Heart Valve Defects Research Articles

ПОСЛЕРОДОВАЯ ПЕРИПАРТАЛЬНАЯ КАРДИОМИОПАТИЯ КАК РЕДКАЯ ПРИЧИНА СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТИ: СЛУЧАЙ ИЗ ПРАКТИКИ

Abstract. Introduction. Peripartum cardiomyopathy is a rare, idiopathic myocardial disease occurring during pregnancy or within 5 months after delivery and characterized by the decreased contractility of the left ventricular myocardium. Insufficient awareness of physicians about this rare pathology creates prerequisites for the description of interesting clinical observations. This article presents a case follow-up (for 5 months) of female patient R. with diagnosed peripartum cardiomyopathy at the age of 31 years after childbirth. Before and during pregnancy, no risk factors or pathology of cardiovascular system, or myocardium exposure to toxic substances were identified. Patient R. first sought medical attention 3 months after her fourth delivery (in total, there were 5 pregnancies and 4 deliveries without pathologies) and prolonged breastfeeding, symptoms of heart failure appeared and rapidly progressed. Aim. To present a clinical case of peripartum cardiomyopathy developed in the postpartum period. Materials and Methods. A clinical case of peripartum cardiomyopathy of patient R. was analzed, who voluntarily signed the informed consent for examination and permission to anonymously publish personal medical information. Results and Discussion. Peripartum cardiomyopathy is a diagnosis of exclusion; therefore, an important stage is differential diagnosis with manifestations of pre-eclampsia and myocarditis. Untimely diagnosis of peripartum cardiomyopathy, in some cases, is due to lack of physicians’ awareness. An important criterion for diagnosing peripartum cardiomyopathy is the absence of any previously diagnosed cardiovascular diseases; therefore, the first priority is to exclude heart valve defects and dilated cardiomyopathy. In addition, it is necessary to exclude pregnancy-mediated hemodynamic changes, as well as differential diagnosis with such conditions as myocarditis, Takotsubo syndrome, pulmonary embolism, acute coronary syndrome, and human immunodeficiency virus. Conclusions. Thus, the factors contributing to the development of peripartum cardiomyopathy in patient R. were as follows: Age over 30 years, 4 childbirths, iron deficiency anemia. Three diagnostic criteria have formed the basis for the diagnosis of peripartum cardiomyopathy: 1) debut of heart failure within 5 months after delivery; 2) no newly diagnosed heart disease more than 1 month before delivery or any other causes of chronic heart failure; and 3) left ventricular dysfunction according to the findings of echocardioscopy and magnetic resonance imaging with the ejection fraction decreased down to 13 %.

Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development

A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG’s involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5–E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG’s involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment.Key messagesOur examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice.Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway.Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.

Immune Shielding of Human Heart Valves: A Proof-of-Concept Study of HLA-Targeting Therapy for Transplantations

Children born with defective heart valves require multiple donor valve replacements throughout life, because these cannot grow and can cause early failure through immune degeneration. This study tests the lentiviral delivery of viral immune evasion genes US2 and human serpin 9 to shield human heart valves from immune rejection. The results show we can efficiently down-regulate human leukocyte antigen expression in heart valve cells and in intact heart valve tissue resulting in decreased activity of a human leukocyte antigen-reactive CD8+ T-cell clone without inducing cytotoxicity. This study demonstrates immune shielding of human heart valves and brings us closer to a durable valve graft in pediatric patients.

Intermittent hypoxic preconditioning reduces the risk of peri- and postoperative complications during on-pump cardiac surgery

