Gross morphology and morphometry of native and decellularized heart valves of caprine: A comparative study.

The gross morphological examination of native caprine heart valves revealed distinctive structural characteristics of the caprine's cardiac anatomy. Four primary orifices were identified, each protected by thin, valve-like structures. Atrioventricular orifices featured tricuspid and bicuspid valves, while the aorta and pulmonary arteries were guarded by semilunar valves. Within the atrioventricular apparatus, distinct features were observed including the tricuspid valve's three leaflets and the bicuspid valve's anterior and posterior leaflets. Ultrasonography provided insights into valve thickness and chordae tendineae lengths. Morphometric studies compared leaflets/cusps within individual native valves, showcasing significant variations in dimensions. Comparative analysis between native and decellularized valves highlighted the effects of decellularization on leaflet thickness and chordae tendineae lengths. Decellularized valves exhibited reduced dimensions compared to native valves, indicating successful removal of cellular components. While some dimensions remained unchanged post-decellularization, significant reductions were observed in leaflet thicknesses and chordae tendineae lengths. Notably, semilunar valve cusps displayed varying responses to decellularization, with significant reductions in cusp lengths observed in the aortic valve, while the pulmonary valve exhibited more subtle changes. These findings underscore the importance of understanding structural alterations in heart valves post-decellularization, providing valuable insights for tissue engineering applications and regenerative medicine.

Pulmonary valve morphometry revisited: Clinical implications for valvular and supravalvular interventions.

In this cadaver-based study, we aimed to present a novel approach to pulmonary valve (PV) anatomy, morphometry, and geometry to offer comprehensive information on PV structure. The 182 autopsied human hearts were investigated morphometrically. The largest PV area was seen for the coaptation center plane, followed by basal ring and the tubular plane (626.7 ± 191.7 mm2 vs. 433.9 ± 133.6 mm2 vs. 290.0 ± 110.1 mm2 , p < 0.001). In all leaflets, fenestrations are noted and occur in 12.5% of PVs. Only in 31.3% of PVs, the coaptation center is located in close vicinity of the PV geometric center. Similar-sized sinuses were found in 35.7% of hearts, in the remaining cases, significant heterogeneity was seen in size. The mean sinus depth was: left anterior 15.59 ± 2.91 mm, posterior: 16.04 ± 2.82 mm and right anterior sinus: 16.21 ± 2.81 mm and the mean sinus height: left anterior 15.24 ± 3.10 mm, posterior: 19.12 ± 3.79 mm and right anterior sinus: 18.59 ± 4.03 mm. For males, the mean pulmonary root perimeters and areas were significantly larger than those for females. Multiple forward stepwise regression model showed that anthropometric variables might predict the coaptation center plane (sex, age, and heart weight; R2  = 33.8%), tubular plane (sex, age, and BSA; R2  = 20.5%) and basal ring level area (heart weight and sex; R2  = 17.1%). In conclusion, the largest pulmonary root area is observed at the coaptation center plane, followed by the basal ring and tubular plane. The PV geometric center usually does not overlap valve coaptation center. Significant heterogeneity is observed in the size of sinuses and leaflets within and between valves. Anthropometric variables may be used to predict pulmonary root dimensions.

On the shape and structure of the murine pulmonary heart valve.

Murine animal models are an established standard in translational research and provides a potential platform for studying heart valve disease. To date, studies on heart valve disease using murine models have been hindered by a lack of appropriate methodologies due to their small scale. In the present study, we developed a multi-scale, imaging-based approach to extract the functional structure and geometry for the murine heart valve. We chose the pulmonary valve (PV) to study, due to its importance in congenital heart valve disease. Excised pulmonary outflow tracts from eleven 1-year old C57BL/6J mice were fixed at 10, 20, and 30 mmHg to simulate physiological loading. Micro-computed tomography was used to reconstruct the 3D organ-level PV geometry, which was then spatially correlated with serial en-face scanning electron microscopy imaging to quantify local collagen fiber distributions. From the acquired volume renderings, we obtained the geometric descriptors of the murine PV under increasing transvalvular pressures, which demonstrated remarkable consistency. Results to date suggest that the preferred collagen orientation was predominantly in the circumferential direction, as in larger mammalian valves. The present study represents a first step in establishing organ-level murine models for the study of heart valve disease.

Impact of Patient Prosthesis Mismatch on the Outcome of Transcatheter Pulmonic Valve Implantation.

