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1.
JTCVS Open ; 18: 52-63, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38690412

RESUMEN

Objective: Ischemic mitral regurgitation is prevalent and associated with high surgical risk. With the less-invasive option of transcatheter edge-to-edge repair, the optimal patient selection for mitral valve operation for ischemic mitral regurgitation remains unclear. We sought to identify high-risk features in this group to guide patient selection. Methods: Using the Cardiothoracic Surgery Trial Network's severe ischemic mitral regurgitation trial data, we identified patient and echocardiographic characteristics associated with an increased risk of 2-year mortality using the support vector classifier and Cox proportional hazards model. We identified 6 high-risk features associated with 2-year survival. Patients were categorized into 3 groups, each having 1 or less, 2, or 3 or more of the 6 identified high-risk features. Results: Among the 251 patients, the median age was 69 (Q1 62, Q3 75) years, and 96 (38%) were female. Two-year mortality was 21% (n = 53). We identified 6 high-risk preoperative features: age 75 years or more (n = 69, 28%), prior sternotomy (n = 49, 20%), renal insufficiency (n = 69, 28%), gastrointestinal bleeding (n = 15, 6%), left ventricular ejection fraction less than 40% (n = 131, 52%), and ventricular end-systolic volume index less than 50 mL/m2 (n = 93, 37%). In patients who had 1 or less, 2, and 3 or more high-risk features, 90-day mortality was 4.2% (n = 5), 9.9% (n = 4), and 20.0% (n = 10), respectively (P = .006), and 2-year mortality was 10% (n = 12), 22% (n = 18), and 46% (n = 23) (P < .001), respectively. Conclusions: We developed the 3-strike score by identifying high-risk preoperative features for mitral valve surgery for ischemic mitral regurgitation. Patients having 3 or more of such high-risk features should undergo careful evaluation for surgical candidacy given the high early and late mortality after mitral valve operations.

2.
N Engl J Med ; 390(17): 1572-1583, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38588025

RESUMEN

BACKGROUND: Among low-risk patients with severe, symptomatic aortic stenosis who are eligible for both transcatheter aortic-valve implantation (TAVI) and surgical aortic-valve replacement (SAVR), data are lacking on the appropriate treatment strategy in routine clinical practice. METHODS: In this randomized noninferiority trial conducted at 38 sites in Germany, we assigned patients with severe aortic stenosis who were at low or intermediate surgical risk to undergo either TAVI or SAVR. Percutaneous- and surgical-valve prostheses were selected according to operator discretion. The primary outcome was a composite of death from any cause or fatal or nonfatal stroke at 1 year. RESULTS: A total of 1414 patients underwent randomization (701 to the TAVI group and 713 to the SAVR group). The mean (±SD) age of the patients was 74±4 years; 57% were men, and the median Society of Thoracic Surgeons risk score was 1.8% (low surgical risk). The Kaplan-Meier estimate of the primary outcome at 1 year was 5.4% in the TAVI group and 10.0% in the SAVR group (hazard ratio for death or stroke, 0.53; 95% confidence interval [CI], 0.35 to 0.79; P<0.001 for noninferiority). The incidence of death from any cause was 2.6% in the TAVI group and 6.2% in the SAVR group (hazard ratio, 0.43; 95% CI, 0.24 to 0.73); the incidence of stroke was 2.9% and 4.7%, respectively (hazard ratio, 0.61; 95% CI, 0.35 to 1.06). Procedural complications occurred in 1.5% and 1.0% of patients in the TAVI and SAVR groups, respectively. CONCLUSIONS: Among patients with severe aortic stenosis at low or intermediate surgical risk, TAVI was noninferior to SAVR with respect to death from any cause or stroke at 1 year. (Funded by the German Center for Cardiovascular Research and the German Heart Foundation; DEDICATE-DZHK6 ClinicalTrials.gov number, NCT03112980.).


Asunto(s)
Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Femenino , Humanos , Masculino , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/mortalidad , Prótesis Valvulares Cardíacas , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Implantación de Prótesis de Válvulas Cardíacas/mortalidad , Estimación de Kaplan-Meier , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/instrumentación , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Factores de Riesgo , Alemania
3.
EuroIntervention ; 20(5): e281-e288, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38436368

