Congenital Valvular Defects Research Articles

Compound Heterozygous PLD1 Variants in Right-Sided Heart Malformations

We report a three-year-old male child who presented with congenital valvular defects, right ventricular malformation, and initial developmental delay. Genome sequencing showed rare deleterious biallelic missense variants in <i>PLD1</i>. In his parents’ second pregnancy, echocardiogram at 13 weeks gestation revealed right-sided cardiac malformations resembling the clinical presentation of the family’s first child. Targeted DNA analysis showed that the fetus carried the same biallelic <i>PLD1</i> variants as their older sibling. This case helps to further delineate the clinical spectrum of <i>PLD1</i>-related defects and highlights the value of both genome sequencing in congenital heart disease and early fetal echocardiography to establish phenotype.

Stress echocardiography. Part II: Stress echocardiography in conditions other than coronary heart disease.

Stress echocardiography (stress echo), with use of both old and new ultrasonographic cardiac function imaging techniques, has nowadays become a widely available, safe and inexpensive diagnostic method. Cardiac stress, such as exercise or an inotropic agent, allows for dynamic assessment of a wide range of functional parameters describing ventricles, heart valves and pulmonary circulation. In addition to diagnosis of ischemic heart disease, stress echocardiography is also used in patients with acquired and congenital valvular defects, hypertrophic cardiomyopathy, dilated cardiomyopathy as well as diastolic and systolic heart failure. Physical exercise is the recommended stressor in patients with aortic and especially mitral valvular disease. Nevertheless, dobutamine stress echo is useful for the assessment of contractile and flow reserve in aortic stenosis with reduced left ventricular ejection fraction. Stress echo should always be performed by an appropriately trained cardiologist assisted by a nurse or another doctor, in the settings of an adequately equipped echocardiographic laboratory and with compliance to safety requirements. Moreover, continuous education of cardiologists performing stress echo is needed.

Stem Cell Cytoskeletal Responses to Pulsatile Flow in Heart Valve Tissue Engineering Studies.

Heart valve replacement options remain exceedingly limited for pediatric patients because they cannot accommodate somatic growth. To overcome this shortcoming, heart valve tissue engineering using human bone marrow stem cells (HBMSCs) has been considered a potential solution to the treatment of critical congenital valvular defects. The mechanical environments during in vitro culture are key regulators of progenitor cell fate. Here, we report on alterations in HBMSCs, specifically in their actin cytoskeleton and their nucleus under fluid-induced shear stresses of relevance to heart valves. HBMSCs were seeded in microfluidic channels and were exposed to the following conditions: pulsatile shear stress (PSS), steady shear stress (SS), and no flow controls (n = 4/group). Changes to the actin filament structure were monitored and subsequent gene expression was evaluated. A significant increase (p < 0.05) in the number of actin filaments, filament density and angle (between 30° and 84°), and conversely a significant decrease (p < 0.05) in the length of the filaments were observed when the HBMSCs were exposed to PSS for 48 h compared to SS and no flow conditions. No significant differences in nuclear shape were observed among the groups (p > 0.05). Of particular relevance to valvulogenesis, klf2a, a critical gene in valve development, was significantly expressed only by the PSS group (p < 0.05). We conclude that HBMSCs respond to PSS by alterations to their actin filament structure that are distinct from SS and no flow conditions. These changes coupled with the subsequent gene expression findings suggest that at the cellular level, the immediate effect of PSS is to initiate a unique set of quantifiable cytoskeletal events (increased actin filament number, density and angle, but decrease in filament length) in stem cells, which could be useful in the fine-tuning of in vitro protocols in heart valve tissue engineering.

Cardiac, mandibular and thymic phenotypical association indicates that cranial neural crest underlies bicuspid aortic valve formation in hamsters.

Bicuspid aortic valve (BAV) is the most prevalent human congenital cardiac malformation. It may appear isolated, associated with other cardiovascular malformations, or forming part of syndromes. Cranial neural crest (NC) defects are supposed to be the cause of the spectrum of disorders associated with syndromic BAV. Experimental studies with an inbred hamster model of isolated BAV showed that alterations in the migration or differentiation of the cardiac NC cells in the embryonic cardiac outflow tract are most probably responsible for the development of this congenital valvular defect. We hypothesize that isolated BAV is not the result of local, but of early alterations in the behavior of the NC cells, thus also affecting other cranial NC-derived structures. Therefore, we tested whether morphological variation of the aortic valve is linked to phenotypic variation of the mandible and the thymus in the hamster model of isolated BAV, compared to a control strain. Our results show significant differences in the size and shape of the mandible as well as in the cellular composition of the thymus between the two strains, and in mandible shape regarding the morphology of the aortic valve. Given that both the mandible and the thymus are cranial NC derivatives, and that the cardiac NC belongs to the cephalic domain, we propose that the causal defect leading to isolated BAV during embryonic development is not restricted to local alterations of the cardiac NC cells in the cardiac outflow tract, but it is of pleiotropic or polytopic nature. Our results suggest that isolated BAV may be the forme fruste of a polytopic syndrome involving the cranial NC in the hamster model and in a proportion of affected patients.

Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy.

Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). These aortic phenotypes appear to be independent of BAV phenotype, have different embryologic origins and have unique etiologic factors, notably, regarding the role of hemodynamic changes inherent to the BAV phenotype. Further, in contrast to Marfan syndrome, the AAD seen with BAV is infrequently present as a strongly inherited syndromic phenotype; rather, it appears to be a less-penetrant, milder phenotype. Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. Although it is an attractive hypothesis to ascribe common mechanisms to BAV and AAD, thus far the genetic etiologies of AAD have not been associated to the genetic etiologies of BAV, notably, not including BAV variants in NOTCH1 and GATA4.

Options for Incidental Moderate Aortic Stenosis During Concomitant Valve Surgery: A Clinical Update for the Perioperative Echocardiographer.

nearly 10% over age 80 years, with eventual progression to severe AS once mild obstruction has developed. 3 Furthermore, adults with congenital heart disease comprise a growing proportion of patients with VHD, with published data pointing to approximately 1 million adult patients in the US alone. 4,5 More than 50% of these patients will need repeat cardiac surgery. 6 Bicuspid aortic valve, a common cause of AS in adults, is the most common congenital valvular defect, with an estimated prevalence of 1% to 2% in the general population. 7 The costs of AS alone as a component of valvular heart disease have been estimated to have an annual direct cost of at least $1 billion. 8 Given that AS is common in patients with valvular heart disease, the clinical scenario of incidental AS in adult cardiac surgical patients presenting for valvular surgery will fall into the practice of the perioperative echocardiographer. This expert review will outline the management options for this scenario in the era of detailed guidelines, 3-dimensional (3D) echocardiography, and transcatheter aortic valve replacement (TAVR). 9

Accurate Assessment of Aortic Stenosis

Aortic valve (AV) stenosis is one of the most common valvular diseases and is the third most common cardiovascular disease in developed countries. It occurs in ≈2.8% of patients ≥75 years of age and can occur because of degenerative calcification and congenital valvular defects such as bicuspid AVs or rheumatic disease.1–3 Calcific aortic stenosis (AS) is associated with increased leaflet stiffness and a narrowed AV orifice, resulting in increased pressure gradients across the valve. The presence of a bicuspid AV significantly increases the risk of AS.4 The natural history of AS is a prolonged asymptomatic period, with progressive reduction of the AV orifice area due to sclerosis initially, culminating in calcific AS. This is accompanied by a corresponding increase in the transaortic pressure gradient (Δ P ) and myocardial pressure overload. Through the preload reserve, the left ventricle (LV) compensates for the increased workload until the sarcomeres stretch to their maximum diastolic length. Once the preload reserve is exhausted, increases in afterload are accompanied by a reduction in stroke volume (SV), resulting in afterload mismatch. Ultimately, this causes LV hypertrophy, associated with an enlargement of cardiac myocytes and increased LV wall thickness.5 Initial diagnosis of AS typically occurs during routine physical examination with the presence of a heart murmur, click, or other abnormal sounds, but undiagnosed patients may experience the onset of severe symptoms such as angina, syncope, and heart failure. Without intervention, patient mortality typically occurs within 5 years of the onset of symptoms.6–11 Multiple studies and reviews have focused on the clinical aspects of this disease, including disease progression, markers of disease severity, treatment guidelines, and outcomes.1–3,6,12–16 Very few reviews have focused on the hemodynamic principles underlying AS and on comparing data obtained across different …

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.

Survey of cardiovascular disease among Africans in the vicinity of the Albert Schweitzer hospital in 1960

In a six month survey at the Albert Schweitzer Hospital near Lambaréné, in the Republic of Gabon, West Africa, one half of nearly 800 natives were found to have some type of cardiovascular disease. The rate was over twice as great among patients at the hospital as among residents in neighboring villages made up of seven principal tribal groups represented at the hospital. Rheumatic heart disease was the most common entity with a prevalence rate for mitral stenosis of nearly 6 per cent. This was the only disease found to have a significantly different prevalence in different tribes; the most Europeanized Bantu group had almost none and the largest group, which is non-Bantu, appeared to have the most. Hypertensive and congenital cardiovascular diseases were also common, but coronaryheart disease, so far as we could determine, was practically nonexistent. The reason for this rarity was not possible to determine, but it is evident that diet and many other factors thought to have a causal relationship among these people are quite different from those in the United States. Endomyocardial fibrosis and other cardiopathies uncommon in the United States are quite prevalent in this part of Africa, again with the causative factors unknown. The importance of follow-up study of these people to provide better understanding of these enigmatic diseases is stressed, and the importance of providing surgical correction when indicated for rheumatic and congenital valvular defects is pointed out.