subvalvular apparatus (n = 10) was involved, tricuspid valve replacement was performed more frequently.Mortality in patients with isolated TVE undergoing cardiac surgery is high. In half of the cases, TVr was achieved but was less likely in patients with affected subvalvular apparatus.

Background: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. Methods: We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rare variants of high imputation quality as validated by whole genome sequencing. Results: Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P =1.49×10 −8 ) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P =1.46×10 − 8 ) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9 . A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P =2.6×10 − 8 ) physically interacts with NCAM1 ( P FDR =1.86×10 − 27 ), a neural adhesion molecule acting in cardiac development. Importantly, while each individual malformation displayed substantial heritability (observed h2 ranging from 0.26 for complex malformations to 0.37 for left ventricular outflow tract obstructive disease) the risk for different CHD malformations appeared to be separate, without genetic correlation measured by linkage disequilibrium score regression or regional colocalization. Conclusions: We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation.

Atrial functional mitral regurgitation (AFMR) is a subtype of functional mitral regurgitation due to longstanding atrial fibrillation (AF) or heart failure with preserved ejection fraction. The variation in AFMR' definition and the common mode of treatment described in the literature remain unknown.We performed a scoping review of studies that surgically treated AFMR to characterize the existing variability in the definition of AFMR, the type of operations performed for AFMR valvulopathy, and the treatment for the chronic AF. We searched Medline, EMBASE, Cochrane Library, Scopus, and Web of Science since their inceptions for studies of patients affected by AFMR and surgically treated for their valvulopathy.Twelve studies (n = 494 patients) met eligibility criteria. All studies excluded patients with signs of left ventricular (LV) dysfunction, but the way additional parameters were used to define AFMR at a more granular level varied across studies: nine studies (75%) used the presence of AF to define their AFMR cohorts, with five (41.2%) requiring a history of AF of1 year; additionally, the threshold values for the LV ejection fraction differed (45%-55%). Isolated mitral annuloplasty was performed in 96.2% of patients. Broad variability was detected in the proportion of patients undergoing the Cox-Maze procedure (range, 17.8%-79.5%), pulmonary vein isolation (0.0%-66.7%), and left atrial appendage ligation (0.0%-100.0%).AFMR remains variably defined in surgical studies, making comparisons across studies difficult. Mitral annuloplasty was most commonly performed. The proportion of AFMR patients undergoing concomitant procedures for AF varied substantially.

Tricuspid regurgitation is common in patients with severe degenerative mitral regurgitation. However, the evidence base is insufficient to inform a decision about whether to perform tricuspid-valve repair during mitral-valve surgery in patients who have moderate tricuspid regurgitation or less-than-moderate regurgitation with annular dilatation.We randomly assigned 401 patients who were undergoing mitral-valve surgery for degenerative mitral regurgitation to receive a procedure with or without tricuspid annuloplasty (TA). The primary 2-year end point was a composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation by two grades from baseline or the presence of severe tricuspid regurgitation, or death.Patients who underwent mitral-valve surgery plus TA had fewer primary-end-point events than those who underwent mitral-valve surgery alone (3.9% vs. 10.2%) (relative risk, 0.37; 95% confidence interval [CI], 0.16 to 0.86; P = 0.02). Two-year mortality was 3.2% in the surgery-plus-TA group and 4.5% in the surgery-alone group (relative risk, 0.69; 95% CI, 0.25 to 1.88). The 2-year prevalence of progression of tricuspid regurgitation was lower in the surgery-plus-TA group than in the surgery-alone group (0.6% vs. 6.1%; relative risk, 0.09; 95% CI, 0.01 to 0.69). The frequencies of major adverse cardiac and cerebrovascular events, functional status, and quality of life were similar in the two groups at 2 years, although the incidence of permanent pacemaker implantation was higher in the surgery-plus-TA group than in the surgery-alone group (14.1% vs. 2.5%; rate ratio, 5.75; 95% CI, 2.27 to 14.60).Among patients undergoing mitral-valve surgery, those who also received TA had a lower incidence of a primary-end-point event than those who underwent mitral-valve surgery alone at 2 years, a reduction that was driven by less frequent progression to severe tricuspid regurgitation. Tricuspid repair resulted in more frequent permanent pacemaker implantation. Whether reduced progression of tricuspid regurgitation results in long-term clinical benefit can be determined only with longer follow-up. (Funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research; ClinicalTrials.gov number, NCT02675244.).

