Maturation of heart valve cell populations during postnatal remodeling.

Heart valve cells mediate extracellular matrix (ECM) remodeling during postnatal valve leaflet stratification, but phenotypic and transcriptional diversity of valve cells in development is largely unknown. Single cell analysis of mouse heart valve cells was used to evaluate cell heterogeneity during postnatal ECM remodeling and leaflet morphogenesis. The transcriptomic analysis of single cells from postnatal day (P)7 and P30 murine aortic (AoV) and mitral (MV) heart valves uncovered distinct subsets of melanocytes, immune and endothelial cells present at P7 and P30. By contrast, interstitial cell populations are different from P7 to P30. P7 valve leaflets exhibit two distinct collagen- and glycosaminoglycan-expressing interstitial cell clusters, and prevalent ECM gene expression. At P30, four interstitial cell clusters are apparent with leaflet specificity and differential expression of complement factors, ECM proteins and osteogenic genes. This initial transcriptomic analysis of postnatal heart valves at single cell resolution demonstrates that subpopulations of endothelial and immune cells are relatively constant throughout postnatal development, but interstitial cell subpopulations undergo changes in gene expression and cellular functions in primordial and mature valves.

Evidence of subannular and left ventricular morphological differences in patients with bicuspid versus tricuspid aortic valve stenosis: magnetic resonance imaging-based analysis.

Objectives: Prospective analysis of left ventricular (LV) morphological/functional parameters in patients with bicuspid versus tricuspid aortic valve (TAV) stenosis undergoing aortic valve replacement (AVR) surgery. Methods: A total of 190 consecutive patients with BAV ( n = 154) and TAV stenosis ( n = 36) (mean age 61 ± 8 years, 65% male) underwent AVR ± concomitant aortic surgery from January 2012 through May 2015. All patients underwent preoperative cardiac magnetic resonance imaging in order to evaluate: (i) left ventricular outflow tract (LVOT) dimensions, (ii) length of anterior mitral leaflet (AML), (iii) end-systolic and end-diastolic LV wall thickness, (iv) LV area, (v) LV end-systolic and end-diastolic diameters (LVESD, LVEDD), (vi) LV end-diastolic and end-systolic volumes (LVEDV, LVESV) and (vii) maximal diameter of aortic root. These parameters were compared between the two study groups. Results: The LVOT diameter was significantly larger in BAV patients (21.7 ± 3 mm in BAV vs 18.9 ± 3 mm in TAV, P < 0.001). Moreover, BAV patients had significantly longer AML (24 ± 3 mm in BAV vs 22 ± 4 mm in TAV, P = 0.009). LVEDV and LVESV were significantly larger in BAV patients (LVEDV: 164.9 ± 68.4 ml in BAV groups vs 126.5 ± 53.1 ml in TAV group, P = 0.037; LVESV: 82.1 ± 57.9 ml in BAV group vs 52.9 ± 25.7 ml in TAV group, P = 0.008). A strong linear correlation was found between LVOT diameter and aortic annulus diameter in BAV patients ( r = 0.7, P < 0.001), whereas significantly weaker correlation was observed in TAV patients ( r = 0.5, P = 0.006, z = 1.65, P = 0.04). Presence of BAV morphology was independently associated with larger LVOT diameters (OR 9.0, 95% CI 1.0-81.3, P = 0.04). Conclusions: We found relevant differences in LV morphological/functional parameters between BAV and TAV stenosis patients. Further investigations are warranted in order to determine the cause of these observed differences.

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.

Annulus upsizing for mitral valve re-replacement in children.