Patient prosthesis mismatch (PPM) is an important factor of the outcome in transcatheter aortic valve implantation. However, the impact of PPM in transcatheter pulmonic valve implantation (TPVI) has not been studied. Based on the narrowest valve stent diameters in two views of fluoroscopy, internal geometric orifice area (GOA) of the valve stent was calculated and indexed by body surface area (BSA), deriving iGOA. To define PPM in TPVI, receiver operating characteristics (ROC) curve analysis for iGOA for predicting significant residual right ventricular outflow tract (RVOT) gradient was used to derive the optimal cut-off value of iGOA. Our cohort were divided into 2 groups: PPM versus non-PPM. The clinical data were compared between 2 groups. TPVI was performed using Melody valve in 101 patients. Significant RVOT residual pressure gradient (≥ 15 mmHg) was observed in 31 patients (39.6%). Over a mean follow up periods of 6.9 ± 2.7 years, 22 patients (21.8%) required repeat interventions (16 transcatheter, 11 surgical, and both in 5 patients). Based on the ROC analysis, the best cut-off value of iGOA was 1.25 cm2/m2 (area under the curve 0.873, p < 0.001) to define PPM. PPM was present in 42 patients (42%). On the Kaplan-Meier survival analysis, PPM was associated with the need of repeat intervention (p = 0.02). In conclusion, in TPVI, PPM was a strong predictor for the need of re-intervention. Considering PPM, target diameter of valve stent would depend on the patient body size and should be taken into account for optimal outcome of TPVI.

Pigmentation of the aortic and pulmonary valves in C57BL/6J x Balb/cByJ hybrid mice of different coat colours.

Neural crest-derived melanocytes have been recorded in several parts of the mammalian heart but not in the pulmonary valve. We report here the presence of melanin-containing cells in the leaflets (cusps) of both the aortic and pulmonary valves. A total of 158 C57BL/6J x Balb/cByJ hybrid mice exhibiting four coat colours, namely black, white, agouti and non-agouti brown, were examined. We sought for any relationship between the presence of melanocytes in the valves and the coat colour of the animals. The pigmentation levels of the leaflets were accomplished using a scale of five pigment intensities. White mice lacked pigment in the heart. In 10.5% of the remaining animals, there were melanocytes in the pulmonary valve leaflets. Thus, this is the first study to report the presence of such cells in the pulmonary valve of mammals. Melanocytes occurred in the leaflets of the aortic valves of 87.2% of mice. The incidence of melanocytes and the pigmentation level of the leaflets did not statistically differ according to the coat colours of the animals. This disagrees with previous observations, indicating that the amount of melanocytes in the heart reflects that of the skin. The incidence and distribution of melanocytes in aortic and pulmonary valves are consistent with the notion that the formation of the arterial valves is mediated by specific subpopulations of neural crest cells. We hypothesize that melanocytes, even not producing melanin, may be more frequent in the heart than previously thought, exerting presumably an immunological function.

A geometric model for the human pulmonary valve in its fully open case.

The human pulmonary valve, one of the key cardiac structures, plays an important role in circulatory system. However, there are few mathematical models to accurately simulate it. In this paper, we establish a geometric model of the normal human pulmonary valve from a mathematical perspective in the fully opening case. Based on the statistical data of the human pulmonary valves, we assume that the motions of the three cusps are symmetrical in the cardiac cycle. Thus, we first propose that each cusp is a part of the cylindrical shell according to its structure and physiological feature. The parameters for the pulmonary valve cusps in three-dimensional space are obtained by the fitting functions. We verify the accuracy of our results by comparing the areas of the pulmonary valve and pulmonary valve flap.

Imaging of the pulmonary valve in the adults.