Mitral valve repair durability currently plays a key role in operative decision making and in defining optimal surgical practice. However, mitral valve durability outcomes measures are not captured by national registries and limited to centers that publish their outcomes. In this study, we aim to describe the scope of institutions represented by reports describing durability outcomes after mitral valve repair within the contemporary literature.A scoping review of the literature was performed to extract abstracts potentially reporting mitral valve operation outcomes published between 2000-2019. 370 full text articles reporting mitral valve durability outcomes by either reoperation rate or rate of recurrent mitral regurgitation met criteria for analysis. Study characteristics including case volume, country and institution of origin, and surgeon volume were extracted and used to calculate the proportion of total cases in the top 3, 5, and 10 represented countries and institutions by the sum of reported mitral valve repairs described. The top 5 of 21 countries represented 78.9% of the mitral valve repair cases described. The top 3 most represented institutions described 20,120 (37.3%) of all mitral valve repairs in 58 (33.9%) single-center studies.Published mitral valve repair durability data must be interpreted with caution when used to derive policies and practice recommendations that govern the cardiovascular community at large.

Objectives The aim of this study was to evaluate clinical characteristics, mechanisms of failure, and outcomes of transcatheter aortic valve replacement (TAVR) explantation. Background Surgical explantation following TAVR may be required for structural valve degeneration, paravalvular leak, infection, or other reasons. However, in-depth data on indications and outcomes are lacking. Methods Data from a multicenter, international registry (EXPLANT-TAVR) of patients who underwent TAVR explantation were reviewed retrospectively. Explantations performed during the same admission as initial TAVR were excluded. Clinical and echocardiographic outcomes were evaluated. Median follow-up duration was 6.7 months (interquartile range [IQR]: 1.0-18.8 months) after TAVR explantation and was 97.7% complete at 30 days and 86.1% complete at 1 year. Results From November 2009 to September 2020, 269 patients across 42 centers with a mean age of 72.7 ± 10.4 years underwent TAVR explantation. About one quarter (25.9%) were deemed low surgical risk at index TAVR, and median Society of Thoracic Surgeons risk at TAVR explantation was 5.6% (IQR: 3.2%-9.6%). The median time to explantation was 11.5 months (IQR: 4.0-32.4 months). Balloon-expandable and self-expanding or mechanically expandable valves accounted for 50.9% and 49.1%, respectively. Indications for explantation included endocarditis (43.1%), structural valve degeneration (20.1%), paravalvular leak (18.2%), and prosthesis-patient mismatch (10.8%). Redo TAVR was not feasible because of unfavorable anatomy in 26.8% of patients. Urgent or emergency cases were performed in 53.1% of patients, aortic root replacement in 13.4%, and 54.6% had concomitant cardiac procedures. Overall survival at last follow-up was 76.1%. In-hospital, 30-day, and 1-year mortality rates were 11.9%, 13.1%, and 28.5%, respectively, and stroke rates were 5.9%, 8.6%, and 18.7%, respectively. Conclusions The EXPLANT-TAVR registry reveals that surgical risks associated with TAVR explantation are not negligible and should be taken into consideration in the lifetime management of aortic stenosis.

