etiology of valvular heart disease in the 21st century

7/27/2019 Etiology of Valvular Heart Disease in the 21st Century

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Turning Basic Research into Clinical Success

Cardiology 2013;126:139152

DOI: 10.1159/000354221

Etiology of Valvular Heart Disease in the21st Century

Konstantinos Dean Boudoulasa Jeffrey S. Borerb Harisios Boudoulasa, c, d

aDivision of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, bDivision of Cardiovascular

Medicine, The Howard Gilman Institute for Heart Valve Diseases and the Schiavone Institute for Cardiovascular

Translational Research, State University of New York Downstate Medical Center, Brooklyn, N.Y., USA; cBiomedical

Research Foundation, Academy of Athens, Athens, and dAristotelian University of Thessaloniki, Thessaloniki, Greece

thies or other causes of myocardial dysfunction can resultin mitral and/or tricuspid regurgitation, even in the ab-sence of intrinsic structural valve abnormalities, presum-ably due to abnormal mechanical stresses that lead to thedistortion of normal valves and of the subvalvular appa-ratus; similarly, aortic regurgitation can develop from ab-normal mechanical stresses acting on an intrinsically nor-mal aortic valve in the setting of aortic root disease anddilatation [1, 2].

Changing Distribution of VHD Etiologies and

Contributing Factors

The distribution of VHD etiologies has changed mark-edly over the last 6070 years. Several factors have con-tributed to this alteration (fig. 1). Rheumatic fever andsyphilis, very common causes of VHD in the first half of

the last century, have almost disappeared in industrial-ized countries. Increased life expectancy over the last sev-eral decades has enabled expression of progressive struc-tural alterations associated with aging including aorticvalvular calcification and mitral valve mechanical distor-tion from floppy mitral valve (FMV)/mitral valve pro-lapse (MVP) resulting in significant aortic stenosis andmitral regurgitation, respectively [3]. The incidence ofischemic cardiomyopathy has increased as mortality

Key Words

Valvular heart disease Calcification Atherosclerosis

Etiology

Abstract

A metamorphosis in the etiology of valvular heart disease

(VHD) has occurred over the last 6 decades. In this review, the

factors contributing to this metamorphosis, the common

causes of VHD today, the relationship of valvular calcification

to atherosclerosis and the interrelationship of VHD with oth-

er systems/organs are presented.

Copyright 2013 S. Karger AG, Basel

Valvular heart disease (VHD) can be defined as astructural or functional abnormality of a cardiac valve.This is a generic term that includes several etiologic enti-

ties with different pathophysiologic mechanisms, presen-tations and natural histories. Disruption of the anatomicintegrity of a cardiac valve may produce valvular stenosis,valvular regurgitation or a combination of the two. Struc-tural abnormalities of a cardiac valve often produce sur-face phenomena, which may be associated with plateletaggregation and microorganism accumulation predis-posing to thromboembolism and infective endocarditis.In addition to intrinsic valve pathologies, cardiomyopa-

Received: June 10, 2013

Accepted after revision: July 1, 2013

Published online: August 24, 2013

Konstantinos Dean Boudoulas, MDDivision of Cardiovascular Medicine, The Ohio State University473 W. 12th Avenue, Suite 200Columbus, Ohio 43220 (USA)E-Mail kdboudoulas @ osumc.edu

2013 S. Karger AG, Basel00086312/13/12630139$38.00/0

www.karger.com/crd


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from myocardial infarction has fallen, and heart failuremanagement has improved, prolonging survival; the ven-

tricular morphologic distortion of cardiomyopathy oftencauses secondary valve dysfunction, magnified in theirexpression associated with prolonged survival. Increasedsurvival among patients with chronic kidney disease, es-pecially those on dialysis, has increased the prevalence ofVHD partially due to pathologic calcification of valvessecondary to hyperparathyroidism that is often present inthese patients. With the increasing prevalence of VHD,there has been a rapid development of and increasing ap-plication of interventions (e.g. valve replacement withprostheses and valve repair) which has replaced the orig-inal disease with a new, less morbid and lethal type. Inaddition, diseases that were not always recognized previ-ously, such as acquired immune deficiency syndrome(AIDS) and Kawasaki disease, are more frequently ob-served and may be associated with VHD [13].