BACKGROUND: Mitral valve replacement remains the last resort for treatment of congenital mitral valve disease. Enlarging the mitral annulus at the time of mitral valve replacement may allow implantation of a larger prosthesis in children. METHODS: All mitral valve replacement procedures from 1990 to 2012 were included, and mitral annulus enlargement techniques were analyzed. A control group of patients undergoing replacement of a previously implanted mechanical mitral valve prosthesis was compared with the cohort of patients who underwent annular enlarging procedures. Primary end points were increases in annulus size and Z score, and freedom from paced rhythm. RESULTS: Among 205 mitral valve replacement procedures, 16 (8%) included techniques to upsize the mitral annulus in 15 patients, all but 1 of whom had undergone prior mitral valve replacement. These patients were compared with a control cohort of 53 patients undergoing mitral valve re-replacement without annulus enlargement. The annulus was upsized by 18% ± 11% (compared with 16% ± 20% in controls, P = .5) using open balloon dilation in 4 patients, radial annular incisions in 5 patients, and patch augmentation of the aorto-mitral continuity in 7 patients. The mean valvar diameter Z score increased from -0.2 ± 1.3 to +1.1 ± 1.4 (P < .001), compared with an increase from -0.3 ± 1.2 to 0.9 ± 1.1 in controls (P < .001). During a mean follow-up of 6.5 ± 6.4 years, 4 of 12 patients required permanent pacing in the upsizing group (predominantly with patch augmentation), versus 5 of 53 patients in the control group. CONCLUSIONS: In children undergoing mitral valve replacement, various techniques can be used to upsize the mitral annulus and allow implantation of a larger prosthesis. There is a nontrivial risk of heart block with annulus upsizing, which deserves further study.

Structural changes of rat mitral valve chordae tendineae during postnatal development.

BACKGROUND AND AIM OF THE STUDY: Mitral valve chordae tendineae are an essential component for correct functioning of the human heart. The microstructural make-up of the chordae is responsible for their tensile properties, and is seen gradually to change with age. However, little is known of the maturation of chordae tendineae and their microstructure. METHODS: To examine such maturation, structural changes in chordae tendineae were studied in rats at 1, 3, 7, 15 and 30 days of postnatal life, and in adult rats. Differences in the chordae microstructure of each age group were observed using light microscopy. The collagen fibril crimp period was determined using polarized light microscopy. RESULTS: At day 1 after birth the chordae had yet to develop, and the lateral sides of the mitral valve leaflets were completely attached to the papillary muscles. Chordae developed through the formation of gaps in the leaflet tissue. From day 7 on, numerous chordae were seen. As the chordae matured, crimped collagen fibrils were formed and began to align in a longitudinally packed core with increasing density. The collagen fibril crimp period increased significantly with the age of the animal. CONCLUSION: Rat chordae tendineae have yet to develop at postnatal day 1. Morphological development and microstructural maturation of the chordae are not completed until adulthood (>30 days). A further understanding of the development of mitral valve chordae tendineae will provide insight for the use of tissue-engineered chordae in surgical repair.

Signaling pathways in mitral valve degeneration.

Heart valves exhibit a highly-conserved stratified structure exquisitely designed to counter biomechanical forces delivered over a lifetime. Heart valve structure and competence is maintained by heart valve cells through a process of continuous turnover extracellular matrix (ECM). Degenerative (myxomatous) mitral valve disease (DMVD) is an important disease associated with aging in both dogs and humans. DMVD is increasingly regarded as a disease with identifiable signaling mechanisms that control key genes associated with regulation and dysregulation of ECM homeostasis. Initiating stimuli for these signaling pathways have not been fully elucidated but likely include both mechanical and chemical stimuli. Signaling pathways implicated in DMVD include serotonin, transforming growth factor ß (TGFß), and heart valve developmental pathways. High circulating serotonin (carcinoid syndrome) and serotoninergic drugs are known to cause valvulopathy that shares pathologic features with DMVD. Recent evidence supports a local serotonin signaling mechanism, possibly triggered by high tensile loading on heart valves. Serotonin initiates TGFß signaling, which in turn has been strongly implicated in canine DMVD. Recent evidence suggests that degenerative aortic and mitral valve disease may involve pathologic processes that mimic osteogenesis and chondrogenesis, respectively. These processes may be mediated by developmental pathways shared by heart valves, bone, and cartilage. These pathways include bone morphogenic protein (BMP) and Wnt signaling. Other signaling pathways implicated in heart valve disease include Notch, nitric oxide, and angiotensin II. Ultimately, increased understanding of signaling mechanisms could point to therapeutic strategies aimed at slowing or halting disease progression.

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.

Perinatal changes in mitral and aortic valve structure and composition.