PURPOSE OF REVIEW: Pulmonary valve is the least imaged of the cardiac valves in adults. This review will address the strengths and the limitations of various imaging modalities that are commonly used for evaluation of pulmonary valve diseases in the adults. RECENT FINDINGS: Valvular pulmonary stenosis is mostly congenital and pulmonary regurgitation is usually an acquired pulmonary valve disease. Combined pulmonary stenosis and pulmonary regurgitation as sequel to previous surgeries for congenital heart diseases is the most common form of pulmonary valve disease in the adults. Transthoracic echocardiography (TTE) is the first-line imaging for the pulmonary valve, however, TTE pose considerable technical limitations in adults secondary to the body habitus, previous surgeries, and imaging artifacts by the interposed foreign tissue. Transesophageal echocardiography is infrequently used because of farther location of the imaging probe from the pulmonary valve precluding optimal imaging. Cardiac computerized tomography (CT) and cardiac MRI are fast emerging as the most preferred imaging modalities for pulmonary valve diseases in the adults.CT is used to obtain precise anatomic information about the pulmonary valve and the contiguous anatomy such as the right ventricular outflow tract, the distal pulmonary arteries including the coronary arteries. MRI by virtue of its high temporal resolution has the unique advantage of obtaining hemodynamic information related to the pulmonary valve; such as quantification of the pulmonary regurgitation, the right ventricle volumes, mass, and the systolic function. Combined imaging with CT and MRI provide anatomic and hemodynamic information in a variety of pulmonary valve diseases; is useful for understanding of the right ventricle adaptive mechanism and remodeling process, for preprocedure planning during percutaneous pulmonary valve implantation and for surveillance of different pulmonary valve diseases. SUMMARY: Multimodality imaging involving a combination of TTE, CT, and (or) MRI are useful to delineate the anatomic and hemodynamic abnormalities associated with different pulmonary valve diseases in the adults.

The composition and biomechanical properties of human cryopreserved aortas, pulmonary trunks, and aortic and pulmonary cusps.

Human cryopreserved allografts of pulmonary and aortic heart valves, aortas and pulmonary trunks are used for valve replacement. However, it is unknown how the composition of these allografts relate to their mechanical properties. Our aims were to correlate the histological compositions and passive mechanical properties of aortic and pulmonary valves and to observe the microcracks of aortas and pulmonary trunks. The following parameters were quantified: ultimate stress; ultimate strain; Young's modulus of elasticity; valve cusp wall thickness; pulmonary and aortic intima-media thickness; area fraction of elastin, collagen and calcification; and length density of elastic fibres. The propagation of experimentally induced microcracks avoided elastic fibres. Ultimate strain was negatively correlated with the area fraction of calcification (r=-0.4) in aortas. Ultimate stress (r=0.27) and Young's modulus in small deformation (r=0.29) and in large deformation (r=0.32) correlated with wall thickness in valve cusps. Young's modulus (r=0.34) and ultimate strain (r=0.31) correlated with intima-media thickness. Ultimate strain correlated with the area fraction of elastin (r=-0.40) and collagen in the arteries (r=0.31). As conventional histology does not fully explain the mechanical properties of cryopreserved grafts, both morphological and biomechanical tests should be used complementarily when characterizing the ageing of the grafts.

Effects of combined cryopreservation and decellularization on the biomechanical, structural and biochemical properties of porcine pulmonary heart valves.

UNLABELLED: Non-fixed, decellularized allogeneic heart valve scaffolds seem to be the best choice for heart valve replacement, their availability, however, is quite limited. Cryopreservation could prolong their shelf-life, allowing for their ideal match to a recipient. In this study, porcine pulmonary valves were decellularized using detergents, either prior or after cryopreservation, and analyzed. Mechanical integrity was analyzed by uniaxial tensile testing, histoarchitecture by histological staining, and composition by DNA, collagen (hydroxyproline) and GAG (chondroitin sulfate) quantification. Residual sodium dodecyl sulfate (SDS) in the scaffold was quantified by applying a methylene blue activation assay (MBAS). Cryopreserved decellularized scaffolds (DC) and scaffolds that were decellularized after cryopreservation (CD) were compared to fresh valves (F), cryopreserved native valves (C), and decellularized only scaffolds (D). The E-modulus and tensile strength of decellularized (D) tissue showed no significant difference compared to DC and CD. The decellularization resulted in an overall reduction of DNA and GAG, with DC containing the lowest amount of GAGs. The DNA content in the valvular wall of the CD group was higher than in the D and DC groups. CD valves showed slightly more residual SDS than DC valves, which might be harmful to recipient cells. In conclusion, cryopreservation after decellularization was shown to be preferable over cryopreservation before decellularization. However, in vivo testing would be necessary to determine whether these differences are significant in biocompatibility or immunogenicity of the scaffolds. STATEMENT OF SIGNIFICANCE: Absence of adverse effects on biomechanical stability of acellular heart valve grafts by cryopreservation, neither before nor after decellularization, allows the identification of best matching patients in a less time pressure dictated process, and therefore to an optimized use of a very limited, but best-suited heart valve prosthesis.

