Symptomatic Valvular and Subvalvular Stenosis: A Case Report.

Aortic stenosis is a common valvular disease that is expected to become more prevalent with the aging population. It is often undiagnosed in socioeconomically deprived groups. Diagnosis relies on echocardiography, and additional imaging techniques such as cardiac computed tomography (CCT) and cardiovascular magnetic resonance (CMR) are increasingly used. Surgical aortic valve replacement is the standard treatment, except for high-risk cases where TAVR is recommended. Subvalvular aortic stenosis (SAS) is the second most common cause of left ventricular outflow tract obstruction. This case report highlights a 72-year-old Hispanic lady with both valvular and subvalvular aortic stenosis, emphasizing the need for specialized care and surgical intervention. Early identification, accurate assessment, and appropriate intervention are crucial for improving outcomes in aortic stenosis and subvalvular stenosis cases.

Cardiac Phenotype and Gene Mutations in RASopathies.

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.

Effect of body mass index on mortality for diabetic patients with aortic stenosis.

BACKGROUND: Several studies suggest an "obesity paradox," associating obesity with better cardiovascular outcomes in patients with type 2 diabetes mellitus (DM) or aortic stenosis (AS) compared to normal or underweight individuals. This study explores the impact of body mass index (BMI) on diabetic patients with AS. METHODS: Between 2014 and 2019, patients with DM who underwent echocardiography were analyzed. Outcomes included all-cause mortality, cardiovascular, and non-cardiovascular death. Patients were categorized as underweight, normal weight, or obese based on BMI (<18.5, 18.5 to 27, and >27 kg/m2, respectively). RESULTS: Among 74,835 DM patients, 734 had AS. Normal weight comprised 65.5% (n=481), underweight 4.1% (N=30), and 30.4% were obese. Over a 6-year follow-up, underweight patients had significantly higher all-cause mortality (HR 1.96, 95% CI 1.22 - 3.14, p = 0.005), while obese patients had significantly lower mortality (HR 0.79, 95% CI 0.68 - 0.91, p=0.001) compared to the normal group. Regarding etiologies, underweight patients had a higher risk of non-cardiovascular death (HR 2.47, 95% CI 1.44-4.25, p = 0.001), while obese patients had a lower risk of cardiovascular death (HR 0.66, 95% CI 0.50-0.86, p=0.003). Subgroup analysis showed a consistent trend without significant interaction. CONCLUSIONS: BMI significantly impacts mortality in DM patients with AS. Being underweight is associated with worse non-cardiovascular death, while obesity is linked to improved cardiovascular death outcomes.

Successful Chemotherapy Treatment for a Tricuspid Valvular Stenosis Patient due to Right Ventricular Lymphoma.

Background: This study presents a patient diagnosed with tricuspid valvular stenosis due to right ventricular lymphoma, who was treated successfully. Case presentation: A 66-year-old man with a history of worsening shortness of breath during activity for the last three weeks sought medical attention. The patient later experienced swelling in the extremities, fluid build-up around the lungs and abdominal fluid accumulation, with no reported chest pain, fever, or weight loss. An echocardiogram found a mass in the lateral wall near the tricuspid valve of the right ventricle, leading to moderate tricuspid stenosis. The cardiac magnetic resonance imaging (MRI) revealed a lumpy, poorly defined mass that invaded the heart muscle and displayed varied enhancement after contrast administration. Suspicion arose for a malignant tumour or metastatic lesion due to its features and contrast uptake capability. A percutaneous biopsy was carried out on the mass in the right ventricle to confirm the diagnosis. The pathology report indicated a diagnosis of non-Hodgkin's lymphoma. After being diagnosed, the patient underwent chemotherapy using the R-CHOP regimen. Over time the symptoms improved, and echocardiograms revealed a decrease in the size of the tumour. After undergoing six rounds of chemotherapy, a cardiac MRI four months later showed no signs of a tumour. After that, the patient resumed their regular activities. Conclusion: Right ventricular tumours are mostly malignant lesions and often have an inferior prognosis. Early diagnosis with imaging techniques and myocardial biopsy is necessary to deliver life-saving treatment quickly. LEARNING POINTS: Right ventricular tumours are mostly malignant lesions and often have an inferior prognosis.Early diagnosis with imaging techniques and myocardial biopsy is necessary to deliver life-saving treatment quickly.Right ventricular lymphoma is a sporadic tumour, but the prognosis is favourable if detected in time.