At birth, the mechanical environment of valves changes radically as fetal shunts close and pulmonary and systemic vascular resistances change. Given that valves are reported to be mechanosensitive, we investigated remodeling induced by perinatal changes by examining compositional and structural differences of aortic and mitral valves (AVs, MVs) between 2-day-old and 3rd fetal trimester porcine valves using immunohistochemistry and Movat pentachrome staining. Aortic valve composition changed more with birth than the MV, consistent with a greater change in AV hemodynamics. At 2 days, AV demonstrated a trend of greater versican and elastin (P  =  0.055), as well as greater hyaluronan turnover (hyaluronan receptor for endocytosis, P  =  0.049) compared with the 3rd-trimester samples. The AVs also demonstrated decreases in proteins related to collagen synthesis and fibrillogenesis with birth, including procollagen I, prolyl 4-hydroxylase, biglycan (all P ≤ 0.005), and decorin (P  =  0.059, trend). Both AVs and MVs demonstrated greater delineation between the leaflet layers in 2-day-old compared with 3rd-trimester samples, and AVs demonstrated greater saffron-staining collagen intensity, suggesting more mature collagen in 2-day-old compared with 3rd-trimester samples (each P < 0.05). The proportion of saffron-staining collagen also increased in AV with birth (P < 0.05). The compositional and structural changes that occur with birth, as noted in this study, likely are important to proper neonatal valve function. Furthermore, normal perinatal changes in hemodynamics often do not occur in congenital valve disease; the corresponding perinatal matrix maturation may also be lacking and could contribute to poor function of congenitally malformed valves.

Results after mitral valve replacement with mechanical prostheses in young children.

OBJECTIVE: We examined outcomes after mitral valve replacement in children younger than 8 years. METHODS: Medical records of patients who underwent mitral valve replacement from 1990 to 2006 were reviewed. Competing-risks methodology determined time-related prevalence and associated factors for death, repeated valve replacement, and survival without reoperation. RESULTS: In total, 79 patients, median age 24 months (40 days-8 years) underwent 91 mitral valve replacements (10 had repeated procedures). Underlying pathology was congenital heart disease in 95% of cases. Forty-six patients (58%) had undergone previous operations. Operative mortality was 18%, 30% for those 2-years old and younger and 6% for those older than 2 years. Competing-risks analysis showed that 10 years after initial mitral valve replacement, 40% of patients had died without repeated replacement, 20% had undergone a second replacement, and 40% remained alive without further replacement. Factors associated with death included higher prosthesis size/patient weight ratio (P < .0001) and longer crossclamp time (P < .0001). Second replacement 6 +/- 4 years after initial replacement was necessary for 10 survivors. At second replacement, larger prostheses were implanted (mean 24 mm vs 19 mm initially). Repeated MVR was associated with younger age at surgery (p = .006). Permanent pacemaker implantation was eventually needed by 11% of hospital survivors. CONCLUSIONS: Mortality and repeated valve replacement are common after mitral valve replacement in children younger than 8 years, especially younger patients with significantly oversized valves. At valve reoperation, larger prostheses could be implanted, suggesting continued annular growth.

Edge-to-edge technique: is it also useful in children?

OBJECTIVE: Mitral valve prolapse is a rare condition and represents a challenge for cardiac surgeons. Many techniques have been described to treat the wide spectrum of abnormalities causing mitral valve regurgitation but the low incidence of these abnormalities is the cause of the relatively poor experience of many institutions. METHODS: From April 2005 to September 2006, five patients underwent isolated mitral valve repair with the edge-to-edge technique for anterior or bileaflet prolapse. Three patients also had a Gore-Tex strip to reinforce the posterior annulus, whereas two had a 26-size soft incomplete ring annuloplasty. RESULTS: There was no death and none of the patients required reoperation. None of the patients had mitral regurgitation more than 1+ at a mean follow-up of 30 months. None of the patients had mitral stenosis or any valve-related event. CONCLUSION: The edge-to-edge technique is a well tolerated and useful technique for the anterior or bileaflet prolapse of the mitral valve. Although many techniques have been described with good results, in many anatomical settings and in small patients, edge-to-edge is a good option and might not interfere with the growth of the valve. Early results are encouraging but a longer follow-up is needed to evaluate the long-term prognosis.

