Congenital Valve Malformations Research Articles

Identification of congenital aortic valve malformations in juvenile natriuretic peptide receptor 2-deficient mice using high-frequency ultrasound.

Mouse models of congenital aortic valve malformations are useful for studying disease pathobiology, but most models have incomplete penetrance [e.g., ∼2 to 77% prevalence of bicuspid aortic valves (BAVs) across multiple models]. For longitudinal studies of pathologies associated with BAVs and other congenital valve malformations, which manifest over months in mice, it is operationally inefficient, economically burdensome, and ethically challenging to enroll large numbers of mice in studies without first identifying those with valvular abnormalities. To address this need, we established and validated a novel in vivo high-frequency (30 MHz) ultrasound imaging protocol capable of detecting aortic valvular malformations in juvenile mice. Fifty natriuretic peptide receptor 2 heterozygous mice on a low-density lipoprotein receptor-deficient background (Npr2+/-;Ldlr-/-; 32 males and 18 females) were imaged at 4 and 8 wk of age. Fourteen percent of the Npr2+/-;Ldlr-/- mice exhibited features associated with aortic valve malformations, including 1) abnormal transaortic flow patterns on color Doppler (recirculation and regurgitation), 2) peak systolic flow velocities distal to the aortic valves reaching or surpassing ∼1,250 mm/s by pulsed-wave Doppler, and 3) putative fusion of cusps along commissures and abnormal movement elucidated by two-dimensional (2-D) imaging with ultrahigh temporal resolution. Valves with these features were confirmed by ex vivo gross anatomy and histological visualization to have thickened cusps, partial fusions, or Sievers type-0 bicuspid valves. This ultrasound imaging protocol will enable efficient, cost effective, and humane implementation of studies of congenital aortic valvular abnormalities and associated pathologies in a wide range of mouse models.NEW & NOTEWORTHY We developed a high-frequency ultrasound imaging protocol for diagnosing congenital aortic valve structural abnormalities in 4-wk-old mice. Our protocol defines specific criteria to distinguish mice with abnormal aortic valves from those with normal tricuspid valves using color Doppler, pulsed-wave Doppler, and two-dimensional (2-D) imaging with ultrahigh temporal resolution. This approach enables early identification of valvular abnormalities for efficient and ethical experimental design of longitudinal studies of congenital valve diseases and associated pathologies in mice.

Insights into the Inherited Basis of Valvular Heart Disease.

PURPOSEOF REVIEW: Increases in the availability of genetic data and advances in the tools and methods for their analyses have enabled well-powered genetic association studies that have significantly enhanced our understanding of the genetic factors underlying both rare and common valve diseases. Valvular heart diseases, such as congenital valve malformations and degenerative valve lesions, increase the risk of heart failure, arrhythmias, and sudden death. In this review, we provide an updated overview of our current understanding of the genetic mechanisms underlying valvular heart diseases. With a focus on discoveries from the past 5years, we describe recent insights into genetic risk and underlying biological pathways. RECENT FINDINGS: Recently acquired knowledge around valvular heart disease genetics has provided important insights into novel mechanisms related to disease pathogenesis. Newly identified risk loci associated valvular heart disease mainly regulate the composition of the extracellular matrix, accelerate the endothelial-to-mesenchymal transition, contribute to cilia formation processes, and play roles in lipid metabolism. Large-scale genomic analyses have identified numerous risk loci, genes, and biological pathways associated with degenerative valve disease and congenital valve malformations. Shared risk genes suggest common mechanistic pathways for various valve pathologies. More recent studies have combined cardiac magnetic resonance imaging and machine learning to offer a novel approach for exploring genotype-phenotype relationships regarding valve disease. Progress in the field holds promise for targeted prevention, particularly through the application of polygenic risk scores, and innovative therapies based on the biological mechanisms for predominant forms of valvular heart diseases.

Improvement of Dyspnea and Palpitations of Cardiac Origin Using Comprehensive Traditional Korean Medicine Treatment Including <italic>Bangibokryeong-tang</italic> (<italic>Fangji Fuling</italic> Decoction) : A Case Report

This case report demonstrates the effect of modified <i>Bangibokryeong-tang</i> (<i>Fangji Fuling</i> Decoction), a traditional herbal prescription in treating dyspnea and palpitations, symptoms that often lead to anxiety and reduced quality of life of cardiac patients. A female patient in her late 70s with congenital valve malformation and atrial fibrillation presented with dyspnea and palpitations, each rated at a severity of 8 on a numeric rating scale (NRS). After voluntarily discontinuing Western medication, she received modified BGBRT for 25 days, leading to significant symptom relief and NRS improvement to 0-2. The patient reported maintaining an improved condition and showed a significant increase in vitality. This improvement was sustained for 7 months, but the symptoms recurred; thus, modified BGBRT was restarted. Modified BGBRT showed substantial effects on persistent cardiac-origin dyspnea and palpitations. Thus, this TKM has the potential to manage symptoms and enhance the quality of life of cardiac patients.

