Physiological Growth, Remodeling Potential, and Preserved Function of a Novel Bioprosthetic Tricuspid Valve: Tubular Bioprosthesis Made of Small Intestinal Submucosa-Derived Extracellular Matrix.

BACKGROUND: Prosthetic valves currently used in children lack the ability to grow with the patient and often require multiple reoperations. Small intestinal submucosa-derived extracellular matrix (SIS-ECM) has been used successfully as a patch for repair in various tissues, including vessels, valves, and myocardium. OBJECTIVES: This study sought to assess the remodeling potential of a tubular tricuspid valve (TV) bioprosthesis made of SIS-ECM by evaluating its growth, structure, and function in a growing ovine model. METHODS: A total of 12 3-month-old lambs were studied for a period of 3 or 8 months. SIS-ECM TVs were placed in 8 lambs; conventional bioprosthetic valves and native valves (NV) were studied as controls. All lambs underwent serial echocardiography, measuring annulus diameter and valve and right ventricular function. RESULTS: The SIS-ECM valves demonstrated an incremental increase in annular diameter similar to NV. SIS-ECM valve function was normal in 7 of 8; 1 valve had severe regurgitation due to a flail leaflet. Explanted SIS-ECM valves approximated native tissue in gross appearance. Histopathology demonstrated migration of resident mesenchymal cells into the scaffold and trilaminar ECM organization similar to an NV, without inflammation or calcification at 8 months. Ex vivo mechanical testing of SIS-ECM valve tissue showed normalization of the elastic modulus by 8 months. CONCLUSIONS: In an ovine model, tubular SIS-ECM TV bioprostheses demonstrate "growth" and a cell-matrix structure similar to mature NVs while maintaining normal valve function. The SIS-ECM valve may provide a novel solution for TV replacement in children and adults.

Developmental changes in left and right ventricular function evaluated with color tissue Doppler imaging and strain echocardiography.

AIMS: We evaluated the systolic and diastolic functions of both ventricles from the early neonatal period to adolescence using color tissue Doppler imaging and 2-dimensional tissue tracking echocardiography. METHODS: We examined 100 healthy children (aged 1-5 days, n = 20; 1 month, n = 20; 1 year, n = 20; 6-7 years, n = 20; and 12-13 years, n = 20). Blood flow velocities in the mitral and tricuspid valves (E) were obtained with pulsed Doppler imaging, and longitudinal systolic (S') and early diastolic (E') peak velocities at the mid free wall segment of both ventricles were obtained with color tissue Doppler imaging. For longitudinal strain imaging, systolic peak values were obtained at the same position. In addition, peak systolic radial strain was obtained from a short-axis view of the left ventricle using the tissue tracking method. The E/E' ratio was calculated. RESULTS: Regarding systolic indices, S' increased during development and stabilized at 6 to 7 years, and longitudinal strain reached values of the 12- to 13-year-old group at 1 year of age in both ventricles. Like longitudinal strain, radial strain in the left ventricle reached values of the 12- to 13-year-old group at the age of 1 year. Similarly, the E/E' ratio was high at 1 month or younger and decreased by 1 year. CONCLUSIONS: Systolic and diastolic variables change markedly from birth to 1 year of age and show only small changes thereafter.

Mitral and tricuspid valve repair and growth in unbalanced atrial ventricular canal defects.