Recent data have suggested that certain intrinsic valveabnormalities (calcific aortic stenosis and mitral annularcalcification) may be related to atherosclerosis. However,while metabolic pathways similar to those of atheroscle-rosis exist in the heart valves, current research suggeststhat these pathways deviate at a crucial point from theatherosclerotic pathways and result directly in calcifica-

tion rather than atherosclerosis.Despite the reduction of rheumatic fever in industrial-ized countries, VHD constitutes a major public healthproblem due to the relatively high incidence of heritable/congenital valve disorders, the continual aging of thepopulation and the tendency of valve lesions to worsenwith age [47]. Recent advances in imaging technologyhave allowed early detection in vivo of mild valve dys-function (or even more severe in some cases), previously

clinically silent and undetectable until autopsy (if per-formed) and, even then, not necessarily detectable if thevalve dysfunction was not associated with obvious struc-tural abnormality [28]. In addition, advances in technol-ogy have allowed precise definition of the structural andfunctional abnormalities of VHD, enabling etiologic clas-

sification of VHD in vivo. Accurate etiologic classifica-tion of VHD in vivo has enabled definition of the meta-morphosis of etiology of VHD over time [1, 2, 5, 912].

Recent epidemiologic studies in adults suggested thatthe prevalence of VHD increases from


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Ehlers-Danlos syndrome is often associated withFMV/MVP, aortic root or sinus of Valsalva enlargementand aortic regurgitation. Bicuspid aortic valve may alsobe present.

Adult polycystic kidney disease is associated with aor-tic root dilatation and aortic regurgitation, FMV/MVP,

bicuspid aortic valve and tricuspid valve prolapse.Osteogenesis imperfecta, several of the mucopolysac-charidoses and other metabolic abnormalities may alsobe associated with VHD.

Heritable disorders of connective tissue, as a generalrule, are genetically transmitted like in Marfan syndrome,though the specific genetic variants and pattern of inher-itance are often not known (as in most patients with bi-cuspid aortic valve). Nonetheless, the offspring of pa-

tients with these abnormalities may have the same diseaseand should be evaluated [13].

FMV associated with MVP is considered a connectivetissue disorder and it is present in 23% of the generalpopulation. MVP occurs when one or both mitral leafletsor parts of them extend above the plane of the atrioven-

tricular junction during left-ventricular systole. Progres-sive mitral regurgitation, rupture of the chordae tendin-eae, infective endocarditis, thromboembolic events, car-diac arrhythmias and congestive heart failure are potentialsequelae of FMV/MVP that increase in frequency withage. FMV (diffuse or regional) is the central issue in thegenesis of MVP-mitral valvular regurgitation. FMV/MVP is heritable with dominant transmission and differ-ent degrees of penetrance. At least three gene loci relatedto MVP have been identified (fig. 2). Another rare formis transmitted via chromosome X [3, 1215].

Tricuspid valve prolapse, which also may be associated

with MVP, is considered a connective tissue disorder [3,12].

Annuloaortic ectasia describes aneurysmal dilatationof the aortic annulus and ascending thoracic aorta; in af-fected patients there is evidence of cystic medial degen-eration (necrosis) without evidence of connective tissuedisease in other organs. Aortic regurgitation is usuallypresent in this abnormality [1, 2, 12].

Congenital Valve Disease Etiology UnclearBicuspid aortic valve without clinically significant aor-

tic stenosis at birth is a common congenital abnormalityin adults, with a male predominance. It is estimated thatapproximately 2% of live births have bicuspid aorticvalve. Patients with bicuspid aortic valve may developaortic regurgitation that is apparent relatively early in life,but more commonly, they develop aortic stenosis, gener-ally apparent in the 4th decade of life or later. The rate ofprogression of aortic stenosis in patients with bicuspidaortic valve is related to the variations in bicuspid aorticvalve anatomy and possibly to risk factors related to ath-erosclerosis. A bicuspid aortic valve often is associatedwith aortopathy featuring aortic root dilatation, relatively

high proclivity for aortic dissection or to functional ab-normalities of the aorta. Bicuspid aortic valve may also bepresent in patients with aortic coarctation. Bicuspid aor-tic valve appears to be familial and at least three gene locihave been defined (fig. 2) [1619].