How to counteract the lack of donor tissue in cardiac surgery? Initial experiences with a newly established homograft procurement program

Homograft heart valves may have significant advantages and are preferred for the repair of congenital valve malformations, especially in young women of childbearing age, athletes and in patients with active endocarditis. A growing problem, however, is the mismatch between tissue donation and the increasing demand. The aim of this paper is to describe the initiation process of a homograft procurement program to attenuate the shortage of organs. A comprehensive description of the infrastructure and procedural steps required to initiate a cardiac and vascular tissue donation program combined with a prospective follow-up of all homografts explanted at our institution. Between January 2020 and May 2022, 28 hearts and 12 pulmonary bifurcations were harvested at our institution and delivered to the European homograft bank. Twenty-seven valves (19 pulmonary valves, 8 aortic valves) were processed and allocated for implantation. The reasons for discarding a graft were either contamination (n = 14), or morphology (n = 13) or leaflet damage (n = 2). Five homografts (3 PV, 2 AV) have been cryopreserved and stored while awaiting allocation. One pulmonary homograft with a leaflet cut was retrieved by bicuspidization technique and awaits allocation, as a highly requested small diameter graft. The implementation of a tissue donation program in cooperation with a homograft bank can be achieved with reasonable additional efforts at a transplant center with an in-house cardiac surgery department. Challenging situations with a potential risk of tissue injury during procurement include re-operation, harvesting by a non-specialist surgeon and prior central cannulation for mechanical circulatory support.

Etiology of valvular heart disease-genetic and developmental origins.

Valvular heart disease occurs as either a congenital or acquired condition and advances in medical care have resulted in valve disease becoming increasingly prevalent. Unfortunately, treatments remain inadequate because of our limited understanding of the genetic and molecular etiology of diseases affecting the heart valves. Therefore, surgical repair or replacement remains the most effective option, which comes with additional complications and no guarantee of life-long success. Over the past decade, there have been significant advances in our understanding of cardiac valve development and, not surprisingly, mutations in these developmental genes have been identified in humans with congenital valve malformations. Concurrently, there has been a greater realization that acquired valve disease is not simply a degenerative process. Molecular investigation of acquired valve disease has identified that numerous signaling pathways critical for normal valve development are re-expressed in diseased valves. This review will discuss recent advances in our understanding of the development of the heart valves, as well as the implications of these findings on the genetics of congenital and acquired valvular heart disease.

Transcriptional regulation of heart valve development and disease

Aortic valve disease is estimated to affect 2% of the United States population. There is increasing evidence that aortic valve disease has a basis in development, as congenital valve malformations are prevalent in patients undergoing valve replacement surgery. In fact, a number of genetic mutations have been linked to valve malformations and disease. In the initial stages of aortic valve pathogenesis, the valvular interstitial cells become activated, undergo cell proliferation, and participate in extracellular matrix remodeling. Many of these cell properties are shared with mesenchymal progenitor cells of the normally developing valves and bones. Historically, valve calcification was thought to be a passive process reflecting end-stage disease. However, recent evidence describes the increased expression of transcription factors in diseased AoV that are common to valvulogenic and osteogenic processes. These studies lend support to the idea that a developmental gene program is reactivated in aortic valve disease and may contribute to the molecular mechanisms underlying valve calcification in disease.

Heart Valve Development

In recent years, significant advances have been made in the definition of regulatory pathways that control normal and abnormal cardiac valve development. Here, we review the cellular and molecular mechanisms underlying the early development of valve progenitors and establishment of normal valve structure and function. Regulatory hierarchies consisting of a variety of signaling pathways, transcription factors, and downstream structural genes are conserved during vertebrate valvulogenesis. Complex intersecting regulatory pathways are required for endocardial cushion formation, valve progenitor cell proliferation, valve cell lineage development, and establishment of extracellular matrix compartments in the stratified valve leaflets. There is increasing evidence that the regulatory mechanisms governing normal valve development also contribute to human valve pathology. In addition, congenital valve malformations are predominant among diseased valves replaced late in life. The understanding of valve developmental mechanisms has important implications in the diagnosis and management of congenital and adult valve disease.

Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome

Noonan syndrome (NS) is the most common nonchromosomal genetic disorder associated with cardiovascular malformations. The most prominent cardiac defects in NS are pulmonary valve stenosis and hypertrophic cardiomyopathy. Gain-of-function mutations in the protein tyrosine phosphatase Shp2 have been identified in 50% of NS families. We created a NS mouse model with selective overexpression of mutant Shp2 (Q79R-Shp2) in the developing endocardial cushions. In our model, Cre recombinase driven by the Tie2 promoter irreversibly activates transgenic Q79R-Shp2 expression in the endothelial-derived cell lineage. Q79R-Shp2 expression resulted in embryonic lethality by embryonic day 14.5. Importantly, mutant embryos showed significantly enlarged endocardial cushions in the atrioventricular canal and in the outflow tract. In contrast, overexpression of wild-type Shp2 protein at comparable levels did not enhance endocardial cushion growth or alter the morphology of the mature adult valves. Expression of Q79R-Shp2 was accompanied by increased ERK1/2 activation in a subset of cells within the cushion mesenchyme, suggesting that hyperactivation of this signaling pathway may play a pathogenic role. To test this hypothesis in vivo, Q79R-Shp2-expressing mice were crossed with mice carrying either a homozygous ERK1 or a heterozygous ERK2 deletion. Deletion of ERK1 completely rescued the endocardial cushion phenotype, whereas ERK2 protein reduction did not affect endocardial cushion size. Constitutive hyperactivation of ERK1/2 signaling alone with a transgenic approach resulted in a phenocopy of the valvular phenotype. The data demonstrate both necessity and sufficiency of increased ERK activation downstream of Shp2 in mediating abnormal valve development in a NS mouse model.

Valve Replacement in Children: Early and Late Results

In order to analyze the problems associated with prosthetic valve replacement (PVR) in the pediatric population, we have reviewed 29 children, 3.5 to 15 years of age, who were operated upon from 1970 to 1986. The indications were congenital valve malformations in 16 patients, rheumatic valve disease in 7, degenerative disease in 2 and bacterial endocarditis in 4. Ten children underwent aortic valve replacement (AVR), 14 mitral valve replacement (MVR), 1 tricuspid valve replacement and 4 double valve replacement (mitral-aortic in 3 and mitral-tricuspid in 1). Twenty-one mechanical (11 aortic and 10 mitral) and 12 biological prostheses (8 mitral, 2 aortic, and 2 tricuspid) were implanted. There was 1 hospital death (3.4%). Follow-up data were available for all survivors from 3 to 184 months. There were 8 late deaths (5.9% patient-year), 4 among children with mechanical and 4 among those with biological prostheses. Overall actuarial survival at 14 years is 62.5 +/- 10.2% with no significant difference in survival between AVR (77.8 +/- 14%) and MVR (44.4 +/- 16%) (p = 0.31) at 10 years and between recipients of mechanical (65.7 +/- 13%) or biological prostheses (60.0 +/- 15%) (p = 0.62) at 6 years. No documented embolic or anticoagulant-related complications occurred in the entire series.(ABSTRACT TRUNCATED AT 250 WORDS)

Six-year follow-up of glutaraldehyde-preserved heterografts: With particular reference to the treatment of congenital valve malformations

Glutaraldehyde preservation for the preparation of heterograft valves, a process which we introduced in 1968, has been responsible for considerable improvements in long-term clinical results. We have based this report on results obtained in the first 104 patients operated upon between March, 1968, and March, 1973. Eighty-two patients had acquired valvular disease, and the other 22 had congenital valvular malformations, including 7 with Ebstein's anomaly and 8 with absence of the pulmonary valve. The hospital mortality rate was 18 per cent in the group with congenital disease and 11 per cent in the group with acquired valvular disease. We noted that 6.5 per cent of the deaths occurred in single valve replacement and 16 per cent in multiple valve replacement. Three late deaths were valve related. There were 2 cases of acute bacterial endocarditis postoperatively and 7 cases of valve dysfunction 1, 4, 4.5, and 5 years after the operation. Histologic examination showed no evidence of immunologic reaction. Cusp perforations developed as a result of localized areas of collagen degeneration. In 67 patients, valve function remains excellent. Hemodynamic data are available in 11 patients. The various factors affecting valve preparation and durability are discussed in this report, and the present role of the glutaraldehyde-preserved heterograft valve in cardiac valve replacement is evaluated.