OBJECTIVE: Congenital mitral and tricuspid valve abnormalities in unbalanced atrioventricular canal defects are complex. We designed procedures to both repair and induce growth of hypoplastic atrioventricular valves and ventricles to achieve 2-ventricle repairs. Midterm data were assessed for reliability of catch-up growth, resulting quality of atrioventricular valves, and adequacy of 2-ventricle repairs. METHODS: The 24 consecutive infants (14 female and 10 male) with unbalanced atrioventricular canal defects had significant hypoplasia of 1 atrioventricular valve and/or ventricle (an echocardiography-derived z value of ≤-3.0 standard errors of the mean below expected). Operative approaches included the following: (1) Staged repair was performed, with complete valve repair, partial closure of the atrial septal, and ventricular septal defects, and (usually) pulmonary artery banding. After adequate growth, repair was completed. A vestigial mitral valve (4-7 mm) in 3 patients led to partitioning the large tricuspid valve, creating a second mitral valve. (2) Repair with a shift in atrioventricular valve partitioning was performed to increase hypoplastic atrioventricular valve size. (3) Repair with snared atrial septal defects and ventricular septal defect was performed to allow intracardiac shunting. The hypoplastic atrioventricular valves and hypoplastic ventricles were reassessed on local follow-up (5-15 years). RESULTS: The initial z scores were -2.8 to -7.4 for hypoplastic atrioventricular valves and -1.0 to -7.5 for hypoplastic ventricles. Follow-up z scores were -0.6 to -2.7 for hypoplastic atrioventricular valves and -2.0 to +1.8 for hypoplastic ventricles. Another 11 patients were also judged to be within normal limits. Three reoperations were for mitral valve regurgitation, and 1 reoperation was for mitral valve replacement. One patient died of central nervous system bleed just before extracorporeal membrane oxygenation weaning, and 2 patients died of late potassium overdose, for an 88% survival. Survivors are well with 2-ventricle repairs, and 15 of 19 patients are not taking cardiac medications. CONCLUSIONS: Increasing atrioventricular valve flow reliably induced growth. Valve repair and growth achieved a 2-ventricle repair in all patients.

A biodegradable ring enables growth of the native tricuspid annulus.

BACKGROUND AND AIM OF THE STUDY: The study aim was to assess the growth potential and function of the tricuspid valve (TV) annulus after annuloplasty with the intra-annular biodegradable ring. METHODS: Among 11 children (median age 4.5 years; age range: 0.2-10.9 years) who underwent surgery for severe congenital TV regurgitation, valve repair was completed using a biodegradable annuloplasty ring. The children were followed regularly using transthoracic echocardiography, whereby the TV annulus lateral diameter (TVALD) and valve function were monitored. Rates of valve growth were derived from the slope of the regression equations which related TVALD to the natural logarithm of the body surface area (lnBSA). RESULTS: The children's somatic growth was harmonious throughout the entire follow up period (mean 478 days; range: 171-1,477 days). The TVALD differed significantly at six months and at one and two years after surgery compared to the postoperative value at discharge, rising from 19 mm (range: 15.5-26.0 mm) to 24 mm (range: 19.0-30.0 mm) at the last control examination (p = 0.003), while the related Z-scores remained stable. A significant linear correlation between TVALD and lnBSA was found in 63.6% of patients. The median rate of growth for the whole cohort was 1.96-fold (range: 0.52-5.53-fold) higher than a norm, and correlated strongly and positively with age (r = 0.91; p <0.05). The median postoperative TV insufficiency fraction of 9.8% (range: 0-28.8%) remained constant during the follow up period. The postoperative TV maximal pressure gradient was 5.5 mmHg (range: 3.1-12.2 mmHg), and did not increase over time. CONCLUSION: The implantation of a biodegradable ring does not restrict growth of the native TV annulus; this enabled its stabilization in proportion to the somatic growth in the majority of the children. The TV annulus began to change its dimension at six months postoperatively, which may coincide with its biodegradation. The rate of growth of the TV annulus differed from that in the normal population, and was proportional to the patient age. The increase in TV annulus diameter over time did not have any negative influence on the function of the repaired valve.

Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2.

Defects in heart development are the most common congenital abnormalities in humans, providing a strong incentive to learn more about the underlying causes. Previous studies have implicated the metalloprotease-disintegrins ADAMs (a disintegrin and metalloprotease) 17 and 19 as well as heparin binding EGF-like growth factor (HB-EGF) and neuregulins in heart development in mice. Here, we show that mice lacking both ADAMs 17 and 19 have exacerbated defects in heart development compared to mice lacking either ADAM, providing the first evidence for redundant or compensatory functions of ADAMs in development. Moreover, we identified additional compensatory or redundant roles of ADAMs 9 and 19 in morphogenesis of the mitral valve and cardiac outflow tract. Cell biological studies designed to address the functions of these ADAMs in shedding of HB-EGF uncovered a contribution of ADAM19 to this process, but this was only evident in the absence of the major HB-EGF sheddase, ADAM17. In addition, ADAM17 emerged as the major sheddase for neuregulins beta1 and beta2 in mouse embryonic fibroblasts. These results raise the possibility that ADAMs 9, 17, and 19 contribute to heart development in humans and have implications for understanding the mechanisms underlying congenital heart disease.