Coarctation of the aorta may be associated with bicus-pid aortic valve, aortic stenosis, aortic regurgitation andaortopathy. Congenital mitral stenosis is extremely rarein adults. Mitral regurgitation may be present in atrioven-

Table 1. Etiologies of VHD

I. Heritable congenitali. Heritable disorders of connective tissue (Marfan

syndrome, Ehlers-Danlos syndrome, polycystickidney disease and isolated abnormalities)

ii. Congenital valve disease and etiology unclear (bicuspidaortic valve disease, endocardial cushion defectswith mitral clefts)

iii. Environmentally determined (pulmonic stenosis inmaternal/fetal infection, e.g. rubella)

II. Inflammatory immunologic (rheumatic fever, syphilis,AIDS, Kawasaki disease, ankylosing spondylitis,systemic lupus erythematosus and antiphospholipidsyndrome)

III. Endocardial disordersi. Noninfective (NBTE)ii. Infective

IV. Myocardial diseases (ischemic-nonischemic andhypertrophic cardiomyopathy) diseases of other

organs

V. Neoplastic (carcinoid, myxoma and fibroelastoma)

VI. Degenerative (related to aging, possible genetic andenvironmental predisposing factors)

VII. Iatrogenic valve disease: surgical valve repair andinterposition of devices (valvulotomy, reconstructionand valve replacement)

VIII. Drugs and physical agents (e.g. radiation and trauma)

IX. Infiltrative (mucopolysaccharidoses and hypereosinophilicsyndrome)

X. Idiopathic

Modified from [1] and [2].


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tricular septal defects and corrected transposition of the

great vessels. Aortic regurgitation may be present in pa-tients with a high ventricular septal defect. Pulmonic re-gurgitation is often seen in patients with tetralogy of Fal-lot [1, 2, 20].

Environmentally Determined VHDCongenital pulmonic stenosis, whether or not associ-

ated with other congenital anomalies, may be seen whenthe mother is exposed during pregnancy to an infection,especially rubella [21]. This type of valve disease is notcommon today in industrialized countries.

Inflammatory ImmunologicRheumatic fever primarily affects the mitral and aortic

valves, though in some populations, particularly in SouthAmerica, for unclear reasons tricuspid involvement isalso relatively common [22, 23]. The initial clinical pre-sentation of rheumatic mitral valvulitis is mitral regurgi-tation. The most common chronic valvular abnormalityresulting from rheumatic fever is mitral stenosis. Aorticvalve insufficiency is also common, sometimes associatedwith aortic stenosis; however, pure aortic stenosis is sel-dom of rheumatic etiology and some authorities claim it

never occurs [24, 25]. Although the incidence of rheu-matic fever has decreased dramatically in industrializedcountries, it is still very common in developing countries[1, 2].

Despite the significant reduction in cardiovascularsyphilis, cases still occur. Aortitis occurs in the tertiaryform of syphilis in 7080% of patients. Aortic regurgita-tion is the most common complication of syphilitic aor-titis.

Cardiac involvement in AIDS includes myocardial,

pericardial or endocardial disease with valvular involve-ment. The most common valvular lesion reported in pa-tients with AIDS is nonbacterial thrombotic endocarditis(NBTE) with valvular vegetation formation that can bepresent on all four valves, though left-sided lesions aremore common. Vegetations consist of platelets within afibrin mesh and few inflammatory cells. Thromboembol-ic phenomena may occur, but clinically are underestimat-ed compared to autopsy studies [26].

Kawasaki disease is an acute febrile illness that affectsinfants and young children. Vasculitis of common arter-ies may occur in 20% of the patients. Less often, mitralregurgitation, acute or chronic, may also be seen [27].

Aortic regurgitation, secondary to aortic dilatation, isthe primary valvular abnormality seen in patients withankylosing spondylitis. The aortic annulus is dilated andtherefore the cusps cannot coapt to completely cover thearea of valve outflow. Mitral valvular regurgitation canalso occur.

