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The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-nonhuman primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pigs with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes), whose hearts and kidneys have now been studied in preclinical human xenotransplantation models with brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed with hearts from this 10 GE pig at the University of Maryland. Although this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.
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Animales Modificados Genéticamente , Trasplante Heterólogo , Animales , Trasplante Heterólogo/métodos , Humanos , Porcinos , Ingeniería Genética/métodos , Trasplante de Corazón/métodosRESUMEN
While studying the aortic valve in isolation has facilitated the development of life-saving procedures and technologies, the dynamic interplay of the aortic valve and its surrounding structures is vital to preserving their function across the wide range of conditions encountered in an active lifestyle. Our view is that these structures should be viewed as an integrated functional unit, herein referred to as the aortic valve apparatus (AVA). The coupling of the aortic valve and root, left ventricular outflow tract, and blood circulation is crucial for AVA's functions: unidirectional flow out of the left ventricle, coronary perfusion, reservoir function, and supporting left ventricular function. In this review, we explore the multiscale biological and physical phenomena that underly the simultaneous fulfilment of these functions. A brief overview of the tools used to investigate the AVA is included, such as: medical imaging modalities, experimental methods, and computational modelling, specifically fluid-structure interaction (FSI) simulations, is included. Some pathologies affecting the AVA are explored, and insights are provided on treatments and interventions that aim to maintain quality of life. The concepts explained in this paper support the idea of AVA being an integrated functional unit and help identify unanswered research questions. Incorporating phenomena through the molecular, micro, meso and whole tissue scales is crucial for understanding the sophisticated normal functions and diseases of the AVA.
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Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Femenino , Masculino , Humanos , Adulto , Penetrancia , Cardiomiopatías/genética , Cardiomiopatía Dilatada/genética , Frecuencia de los GenesRESUMEN
Myocardial infarction (MI) is characterized by a significant loss of cardiomyocytes (CMs), and it is suggested that reactive oxygen species (ROS) are involved in cell cycle arrest, leading to impaired CM renewal. Thioredoxin-1 (Trx-1) scavenges ROS and may play a role in restoring CM renewal. However, the truncated form of Trx-1, Trx-80, can compromise its efficacy by exerting antagonistic effects. Therefore, a Trx-1 mimetic peptide called CB3 was tested as an alternative way to restore CMs. This study aimed to investigate the effects of Trx-1, Trx-80, and CB3 on mice with experimental MI and study the underlying mechanism of CB3 on CMs. Mouse cardiac parameters were quantified by echocardiography, and infarction size and fibrosis determined using Trichrome and Picro-Sirius Red staining. The study found that Trx-1 and CB3 improved mouse cardiac function, reduced the size of cardiac infarct and fibrosis, and decreased the expression of cardiac inflammatory markers. Furthermore, CB3 polarized macrophages into M2 phenotype, reduced apoptosis and oxidative stress after MI, and increased CM proliferation in cell culture and in vivo. CB3 effectively protected against myocardial infarction and could represent a new class of compounds for treating MI.
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Infarto del Miocardio , Tiorredoxinas , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Tiorredoxinas/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Péptidos/metabolismo , Apoptosis , Fibrosis , Remodelación Ventricular , Miocardio/metabolismo , Modelos Animales de EnfermedadRESUMEN
Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten [273, 54.3%] vs placebo [230, 45.7%] adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI [1.28, 2.88]), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI [1.66, 2.67]), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI [0.21, 0.40], p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI [4.80, 11.37], P < 0.00001) troponin levels and N-terminal pro-B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events. Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.
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Cardiomiopatía Hipertrófica , Humanos , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/fisiopatología , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/efectos adversos , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , BencilaminasRESUMEN
Half a century after the first pulmonary autograft operation (Ross operation), performed in 1967 by Donald Ross in central London, there is a very strong conviction that the Ross operation is the best available valve substitute today, not only for children, but also for younger and older adults. The Ross operation has stimulated a lot of science to do with tissue-engineering and biology of heart valves, which is a promising avenue for the future. For one of us (M.Y.), it has certainly been a privilege to be associated with the comeback of the Ross operation.
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Insuficiencia de la Válvula Aórtica , Estenosis de la Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Válvula Pulmonar , Niño , Humanos , Anciano , Autoinjertos/cirugía , Válvula Pulmonar/cirugía , Trasplante Autólogo , Reoperación , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/cirugía , Resultado del TratamientoRESUMEN
AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls. METHODS AND RESULTS: Prospective Egyptian patients (n = 514) and controls (n = 400) underwent clinical phenotyping and genetic testing. Rare variants in 13 validated HCM genes were classified according to standard clinical guidelines and compared with a prospective HCM cohort of majority European ancestry (n = 684). A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10-7), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (five-fold greater than European patients), highlighting the importance of recessive inheritance in consanguineous populations. Finally, rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10-5) due to the underrepresentation of Middle Eastern populations in current reference resources. This proportion increased to 53.3% after incorporating methods that leverage new ancestry-matched controls presented here. CONCLUSION: Studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.
