Mitral valve prolapse (MVP) has been described as the most common valvular abnormality contributing to mitral regurgitation [1], accompanied by late systolic murmur and associated with 1 or both of the redundant, floppy mitral leaflets in the left atrium. With the steadily decreasing rate of rheumatic heart valve disease, mitral valve prolapse has become the leading cause of mitral valve surgery for isolated mitral insufficiency in industrialized countries [2]. Several clinical studies have reported prevalence rates ranging from 5% to 15% and even as high as 35% [3–7] among specific populations. The controversies have not ceased in spite of the introduction of echocardiography and the established guidelines for diagnosis of MVP. Nowadays, based on echocardiography, large sample database and more realistic representation, the prevalence of mitral valve prolapse was found to be less than 1% in a cohort of healthy teenage students, young athletes and patients undergoing echocardiography for clinical reasons [8–10]. While the negative events associated with congestive heart failure, progressive mitral insufficiency, bacterial endocarditis, thromboembolism and even sudden death may emerge at the endpoint in the course of aging and occur far more frequently in patients with MVP compared to controls, which have been determined. However, the natural course of mitral valve prolapse is markedly heterogeneous, varying from benign with a normal lifespan to malignant manifestation with significant morbidity and mortality caused by the progressive valvular regurgitation. Hence, management of this potentially malignant entity should consider the underlying etiology and perform close follow-up to allow for early identification of the subjects requiring medical or surgical intervention. However, the underlying causative pathogenesis is incompletely understood. A view that mitral valve prolapse has a well-recognized concerning with heritable genetic connective tissue disorders [11–13], is the most popular and feasible mechanism among the several putative hypotheses. A familial basis for this circumstance has long been established with an autosomal dominant mode of inheritance [14]; nevertheless, the variable penetrance is probably influenced by age, sex and autonomic nervous state, manifesting a marked heterogeneity of clinical presentation even between affected members of the same family. Hence, we wondered whether there is any environmental factor that has a triggering role in the development of mitral valve prolapse.

Patients with mitral valve prolapse were found to be associated with the coexistence of symptoms that cannot be explained on the basis of valvular regurgitation alone. Various accompanying symptoms including palpitations, orthostatic rhythm disturbances, atypical chest pain, exertional dyspnea and neuropsychiatric symptoms [15,16] have been referred to as “mitral valve prolapse syndrome”. Abnormal autonomic regulation has been reported to be responsible for symptomatic subjects with a complex of presenting symptoms such as elevated circulating concentrations of catecholamines and enhanced β receptor affinity, suggesting the existence of a hyperadrenergic state, diminished vagal tone and other autonomic malfunctions [17]. Moreover, decreased heart rate variability (HRV), indicating an imbalance in the cardiac autonomic responsiveness, had been well documented in symptomatic patients [18]. This autonomic imbalance parameter contributes to disease progression, is an indicator of disease pathogenesis, and is a better predictor of poor prognosis than other hemodynamic measures in heart-related diseases [19]. In addition, female sex was found to be a notable predominance by the Framingham Study, especially among young women [20] who were prone to dysautonomias. Mitral valve prolapse is absent from echocardiographs in newborns [21], and an autosomal dominant mode did not express, even in members of the same family, suggesting that clinical presentation of patients with MVP might exhibit complex interactions with environmental factors. Hence, it is hypothesized that autonomic dysregulation may be a key determinant in the origin and progression of mitral valve prolapse. Such a hypothesis not only accounts for the seemingly disparate syndromes and valvular disorder, but also has future implications for biopharmaceutical and mechanical treatment.

Dysautonomia leading to improper modulation of cellular synthetic metabolism in mitral valves can describe the gross property as well as histological changes taking place in the pathogenesis of mitral valve prolapse. We propose that autonomic dysfunction has a facilitatory role in the pathogenesis of mitral prolapse. In a manner similar to other organic systems, autonomic imbalance of mitral valves gives rise to a circumstance of hypersensitivity or of susceptibility to remolding in the extracellular matrix and phenotype transiting in cellular components.