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Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, genome sequencing (GS), RNA-seq, and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined GS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints matches the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2 Mb region on chromosome 9 and a SINE element insertion at the more distal breakpoint. Interestingly, this genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by both RNA-seq and Sanger sequencing on blood samples from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype–phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p24 segregating with a familial congenital heart defect, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.

Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

Aortic stenosis (AS) is a common degenerative valvular disease in elderly patients, causing obstruction of left ventricular outflow and presenting with symptoms such as angina, syncope, and heart failure. Although surgical aortic valve replacement (SAVR) remains the gold standard, its high perioperative risk in frail patients has led to the adoption of transcatheter aortic valve implantation (TAVI) as a less invasive and effective alternative. The transfemoral (TF) access route is generally preferred, but severe peripheral arterial disease may limit its feasibility. We report the case of a 71-year-old woman with critical AS complicated by multiple comorbidities, including extensive vascular calcifications, a porcelain aorta, and significant subrenal abdominal aortic stenosis. Multimodal imaging, including computed tomography, was essential for procedural planning, revealing complex iliofemoral anatomy unsuitable for conventional device passage without intervention. Intravascular lithotripsy (IVL) was used to disrupt calcific plaques and facilitate safe vascular access. The TAVI procedure was successfully performed under local anesthesia via TF access using a 65 cm GORE® DRYSEAL Flex Introducer Sheath (W. L. Gore & Associates, Flagstaff, AZ, USA) (18-Fr). After balloon valvuloplasty performed over a SAFARI2™ Pre-Shaped TAVI Guidewire, Extra Small (Boston Scientific, Marlborough, MA, USA) Curve in the left ventricle, a self-expanding Medtronic Evolut™ FX 26 (Medtronic, Minneapolis, MN, USA)mm transcatheter valve was implanted. Postoperative imaging confirmed optimal valve function and vascular integrity without complications. This case highlights the role of IVL as an innovative adjunctive technique enabling TF-TAVI in patients with challenging vascular anatomy, thereby expanding treatment options for high-risk individuals with severe AS.

Physics-Informed Neural Networks (PINNs) are a new class of machine learning algorithms that are capable of accurately solving complex partial differential equations (PDEs) without training data. By introducing a new methodology for fluid simulation, PINNs provide the opportunity to address challenges that were previously intractable, such as PDE problems that are ill-posed. PINNs can also solve parameterized problems in a parallel manner, which results in favorable scaling of the associated computational cost. The full potential of the application of PINNs to solving fluid dynamics problems is still unknown, as the method is still in early development: many issues remain to be addressed, such as the numerical stiffness of the training dynamics, the shortage of methods for simulating turbulent flows and the uncertainty surrounding what model hyperparameters perform best. In this paper, we investigated the accuracy and efficiency of PINNs for modeling aortic transvalvular blood flow in the laminar and turbulent regimes, using various techniques from the literature to improve the simulation accuracy of PINNs. Almost no work has been published, to date, on solving turbulent flows using PINNs without training data, as this regime has proved difficult. This paper aims to address this gap in the literature, by providing an illustrative example of such an application. The simulation results are discussed, and compared to results from the Finite Volume Method (FVM). It is shown that PINNs can closely match the FVM solution for laminar flow, with normalized maximum velocity and normalized maximum pressure errors as low as 5.74% and 9.29%, respectively. The simulation of turbulent flow is shown to be a greater challenge, with normalized maximum velocity and normalized maximum pressure errors only as low as 41.8% and 113%, respectively.

OBJECTIVE: Pregnancy can increase gradients across the heart valves and consequently deteriorates maternal and fetoneonatal conditions. Hence, pregnancy during heart valve diseases can be challenging and we need to risk stratify patients before conception. We tried to assess the role of preconception consultation using treadmill stress echocardiography (TSE) testing for identifying pregnancy outcomes in women with mitral valve stenosis (MS) or aortic valve stenosis (AS). METHODS: Pregnant patients with a diagnosis of MS or AS were evaluated from January 2015 to December 2018. First group included patients undergoing the TSE testing and they were permitted to get pregnant if they met pre-defined criteria. Second group comprised women who did not undergo TSE testing. Maternal and fetoneonatal outcomes were also recorded. RESULTS: A total of 29 and 18 patients with MS and AS, respectively, were recruited. Among MS patients, individuals without TSE had more functional deterioration (11.1% vs. 35%) and more fetoneonatal events (FNE) (22.2% vs. 55%) compared with those undergoing TSE. The rates of maternal events and mitral valvuloplasty during pregnancy were significantly higher in patients without TSE compared with those undergoing TSE (p=0.015 and p=0.042, respectively). Among AS patients, maternal and FNE were higher in patients without TSE compared with those undergoing TSE, but those were comparable. CONCLUSION: Pregnant patients with the left-sided valvular stenosis who received preconception TSE testing had better outcomes compared with those who did not undergo preconception consultation. This underscores the utility of stress echocardiography in the risk stratification of pregnancies. Keywords: Aortic valve; mitral valve; pregnancy; stress echocardiography; valvular stenosis.