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.

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.

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.

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, whole-genome sequencing (WGS), RNA-seq and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined WGS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints match the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2Mb region on chromosome 9 with a SINE element insertion at the more distal breakpoint. Interestingly, this hypothesized genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by RNA-seq on blood 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 9p segregating with a familial congenital clinical trait, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.

Preconception consultation using treadmill exercise stress echocardiography for pregnant women with the left-sided heart valve stenosis: A preliminary report.

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.

Cardiac sympathetic dysfunction in left ventricular hypertrophy caused by arterial hypertension and degenerative aortic stenosis.

BACKGROUND: To evaluate cardiac sympathetic innervation in hypertensive patients with left ventricular (LV) hypertrophy (H) and aortic stenosis (AS) submitted to transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Twenty-two hypertensive elders (82 ± 5 years) with severe AS and significant LVH (> 122 g·m-2 in women and > 149 g·m-2 in men) were compared with 14 patients with uncomplicated essential hypertension (HT) with similar degree of LVH and 10 controls. 123I-metaiodobenzylguanidine (MIBG) and 99mTc-tetrofosmin SPECT acquisitions were obtained to assess sympathetic innervation and LV perfusion. The innervation/perfusion mismatch score was taken as an indicator of cardiac sympathetic dysfunction. The imaging protocol was repeated 6 months after TAVI. Regional MIBG uptake was more heterogeneous in HT and AS patients than controls, and therefore, innervation/perfusion mismatch score was higher in both AS (9 ± 8) and HT (5 ± 2) than controls (1 ± 1, P < .001). On multivariate analysis, significant LVH was the major predictor of impaired LV sympathetic innervation (OR 19.45, 95% CI 1.87-201.92; P = .013). After TAVI, no differences in measures of LV sympathetic innervation were evident, although only a marginal LV mass reduction was observed (- 5.4 ± 2.4 g). CONCLUSIONS: Cardiac sympathetic innervation is impaired in patients with LVH, either with AS or not, and is not impacted significantly by TAVI procedure.

Transthoracic Vector Flow Imaging in Pediatric Patients with Valvular Stenosis - A Proof of Concept Study.

Purpose Continuous wave Doppler ultrasound is routinely used to detect cardiac valve stenoses. Vector flow imaging (VFI) is an angle-independent real-time ultrasound method that can quantify flow complexity. We aimed to evaluate if quantification of flow complexity could reliably assess valvular stenosis in pediatric patients. Materials and Methods Nine pediatric patients with echocardiographically confirmed valvular stenosis were included in the study. VFI and Doppler measurements were compared with transvalvular peak-to-peak pressure differences derived from invasive endovascular catheterization. Results Vector concentration correlated with the catheter measurements before intervention after exclusion of one outlier (r=-0.83, p=0.01), whereas the Doppler method did not (r=0.49, p=0.22). The change in vector concentration after intervention correlated strongly with the change in the measured catheter pressure difference (r=-0.86, p=0.003), while Doppler showed a tendency for a moderate correlation (r=0.63, p=0.07). Conclusion Transthoracic flow complexity quantification calculated from VFI data is feasible and may be useful for assessing valvular stenosis severity in pediatric patients.

Acute rheumatic fever - A pathological analysis of clinically missed cases.

BACKGROUND: 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. AIMS: This study aims to analyze pathological profiles of such cases and their importance in context of clinical presentation and Jones criteria. MATERIALS AND METHODS: 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). STATISTICAL ANALYSIS: Nil. RESULTS: 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%). CONCLUSIONS: 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.

Homozygous Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis.Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases.This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing.