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Cardiomiopatía Hipertrófica , Etnicidad , Humanos , Consanguinidad , Estudios Prospectivos , Pruebas Genéticas , Cardiomiopatía Hipertrófica/diagnóstico , MutaciónRESUMEN
Calcific aortic valve disease affects the aortic side of the valve, exposed to low magnitude multidirectional ("disturbed) blood flow, more than it affects the ventricular side, exposed to high magnitude uniaxial flow. Overt disease is preceded by endothelial dysfunction and inflammation. Here we investigate the potential role of the transforming growth factor-ß (TGF-ß) receptor ALK5 in this process. Although ECs are always subject to shear stress due to blood flow, and their responses to shear stress are important in healthy valve development and homeostasis, low magnitude multidirectional flow can induce pathophysiological changes. Previous work has shown ALK5 to be an important mechanosensor. ALK5 transduces mechanically sensed signals via the activation of the SMAD2/3 transcriptional modulators. However, it is currently unclear precisely how ALK5-mediated shear stress responses translate into pathological changes under conditions of chronically disturbed flow. Here, we demonstrate that ALK5 mechanosensory signalling influences flow-induced endothelial leukocyte adhesion and paracellular permeability. Low magnitude multidirectional flow resulted in downregulation of the receptor, accompanied by increased SMAD2 phosphorylation, in human umbilical vein endothelial cell (HUVEC) monolayers. These changes correlated with elevated monocyte adhesion and significantly increased transendothelial transport of an albumin-sized tracer. These effects were abolished by inhibition of ALK5 kinase activity. Analysis of ALK5 expression patterns in porcine aortic valve tissue corroborated the findings from cell-based experiments. Together, these results suggest that ALK5 has a role in shear stress-associated cardiovascular disease pathology, emphasising the importance of further mechanistic investigations and supporting it as a potential therapeutic target.
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Proteínas Serina-Treonina Quinasas , Receptores de Factores de Crecimiento Transformadores beta , Animales , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , PorcinosRESUMEN
Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Ventrículos Cardíacos , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar , Estudios Retrospectivos , Disfunción Ventricular Derecha/tratamiento farmacológico , Función Ventricular DerechaRESUMEN
RNS60 is a physically modified saline solution hypothesized to contain oxygen nanobubbles. It has been reported to reduce ischemia/reperfusion injury in a pig model of acute myocardial infarction. We investigated the effects of RNS60 during cardiac hypoxia in mice and as an additive to cardioplegic solution in rat hearts. ApoE-/-LDLr-/- mice were treated by intravenous injection of RNS60 or saline as a control while monitoring the ECG and post-hypoxic serum release of troponin T and creatine kinase activity. Hearts infused with Custodiol containing 10% RNS60 or saline as the control were subjected to 4 h of 4 °C preservation, followed by an assessment of myocardial metabolites, purine release, and mechanical function. RNS60 attenuated changes in the ECG STU area during hypoxia, while the troponin T concentration and creatine kinase activity were significantly higher in the serum of the controls. During reperfusion after 4 h of cold ischemia, the Custodiol/RNS60-treated hearts had about 30% lower LVEDP and better dp/dtmax and dp/dtmin together with a decreased release of purine catabolites vs. the controls. The myocardial ATP, total adenine nucleotides, and phosphocreatine concentrations were higher in the RNS60-treated hearts. This study indicates that RNS60 enhances cardioprotection in experimental myocardial hypoxia and under conditions of cardioplegic arrest. Improved cardiac energetics are involved in the protective effect, but complete elucidation of the mechanism requires further study.
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LVAD therapy is an effective rescue in acute and especially chronic cardiac failure. In several scenarios, it provides a platform for regeneration and sustained myocardial recovery. While unloading seems to be a key element, pharmacotherapy may provide powerful tools to enhance effective cardiac regeneration. The synergy between LVAD support and medical agents may ensure satisfying outcomes on cardiomyocyte recovery followed by improved quality and quantity of patient life. This review summarizes the previous and contemporary strategies for combining LVAD with pharmacotherapy and proposes new therapeutic targets. Regulation of metabolic pathways, enhancing mitochondrial biogenesis and function, immunomodulating treatment, and stem-cell therapies represent therapeutic areas that require further experimental and clinical studies on their effectiveness in combination with mechanical unloading.