Atrioventricular valves of the mouse: II. Light and transmission electron microscopy.

BACKGROUND: Mouse atrioventricular (AV) valves present a number of conspicuous morphologic differences with human AV valves. Given the existence of these differences, it is important to know the structural organization of mouse AV valves. Since the mouse is often considered to be a good animal model for developmental and anatomical studies, the presence of significant differences in structure may render comparative studies difficult. In addition, we wished to learn about the existence of structural changes in the mouse AV valves with age. METHODS: The structural organization of mouse AV valves from 21 days to 1 year of age was studied by polarizing microscopy and by conventional light and transmission electron microscopy. RESULTS: Polarizing microscopy reveals the presence of a system of birefringent fibers that consist of collagen bundles that organize like tendons. The spatial organization of these fibers is different in the two AV valves, reflecting differences in the anatomy of the entire valvular complex. Interstitial cells (IC) are of two different phenotypes: some are typical fibroblasts, while some others share smooth muscle cell characteristics. In addition, small areas of fibrocartilage are also observed. The compactness and thickness of the collagen bundles increase with age. Also with age, the basement membranes become thickened or multilayered, and matrix vesicles and deposits of amyloid P can be observed. CONCLUSIONS: The collagenous birefringent fibers form an internal skeleton that should transmit the cycling stress evenly over the entire leaflets. IC should help to maintain the structure and deformability of the valve tissue and appear actively involved in the synthesis and renewal of extracellular material. The cartilaginous foci appear to be a normal component of the valve tissue. The structural changes observed in old animals appear to be related to the degenerative processes which take place in normal valvular tissues with age. Despite the structural differences, age changes appear to be similar in the AV valves of mouse and man.

Growth dynamics of the heart from perinatal period to childhood.

In order to obtain information useful for the diagnosis of fetus and newborn heart disease, we established a theoretical model of perinatal cardiac growth. We measured with the use of ultrasonic cross-section imaging system the mitral valve ring dimension, tricuspid valve ring dimension, and total cardiac dimension as morphological parameters of the heart in 45 cases composed of fetuses and children. The obtained data were entered into a computer. With the use of these data, simulation was made on the basis of the general theory of biological development. The present simulation showed that from the fetal stage to childhood the growth rates of the foregoing three morphological parameters mutually differ, but during the period of growth to the age of 12 years of the present study, they all demonstrated continuous growth up to 3 1/2 years after birth when they reached a growth saturation level.

Development of the autonomic ground plexus in the atrioventricular valves of the rat.

The development of the adrenergic and cholinergic innervation of the rat atrioventricular valves was studied in whole mount stretch preparations. Specimens obtained from rats ageing 2-30 days were processed for the histofluorescence and enzyme histochemical demonstration of monoamines and acetylcholinesterase (AChE) activity, respectively. Adrenergic and AChE-positive nerve fibres could be detected from the 9-10th postnatal days onwards. Fluorescence microscopy showed the presence of many brightly fluorescent mast cells in the close vicinity of the ingrowing terminals. The presence of mast cells during early stages of development of the ground plexus may be related either to the preneural state of the tissue or the structural and/or functional maturation of the autonomic nerve terminals.

Late right ventricular reconstruction following valvotomy in pulmonary atresia with intact ventricular septum.

Experience over two decades in the surgical management of pulmonary atresia with intact ventricular septum demonstrates that eventual right ventricular (RV) reconstruction is possible in the majority of patients surviving valvotomy in infancy. Ten of 17 operative survivors of early valvotomy have eventually received a patch graft to the RV outflow tract, with no reoperative deaths (mean follow-up, 7.4 years). RV systolic pressures, suprasystemic prior to reoperation, are near normal after outflow patch reconstruction. Serial cineangiograms show evidence of RV growth by measurement of tricuspid annulus diameter (TAD), and demonstrate a rate of growth [d(TAD)/d(body length)] greater than a normal rate derived from autopsy data. The mean TAD growth rate is significantly greater than that of patients with less favorable ventricle types treated with a systemic-pulmonary shunt alone. Measurement of TAD is a useful method for following RV growth, and may aid in selecting patients for RV reconstruction.