Aim. To assess the effect of intermittent hypoxic-hyperoxic exposures (IHHE) on the outcomes of on-pump cardiac surgery.Material and methods. This prospective, single-center, randomized, controlled study was conducted in 110 patients with heart valve defects and/or aortic pathology from the cardiac surgery clinic of the I. M. Sechenov First Moscow State Medical University. The total sample was randomly divided into a group of patients who underwent IHHE (n=66) and a control group of patients who underwent placebo procedures with ambient air (n=44). The frequency and structure of intra-and postoperative complications were analyzed within 30 days after surgery. The presence of cognitive impairment, as well as serum troponin I and lactate concentrations were analyzed before and after surgery.Results. Peri- and early postoperative complications such as cardiac death, non-fatal infarction and acute heart failure occurred significantly less frequently in patients treated with IHHE compared with placebo group (1,6% vs 16,7%, p=0,009; 1,6% vs 16,7%, p=0,009; 6,3% vs 33,3%, p<0,001, respectively). The median troponin I values 24 hours after surgery were 1,068 ng/ml (0,388-1,397 ng/ml) in the IHHE group and were significantly lower compared to the control group (1,980 ng/ml (1,068-3,239 ng/ml)). The serum lactate level after surgery was 1,8±0,7 mmol/l in the IHHE group and was significantly lower compared to the control group — 2,4±1,2 (p=0,05). Cognitive function, assessed by MOCA and MMSE tests, turned out to be significantly higher in patients who underwent a preoperative IHHE. No significant complications or serious adverse events were observed during the IHHE procedures.Conclusion. The use of individually adapted hypoxic preconditioning procedures reduces the incidence of peri- and postoperative complications, which is accompanied by a lower ischemia-reperfusion myocardial injury during artificial circulation with preservation of cognitive functions. IHHE procedures ramp up prehabilitation of patients referred for on-pump surgery of heart defects and aortic pathology.

Semilunar valve growth and function 10 years after infant heart transplantation: Predicting long-term outcomes of partial heart transplants.

Partial heart transplants are a new type of pediatric transplant that replace defective heart valves with the parts of matched donor hearts containing the necessary valves. Short-term outcomes of partial heart transplants are excellent, but long-term outcomes are unknown. In order to predict the long-term outcomes of partial heart transplants, we evaluated long-term growth and function of semilunar heart valves transplanted in infancy as part of a heart transplant. All children who underwent infant heart transplantation at a single center from 1997 to 2014 were included in this study. Children in whom echocardiograms after heart transplantation and after 10 years were not available for review were excluded. The echocardiograms were reviewed by two authors to analyze semilunar valve annulus diameters, Z-scores, peak valve gradients, and valve regurgitation. Statistical difference was determined using two-tailed, paired sample t-tests with Bonferroni correction for multiple comparisons. Data from 15 patients were analyzed. The aortic valve annulus averaged 1.3 cm (range 0.7-1.8 cm) immediately after transplantation and grew to an average of 1.7 cm (range 1.4-2.3 cm) after 10 years (p < .001). After 10 years, the aortic valve peak gradient avereraged 5.1 mmHg (range 2.1-15.5 mmHg) and none of the valves had more than trivial regurgitation. The pulmonary valve annulus averaged 1.5 cm (range 1.1-2.5 cm) immediately after transplantation and grew to an average of 2.1 cm (range 1.0-2.9 cm) after 10 years (p < .001). After 10 years, the pulmonary valve peak gradient averaged 4.3 mmHg (range 1.1-13.8 mmHg), and 7% of valves had moderate regurgitation. Semilunar heart valves transplanted in infancy as part of a heart transplant demonstrate statistically significant growth and excellent function after 10 years. This predicts excellent long-term outcomes of partial heart transplants.

Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease.

Congenital heart disease (CHD) is the most common birth defect and heart valve defects are the most common cardiac defect, accounting for over 25% of all congenital heart diseases. To date, more than 400 genes have been linked to CHD, the genetic analysis of CHD cases is crucial for both clinical management and etiological determination. Patients with autosomal-recessive variants of PLD1 are predisposed to Cardiac Valvular Dysplasia-1 (CVDP1), which predominantly affects the right-sided heart valves, including the pulmonic, tricuspid, and mitral valves. Databases were utilized to predict the impact of the c.1062-59A>G variant on splicing. Whole-exome sequencing (WES), reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and TA clone sequencing were conducted on both the parents and the fetus. A compound heterozygous variation in the PLD1(NM_002662.5):c.1937G>C (p. G646A) from the father and PLD1(NM_002662.5):c.1062-59A>G from the mother, was identified and confirmed in the fetus. The c.1937G>C (p. G646A) and the c.1062-59A>G variants were all classified as variant of uncertain significance (VUS) per ACMG guidelines. RT-PCR and TA clone sequencing revealed a 76-bp intronic insertion and exon 11 skipping in the proband and her mother's transcripts, causing a frameshift and premature stop codon in PLD1. Consequently, after being informed about the risks of their variant of unknown significance (VUS), the couple chose pre-implantation genetic testing for monogenic disorders (PGT-M) and had a healthy child. Our study identified novel variants to expand the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options.