Growth of mitral annulus in the pediatric patient after suture annuloplasty of the entire posterior mitral annulus.

When mitral annuloplasty is performed in small children, room for annular growth should be allowed. However, it has not been reported how the valve develops after mitral annuloplasty of the entire posterior annulus. We report a case showing traces of annular growth at redo surgery. A female patient suffering from mitral valve insufficiency due to annular dilatation underwent modified Paneth plasty with Kay-Wooler commissural plication annuloplasty at the age of two years one month. In redo surgery 8.4 years after initial repair, enlargement of the commissural portion of the posterior annulus in addition to enlargement of the anterior leaflet and anterior annulus was observed. Modified Paneth plasty reinforced with a pericardial strip and Kay-Wooler annuloplasty of the posteromedial commissure were performed. Mitral orifice size measured with the Hegar dilator was 18 mm after the re-repair, increasing from 16 mm after the initial repair. Taking into account the normal mitral annulus diameter related to body surface area (BSA) of 16 mm at initial operation and 20 mm at redo surgery, the increase in mitral orifice size from 16 mm to 18 mm in this patient may be regarded as the annular growth in 8.4 years.

Mitral valvular interstitial cells demonstrate regional, adhesional, and synthetic heterogeneity.

BACKGROUND/AIMS: Because various regions of the mitral valve contain distinctive extracellular matrix enabling the tissues to withstand diverse mechanical environments, we investigated phenotype and matrix production of porcine valvular interstitial cells (VICs) from different regions. METHODS: VICswere isolated from the chordae (MCh), the center of the anterior leaflet (AlCtr), and the posterior leaflet free edge (PlFree), then assayed for metabolic, growth, and adhesion rates; collagen and glycosaminoglycan (GAG) production, and phenotype using biochemical assays, flow cytometry, and immunocytochemistry. RESULTS: The AlCtr VICs exhibited the fastest metabolism but slowest growth. PlFree cells grew the fastest, but demonstrated the least smooth muscle alpha-actin, vimentin, and internal complexity. AlCtr VICs secreted less collagen into the culture medium but more 4-sulfated GAGs than other cells. Adhesion-based separation resulted in altered secretion of sulfated GAGs by MCh and AlCtr cells but not by the PlFree cells. CONCLUSIONS: VICs isolated from various regions of the mitral valve demonstrate phenotypic differences in culture, corresponding to the ability of the mitral valve to accommodate the physical stresses or altered hemodynamics that occur with injury or disease. Further understanding of VIC and valve mechanobiology could lead to novel medical or tissue engineering approaches to treat valve diseases.

Age-related changes in collagen synthesis and turnover in porcine heart valves.

BACKGROUND AND AIM OF THE STUDY: Although the six-month-old pig is commonly used as a model to study human heart valve biology and various age-specific valve diseases, the correlation of porcine valve biology and development with that of humans has not been thoroughly assessed. Given the important role of the matrix in valve function, the aim of this study was to characterize porcine valve matrix structure and collagen turnover during development and aging. METHODS: Porcine aortic valves (AV) and mitral valves (MV) were examined throughout fetal development and postnatally at six weeks, six months and six years, using Movat pentachrome staining and immunohistochemistry for collagen III, markers of collagen synthesis (molecular chaperone HSP47, hydroxylating enzyme prolyl-4-hydroxylase (P4H), cross-linking enzyme lysyl oxidase (LOX)) and collagen degradation (matrix metalloproteinase (MMP)-13), and a marker of an 'activated' cellular phenotype, smooth muscle alpha-actin (SMalphaA). An analysis of variance was used to compare the staining intensities. RESULTS: Cell density measurements showed layer differentiation in the first trimester (p < 0.003), and this decreased ten-fold from the second trimester to six years of age (p < 0.025). Matrix turnover was identified by the co-localization of P4H, HSP47 and MMP13, and correlated to an 'activated' cellular phenotype. SMalphaA expression was noted on the inflow surface of both valves. P4H and LOX were maximally expressed around mature collagen (p < 0.001). P4H increased during fetal development (p < 0.01) and in the six-year-old AV fibrosa (p < 0.05). Collagen-related markers were consistently higher in the AV than MV (HSP47 in fetal; P4H, Col III, and LOX in six-year-old). CONCLUSION: The substantial matrix changes shown in this porcine study provide further insight into the role of matrix turnover during development and aging and should be considered when using the porcine animal model to study age-specific human diseases.