Enabling Multiphoton and Second Harmonic Generation Imaging in Paraffin-Embedded and Histologically Stained Sections.

Nonlinear microscopy, namely multiphoton imaging and second harmonic generation (SHG), is an established noninvasive technique useful for the imaging of extracellular matrix (ECM). Typically, measurements are performed in vivo on freshly excised tissues or biopsies. In this article, we describe the effect of rehydrating paraffin-embedded sections on multiphoton and SHG emission signals and the acquisition of nonlinear images from hematoxylin and eosin (H&E)-stained sections before and after a destaining protocol. Our results reveal that bringing tissue sections to a physiological state yields a significant improvement in nonlinear signals, particularly in SHG. Additionally, the destaining of sections previously processed with H&E staining significantly improves their SHG emission signals during imaging, thereby allowing sufficient analysis of collagen in these sections. These results are important for researchers and pathologists to obtain additional information from paraffin-embedded tissues and archived samples to perform retrospective analysis of the ECM or gain additional information from rare samples.

Age-Dependent Changes in Geometry, Tissue Composition and Mechanical Properties of Fetal to Adult Cryopreserved Human Heart Valves.

There is limited information about age-specific structural and functional properties of human heart valves, while this information is key to the development and evaluation of living valve replacements for pediatric and adolescent patients. Here, we present an extended data set of structure-function properties of cryopreserved human pulmonary and aortic heart valves, providing age-specific information for living valve replacements. Tissue composition, morphology, mechanical properties, and maturation of leaflets from 16 pairs of structurally unaffected aortic and pulmonary valves of human donors (fetal-53 years) were analyzed. Interestingly, no major differences were observed between the aortic and pulmonary valves. Valve annulus and leaflet dimensions increase throughout life. The typical three-layered leaflet structure is present before birth, but becomes more distinct with age. After birth, cell numbers decrease rapidly, while remaining cells obtain a quiescent phenotype and reside in the ventricularis and spongiosa. With age and maturation-but more pronounced in aortic valves-the matrix shows an increasing amount of collagen and collagen cross-links and a reduction in glycosaminoglycans. These matrix changes correlate with increasing leaflet stiffness with age. Our data provide a new and comprehensive overview of the changes of structure-function properties of fetal to adult human semilunar heart valves that can be used to evaluate and optimize future therapies, such as tissue engineering of heart valves. Changing hemodynamic conditions with age can explain initial changes in matrix composition and consequent mechanical properties, but cannot explain the ongoing changes in valve dimensions and matrix composition at older age.

A Novel Predictive Value for the Transannular Patch Enlargement in Repair of Tetralogy of Fallot.

BACKGROUND: In tetralogy of Fallot, whether relieving right ventricular outflow tract obstruction requires transannular patch enlargement (TAPE) of the pulmonary valve depends on pulmonary valvular annulus size. The z-score of pulmonary annulus is most commonly used as a predictor of the need for TAPE. However, the z-score is a complex value affected by height, body weight, body surface area, and different reference populations. Therefore, we hypothesized that the great artery annulus size ratio (pulmonary valvular annulus size to aortic valve annuls size [GA ratio]) may be a better predictor of the need for TAPE. METHODS: We analyzed 122 patients retrospectively who had undergone total correction of tetralogy of Fallot between January 2007 and March 2015. We categorized the patients into two groups, TAPE versus non-TAPE. Great arterial annuli sizes were evaluated in each group, and the GA ratio cutoff values for TAPE were calculated. RESULTS: In total, 40 patients (32.8%) required TAPE. Both GA ratios and z-scores were smaller in the TAPE group than in the non-TAPE group (0.51 versus 0.67, p < 0.0001, and -2.46 versus -0.85, p < 0.0001, respectively). In receiver operating characteristics analyses, the z-score and GA ratio cutoff values were -1.67 (area under the curve = 0.797) and 0.56 (area under the curve = 0.900), respectively, demonstrating that the GA ratio was a more powerful diagnostic tool as a predictor of TAPE (p = 0.014). CONCLUSIONS: Our results suggest that the GA ratio is a useful predictor for TAPE and can be applied readily and simply in clinical practice.

A case of a quadricuspid pulmonary valve in a Japanese female.