Prosthetic heart valves in the work of a cardiological nurse

Valvular defects are one of the most frequent causes of valvular insufficiency. Among acquired defects, they rank first in Europe and are the most common cause of heart surgery (46.6% of all planned heart operations in Russia in 2015). Meanwhile, there are no major modern studies of the epidemiology and treatment of these pathologies. The population is rapidly aging, and therefore valve pathologies are more and more common; being acquired, they develop for decades and usually manifest themselves at the age of over 40 years. Treatment of heart valve defects by conservative methods is symptomatic, since it is impossible to reverse morphofunctional tissue changes. The only way to finally defeat the disease is surgical inter vention and transplantation of a new valve.

Templated Assembly of Silk Fibroin for a Bio‐Feedstock‐Derived Heart Valve Leaflet

AbstractBioprosthetic valves are employed to replace defective heart valves. However, structural degeneration is prevalent in bioprosthetic valves because the heart valve leaflets are exposed to extreme and repetitive cardiovascular pressure. Herein, a silk fibroin‐based heart valve leaflet, which executes the physiological role of a heart valve, is developed. To this end, a templated assembly technology is developed. Notably, a physically optimal hierarchical structure for replacing the natural heart valve leaflet is realized by numerous firmly stacked β‐sheet crystals distributed within collective tyrosine‐reinforcing amorphous strands. Almost half (46.9%) of the silk fibroin‐based heart valve leaflet comprises strongly stacked β‐sheet crystals, leading to a 292% enhancement in stacking strength. The templated assembly results in the entanglement of amorphous strands, upregulating the non‐covalent interactions within the tyrosine. Consequently, the strength is enhanced by 1380% compared to native silk fibroin. Moreover, the templated assembly enhances the static and dynamic mechanical properties, thereby delivering a desirable performance for its use in heart valve replacement. Interestingly, the aortic valve composed of silk fibroin‐based leaflets does not fail under the cardiovascular pressure of 60–180 mmHg. Furthermore, the valve performance is satisfactory and surmounts the requirements of the industrial standard ISO 5840.

Crk and Crkl Are Required in the Endocardial Lineage for Heart Valve Development.

Background Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal transformation and the subsequent endocardial cushion remodeling. Genetic variants that affect these developmental processes can lead to congenital heart valve defects. Crk and Crkl are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of Crk and Crkl in the endocardial lineage during heart valve development. Methods and Results We deleted Crk and Crkl specifically in the endocardial lineage. The resultant heart valve morphology was evaluated by histological analysis, and the underlying cellular and molecular mechanisms were investigated by immunostaining and quantitative reverse transcription polymerase chain reaction. We found that the targeted deletion of Crk and Crkl impeded the remodeling of endocardial cushions at the atrioventricular canal into the atrioventricular valves. We showed that apoptosis was temporally increased in the remodeling atrioventricular endocardial cushions, and this developmentally upregulated apoptosis was repressed by deletion of Crk and Crkl. Loss of Crk and Crkl also resulted in altered extracellular matrix production and organization in the remodeling atrioventricular endocardial cushions. These morphogenic defects were associated with altered expression of genes in BMP (bone morphogenetic protein), connective tissue growth factor, and WNT signaling pathways, and reduced extracellular signal-regulated kinase signaling activities. Conclusions Our findings support that Crk and Crkl have shared functions in the endocardial lineage that critically regulate atrioventricular valve development; together, they likely coordinate the morphogenic signals involved in the remodeling of the atrioventricular endocardial cushions.