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.

Pulmonary venous flow from fetal to neonatal period.

There are few reports about the effect of fetal or transitional circulation on the pulmonary venous flow. The purposes of this study were to investigate flow patterns of the pulmonary vein serially from fetal to neonatal period and to determine the relationship between pulmonary venous flow and other parameters from aortic and mitral valve. Pulmonary venous flow velocity was analyzed in 21 normal term human fetuses. Postnatal follow-up studies were performed at 1, 6, 24 h, 3 days, 1 week and 1 month. In each time point, pulsed Doppler echocardiography was used to interrogate right upper pulmonary vein, mitral and aortic valve. The measured parameters of pulmonary vein were heart rate, velocity time integral (VTI), and velocities at systolic peak (S), at diastolic peak (D), at nadir between S and D (O), and at nadir between D and the next S (X). E/A ratio and VTI were measured for mitral valve and peak systolic velocity and VTI for aortic valve. Pulmonary venous flow in fetus was phasic and continuous with low velocity. One hour after birth, without a change of flow pattern, all velocities increased dramatically. These high velocities showed a significant decrease during 24 h after birth. Three days after birth, the velocity decreased slightly and flow pattern changed from continuous to interrupted pattern with or without atrial reversal. No Doppler parameters from aortic or mitral valve showed any correlation with parameters from pulmonary vein. In conclusion, the flow pattern of the pulmonary vein in fetus may result from low pulmonary flow and decreased capacitance of the pulmonary venous system. Sudden increase in the pulmonary flow after birth is likely to be responsible for the highest velocities recorded immediately after birth. Left to right shunt through the ductus arteriosus may also contribute to the flow pattern observed in the first several days, as do changes in reservoir function of the pulmonary vein.

[Surgery for mitral regurgitation in children].

In pediatric patients, mitral valve (MV) repair is preferable than MV replacement because of no need for anticoagulation and its feasibility in small children. However, long-term outcome of MV repair is still unclear. In the present study, fifty-two pediatric patients who underwent MV repair (n = 46) and MV replacement (n = 6) against mitral regurgitation (MR) between January 1970 and December 1996 were evaluated. 46 patients had associated diseases. Mitral annuloplasty was applied in 20 patients (by Kay method (n = 14) and Paneth-Burr method (n = 6) before and after 1991, respectively). Freedom from reoperation rate in patients with partial endocardial cushion defect (ECD) was significantly lower than that in other patients after MV repair, which was significantly higher than that in patients with MV replacement. Diameter of mitral annulus grew within normal range after MV repair. In conclusion, MV repair may provide better outcomes with respect to reoperation and growth of MV in pediatric patients except with partial ECD.

Artificial chordae for mitral valve reconstruction in children.

BACKGROUND: Congenital mitral regurgitation continues to present a challenge for cardiac surgeons because of the diversity of the anatomy of the congenitally malformed mitral valve. We undertook aggressive repair of the mitral valve with artificial chordae for reconstruction of the prolapsed anterior leaflet in some children. The short-term results are reported herein. METHODS: Three patients with isolated congenital mitral regurgitation underwent mitral valve repair with use of expanded polytetrafluoroethylene sutures as artificial chordae. RESULTS: There have been no late deaths and no valve-related complications. Serial follow-up echocardiographic examinations have not revealed any increase in the severity of mitral regurgitation with continuing patient growth up to 39 months after the operation. CONCLUSIONS: When combined with other conservative methods of mitral valve repair, chordal replacement with expanded polytetrafluoroethylene sutures in children undergoing mitral valve reconstruction produces good short-term results. We believe that it delays and possibly prevents the need for a mechanical prosthesis with its associated complications in this young patient population.

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.