Acute rheumatic fever (ARF) and its post-inflammatory sequel chronic rheumatic heart disease (RHD) are endemic in the Indian setting. Despite the updated Jones criteria, many cases of ARF remain undiagnosed or are missed. This study aims to analyze pathological profiles of such cases and their importance in context of clinical presentation and Jones criteria. A 22-year retrospective observational study of ARF was conducted in the Department of Pathology in a tertiary care institute. The cases were categorized as 1. Those fulfilling and 2. those partially or not fulfilling the Jones Criteria. Based on the autopsy findings, the lesions were classified as categorized mitral stenosis and/or regurgitation (MS ± MR) and pure mitral regurgitation (MR). Nil. In 22 years, among 697 cases of autopsied cases of RHD, there were 59 cases (8.5%) of ARF. Among them, seven cases fulfilled the Jones criteria; five of them were clinically diagnosed. The remaining 52 cases (88.1%, 34 with MS ± MR and 18 with MR) did not fulfill or partially fulfilled the Jones criteria and were not diagnosed. A total of 18 patients (30.5%) had the first attack of ARF, whereas recurrences were noted in the remaining patients (69.5%). The study indicates that the typical manifestations of ARF under Jones criteria may not be present, especially in cases with recurrence. Hence, a presumptive or possible diagnosis of ARF can be made with presence of minor criteria or strong clinical suspicion in such cases.

Background Transcatheter aortic valve implantation (TAVI) is a proven alternative to open heart surgery in elderly patients. Pulmonary hypertension (PH) is known as a significant risk factor in patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement. However, the prognostic impact of PH in high-risk patients undergoing TAVI is still unknown. The aim of this study was to gain more insight in the clinical outcome and mortality of patients with PH after TAVI. Methods and results Between July 2009 and September 2012, a total of 439 patients were treated by TAVI in conjunction with a complete invasive right heart study at our institution. Patients were divided into two groups with regard to their pulmonary arterial mean pressure (PAMP) before TAVI (A: PAMP < 25 mmHg and B: PAMP ≥ 25 mmHg). Patients with baseline PH had a significantly higher logES (A: 19.40 vs. B: 28.17 %; p  < 0.001) and were more frequently in NYHA functional class IV (A: 15.4 vs. B: 25.1 %; p  = 0.013). Invasive right heart data demonstrated an immediate improvement after TAVI in patients with PH. Despite a similar clinical benefit among survivors, 30-day and 1-year mortality were higher in patients with PH (30-day mortality: A: 4.8 vs. B: 10.4 %; p  = 0.021, 1 year mortality: A: 13.9 vs. B: 23.4 %; p  = 0.014). Conclusions Pulmonary hypertension is an independent risk factor for survival after TAVI. Nevertheless, TAVI leads to an acute improvement of nearly all invasively assessed variables in patients with PH, with a similar improvement in functional NYHA class compared to patients without PH, indicating a similar benefit among survivors.

Valvular aortic stenosis (AS) is a progressive disease that affects 2% of the population aged 65 years or older. The major cause of valvular AS in adults is calcification and fibrosis of a previously normal tricuspid valve or a congenital bicuspid valve, with rheumatic AS being rare in the United States. Once established, the rate of progression of valvular AS is quite variable and impossible to predict for any particular patient. Symptoms of AS are generally insidious at onset, though development of any of the three cardinal symptoms of angina, syncope, or heart failure portends a poor prognosis. Management of symptomatic AS remains primarily surgical, though transcatheter aortic valve replacement (TAVR) is becoming an accepted alternative to surgical aortic valve replacement (SAVR) for patients at high or prohibitive operative risk.

A six-year-old female goat was presented to the veterinary teaching hospital of the University of the West Indies with a history of progressive hind-limb paresis lasting two weeks. The doe developed a grade 6/6 holosystolic murmur during hospitalisation. Echocardiography revealed vegetative growths attached to cusps of the mitral and aortic valves. There was an accelerated aortic flow at 2.9 m/s and aortic insufficiency. The aortic vegetation was prolapsing into the left ventricle during diastole, causing it to contact the septal mitral valve leaflet. A diagnosis of mitral and aortic vegetative endocarditis, with a mitral kissing vegetation and mild aortic stenosis, was reached. The patient was placed on broad-spectrum antimicrobials. A short-term follow-up showed no resolution of clinical signs, and the animal eventually died. Post-mortem examination showed severe vegetative, fibrino-necrotic, aortic and mitral valve lesions. The goat also had a severe fibrino-suppurative mastitis. Histopathology confirmed the lesions to be vegetative endocarditis.

Although ischemic heart disease remains the leading cause of cardiac-related morbidity and mortality in the industrialized countries, a growing number of mainly elderly patients will experience a problem of valvular heart disease (VHD), often requiring surgical intervention at some stage. Doppler-echocardiography is the most popular imaging modality used in the evaluation of this disease entity. It encompasses, however, some non-negligible constraints which may hamper the quality and thus the interpretation of the exam. Cardiac catheterization has been considered for a long time the reference technique in this field, however, this technique is invasive and considered far from optimal. Cardiovascular magnetic resonance imaging (MRI) is already considered an established diagnostic method for studying ventricular dimensions, function and mass. With improvement of MRI soft- and hardware, the assessment of cardiac valve function has also turned out to be fast, accurate and reproducible. This review focuses on the usefulness of MRI in the diagnosis and management of VHD, pointing out its added value in comparison with more conventional diagnostic means.