АНАЛИЗ ФАКТОРОВ, АССОЦИИРУЮЩИХСЯ С УХУДШЕНИЕМ КАЧЕСТВА ЖИЗНИ И ЭМОЦИОНАЛЬНОГО СОСТОЯНИЯ ПОСЛЕ ОПЕРАЦИИ ПО КОРРЕКЦИИ ПРИОБРЕТЕННЫХ ПОРОКОВ СЕРДЦА

Introduction. The assessment of factors associated with the deterioration of the quality of life (QOL) and emotional state after heart surgery suggests the possibility of their timely elimination and, as a result, a faster return to working capacity and socialization of a patient with acquired heart disease. Target. Identification of factors affecting the deterioration of QoL and emotional state of patients undergoing surgical correction of acquired heart valve defects in the postoperative period. Materials and methods. The study included 103 patients (median age 60.0 years [51.0; 66.0]) from November 2020 to October 2022 who underwent surgical correction of mitral valve disease or in combination with correction of aortic valve disease and /or tricuspid valves. To assess the level of QOL, patients filled out the questionnaire "Shot Form-36 health status survey" (SF-36), to assess the emotional state of the Hospital Anxiety and Depression Scale (HADS) before surgical treatment, on the 7th, 30th day, a year later after the intervention. Results. According to regression analysis, the presence of preoperative atrial fibrillation (AF) was associated with a decrease in the physical component of health according to the SF-36 questionnaire by B-factor = -6.39; p=0.002 before surgery, and B-factor = -10.92; p=0.03 one week after the operation, as well as with a decrease in the mental health component on the 30th day (B-coefficient = -12.66; p=0.006). With an increase in age by 1 unit, the initial level of the physical component of health decreased by B-coefficient = -0.21 (p=0.014). There was an association of males with levels of anxiety (B-value = 3.58; p=0.002) and depression (B-value = 3.04; p=0.002) assessed before and one week after surgery: B-value = 2.34; p=0.03 and B-factor=2.47; p=0.02, respectively, as well as with a higher level of anxiety after a month (B-factor = 2.79; p=0.03). Patients were divided into groups with the presence (group 1) or absence (group 2) of pulmonary hypertension (PH) before surgery according to echocardiography. On the 7th day after the operation, group 1 noted an improvement in mental health (MH; p=0.03), regardless of the increase in the intensity of the pain syndrome (BP; p=0.005). Patients without PH noted a worsening of QoL in terms of self-service and freedom of movement (PF, p=0.04), because of the pain syndrome they considered their QoL to be lower compared to preoperative (BP; p=0.03). On the 7th day in the group without PH, the median level of anxiety decreased by 3 points, in the group with PH only by 1.5 points (p=0.04). The level of depression by the 30th day decreased to 1 point in both groups, remaining stable throughout the year. A month later, the PH group noted an increase in physical capabilities (PF; p=0.03), an increase in overall health (GH; p=0.003), an increase in physical (p&lt;0.0001) and mental (p=0.006) components of QoL , and patients without PH indicated a limitation in the performance of work duties (RP, p=0.047). During the year after the operation, the PH group noted a decrease in pain intensity (BP, p=0.003), an improvement in the emotional state (RE, p=0.04), an increase in the possibility of self-care and free movement (PF, p=0.00008), work responsibilities (RP, p=0.001), which increased overall health (GH, p=0.002), vitality (VT, p=0.0002) and increased social contacts (SF, p=0.001). The quality of life of patients from the group without PH improved only on three points with less significant dynamics: physical functioning (PF, p=0.03), pain intensity (BP, p=0.01) and vital activity (VT, p=0.04 ). Conclusion. The factors influencing the deterioration of QoL and emotional state after surgical correction of PPS are: the presence of preoperative AF, male gender. And the presence of PH before defect correction is associated with better QoL and emotional status after the intervention compared to patients without PH, which may be due to a more severe condition before surgery in people with PH.

A Deep Neural Network for Heart Valve Defect Classification From Synchronously Recorded ECG and PCG

A Deep Neural Network for Heart Valve Defect Classification From Synchronously Recorded ECG and PCG

Characterization of the Zebrafish Elastin a (elnasa12235) Mutant: A New Model of Elastinopathy Leading to Heart Valve Defects.

Elastic fibers are extracellular macromolecules that provide resilience and elastic recoil to elastic tissues and organs in vertebrates. They are composed of an elastin core surrounded by a mantle of fibrillin-rich microfibrils and are essentially produced during a relatively short period around birth in mammals. Thus, elastic fibers have to resist many physical, chemical, and enzymatic constraints occurring throughout their lives, and their high stability can be attributed to the elastin protein. Various pathologies, called elastinopathies, are linked to an elastin deficiency, such as non-syndromic supravalvular aortic stenosis (SVAS), Williams-Beuren syndrome (WBS), and autosomal dominant cutis laxa (ADCL). To understand these diseases, as well as the aging process related to elastic fiber degradation, and to test potential therapeutic molecules in order to compensate for elastin impairments, different animal models have been proposed. Considering the many advantages of using zebrafish, we here characterize a zebrafish mutant for the elastin a paralog (elnasa12235) with a specific focus on the cardiovascular system and highlight premature heart valve defects at the adult stage.

Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction.

Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.

Does variable RBE affect toxicity risks for mediastinal lymphoma patients? NTCP-based evaluation after proton therapy treatment

IntroductionMediastinal lymphoma (ML) is a solid malignancy affecting young patients. Modern combined treatments allow obtaining good survival probability, together with a long life expectancy, and therefore with the need to minimize treatment-related toxicities. We quantified the expected toxicity risk for different organs and endpoints in ML patients treated with intensity-modulated proton therapy (IMPT) at our centre, accounting also for uncertainties related to variable RBE. MethodsTreatment plans for ten ML patients were recalculated with a TOPAS-based Monte Carlo code, thus retrieving information on LET and allowing the estimation of variable RBE. Published NTCP models were adopted to calculate the toxicity risk for hypothyroidism, heart valve defects, coronary heart disease and lung fibrosis. NTCP was calculated assuming both constant (i.e. 1.1) and variable RBE. The uncertainty associated with individual radiosensitivity was estimated by random sampling α/β values before RBE evaluation. ResultsVariable RBE had a minor impact on hypothyroidism risk for 7 patients, while it led to significant increase for the remaining three (+24% risk maximum increase). Lung fibrosis was slightly affected by variable RBE, with a maximum increase of ≅ 1%. This was similar for heart valve dysfunction, with the exception of one patient showing an about 10% risk increase, which could be explained by means of large heart volume and D1 increase. DiscussionThe use of NTCP models allows for identifying those patients associated with a higher toxicity risk. For those patients, it might be worth including variable RBE in plan evaluation.

Transcatheter Aortic Valve Implantation in Multivalvular Heart Disease

Transcatheter Aortic Valve Implantation in Multivalvular Heart Disease Abstract. The prevalence of multivaluvular heart disease is high in patients undergoing transcatheter aortic valve implantation (TAVI). The most common combination is aortic valve stenosis (AS) and mitral regurgitation, followed by the combination of AS with a tricuspid regurgitation or mitral stenosis. Grading of multivalvular disease is challenging and can quickly lead to underestimation of the disease stage. Therefore, a profound knowledge of pathophysiologic interactions is essential, and the patient should always undergo multimodal evaluation. After a successful TAVI intervention, secondary heart valve defects may improve, deteriorate, or remain unchanged. Due to the still sparse scientific data in this field, the role of the heart team remains central to provide the patient with an individually adapted therapy plan.

Long-term incidence of infective endocarditis among patients with congenital heart disease

Patients with congenital heart disease (CHD) are at lifelong high risk of infective endocarditis (IE). The risk of IE presumably differs among different CHD, but little knowledge exists on the area. In this observational cohort study, all CHD-patients born in 1977 to 2018 were identified using Danish nationwide registries and followed from the date of birth until first-time IE, emigration, death, or end of study (December 31, 2018). The comparative risk of IE among CHD-patients vs age- and sex-matched controls from the background population was assessed. The risk of IE was stratified according to the type of CHD and factors associated with IE including sex and relevant time-varying coefficients (ie, cyanosis, cardiac prostheses, diabetes mellitus, chronic kidney disease, and cardiac implantable electronic devices) were examined using Cox-regression analysis. A total of 23,464 CHD-patients (50.0% men) were identified and matched with 93,856 controls. During a median follow-up of 17.7 years, 217(0.9%) CHD-patients and 4(0.0%) controls developed IE, corresponding to incidence rates of 5.2(95%CI 4.6-6.0) and 0.02(95%CI 0.01-0.1) per 10,000 person-years, respectively. The incidence of IE was greatest among patients with tetralogy of fallot, malformations of the heart chambers (including transposition of the great arteries, univentricular heart, and truncus arteriosus), atrioventricular septal defects, and heart valve defects. Factors associated with IE among CHD-patients included male sex, cyanosis, cardiac prostheses, chronic kidney disease, and cardiac implantable electronic devices. CHD-patients have a substantially higher associated incidence of IE than the background population. With the increasing longevity of these patients, relevant guidelines concerning preventive measures are important.

