Atrioventricular valve development commences with an EMT event whereby endocardial cells transform into mesenchyme. The molecular events that induce this phenotypic change are well understood and include many growth factors, signaling components, and transcription factors. Besides their clear importance in valve development, the role of these transformed mesenchyme and the function they serve in the developing prevalve leaflets is less understood. Indeed, we know that these cells migrate, but how and why do they migrate? We also know that they undergo a transition to a mature, committed cell, largely defined as an interstitial fibroblast due to their ability to secrete various matrix components including collagen type I. However, we have yet to uncover mechanisms by which the matrix is synthesized, how it is secreted, and how it is organized. As valve disease is largely characterized by altered cell number, cell activation, and matrix disorganization, answering questions of how the valves are built will likely provide us with information of real clinical relevance. Although expression profiling and descriptive or correlative analyses are insightful, to advance the field, we must now move past the simplicity of these assays and ask fundamental, mechanistic based questions aimed at understanding how valves are ‘built”. Herein we review current understandings of atrioventricular valve development and present what is known and what isn’t known. In most cases, basic, biological questions and hypotheses that were presented decades ago on valve development still are yet to be answered but likely hold keys to uncovering new discoveries with relevance to both embryonic development and the developmental basis of adult heart valve diseases. Thus, the goal of this review is to remind us of these questions and provide new perspectives on an old theme of valve development.

These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.

OBJECTIVE To describe clinical characteristics and surgical outcomes for kittens with phimosis and to develop a system to classify phimosis on the basis of gross pathological lesions. ANIMALS 8 kittens with phimosis. PROCEDURES Medical record databases of 2 veterinary teaching hospitals were searched to identify records of cats ≤ 20 weeks old (ie, kittens) with phimosis that underwent surgical intervention between 2009 and 2017. For each kitten, information extracted from the record included signalment, history, clinical signs, physical examination findings, treatments, and details regarding the surgical procedure performed, postoperative complications, and outcome. RESULTS The most common clinical signs were stranguria (n = 6), marked preputial swelling (5), and a small (6) or inevident (2) preputial orifice. Six kittens had type 1 phimosis (generalized preputial swelling owing to urine pooling without penile-preputial adhesions) and underwent circumferential preputioplasty. Two kittens had type 2 phimosis (focal preputial swelling and urine pooling in the presence of penile-preputial adhesions) and underwent preputial urethrostomy. No postoperative complications were recorded for kittens that underwent preputial urethrostomy. All 6 kittens that underwent circumferential preputioplasty had some exposure of the tip of the penis immediately after surgery, which typically resolved over time. At the time of last follow-up (mean, 1.4 years after surgery), all 8 patients were able to urinate and had no signs of phimosis recurrence. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that circumferential preputioplasty and preputial urethrostomy could be used to successfully manage kittens with type 1 and type 2 phimosis, respectively.

MYBPC3 mutations cause hypertrophic cardiomyopathy, which is frequently associated with mitral valve (MV) pathology. We reasoned that increased MV size is caused by localized growth factors with paracrine effects. We used high-resolution echocardiography to compare Mybpc3-null, heterozygous, and wild-type mice (n = 84, aged 3–6 months) and micro-CT for MV volume (n = 6, age 6 months). Mybpc3-null mice showed left ventricular hypertrophy, dilation, and systolic dysfunction compared to heterozygous and wild-type mice, but no systolic anterior motion of the MV or left ventricular outflow obstruction. Compared to wild-type mice, echocardiographic anterior leaflet length (adjusted for left ventricular size) was greatest in Mybpc3-null mice (1.92 ± 0.08 vs. 1.72 ± 0.08 mm, p < 0.001), as was combined leaflet thickness (0.23 ± 0.04 vs. 0.15 ± 0.02 mm, p < 0.001). Micro-CT analyses of Mybpc3-null mice demonstrated increased MV volume (0.47 ± 0.06 vs. 0.15 ± 0.06 mm3, p = 0.018) and thickness (0.35 ± 0.04 vs. 0.12 ± 0.04 mm, p = 0.002), coincident with increased markers of TGFβ activity compared to heterozygous and wild-type littermates. Similarly, excised MV from a patient with MYBPC3 mutation showed increased TGFβ activity. We conclude that MYBPC3 deficiency causes hypertrophic cardiomyopathy with increased MV leaflet length and thickness despite the absence of left ventricular outflow-tract obstruction, in parallel with increased TGFβ activity. MV changes in hypertrophic cardiomyopathy may be due to paracrine effects, which represent targets for therapeutic studies.

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