RESUMEN

BACKGROUND: Data comparing transcatheter mitral valve implantation (TMVI) with surgical mitral valve replacement (SMVR) are lacking. AIMS: This study sought to compare the 30-day Valve Academic Research Consortium (VARC)-3 device success of TMVI with that of SMVR. METHODS: Matching protocol combined exact matching (sex, atrial fibrillation, previous surgical aortic valve replacement [SAVR] or coronary artery bypass grafting [CABG]), coarsened exact matching (age) and propensity score matching (body mass index, mitral valve pathology and concomitant tricuspid regurgitation). RESULTS: A total of 40 Tendyne TMVI and 80 SMVR patients with similar baseline characteristics were analysed (TMVI vs SMVR): age (78 years [interquartile range [{IQR} 75; 80] vs 78 years [IQR 73; 80]; p=0.8), female (60% vs 60%; p=1.0), atrial fibrillation (67.5% vs 63.7%; p=0.8), previous SAVR (12.5% vs 10.0%; p=0.8), previous CABG (20.0% vs 16.2%; p=0.8), body mass index (25.54 kg/m² vs 25.24 kg/m²; p=0.7) and valve pathology (mitral regurgitation: 70.0% vs 73.8%, mitral stenosis: 7.5% vs 3.8%, and mixed disease: 22.5% vs 22.5%; p=0.6). Most baseline characteristics not included in the matching model were balanced among the TMVI/SMVR cohorts: European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (5.8% [IQR 2.9; 7.5] vs 4.2% [IQR 2.4; 6.8]; p=0.3) and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score (5.2% [IQR 3.2; 8.6] vs 4.1% [IQR 3.3; 6.1]; p=0.076). Coronary artery disease (67.5% vs 32.5%; p<0.001) and previous percutaneous coronary intervention (47.5% vs 25.0%; p=0.023) differed among groups. Mitral VARC (MVARC) device success at 30 days was achieved in 82.5% of patients after TMVI and 57.5% of patients after SMVR (p=0.04). MVARC procedural success at 30 days was 75.0% after TMVI versus 52.5% after SMVR (p=0.07). Thirty-day mortality (2.5% vs 3.8%; p=0.47), technical success (97.5% vs 97.5%; p=1.0), major bleeding (17.5% vs 18.7%; p=0.087), stroke (5.0% vs 4.9%; p=1.0) and postoperative haemodialysis (7.5% vs 5.2%; p=0.4) were similar in both groups. CONCLUSIONS: Patients with intermediate surgical risk, according to STS-PROM and EuroSCORE II, demonstrated higher rates of MVARC device at 30 days after TMVI compared to 30 days after SMVR. Rates of survival and procedural success, neurological, renal and bleeding complications were similar. Transfusion count and length of stay were lower after TMVI. For elderly patients at intermediate risk, a TMVI eligibility assessment may be considered.


Asunto(s)
Fibrilación Atrial , Insuficiencia de la Válvula Mitral , Estenosis de la Válvula Mitral , Cirujanos , Anciano , Humanos , Femenino , Válvula Mitral/cirugía , Fibrilación Atrial/cirugía , Insuficiencia de la Válvula Mitral/cirugía
4.
J Am Heart Assoc ; 13(9): e033324, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38390804

RESUMEN

BACKGROUND: Multidisciplinary heart team (HT) evaluation is recommended for patients with severe primary mitral regurgitation to optimize treatment decisions. However, its impact on patient outcomes remains unknown. We evaluated the impact of implementing mitral HT on patient survival. METHODS AND RESULTS: We conducted a retrospective cohort study of patients with new diagnoses of severe primary mitral regurgitation in a large healthcare network echocardiogram database between 2016 and 2020. We compared the incidence of multidisciplinary evaluation by structural cardiology and cardiac surgery services and 2-year survival before and after mitral HT implementation. The 1:1 propensity-score matching between pre- and post-mitral HT used Society of Thoracic Surgeons Predicted Risk of Mortality for mitral repair, age, sex, race, heart failure symptoms, inpatient setting, history of MI, and dementia as covariates. Logistic regression identified variables associated with the likelihood of undergoing multidisciplinary evaluation. Among 70 510 echocardiograms performed, 391 patients had severe primary mitral regurgitation (median age, 77 years; 46% women). Multidisciplinary evaluation increased from 29% to 89% (P<0.001), and intervention increased from 24% to 75% following mitral HT implementation (P<0.001). Among 180 propensity-score matched patients, mortality was lower post-mitral HT at 2 years (19% versus 32%, P=0.04). The multivariable model showed that mitral HT implementation and heart failure symptoms were associated with higher odds of undergoing multidisciplinary evaluation (OR [odds ratio], 18.7 and 2.72, respectively), whereas female sex and older age were associated with lower odds (OR, 0.39 and 0.93, respectively). CONCLUSIONS: Implementation of mitral HT was associated with drastic improvement in multidisciplinary evaluation for patients with severe primary mitral regurgitation. This coincided with higher proportions of patients undergoing mechanical correction of MR and improved overall patient survival.