Objectives The aim of this study was to determine clinical and echocardiographic characteristics, mechanisms of failure, and outcomes of mitral valve (MV) surgery after transcatheter edge-to-edge repair (TEER). Background Although >100,000 mitral TEER procedures have been performed worldwide, longitudinal data on MV surgery after TEER are lacking. Methods Data from the multicenter, international CUTTING-EDGE registry were retrospectively analyzed. Clinical and echocardiographic outcomes were evaluated. Median follow-up duration was 9.0 months (interquartile range [IQR]: 1.2-25.7 months) after MV surgery, and follow-up was 96.1% complete at 30 days and 81.1% complete at 1 year. Results From July 2009 to July 2020, 332 patients across 34 centers underwent MV surgery after TEER. The mean age was 73.8 ± 10.1 years, median Society of Thoracic Surgeons risk for MV repair at initial TEER was 4.0 (IQR: 2.3-7.3), and primary/mixed and secondary mitral regurgitation were present in 59.0% and 38.5%, respectively. The median interval from TEER to surgery was 3.5 months (IQR: 0.5-11.9 months), with overall median Society of Thoracic Surgeons risk of 4.8% for MV replacement (IQR: 2.8%-8.4%). The primary indication for surgery was recurrent mitral regurgitation (33.5%), and MV replacement and concomitant tricuspid surgery were performed in 92.5% and 42.2% of patients, respectively. The 30-day and 1-year mortality rates were 16.6% and 31.3%, respectively. On Kaplan-Meier analysis, the actuarial estimates of mortality were 24.1% at 1 year and 31.7% at 3 years after MV surgery. Conclusions In this first report of the CUTTING-EDGE registry, the mortality and morbidity risks of MV surgery after TEER were not negligible, and only

Current guidelines recommend intervention in subjects with severe symptomatic aortic stenosis (AS), even though any degree of AS is associated with a higher risk of mortality. We investigated the association between the degree of AS, delineated by transvalvular flow velocity, and patient morbidity and mortality.Medically managed patients aged 40-95 years with maximum flow velocity (VThe VA direct, strong correlation exists between the degree of AS and cardiac structural changes and mortality. Patients with V

OBJECTIVES Calcified or fibrotic cusps in patients with bicuspid aortic valves and aortic regurgitation complicate successful aortic valve (AV)-repair. Aortic valve neocuspidization (AVNeo) with autologous pericardium offers an alternative treatment to prosthetic valve replacement. We compared patients with regurgitant bicuspid valves undergoing AV-repair or AVNeo. METHODS We retrospectively analysed patients with regurgitant bicuspid valves undergoing AV-repair or AVNeo. We focused on residual regurgitation, pressure gradients and effective orifice area, determined preoperatively and at discharge. RESULTS AV-repair was performed in 61 patients (mean age: 43.2 ± 11.3 years) and AVNeo in 22 (45.7 ± 14.1). Prior to the operation patients of the AV-repair group showed severe regurgitation in 38 cases (62.3%) and moderate in 23 (37.6%); in the AVNeo group, all patients exhibited severe regurgitation. Postoperatively, 57 patients (93.4%) patients had no or mild regurgitation after AV-repair and 21 (95.4%) after AVNeo. In AVNeo-patients, peak (10.6 ± 3.1 mmHg vs 22.7 ± 11 mmHg, P CONCLUSIONS Compared to AV-repair, patients AVNeo showed lower mean pressure gradients and larger orifice areas at discharge. The functional result was not different.

The heart is a heterocellular organ consisting of several cell types including cardiomyocytes. Cell-type specific gene expression and response to stimuli is modulated by active distal regulatory elements termed enhancers. Cardiac enhancers are enriched for disease-associated variants and spatially interact with distal target promoters. However, enhancer-promoter interactions and spatial chromatin organization of human adult cardiac myocytes have not been analyzed so far limiting the interpretation of disease-associated regulatory elements in these cells. Here we generated high resolution spatial chromatin interaction data for atrial, left ventricular and failing human adult cardiac myocytes and identified cell-type specific interaction signatures. An integrative analysis with comprehensive epigenetic data reveals cardiac myocyte-specific, chamber-specific and disease-relevant enhancer-promoter interactions in cardiac myocytes. We further identified the cardiac disease risk association of promoter-interacting versus non-interacting enhancers and experimentally proofed the functional importance of enhancers harboring long QT risk loci. Our data shows that decoding cell type-specific regulatory elements and their interacting promoters provides insights into regulatory mechanisms essential for cell function and genetic risk factors as demonstrated here for human cardiac myocytes. This data will facilitate the interpretation of non-coding genetic risk factors in future genome-wide association studies. These data will allow predicting whether non-coding genetic variants promote disease in adult cardiac myocytes or not.