Bicuspid Aortic Valve-Associated Regulatory Regions Reveal GATA4 Regulation and Function During Human-Induced Pluripotent Stem Cell-Based Endothelial-Mesenchymal Transition-Brief Report.

The endothelial-mesenchymal transition (EndoMT) is a fundamental process for heart valve formation and defects in EndoMT cause aortic valve abnormalities. Our previous genome-wide association study identified multiple variants in a large chromosome 8 segment as significantly associated with bicuspid aortic valve (BAV). The objective of this study is to determine the biological effects of this large noncoding segment in human induced pluripotent stem cell (hiPSC)-based EndoMT. A large genomic segment enriched for BAV-associated variants was deleted in hiPSCs using 2-step CRISPR/Cas9 editing. To address the effects of the variants on GATA4 expression, we generated CRISPR repression hiPSC lines (CRISPRi) as well as hiPSCs from BAV patients. The resulting hiPSCs were differentiated to mesenchymal/myofibroblast-like cells through cardiovascular-lineage endothelial cells for molecular and cellular analysis. Single-cell RNA sequencing was also performed at different stages of EndoMT induction. The large deletion impaired hiPSC-based EndoMT in multiple biallelic clones compared with their isogenic control. It also reduced GATA4 transcript and protein levels during EndoMT, sparing the other genes nearby the deletion segment. Single-cell trajectory analysis revealed the molecular reprogramming during EndoMT. Putative GATA-binding protein targets during EndoMT were uncovered, including genes implicated in endocardial cushion formation and EndoMT process. Differentiation of cells derived from BAV patients carrying the rs117430032 variant as well as CRISPRi repression of the rs117430032 locus resulted in lower GATA4 expression in a stage-specific manner. TWIST1 was identified as a potential regulator of GATA4 expression, showing specificity to the locus tagged by rs117430032. BAV-associated distal regions regulate GATA4 expression during hiPSC-based EndoMT, which in turn promotes EndoMT progression, implicating its contribution to heart valve development.

Robust classification of heart valve sound based on adaptive EMD and feature fusion.

Cardiovascular disease (CVD) is considered one of the leading causes of death worldwide. In recent years, this research area has attracted researchers' attention to investigate heart sounds to diagnose the disease. To effectively distinguish heart valve defects from normal heart sounds, adaptive empirical mode decomposition (EMD) and feature fusion techniques were used to analyze the classification of heart sounds. Based on the correlation coefficient and Root Mean Square Error (RMSE) method, adaptive EMD was proposed under the condition of screening the intrinsic mode function (IMF) components. Adaptive thresholds based on Hausdorff Distance were used to choose the IMF components used for reconstruction. The multidimensional features extracted from the reconstructed signal were ranked and selected. The features of waveform transformation, energy and heart sound signal can indicate the state of heart activity corresponding to various heart sounds. Here, a set of ordinary features were extracted from the time, frequency and nonlinear domains. To extract more compelling features and achieve better classification results, another four cardiac reserve time features were fused. The fusion features were sorted using six different feature selection algorithms. Three classifiers, random forest, decision tree, and K-nearest neighbor, were trained on open source and our databases. Compared to the previous work, our extensive experimental evaluations show that the proposed method can achieve the best results and have the highest accuracy of 99.3% (1.9% improvement in classification accuracy). The excellent results verified the robustness and effectiveness of the fusion features and proposed method.

The risk spectrum of infective endocarditis among patients with congenital heart diseases