Asunto(s)
Insuficiencia de la Válvula Mitral , Grupo de Atención al Paciente , Humanos , Insuficiencia de la Válvula Mitral/mortalidad , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Femenino , Masculino , Anciano , Estudios Retrospectivos , Grupo de Atención al Paciente/organización & administración , Índice de Severidad de la Enfermedad , Ecocardiografía , Anciano de 80 o más Años , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Válvula Mitral/fisiopatología , Puntaje de Propensión , Tasa de Supervivencia/tendencias
6.
Ann Thorac Surg ; 117(1): 96-104, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37595861

RESUMEN

BACKGROUND: Contemporary national utilization and comparative safety data of robotic mitral valve repair for degenerative mitral regurgitation compared with nonrobotic approaches are lacking. The study aimed to characterize national trends of utilization and outcomes of robotic mitral repair of degenerative mitral regurgitation compared with sternotomy and thoracotomy approaches. METHODS: Patients undergoing intended mitral repair of degenerative mitral regurgitation in The Society of Thoracic Surgeons Adult Cardiac Surgery Database between 2015 and 2021 were examined. Mitral repair was performed in 61,322 patients. Descriptive analyses characterized center-level volumes and outcomes. Propensity score matching separately identified 5540 pairs of robotic vs thoracotomy approaches and 6962 pairs of robotic vs sternotomy approaches. Outcomes were operative mortality, composite mortality and major morbidity, postoperative length of stay, and conversion to mitral replacement. RESULTS: Through the 7-year study period, 116 surgeons across 103 hospitals performed mitral repair robotically. The proportion of robotic cases increased from 10.9% (949 of 8712) in 2015 to 14.6% (1274 of 8730) in 2021. In both robotic-thoracotomy and robotic-sternotomy matched pairs, mortality and morbidity were not significantly different, whereas the robotic approach had lower conversion (1.2% vs 3.1% for robotic-thoracotomy and 1.0% vs 3.7% for robotic-sternotomy), shorter length of stay, and fewer 30-day readmissions. Mortality and morbidity were lower at higher-volume centers, crossing the national mean mortality and morbidity at a cumulative robotic mitral repair case of 40. CONCLUSIONS: Robotic mitral repair is a safe and effective approach and is associated with comparable mortality and morbidity, a lower conversion rate, a shorter length of stay, and fewer 30-day readmissions than thoracotomy or sternotomy approaches.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Insuficiencia de la Válvula Mitral , Procedimientos Quirúrgicos Robotizados , Adulto , Humanos , Insuficiencia de la Válvula Mitral/cirugía , Válvula Mitral/cirugía , Resultado del Tratamiento , Esternotomía , Procedimientos Quirúrgicos Mínimamente Invasivos , Estudios Retrospectivos
7.
Stem Cell Res ; 74: 103261, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38100916

RESUMEN

The identification of TBX5-related regulatory sequences in genes essential for heart development is hampered by the absence of antibodies which allow precipitation of TBX5:DNA complexes. Employing CRISPR/Cas9 technology, we have inserted a FLAG-tag sequence at the end of exon 9 of the TBX5 gene prior to the stop codon by homologous recombination. The translated TBX5-FLAG fusion protein of the three iPSC lines can effectively be precipitated by anti-FLAG antibodies and, thus, allow the detection of specific TBX5-binding sites and their associated genes.


Asunto(s)
Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes Inducidas/metabolismo , Sistemas CRISPR-Cas/genética , Recombinación Homóloga , Exones/genética
13.
Front Cardiovasc Med ; 10: 1252163, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37727303