Systemic lupus erythematosus may produce mitralvalve and tricuspid valve disease (Libman-Sacks). It hasbeen suggested that the presence of antibodies againstphospholipids is associated with a higher incidence of

valvular abnormalities in patients with lupus [1, 2].Antiphosphilipid syndrome is defined as elevated se-rum levels of antiphospholipid antibodies associated withthromboembolic phenomena without diagnostic criteriaof systemic lupus erythematosus or any other disease thatmay be responsible for the antibodies. Studies have shownan association of this syndrome with mitral or aortic valvethickening, which may be associated with mitral or aorticregurgitation [28]. Other studies have suggested, howev-

a b

Fig. 2.a Genetics of FMV/MVP. Arrow =proband, circle = females, squares = males,shaded symbols = family members withFMV/MVP or mitral regurgitation, diago-nal slashes through symbols = deceasedmembers (pedigree modified from [3]).b. = Year born; CHF = congestive heart fail-ure; MVR = mitral valve regurgitation.b Genetics of bicuspid aortic valve disease.


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er, that certain forms of VHD stimulate generation of an-tiphospholipid antibodies, which in turn predispose tothromboembolic events [2931].

Endocardial DisordersNoninfective Disorders

NBTE, called marantic endocarditis in earlier litera-ture, most often occurs in patients with malignant dis-ease, but may also complicate other wasting diseases suchas uremia and AIDS. Endothelial damage caused by cir-culating cytokines, tumor necrosis factor, interleukinsand others, which are increased in patients with malig-nancy or chronic wasting diseases, may trigger plateletdeposition. Sterile vegetations in Libman-Sacks endocar-ditis, a form of NBTE, sometimes develop in patients withsystemic lupus erythematosus and the antiphospholipidsyndrome [28]. NBTE used to be diagnosed at autopsy,but with current imaging techniques (e.g. 2- and 3-di-

mensional transesophageal echocardiography) NBTEcan be identified in vivo [5].

Infective DisordersIn the 19th century, Sir William Osler defined infec-

tive endocarditis as, Inflammation of the lining mem-branes of the heart usually confined in the valves, sothe term is practically synonymous with valvular endo-carditis [1, 2]. Since that time, the nature of infectiveendocarditis has changed. Major factors have contrib-uted to the metamorphosis of infective endocarditis overthe last 56 decades including the almost complete dis-appearance of rheumatic fever and syphilis in industrial-ized countries (previously the two most common causesof VHD and therefore the most common predisposingfactors for infective endocarditis in the past), increasedlife expectancy, the use of implantable cardioverter defi-brillators and intracardiac leads for pacing as well as theimplantation of other devices intended for more or lesspermanent residence in the body, the use of catheters in-dwelling for hours or days for hemodynamic monitoringor fluid or drug infusion, increasing numbers of patientswith prosthetic valves, transplanted organs (kidney,

heart and liver) and increasing numbers of immunocom-promised patients for reasons other than prophylaxis fororgan transplantation. Although endocarditis can devel-op in previously normal valves, it occurs most oftenwhen VHD or congenital heart disease already exist. Animportant factor in the development of infective endo-carditis is the abnormal surface area of the valve ratherthan the leakage of the valve per se. Infective endocardi-tis is often seen in patients with FMV/MVP, even with

minimal or absent mitral regurgitation, but has almostnever been described in patients with cardiomyopathyand significant mitral or tricuspid regurgitation, whogenerally have a normal valve surface area. Infective en-docarditis may result in vegetations, acute valvular re-gurgitation and thromboembolic phenomena. In intra-

venous-drug abusers, acute tricuspid or pulmonic valveendocarditis is particularly common. Incidence of infec-tive endocarditis is estimated as 45 cases per 100,000person-years with a male to female ratio of 2 to 2.5: 1. Theincidence of infective endocarditis increases with age andis thus less common in children [1, 2, 3234]. The distri-bution of infective endocarditis ranges from 24 to 45%for the mitral valve alone, from 5 to 36% for the aorticvalve alone and 5 to 35% for the aortic and mitral valvescombined [1, 2].