BACKGROUND: Pulmonary atresia (PA) is a kind of congenital heart disease characterized by right ventricular outflow tract obstruction. It is divided into PA with intact ventricular septum (PA/IVS) whose favorable form is pulmonary valvular stenosis (PS), and PA with ventricular septal defect (PA/VSD) whose favorable form is tetralogy of Fallot (TOF). Due to limitations in genetics etiology, whole-exome sequencing (WES) was utilized to identify new variants associated with the diseases. METHODS: The data from PS-PA/IVS (n = 74), TOF-PA/VSD (n = 100), and 100 controls were obtained. The common sites between PS and PA/IVS, PA/VSD and TOF, were compared. The novel rare damage variants, and candidate genes were identified by gene-based burden analysis. Finally, the enrichment analysis of differential genes was conducted between case and control groups. RESULTS: Seventeen rare damage variants located in seven genes were predicted to be associated with the PS through burden analysis. Enrichment analysis identified that the Wnt and cadherin signaling pathways were relevant to PS-PA/IVS. CONCLUSION: This study put forth seven candidate genes (APC, PPP1R12A, PCK2, SOS2, TNR, MED13, and TIAM1), resulting in PS-PA/IVS. The Wnt and cadherin signaling pathways were identified to be related to PS-PA/IVS by enrichment analysis. This study provides new evidence for exploring the genetic mechanism of PS-PA/IVS.

Elabela: A Novel Biomarker for Right Ventricular Pressure Overload in Children With Pulmonary Stenosis or Pulmonary Atresia With Intact Ventricular Septum.

Background: Assessing right ventricular overload in children is challenging. We conducted this study involving children with pulmonary valvular stenosis (PS) or pulmonary atresia with intact ventricular septum (PA/IVS) to evaluate the potential of a new endogenous ligand of apelin receptor, Elabela (ELA), as a potential biomarker for right heart overload. Methods: In this prospective cohort study, a total of 118 congenital heart diseases patients with right ventricle outflow tract obstruction were recruited from 2018 to 2019. Among them, 44 isolated PS and 7 PA/IVS patients were selected. Their venous blood was collected, and all patients underwent an echocardiographic examination. Among them, post-operative blood was collected from 24 patients with PS after percutaneous balloon pulmonary valvuloplasty. The plasma ELA concentration was measured using enzyme-linked immunosorbent assay. Results: The ELA was significantly associated with the peak transvalvular pulmonary gradient (r = -0.62; p = 0.02), thus reflecting the severity of PS or PA/IVS. The ELA significantly increased at 3 days after intervention, when mechanical obstruction of the right outflow tract was relieved. Based on the receiver-operator characteristic curve results, ELA could be a risk factor for duct dependence in patients with critical PS or PA/IVS who are younger than 6 months (AUC: 0.82). Conclusion: ELA concentration and severity of PS or PA/IVS had a significant negative correlation, indicating that ELA might be a novel biomarker for right ventricular afterload and reflect the immediate pressure changes in the right heart. Furthermore, ELA could predict duct-dependency in PS and PA/IVS patients, as valuable as classical echocardiographic indexes.

Cardiac Magnetic Resonance in Valvular Heart Disease: Assessment of Severity and Myocardial Remodeling.

Cardiac magnetic resonance (CMR) has emerged as the gold standard in assessing ventricular mass, volume, and systolic function. Due to these and other strengths, CMR has increasingly been used to study valvular heart disease (VHD) and resultant cardiac remodeling. By using CMR to assess flow, limitations in echocardiographic assessment of VHD can be overcome, particularly in regurgitant lesions. The following article reviews the current role of CMR imaging in studying disease severity and myocardial remodeling in patients with VHD.

Frequency Responses of Conventional and Amplified Stethoscopes for Measuring Heart Sounds.

