TOPICS

Mitral Valve Prolapse and the Association with Cutaneous Mucin Infiltration (“Cardiocutaneous Mucinosis”)

Uzma Farooq, MD; Sonal Choudhary, MD; Michael P. McLeod, MS; Daniele Torchia, MD; Paolo Romanelli, MD

Dr. Farooq, MD, is from Kendall Medical Laboratory, Coral Gables, Florida; Drs. Choudhary, Torchia, and Romanelli and Mr. McLeod are from Department of Dermatology and Cutaneous Surgery,University of Miami Miller School of Medicine, Miami, Florida

Disclosure: The authors report no relevant conflicts of interest.

Abstract
Mitral valve prolapse is the most common disorder of the cardiac valves in people in the United States. It can present as both primary and secondary disorders, and when associated with myxomatous changes in the skin, the term cardiocutaneous mucinosis can be used to describe this entity. Patients with mitral valve prolapse may have cutaneous findings on histological analysis that may indicate its severity and complication rate. (J Clin Aesthet Dermatol. 2013;6(5):24–26.)

Mitral valve prolapse (MVP) is the most common disorder of the cardiac valves in people in the United States, affecting approximately 3 to 5 percent of the population.[1–4] It is defined by the pathologic systolic billowing or upward displacement of one or both of the mitral valve leaflets superiorly into the left atrium.[1,2] The redundant, hooded mitral valve leaflets are usually attached to stretched and thin-appearing chordae tendineae.[5] Inheritance is believed to be autosomal dominant with great variability in expression, and a locus for inherited MVP has been found on chromosome 13.6 Two-thirds of adult patients with MVP are females.[1] It can occur as a primary disease with characteristic gross and microscopic pathologic findings. The latter consist of collagen dissolution supplanted by myxomatous degeneration of the valve secondary to proteoglycan accumulation on the valve, resulting in a larger mitral valve, as well as a dilated annulus. Examples of primary MVP include the familial form, Marfan syndrome, Ehlers-Danlos syndrome, cutis laxa, pseudoxanthoma elasticum, and an idiopathic form. Secondary MVP does not have the myxomatous changes in the valve leaflets, rather it is a mechanical deformity that results from low left ventricular volume. Causes of secondary MVP include coronary artery disease, rheumatic disease, idiopathic hypertrophic subaortic stenosis, and anorexia nervosa.[2,5] In both primary and secondary MVP, the valve leaflets are large, typified by ballooning cusps that are disproportionate to the left ventricular cavity and subsequently prolapse during systole into the left atrial cavity.[2,4] The correlation of myxomatous degeneration of the mitral valve and simultaneous myxomatous changes in the skin led to the term cardiocutaneous mucinosis.[3]

Clinical features
Most patients with MVP are asymptomatic and have a benign clinical course.[1–4] The diagnosis of MVP is usually made by cardiac auscultation, by which the classic midsystolic click and/or the late systolic murmur are heard.[1,4] The midsystolic click derives from the snapping of the chordae as the voluminous leaflets open like a parachute into the left atrium.5 When MVP is accompanied by palpitations, chest pain, dizziness, fatigue, dyspnea, syncope, and/or panic attacks, the term mitral valve prolapse syndrome is used.[1,2,4,7] Electroencephalography is often normal; in contrast, two dimensional and Doppler echocardiograms are helpful imaging tools for making the diagnosis and assessing the severity of MVP.[1,2,4,8]

Complications of MVP are rare, but can be serious and include chest pain, mitral regurgitation, rupture of the chordae, infective endocarditis, thromboembolism resulting in cerebral ischemia and ophthalmic symptoms, cardiac arrhythmias, and even sudden death.[1,2,4,7,9] In a study by Nishimura et al,[8] approximately 10 percent of patients with asymptomatic or oligosymptomatic, echocardiogram-documented MVP and redundant mitral valve leaflets experienced either infective endocarditis, cerebral ischemia, or sudden death as compared to less than one percent of patients with MVP without redundant valves. Mitral regurgitation is the most common complication of MVP and is often caused by rupture of the chordae; it can be heard on auscultation as a holosystolic or near holosystolic murmur.[1,4] Mitral regurgitation can be initially mild, but can gradually worsen, resulting in distortion and expansion of the left side of the heart, which can lead to atrial fibrillation and congestive heart failure.[1,4] Infectious endocarditis is much less common than mitral regurgitation, and, in one third of cases, it occurs after dental work. Both mitral regurgitation and infective endocarditis are much more likely (60%) in male MVP patients.[1] Cerebral ischemia secondary to fibrin emboli is more common in patients with MVP compared to the general population. These emboli may also end up going into the ophthalmic circulation and causing visual disturbances.[1,2] Sudden death, thought to be a result of arrhythmias, is a rare complication of MVP patients with severe mitral regurgitation.[1] Atrial and ventricular arrhythmias in patients with MVP and subsequent sudden death is well documented; risk factors include female gender and increased thickness of the valve leaflets.9,10 In a study carried out by Anders et al,[7] only 3 out of 6 patients with autopsy-confirmed MVP who died suddenly had any medical history of heart issues. This illustration helps support the concept that even completely asymptomatic patients with MVP can die suddenly and without warning.[7] Corrado et al[11] found MVP as a cause of death in approximately 10 percent of those who died suddenly in a prospective Italian study evaluating causes of sudden death in the population studies (athletes and non-athletes younger than 35 years of age).[11] In aggregate, the risk factors for the above complications of MVP include older age, male gender, and clinical and echocardiographical demonstration of moderate-to-severe mitral regurgitation.[1]