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Insuficiencia Cardíaca , Corazón Auxiliar , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart's contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant's total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model.
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Cardiomiopatía Hipertrófica , Pez Cebra , Actinas/genética , Actinas/metabolismo , Animales , Miosinas Cardíacas/genética , Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Hiperplasia/metabolismo , Mutación , Miocitos Cardíacos/metabolismo , Transcriptoma , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
CD4+ T cells expressing choline acetyltransferase (ChAT) have recently been shown to cause a drop in systemic blood pressure when infused into mice. The aim of this study was to determine if ChAT-expressing T cells could regulate coronary vascular reactivity. Preconstricted segments of epicardial and intramyocardial porcine coronary arteries relaxed in response to Jurkat T cells (JT) that overexpressed ChAT (JTChAT cells). The efficacy of the JTChAT cells was similar in epicardial and intramyocardial vessels with a maximum dilator response to 3 × 105 cells/mL of 38.0 ± 6.7% and 38.7 ± 7.25%, respectively. In contrast, nontransfected JT cells elicited a weak dilator response, followed by a weak contraction. The response of JTChAT cells was dependent on the presence of the endothelial cells. In addition, the response could be significantly reduced by Nω-nitro-l-arginine methyl ester (l-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) in the presence of indomethacin. JTChAT cells, but not JT cells, increased the expression of phosphorylated endothelial nitric oxide synthase (eNOS). JTChAT cells contained significantly greater levels of acetylcholine compared with JT cells; however, the nonselective muscarinic antagonist atropine and the M1 receptor antagonist pirenzepine both failed to block the dilator effect of JTChAT cells. Exogenously added acetylcholine induced only a weak relaxation (â¼10%) at low concentrations, which became a contractile response at higher concentrations. These data illustrate the capacity for cells that express ChAT to regulate coronary vascular reactivity, via mechanisms that are dependent on interaction with the endothelium and in part mediated by the release of nitric oxide.NEW & NOTEWORTHY This study shows ChAT-expressing T cells can induce vasodilation of the blood vessel in the coronary circulation and that this effect relies on a direct interaction between T cells and the coronary vascular endothelium. The study establishes a potential immunomodulatory role for T cells in the coronary circulation. The present findings offer an additional possibility that a deficiency of ChAT-expressing T cells could contribute to reduced coronary blood flow and ischemic events in the myocardium.
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Comunicación Celular , Colina O-Acetiltransferasa/metabolismo , Vasos Coronarios/enzimología , Linfocitos T/enzimología , Vasodilatación , Acetilcolina/metabolismo , Animales , Colina O-Acetiltransferasa/genética , Vasos Coronarios/inmunología , Células Endoteliales/enzimología , Células Endoteliales/inmunología , Humanos , Células Jurkat , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Sus scrofa , Linfocitos T/inmunologíaRESUMEN
PURPOSE: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene-disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance. METHODS: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost's ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes. RESULTS: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4-24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11-29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy. CONCLUSIONS: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions ( https://www.cardiodb.org/cardioboost/ ), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.
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Cardiomiopatías , Mutación Missense , Algoritmos , Área Bajo la Curva , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Humanos , Persona de Mediana Edad , Mutación Missense/genética , VirulenciaRESUMEN
PURPOSE: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. METHODS: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). RESULTS: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. CONCLUSION: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Cardiopatías Congénitas , Cardiomiopatías/genética , Cardiomiopatía Dilatada/genética , Pruebas Genéticas , HumanosRESUMEN
OBJECTIVES: Heterogeneity of structural and electrophysiologic properties of atrial myocardium is common characteristic in hypertrophic cardiomyopathy (HCM). We assessed the dispersion of atrial refractoriness on surface ECG using P-wave dispersion (PWD) and its relation to atrial electromechanical functions using vector velocity imaging (VVI) in HCM population. METHODS: Seventy-nine HCM patients (mean age: 43.7 ± 13 years, 67% male) were compared with 25 healthy individuals as control. P-wave durations, Pmax and Pmin , P-wave dispersion (PWD), and P terminal force (PTF) were measured from 12-lead ECG. LA segmental delay (TTP-d) and dispersion (TTP-SD) of electromechanical activation were derived from atrial strain rate curves. RESULTS: HCM patients had longer PR interval, PW duration, higher PWD, PTF, QTc compared to control (p < .001). HCM patients were classified according to presence of PWD into two groups, group I with PWD > 46 ms (n = 25) and group II PWD ≤ 46 ms (n = 54). Group I showed higher prevalence of female gender, higher PTF, QTc interval, left ventricular outflow tract (LVOT) obstruction, p < .01, LVOT gradient (p < .001), LV mass index (p < .01), E/E' (p < .01), and severe mitral regurgitation (p < .001). Moreover, PWD was associated with increased atrial electromechanical delay (TTP-d) and LA mechanical dyssynchrony (TTP-SD), p < .001. LA segmental delay and dispersion of electromechanical activation were distinctly higher among HCM patient. CONCLUSION: PWD is simple ECG criterion, and it is associated with more severe HCM phenotype and LA electromechanical delay while PTF is linked only to atrial remodeling.