RESUMEN

Background: Data comparing new-generation self-expandable (SEV, Evolut R/PRO) vs. balloon-expandable (BEV, SAPIEN 3/3Ultra) transcatheter heart valve replacement (TAVR) in bicuspid aortic valve stenosis (BAV) is limited. Our aim was to compare 30-day results of SEV and BEV implantations in patients with BAV. Methods: A total of 2009 patients underwent TAVR between April 2015 and June 2021 at our Centre. From our institutional registry, we identified 106 consecutive patients with BAV who underwent TAVR using SEV and BEV. Results: A 106 patients (n = 68 BEV; n = 38 SEV) were included. Mean age was 74.6 ± 8.8 years (BEV) vs.75.3 ± 8.7 years (SEV) (p = 0.670) and Society of Thoracic Surgeons score was 2.6 ± 1.9 (BEV) vs. 2.6 ± 1.6 (SEV) (p = 0.374), respectively. Device landing zone calcium volume (DLZ-CV) was 1168 ± 811 vs. 945 ± 850 mm3 (p = 0.192). Valve Academic Research Consortium (VARC)-3 device success at 30 days was similar (BEV 80.9% vs. SEV 86.8%; p = 0.433). More post-dilatations were performed in SEVs (23.5% BEV vs. 52.6% SEV; p = 0.002). Overall mean gradient at 30 days follow-up was 11.9 ± 4.6 mmHG (BEV) vs. 9.2 ± 3.0 mmHG (SEV) (p = 0.002). A mild-moderate degree of paravalvular leak (PVL) was detected more often in the SEV group (7.4% vs. 13.2%; p = 0.305). A trend towards higher rate of permanent pacemaker implantation was observed in SEV (11.8% vs. 23.7%; p = 0.109). Conclusions: Treatment of BAV revealed similar performance using BEV and SEV. In this retrospective cohort study, hemodynamics were more favorable with the SEV, although there was a trend toward more PVL and significantly more post-dilations.

14.
Dis Model Mech ; 16(5)2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37272385

RESUMEN

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT (EHTIm) patches can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHTIm (15×106 cells) were transplanted within hours after casting. Cryo-injury led to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence of improvement of left-ventricular function after EHTIm transplantation. In a small translational proof-of-concept study, human scale EHTIm patches (4.5×108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHTIm patches, i.e. without precultivation, is feasible, with similar engraftment results to those obtained using matured EHT.


Asunto(s)
Corazón , Miocitos Cardíacos , Humanos , Cobayas , Animales , Ventrículos Cardíacos , Ecocardiografía , Ingeniería de Tejidos/métodos , Diferenciación Celular , Miocardio
15.
Heart ; 109(18): 1394-1400, 2023 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-37376817

RESUMEN

OBJECTIVE: Ventricular secondary mitral regurgitation (SMR) (Carpentier type IIIb) results from left ventricular (LV) remodelling, displacement of papillary muscles and tethering of mitral leaflets. The most appropriate treatment approach remains controversial. We aimed to assess the safety and efficacy of standardised relocation of both papillary muscles (subannular repair) at 1-year follow-up (FU). METHODS: REFORM-MR (Reform-Mitral Regurgitation) is a prospective, multicentre registry that enrolled consecutive patients with ventricular SMR (Carpentier type IIIb) undergoing standardised subannular mitral valve (MV) repair in combination with annuloplasty at five sites in Germany. Here, we report survival, freedom from recurrence of MR >2+, freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiovascular death, myocardial infarction, stroke, MV reintervention and echocardiographic parameters of residual leaflet tethering at 1-year FU. RESULTS: A total of 94 patients (69.1% male) with a mean age of 65.1±9.7 years met the inclusion criteria. Advanced LV dysfunction (mean left ventricular ejection fraction 36.4±10.5%) and severe LV dilatation (mean left ventricular end-diastolic diameter 61.0±9.3 mm) resulted in severe mitral leaflet tethering (mean tenting height 10.6±3.0 mm) and an elevated mean EURO Score II of 4.8±4.6 prior to surgery. Subannular repair was successfully performed in all patients, without operative mortality or complications. One-year survival was 95.5%. At 12 months, a durable reduction of mitral leaflet tethering resulted in a low rate (4.2%) of recurrent MR >2+. In addition to a significant improvement in New York Heart Association (NYHA) class (22.4% patients in NYHA III/IV vs 64.5% patients at baseline, p<0.001), freedom from MACCE was observed in 91.1% of patients. CONCLUSIONS: Our study demonstrates the safety and feasibility of standardised subannular repair to treat ventricular SMR (Carpentier type IIIb) in a multicentre setting. By addressing mitral leaflet tethering, papillary muscle relocation results in very satisfactory 1-year outcomes and has the potential to durably restore MV geometry; nevertheless, long-term FU is mandatory. TRIAL REGISTRATION NUMBER: NCT03470155.


Asunto(s)
Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anuloplastia de la Válvula Mitral/efectos adversos , Anuloplastia de la Válvula Mitral/métodos , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/etiología , Insuficiencia de la Válvula Mitral/cirugía , Estudios Prospectivos , Volumen Sistólico , Sístole , Resultado del Tratamiento , Función Ventricular Izquierda
16.
Stem Cell Res ; 70: 103126, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37253295

RESUMEN

TBX5 is a transcription factor which plays an essential role at different checkpoints during cardiac differentiation. However, regulatory pathways affected by TBX5 still remain ill-defined. We have applied the CRISPR/Cas9 technology using a completely plasmid-free approach to correct a heterozygous causative "loss-of function" TBX5 mutation in an iPSC line (DHMi004-A), that has been established from a patient suffering from Holt-Oram syndrome (HOS). This isogenic iPSC line, DHMi004-A-1, represents a powerful in vitro tool to dissect the regulatory pathways affected by TBX5 in HOS.