Management
Most patients with MVP do not require medication, and the primary care physician should provide reassurance and recommend a healthy lifestyle with exercise. Antibiotic prophylaxis is recommended for patients with MVP who will undergo procedures that can induce bacteremia to prevent infectious endocarditis. Patients with palpitations, mild arrhythmias, chest pain, and/or anxiety may benefit from a beta-blocker. Long-term anticoagulation with warfarin is indicated for those patients who have had a cerebral ischemic event or have persistent arrhythmia that puts them at risk of stroke.[1,2,4] Mitral valve surgery is indicated for those experiencing dyspnea at low levels of daily activity or at a critically low left ventricular systolic function.[1]

Overlap with connective tissue diseases
During embryogenesis, the mitral valve undergoes final differentiation during the sixth week of life in utero, and this also coincides with the time of vertebral and thoracic ossification. Hence, any issue at this stage of development is likely to adversely affect both the mitral valve and the skeleton. This may explain why many patients with MVP also feature skeletal anomalies.[2,4]

Marfan syndrome is an autosomal dominant connective tissue disorder characterized by skeletal, ophthalmic, cutaneous, and cardiac abnormalities. The defective gene encodes for fibrillin-1, a ubiquitous glycoprotein in the elastic fiber system and a component of the extracellular matrix.[12–14] Mortality in Marfan syndrome is mostly the result of cardiovascular complications, including aortic dissection, mitral regurgitation, and MVP.[4,12] Ehlers-Danlos syndrome, another connective tissue disorder with autosomal dominant inheritance, features defective collagen production that results in hyperextensibility, easy bruising, and MVP, among other characteristics.[15,16] In a study carried out by Leier et al16 involving 19 patients with Ehlers-Danlos syndrome, 15 were found to have MVP and 13 had auscultation findings characteristic of MVP as well as echocardiograms positive for MVP.[16]

Pseudoxanthoma elasticum is a rare disorder involving the elastic fibers of the skin, retina, and cardiovascular system. It can have either an autosomal recessive or dominant inheritance pattern, and the defective gene is multi-drug resistance protein 6 (MRP6). Along with the characteristic calcified elastic fibers in the skin and calcified streaks in the retina, MVP is common in this disorder.[17]
Cutis laxa, an autosomal recessive disorder with an elastin gene mutation that results in abnormal elastic fibers in the skin, is marked by inelastic, loose, wrinkled, sagging skin. In addition, these patients can also have cardiac valve abnormalities.[18]

Extravalvular and cutaneous myxoid degeneration
Morales et al autopsied 24 hearts with severe myxomatous change of the mitral valve, and discovered that 18 of them (75.0%) had MVP with sudden death.[19,20] The mitral valves of all non-control subjects showed extensive infiltration of the valve by proteoglycans, forming large myxoid geographic zones with little residual normal fibrosa. Serial sectioning of the cardiac tissue including the cardiac conduction system and histological examination with the use of special stains, such as colloidal iron, demonstrated a significant increase in proteoglycans within the neurilemma, in between the neural fibers, within the ganglia, nerve trunks, walls of intramyocardial blood vessels, membranous and atrial septum, tricuspid valve ring, coronary arteries, attachment sites of chordae tendineae, sino-atrial node, atrioventricular node, and the His-Purkinje conduction tracts. Most of these patients did not have mitral regurgitation.[20] Therefore, this study suggests that a more generalized pathological process is responsible for sudden death in these patients.

A study by Kim et al[21] showed a significant correlation between dysfunction of the temporomandibular joint (TMJ) and MVP. Women under the age of 45 with TMJ dysfunction along with widespread joint hypermobility were evaluated in a study by Westling et al[22] in order to assess the collagen I/III and proteoglycan content in skin biopsies taken from their forearms. Skin biopsies in the patients with TMJ dysfunction revealed lower levels of total collagen as compared to the control group. Total collagen was shown to be negatively correlated to proteoglycan content. In addition, the patients with positive findings for MVP on an echocardiogram showed low collagen and high proteoglycan content in the skin.[22]

Romanelli et al[3] studied skin biopsies taken from the forearm of eight patients (mean age 44.5 years) with known MVP and compared them to the biopsies of healthy control subjects. Two biopsies per patient were taken. One was evaluated with routine hematoxylin and eosin staining plus colloidal iron staining to quantify proteoglycan content on a four-step scale and the other snap frozen and tested for the hexosamine amount.[3] The results showed a significant increase in proteoglycan content in all patients with MVP through both the light microscope analysis (3.4 in MVP versus 1.0 in controls) and the quantitative chemical analysis (0.629mg/g in MVP versus 0.4mg/g in controls).