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Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/fisiopatología , Ecocardiografía/métodos , Electrocardiografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Estudios Transversales , Femenino , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour. METHODS: All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling. RESULTS: Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue. CONCLUSION: All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.
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Neoplasias Cardíacas , Rabdomioma , Esclerosis Tuberosa , Pruebas Genéticas , Neoplasias Cardíacas/genética , Humanos , Mutación , Rabdomioma/genética , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genéticaRESUMEN
Calcific aortic valve disease (CAVD) is an athero-inflammatory process. Growing evidence supports the inflammation-driven calcification model, mediated by cytokines such as interferons (IFNs) and tumor necrosis factor (TNF)-α. Our goal was investigating IFNs' effects in human aortic valve endothelial cells (VEC) and the potential differences between aortic (aVEC) and ventricular (vVEC) side cells. The endothelial phenotype was analyzed by Western blot, qPCR, ELISA, monocyte adhesion, and migration assays. In mixed VEC populations, IFNs promoted the activation of signal transducers and activators of transcription-1 and nuclear factor-κB, and the subsequent up-regulation of pro-inflammatory molecules. Side-specific VEC were activated with IFN-γ and TNF-α in an orbital shaker flow system. TNF-α, but not IFN-γ, induced hypoxia-inducible factor (HIF)-1α stabilization or endothelial nitric oxide synthase downregulation. Additionally, IFN-γ inhibited TNF-α-induced migration of aVEC. Also, IFN-γ triggered cytokine secretion and adhesion molecule expression in aVEC and vVEC. Finally, aVEC were more prone to cytokine-mediated monocyte adhesion under multiaxial flow conditions as compared with uniaxial flow. In conclusion, IFNs promote inflammation and reduce TNF-α-mediated migration in human VEC. Moreover, monocyte adhesion was higher in inflamed aVEC sheared under multiaxial flow, which may be relevant to understanding the initial stages of CAVD.
Asunto(s)
Válvula Aórtica/metabolismo , Células Endoteliales/metabolismo , Interferón-alfa/farmacología , Interferón gamma/farmacología , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/inmunología , Válvula Aórtica/efectos de los fármacos , Válvula Aórtica/inmunología , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/inmunología , Calcinosis/inmunología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Trasplante de Corazón , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/inducido químicamente , Inflamación/inmunología , Monocitos/metabolismo , FN-kappa B/metabolismo , Fenotipo , Factor de Transcripción STAT1/metabolismo , Células THP-1 , Receptores de Trasplantes , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Myosin-binding protein C 3 (MYBPC3) variants are the most common cause of hypertrophic cardiomyopathy (HCM). HCM is a complex cardiac disorder due to its significant genetic and clinical heterogeneity. MYBPC3 variants genotype-phenotype associations remain poorly understood. We investigated the impact of two novel human MYBPC3 splice-site variants: V1: c.654+2_654+4dupTGG targeting exon 5 using morpholino MOe5i5; and V2: c.772+1G>A targeting exon 6 using MOe6i6; located within C1 domain of cMyBP-C protein, known to be critical in regulating sarcomere structure and contractility. Zebrafish MOe5i5 and MOe6i6 morphants recapitulated typical characteristics of human HCM with cardiac phenotypes of varying severity, including reduced cardiomyocyte count, thickened ventricular myocardial wall, a drastic reduction in heart rate, stroke volume, and cardiac output. Analysis of all cardiac morphological and functional parameters demonstrated that V2 cardiac phenotype was more severe than V1. Coinjection with synthetic human MYBPC3 messenger RNA (mRNA) partially rescued disparate cardiac phenotypes in each zebrafish morphant. While human MYBPC3 mRNA partially restored the decreased heart rate in V1 morphants and displayed increased percentages of ejection fraction, fractional shortening, and area change, it failed to revert the V1 ventricular myocardial thickness. These results suggest a possible V1 impact on cardiac contractility. In contrast, attempts to rescue V2 morphants only restored the ventricular myocardial wall hypertrophy phenotype but had no significant effect on impaired heart rate, suggesting a potential V2 impact on the cardiac structure. Our study provides evidence of an association between MYBPC3 exon-specific cardiac phenotypes in the zebrafish model providing important insights into how these genetic variants contribute to HCM disease.