17.
Adv Healthc Mater ; 12(26): e2300904, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37229536

RESUMEN

Here, the study presents a thermally activated cell-signal imaging (TACSI) microrobot, capable of photothermal actuation, sensing, and light-driven locomotion. The plasmonic soft microrobot is specifically designed for thermal stimulation of mammalian cells to investigate cell behavior under heat active conditions. Due to the integrated thermosensitive fluorescence probe, Rhodamine B, the system allows dynamic measurement of induced temperature changes. TACSI microrobots show excellent biocompatibility over 72 h in vitro, and they are capable of thermally activating single cells to cell clusters. Locomotion in a 3D workspace is achieved by relying on thermophoretic convection, and the microrobot speed is controlled within a range of 5-65 µm s-1 . In addition, light-driven actuation enables spatiotemporal control of the microrobot temperature up to a maximum of 60 °C. Using TACSI microrobots, this study targets single cells within a large population, and demonstrates thermal cell stimulation using calcium signaling as a biological output. Initial studies with human embryonic kidney 293 cells indicate a dose dependent change in intracellular calcium content within the photothermally controlled temperature range of 37-57 °C.


Asunto(s)
Robótica , Animales , Humanos , Robótica/métodos , Rayos Láser , Calor , Mamíferos
18.
Circulation ; 147(20): 1518-1533, 2023 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-37013819

RESUMEN

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/ß 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/ß 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.


Asunto(s)
Estenosis de la Válvula Aórtica , Calcinosis , Adulto , Animales , Humanos , Ratones , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/patología , Biglicano/metabolismo , Calcinosis/metabolismo , Células Cultivadas , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Pez Cebra
19.
Circ Genom Precis Med ; 16(3): 258-266, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37026454

RESUMEN

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 (PFDR=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.


Asunto(s)
Cardiopatías Congénitas , Humanos , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Fenotipo , Frecuencia de los Genes , Secuenciación Completa del Genoma , Cromatina , Proteínas Adaptadoras Transductoras de Señales/genética
20.
Int J Surg ; 109(4): 707-715, 2023 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-36912566

RESUMEN

OBJECTIVES: The objective of the European Multicenter Registry to Assess Outcomes in coronary artery bypass grafting (CABG) patients (DuraGraft Registry) was to determine clinical outcomes and quality of life (QoL) after contemporary CABG that included isolated CABG and combined CABG/valve procedures, using an endothelial damage inhibitor (DuraGraft) intraoperatively for conduit preservation. Here, we report outcomes in the patient cohort undergoing isolated CABG. METHODS: The primary outcome was the composite of all-cause death, myocardial infarction (MI), or repeat revascularization (RR) [major adverse cardiac events (MACE)] at 1 year. Secondary outcomes included the composite of all-cause death, MI, RR, or stroke [major adverse cardiac and cerebrovascular events (MACCE)], and QoL. QoL was assessed with the EuroQol-5 Dimension questionnaire. Independent risk factors for MACE at 1 year were determined using Cox regression analysis. RESULTS: A total of 2532 patients (mean age, 67.4±9.2 years; 82.5% male) underwent isolated CABG. The median EuroScore II was 1.4 [interquartile range (IQR), 0.9-2.3]. MACE and MACCE rates at 1 year were 6.6% and 7.8%, respectively. The rates of all-cause death, MI, RR, and stroke were 4.4, 2.0, 2.2, and 1.9%, respectively. The 30-day mortality rate was 2.3%. Age, extracardiac arteriopathy, left ventricular ejection fraction less than 50%, critical operative state, and left main disease were independent risk factors for MACE. QoL index values improved from 0.84 [IQR, 0.72-0.92] at baseline to 0.92 [IQR, 0.82-1.00] at 1 year ( P <0.0001). CONCLUSION: Contemporary European patients undergoing isolated CABG have a low 1-year clinical event rate and an improved QoL.


Asunto(s)
Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Calidad de Vida , Estudios Prospectivos , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular Izquierda , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/métodos , Enfermedad de la Arteria Coronaria/cirugía , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Accidente Cerebrovascular/etiología
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