Failure to decrease the incidence of infective endocar-ditis in the antibiotic era may be related to aging of the

population associated with pathogenetic factors not ap-parent in younger people, increased use of invasive pro-cedures and prosthetic valve implantations, survival intoadulthood of many patients with congenital heart diseasewho would have died in infancy or childhood in earliereras, development of particularly virulent pathogens bynatural selection, recurrence of infective endocarditis inpatients who survived an initial episode, but continue tomanifest predisposing factors (many unknown) and im-proving methodology for detecting the disease. This lastis particularly important because infective endocarditiscan present with a wide variety of symptoms and findingsthat can involve any other organ or system in addition tothe heart. It follows that diagnosis and management re-quire a high index of suspicion, clinical experience, clini-cal judgment and common sense [2].

Myocardial Diseases Diseases of Other OrgansMitral regurgitation and tricuspid regurgitation are

common in patients with ischemic and nonischemic car-diomyopathy (fig. 3). This is related to papillary muscledisplacement due to left-ventricular dilatation, papillarymuscle dysfunction, fibrosis, distortion of the subvalvular

apparatus and dyssynchrony of left-ventricular contrac-tion. Annular dilatation may occur, but at the very latestages of the disease [1, 2, 35, 36]. Chronic left-ventriculardilatation alone is not a common cause of functional mi-tral regurgitation. Studies have shown that the prevalenceof functional mitral regurgitation is very low in left-ven-tricular dilatation secondary to chronic aortic regurgita-tion. In this case, elongation of the mitral valve leafletsappears to prevent mitral regurgitation [37].


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Mitral regurgitation is common in patients with hy-pertrophic cardiomyopathy. It is related to the systolicanterior motion of the mitral valve that may produce ob-struction of the left-ventricular outflow tract as well asmitral regurgitation. A recent study using magnetic reso-nance imaging techniques demonstrated elongated mi-tral valve leaflets independent of other disease variables,which most likely constitutes a primary phenotypic ex-pression of the disease and contributes to left-ventricularoutflow obstruction [38].

Data also suggest that atrial fibrillation can producemitral regurgitation that improves if sinus rhythm is re-stored [39].

Patients with chronic kidney disease, especially thoseon chronic dialysis, often have VHD. Mitral and tricuspidregurgitation have been reported in 38 and 37% of pa-tients, respectively. Mitral annular calcification was pres-ent in 35% of the patients. Aortic calcification, which isoften associated with aortic stenosis or regurgitation, isalso not uncommon [40, 41]. The underlying basis forvalve disease in chronic kidney disease, like the basis of

the unusually high prevalence of coronary artery disease,is not well understood.

Neoplastic VHDCardiac abnormalities occur in 6070% of patients

with carcinoid heart disease, but clinically apparent dis-ease is less common and predominantly involves rightheart valves (only 25% of those with cardiac abnormali-ties develop clinically apparent right-sided VHD). The

tricuspid and the pulmonic valve are the most commonlyaffected in carcinoid heart disease, but, less often, left-sided VHD also has been described. Carcinoid plaquescomposed of fibrous connective tissue with no elastic fi-bers may appear on either the atrial or the ventricular sideof the leaflets [42].

Intracardiac myxomas are the most frequent benigntumors of the heart. Although myxomas have been re-ported as originating from the mitral annulus, the mitralvalve and the aortic valve, most likely, true myxomas ariseonly from the mural endocardium. Left- or right-atrialmyxomas often mimic mitral or tricuspid stenosis [43].Papillary fibroelastomas often arise from the cardiacvalves or occasionally from the ventricular endocardium;rarely, they originate from the right-sided cardiac valves.As there is potential for cerebral or coronary emboliza-tion, surgical excision should be considered, particularlyif tumors are large or mobile; however, rigorous stan-dards to support excision are not available and, thus, clin-ical judgment should be applied for each individual pa-tient. Papillary fibroelastomas may also interfere with

normal valve function [2, 43].