Thus, patients with MVP may have cutaneous findings that correlate with the extent of the disease that may serve as a warning for complications of MVP.[3] The link between MVP with the associated myxoid degeneration of the valve with myxoid degeneration of the skin can aptly be known as cardiocutaneous mucinosis.[3]

References
1.    Devereux RB. Recent developments in the diagnosis and management of mitral valve prolapse. Curr Opin Cardiol. 1995;10:107–116.
2.    Bouknight DP, O’Rourke RA. Current management of mitral valve prolapse. Am Fam Physician. 2000;61:3343–3350, 3353–3354.
3.    Romanelli P, Romanelli R, Rongioletti F, et al. Clinical significance of cutaneous proteoglycan (mucin) infiltration in patients with mitral valve prolapse. J Am Acad Dermatol. 2008;59:168–169.
4.    Cheng TO. Mitral valve prolapse. Dis Mon. 1987;33:481–534.
5.    Levine HJ, Isner JM, Salem DN. Primary versus secondary mitral valve prolapse: clinical features and implications. Clin Cardiol. 1982;5:371–375.
6.    Nesta F, Leyne M, Yosefy C, et al. New locus for autosomal dominant mitral valve prolapse on chromosome 13: clinical insights from genetic studies. Circulation. 2005;112: 2022–2030.
7.    Anders S, Said S, Schulz F, Puschel K. Mitral valve prolapse syndrome as cause of sudden death in young adults. Forensic Sci Int. 2007;171:127–130.
8.    Nishimura RA, McGoon MD, Shub C, et al. Echocardiographically documented mitral-valve prolapse. Long-term follow-up of 237 patients. N Engl J Med. 1985;313:1305–1309.
9.    Knackstedt C, Mischke K, Schimpf T, et al. Ventricular fibrillation due to severe mitral valve prolapse. Int J Cardiol. 2007;116:e101–e102.
10.    Vohra J, Sathe S, Warren R, et al. Malignant ventricular arrhythmias in patients with mitral valve prolapse and mild mitral regurgitation. Pacing Clin Electrophysiol. 1993;16: 387–393.
11.    Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med. 1998;339:364–369.
12.    Milewicz DM, Urban Z, Boyd C. Genetic disorders of the elastic fiber system. Matrix Biol. 2000;19:471–480.
13.    Grahame R, Pyeritz RE. The Marfan syndrome: joint and skin manifestations are prevalent and correlated. Br J Rheumatol. 1995;34:126–131.
14.    Alpendurada F, Wong J, Kiotsekoglou A, et al. Evidence for Marfan cardiomyopathy. Eur J Heart Fail. 2010;12: 1085–1091.
15.    Fernandes NF, Schwartz RA. A “hyperextensive” review of Ehlers-Danlos syndrome. Cutis. 2008;82:242–248.
16.    Leier CV, Call TD, Fulkerson PK, Wooley CF. The spectrum of cardiac defects in the Ehlers-Danlos syndrome, types I and III. Ann Intern Med. 1980;92:171–178.
17.    Combrinck M, Gilbert JD, Byard RW. Pseudoxanthoma elasticum and sudden death. J Forensic Sci. 2011;56:418–22.
18.    Morava E, Guillard M, Lefeber DJ, Wevers RA. Autosomal recessive cutis laxa syndrome revisited. Eur J Hum Genet. 2009;17:1099–1110.
19.    Leite AC, Nascimento OJ, Lima MA, Andrada-Serpa MJ. POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin lesions) syndrome: a South America’s report. Arq Neuropsiquiatr. 2007;65:516–520.
20.    Morales AR, Romanelli R, Boucek RJ, et al. Myxoid heart disease: an assessment of extravalvular cardiac pathology in severe mitral valve prolapse. Hum Pathol. 1992;23:129–137.
21.    Kim SM, Cohen SG, Douglas P. Relationship between internal derangement of TMJ and mitral valve prolapse. J Dent Res. 1989;68:416.
22.    Westling L, Holm S, Wallentin I. Temporomandibular joint dysfunction. Connective tissue variations in skin biopsy and mitral valve function. Oral Surg Oral Med Oral Pathol. 1992;74:709–718.

Share on facebook
Facebook
Share on twitter
Twitter
Share on linkedin
LinkedIn