A supernumerary cusp of the pulmonary valve was incidentally found in an 88-year-old Japanese female during a gross anatomy course. The valve was composed of three equal-sized leaflets and one smaller leaflet. The supernumerary leaflet was located between the anterior and right semilunar leaflets. This pulmonary valve consisted of four pulmonary aortic bulbs. The donated body was a female who had a past history of myocardial infarction and was diagnosed as having ischemic heart disease at the last admission. Tricuspid valve regurgitation and pulmonary hypertension were diagnosed on echocardiography. These findings were considered to have been caused by left heart failure and not by the quadricuspid pulmonary valve. This asymptomatic anatomical variation might have developed from a protrusion between the anterior and right swelling of the outflow tract during semilunar valve development.

Pulmonary Valve Anatomy and Abnormalities: A Pictorial Essay of Radiography, Computed Tomography (CT), and Magnetic Resonance Imaging (MRI).

Given its inconspicuous appearance on radiography, computed tomography (CT), and magnetic resonance imaging (MRI) the pulmonary valve (PV) is often overlooked as an important cause of both cardiac and pulmonary disease. In this pictorial essay, we review the normal appearance of the PV as well as various congenital anomalies including pulmonary atresia, pulmonary stenosis, and valvular fusion anomalies. Infectious entities, degenerative conditions, and malignant lesions are also depicted. We discuss surgical techniques used to repair both congenital and acquired pulmonary valvular diseases and describe postoperative appearances of the PV on imaging.

Pregnancy-induced remodeling of heart valves.

Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves.

A study to determine the contribution to right ventricle stroke volume from pulmonary and tricuspid valve displacement volumes.

BACKGROUND: Describing the systolic function of the right ventricle (RV) is a difficult task due to the complex shape and orientation of the RV. The purpose of this study was to investigate the extent to which the volumes encompassed by the pulmonary and tricuspid valve displacements contribute to the total right ventricle stroke volume (RVSV). METHODS: Twelve healthy volunteers were examined using cardiac magnetic resonance (CMR). Two series of time-resolved axially rotated MR images were acquired that encompassed the tricuspid valve and the pulmonary valve, respectively. The volume related to each valve movement, the tricuspid plane displacement (TPD) and the pulmonary plane displacement (PPD), was determined by delineation in diastole and systole. These volumes, RVSV(TPD) and RVSV(PPD) , were compared to the stroke volume to determine the contributions to the total stroke volume from the TPD and the PPD. The remaining volume of the total RVSV was referred to as RVSV(Other) . An initial in vitro study was carried out to validate the accuracy of volume measurements using axially rotated images. RESULTS: In vitro measurements indicated that the method for volumetric measurements using axially rotated images was a very accurate one, with a mean difference of 0·04 ± 0·10 ml. The in vivo measurements of RVSV(TPD) , RVSV(PPD) and RVSVOther were 45 ± 10%, 13 ± 2% and 42 ± 11%, respectively. CONCLUSIONS: Right ventricle stroke volume is determined by different individual volume changes as follows: RVSV(TPD) together with RVSVOther contributes to almost the entire RVSV in nearly equal proportions, while RVSV(PPD) contributes only a small amount and is approximately 30% of either RVSV(TPD) or RVSV(Other) .

Optimal elastomeric scaffold leaflet shape for pulmonary heart valve leaflet replacement.

Surgical replacement of the pulmonary valve (PV) is a common treatment option for congenital pulmonary valve defects. Engineered tissue approaches to develop novel PV replacements are intrinsically complex, and will require methodical approaches for their development. Single leaflet replacement utilizing an ovine model is an attractive approach in that candidate materials can be evaluated under valve level stresses in blood contact without the confounding effects of a particular valve design. In the present study an approach for optimal leaflet shape design based on finite element (FE) simulation of a mechanically anisotropic, elastomeric scaffold for PV replacement is presented. The scaffold was modeled as an orthotropic hyperelastic material using a generalized Fung-type constitutive model. The optimal shape of the fully loaded PV replacement leaflet was systematically determined by minimizing the difference between the deformed shape obtained from FE simulation and an ex-vivo microCT scan of a native ovine PV leaflet. Effects of material anisotropy, dimensional changes of PV root, and fiber orientation on the resulting leaflet deformation were investigated. In-situ validation demonstrated that the approach could guide the design of the leaflet shape for PV replacement surgery.