Degenerative VHD Related to Aging, PossibleGenetic and Environmental Predisposing FactorsCalcification of the cusps of the aortic valve usually oc-

curs after the 7th decade of life. Calcification begins at theannular base of the cusps and progresses towards the edg-es and apices to create aortic stenosis. Until recently, itwas thought that this pattern was related to processes spe-

Fig. 3. Factors contributing to the develop-ment of mitral regurgitation in ischemicand nonischemic cardiomyopathy.


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cifically associated with aging. However, recent develop-ments suggest that aortic stenosis and atherosclerosis arerelated to the same pathophysiologic mechanisms, in-volving a genetic disorder of metabolic processes (dis-cussed later). Mitral annular calcification occurs primar-ily in elderly patients, but may occur in younger patients

with Marfan syndrome, FMV/MVP or chronic renal dis-ease. Mitral annular calcification may interfere with nor-mal contraction of the mitral annulus, resulting in mitralregurgitation; it is associated with a relatively high inci-dence of cardiovascular events, even in cases with mini-mal valvular dysfunction [44, 45]. Mitral annular calcifi-cation, when particularly severe, can impinge on the left-ventricular inflow path, creating mitral stenosis that canbe hemodynamically important [46].

Iatrogenic Valve Disease: Surgical Valve Repair andInterposition of Devices

By definition, VHD is present after interventionaltherapy (balloon valvuloplasty and reconstructive sur-gery including valve repair or valve replacement). Balloonmitral valvuloplasty is an effective treatment for many pa-tients with valvular mitral stenosis. Long-term results af-ter this procedure depend on the pretherapy characteris-tics of the valve and of the patient. Residual mitral steno-sis is present in most patients after the procedure andmitral regurgitation may also occur. Mitral valve recon-struction is possible in a high percentage of patients withmitral regurgitation due to FMV/MVP. With reconstruc-tive surgery, many of the problems associated with a valveprosthesis may be avoided. Mitral valve repair can also beperformed in some young patients with rheumatic valvu-lar disease; however, the results of repair for rheumaticdisease are often suboptimal and may worsen with timeas the underlying inflammatory process progresses. Pros-thetic heart valves have certain hemodynamic limitationseven when they are functioning according to specifica-tions. These devices represent a type of iatrogenic VHD.Prosthetic valves are prone to several complications suchas mechanical dysfunction as well as thrombosis and en-docarditis, which further compromise valve function [1

3, 47]. Finally, the inability to implant an optimally sizedvalve results in a condition called patient prosthesis mis-match with resulting obstructions to flow that can beclinically obvious and can affect natural history [48].

Drugs and Physical AgentsPatients who have been treated with ergotamine prod-

ucts for migraine headaches may develop VHD. Mitralregurgitation in combination with mitral stenosis and/or

tricuspid stenosis with regurgitation are the most com-mon valvular abnormalities that have been reported.These lesions are characterized by irregular proliferationof myofibroblasts within an avascular myxoid or a collag-enous matrix that encases the leaflets and chordal struc-tures. There is little disruption of the valve structure itself.

The fibrotic endocardial process forms proliferativemounds similar to those seen in patients with carcinoiddisease. The mechanism by which ergot alkaloid agentsinduce valvular disease is unclear. Indeed, the causal rela-tion between drug use and VHD has not been rigorouslydefined. However, the similarities in chemical structureof serotonin, methysergine and ergotamine, and the sim-ilarities in the valvular abnormalities observed after useof these chemicals, strongly suggest common pathophys-iological mechanisms for ergot-alkaloid-associated valvedisease and carcinoid valve disease. Similar valve lesionshave been reported in patients treated with the dopamine

agonists pergoline or garbergoline for Parkinsons dis-ease. Benfluorex, a drug used in diabetic patients (it waswithdrawn from European markets in June 2010), hasbeen reported to increase the incidence of mitral and aor-tic regurgitation [4951]. More recently, the use of3,4-methylenedioxymethamphetamine (Ecstasy) hasbeen reported to be associated with VHD. In certain cas-es, drug-induced VHD may be sufficiently severe to re-quire surgical intervention [51].