BACKGROUND: Frequencies of normal and abnormal heart sounds have previously been reported, but the acoustic analyses of the frequency responses of conventional and amplified stethoscopes for different heart sounds have not yet been reported. OBJECTIVES: To compare the acoustic analysis of frequency responses of three stethoscopes (conventional and amplified) for measuring simulated heart sounds. MATERIALS AND METHODS: This exploratory study used Starkey SLI-ST3, Cardionics E-Scope II (both electronic) and Littmann Classic S.E. II (conventional) stethoscopes, as they share the same basic design with twin ear tubes coupled to ear tips and chest piece options (bell vs. diaphragm modes). Acoustic analyses using the diaphragm were performed in a soundproof booth and frequency response curves at 85 (the largest), 250, 400, 550 and 1050 Hz were compared for three different digitized heart sound simulations: normal, aortic valvular stenosis (AVS) and pulmonic valvular stenosis. RESULTS: Amplified stethoscopes provided the most amplification of normal and abnormal heart sounds across all five frequencies compared with the conventional stethoscope. The Starkey SLI-ST3 stethoscope was better at amplifying normal heartbeats than the Cardionics E-Scope II and Littman Classic S.E. II; however, it came last for amplifying normal heartbeats of ~85 Hz. Cardionics E-Scope II had advantages in amplifying abnormal heartbeats (i.e., aortic valvular stenosis and pulmonic valvular stenosis) over the other two stethoscopes. CONCLUSION: This study showed that amplified stethoscopes provided better amplification of normal and abnormal heart sounds across the five measured frequencies. Therefore, health professionals should interpret manufacturer claims regarding gain (dB) and frequency (Hz) with caution, and those with hearing loss should carefully investigate the "audio performance" of the stethoscopes. Future research should focus on these effects through coupling with hearing aids.

Isolated pulmonary valvular stenosis with equilateral triangle orifice.

Isolated congenital pulmonary valvular stenosis is a relatively common abnormality. A 52-year-old woman with an asymptomatic cardiac murmur since her childhood visited our hospital. The peak pressure gradient across the pulmonary valve (PV) was calculated 25 mmHg by Doppler velocity during the transthoracic echocardiography, the severity was graded into mild. The cardiac computed tomography indicated a dome-shaped PV with an equilateral triangle orifice without commissural fusion. No case has been described in a triangle orifice, it will be necessary to follow up carefully. .

Evaluation of the NuCLEUS-X™ balloon valvuloplasty catheter for severe pulmonic stenosis in dogs.

INTRODUCTION/OBJECTIVES: Balloon instability is commonly encountered during balloon pulmonary valvuloplasty (BPV) and may result in an unsuccessful procedure. The NuCLEUS-X™ catheter is a recently developed BPV catheter with a unique barbell shape and an ordered pattern of inflation that stabilizes the balloon to span the valve annulus before expansion of the balloon center. ANIMALS: Ten client-owned dogs with severe valvular pulmonic stenosis (PS). MATERIALS AND METHODS: Prospective observational study. The BPV procedure was performed by standard technique with use of NuCLEUS-X™ catheters targeting a balloon-to-annulus ratio between 1.2 and 1.5. Balloon stability, safety, and procedural success were assessed. Procedural success was defined as either a reduction in the Doppler transpulmonic PG by at least 50% of the pre-procedural PG or <80 mmHg one month post procedure. RESULTS: Balloon stability centered at the pulmonic valve on the first inflation was achieved in 10/10 cases. The mean PG before BPV was 141 mmHg ±41 mmHg, and the PG after BPV at one month was 83 mmHg ±41 mmHg. Procedural success was achieved in 56% of patients. All dogs survived the BPV, and no major procedural complications were encountered using the NuCLEUS-X™ catheter. CONCLUSIONS: The use of the NuCLEUS-X™ catheter is feasible for BPV in dogs with severe PS. The unique balloon shape provided catheter stability on the first inflation in all dogs, which may be beneficial when stabilization of a conventional BPV catheter cannot be achieved.

Rapid snare sliding technique: An easy approach to difficult percutaneous transmitral commissurotomy.

Rheumatic heart disease (RHD) is a major health hazard in most developing countries as well as sporadically in developed economies with high prevalence rates. Mitral stenosis is among the important morbid valvular conditions accounting for 25% of RHD cases. Percutaneous transmitral commissurotomy (PTMC) using Inoue balloon is the standard treatment for severe mitral stenosis with favorable Wilkins score. In certain cases it is difficult to cross mitral valve (MV) either due to dilated left atrium (LA), low septal puncture, or severe mitral valvular and subvalvular stenosis leading to prolonged procedure time or failure of PTMC procedure. We describe a case of RHD with severe mitral stenosis and dilated LA where crossing MV was difficult and successful PTMC was performed using rapid snare sliding technique to cross the MV. .