Abstract Background Patients with congenital heart disease (CHD) are considered at lifelong high risk of infective endocarditis (IE). The risk of IE presumably differs among different types of CHD, but little knowledge exists on the area. Purpose This study set out to investigate the long-term incidence of IE among CHD-patients and associated risk factors. Methods In this observational cohort study, all patients with CHD born in 1977–2018 were identified using Danish nationwide registries and followed from date of birth until occurrence of first-time IE, emigration, death, or end of study (December 31, 2018). The comparative risk of IE among patients with CHD versus age- and sex-matched controls from the background population was assessed. Moreover, the risk of IE was stratified according to type of CHD and risk factors associated with IE among patients with CHD were examined using Cox regression analysis including sex and relevant time-varying coefficients (i.e., cyanotic yet surgically untreated CHD, CHD repaired with prostheses, diabetes mellitus, chronic kidney disease, and presence of cardiac implantable devices). Results A total of 23,464 patients with CHD (50.0% men) were identified and matched with 93,856 controls from the background population. During a median follow-up of 17.7 years, 217 (0.9%) patients with CHD and 4 (0.0%) controls developed IE, corresponding to incidence rates of 5.2 (95% CI: 4.6–6.0) and 0.02 (95% CI: 0.01–0.1) per 10,000 person-years, respectively. The associated incidence of IE was greatest among patients with tetralogy of Fallot, malformations of the heart chambers (including transposition of the great arteries and truncus arteriosus), atrioventricular septal defects, and heart valve defects (Figure 1). Factors associated with IE among patients with CHD included male sex (HR 1.7 [95% CI, 1.3–2.2]), cyanotic yet surgically untreated CHD (HR 5.2 [95% CI, 3.5–7.7]), cardiac prostheses (HR 5.2 [95% CI, 3.6–7.5]), chronic kidney disease (HR 3.1 [95% CI, 1.3–7.6]), and presence of cardiac implantable electronic devices (HR 3.1 [95% CI, 1.5–6.2]). Conclusions Patients with CHD, especially those with tetralogy of Fallot and malformations of the heart chambers, have a substantially higher incidence of IE than the background population. With an increasing longevity of these patients, relevant guidelines concerning preventive measures are decisive to improve morbidity, mortality, and the quality of life among this growing group of patients. Funding Acknowledgement Type of funding sources: None.

Role of cytokine and Toll-like receptor genes in pathogenesis of inborn heart disease

Sporadic congenital heart disease (CHD) may result from immune disorders in the mother – embryo system and/or constitutional disorders in regulatory systems, including those associated with TLR receptors, cytokines and their receptors. The aim of our study was to investigate associations between cytokine and TLR genes and sporadic congenital heart disease in children. In the main group, 188 children with sporadic (without family history) congenital heart defects were examined. Separate groups of CHD were identified: septal CHD – 98 children; valvular heart disease – 17 children; Fallot tetralogy – 15 children; aorta coarctation – 10 children; fetal drains – 32 children; single ventricle affection – 9 children, and anomalous drainage of v. pulmonalis was diagnosed in 7 children. The control group included 103 age- and sex-matched healthy children. We have determined gene polymorphisms of five genes encoding cytokines and their receptors (IL6 rs1800796, IL6 rs2069827, IL6R rs2228145, IL6R rs2229238, IL8 rs4073, IL10 rs1800871, IL10 rs1800896, IL10 rs1800872, TNF rs1800629, TNF rs361525, TNF rs1799964), four genes Toll-like receptors (TLR: TLR1 rs5743611, TLR1 rs5743551, TLR2 rs5743708, TLR2 rs3804099, TLR4 rs4986791, TLR4 rs4986790, TLR6 rs3775073, TLR6 rs5743810). The dbSNP, SNPinfo, SNPnexus databases were used to select and design test systems. Stepwise logistic regression was the main method of statistical analysis. Clinical diagnosis of congenital heart defects is associated with immune regulatory genes. In particular, the missense mutation TLR6 rs5743810, which was a predictor of congenital valvular heart disease, is of particular importance. Development of congenital heart valve defects and aortic coarctation is associated with intergenic interactions of TLR2 rs5743708 with TLR6 rs5743810, and TLR2 rs5743708 with TLR6 rs3775073, respectively. For congenital heart valve defects, such polymorphic regions are as follows: IL6 rs2069827, IL6R rs2229238, and IL8 rs4073, for aortic coarctation – IL6R rs2228145, IL8 rs4073. Development of septal congenital heart defects is associated with general contribution of polymorphic variants of the TLR genes and cytokines to this pathology. A missense mutation of the TLR4 rs4986790 gene and a TNF rs1799964 mutation leading to increased synthesis of the TNFα molecule, may have a combined effect on this process. In general, contribution of TLR and cytokine genes interactions to the CHD development seems to be not significant.