Although the heart is relatively resistant to the effectsof radiation, damage to the pericardium, myocardium,endocardium, microvasculature and epicardial coronaryarteries after substantial radiation exposure commonlyoccurs with breast cancer, Hodgkins disease and otherthoracic neoplasms. When the endocardium is involved,fibrosis and fibroelastosis may affect the atrioventricularvalves and produce mitral and tricuspid regurgitation(depending on the radiation window, the aortic valve canalso be involved). The effects of radiation on the heart canbe classified as acute and chronic. Acute pericarditis canoccur after radiation therapy, but the more common clin-ical expression of radiation heart disease occurs monthsto years after radiation exposure, often complicated by

severe calcification [52]. Surgical remediation of suchvalve disease is often particularly difficult because of as-sociated radiation damage to the pleura hindering post-surgical recovery [1, 2, 52].

Aortic regurgitation is the most common clinicallyrecognized valvular disease after chest trauma, common-ly secondary to aortic valve rupture or cusp perforation.In autopsy studies, rupture of the atrioventricular valvehas been reported to be more common than rupture of


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the aortic valve, but this is usually associated with othersignificant cardiac injuries and frequently with cardiacrupture. Consequently, rupture of the aortic valve hasbeen reported more frequently in clinical series. Isolatedmitral valve rupture, however, may occur after chest trau-ma. Rupture of the left-sided papillary muscle results in

massive mitral regurgitation and death. Survival has oc-curred with a lesser degree of mitral regurgitation result-ing from rupture of the head of a papillary muscle, rup-ture of chordae tendinae or a tear in one of the leaflets.Various degrees of mitral regurgitation can also occurfrom simple contusion of the papillary muscle, rupture ofchordae tendinae or torn leaflets [1, 2].

Infiltrative VHDMucopolysaccharidoses are a group of rare heritable

diseases caused by a deficiency of lysosomal enzymes inthe metabolism of glycosoaminoglycans. Mucopolysac-

charidoses have been divided into seven major types. Car-diac diseases include myocardial hypertrophy, pulmo-nary and arterial hypertension, valvular disease and coro-nary occlusion. Though VHD is not a feature of all formsof mucopolysaccharidoses, mitral, tricuspid or aortic re-gurgitation may be present in some [53].

Two forms of hypereosinophilic syndrome are recog-nized: tropical eosinophilic endomyocardial fibrosis andnontropical eosinophilic myocardial disease, which is of-ten referred to as Lfflers syndrome. This is character-ized by eosinophilia in the peripheral blood and eosino-philic infiltration of the endocardium. This results in asevere form of restrictive myocardial disease. Mitral and/or tricuspid regurgitation may also be present [54, 55].

Idiopathic VHDIn rare instances, the underlying etiology of VHD may

not be determinable; however, with advances in technol-ogy today, these cases are rare.

Etiology of Isolated Valve Disease

Generally, the clinical effects of VHD develop slowlyeven when the valve disease is severe. In certain cases,however, an acute process may result in clinically abruptexpression of regurgitation. The pathophysiology andclinical presentation in acute valve regurgitation is differ-ent from that of chronic regurgitation. In acute VHD, de-pending on the severity of the lesion and hemodynamicconsequences, emergency surgery may be necessary [13,56, 57].

The etiologies of isolated mitral valve disease, aorticvalve disease, tricuspid valve disease and pulmonic valvedisease are shown in table 2 and table 3. In industrializednations, tricuspid regurgitation is most often functional(i.e. due to annular stretch and malcoaptation of leaflets)

Table 2. Mitral valve and aortic valve disease

A. Mitral valve diseaseChronic mitral regurgitation

FMV/MVP, isolated or part of recognized connectivetissue disorders syndrome

CongenitalChronic rheumatic valvulitisMitral annular calcificationCardiomyopathy (ischemic, nonischemic and

hypertrophic)Diseases of other organs (renal failure and carcinoid)Postinterventional therapy (valvuloplasty,

reconstruction and replacement)Drugs and physical agents (radiation and trauma)

Acute mitral regurgitationInfective endocarditisSevere papillary muscle dysfunction or ruptureChordae tendineae rupture

Mitral stenosisCongenital

RheumaticPostinterventional therapyMitral annular calcification

B. Aortic valve diseaseChronic aortic regurgitation

Congenital bicuspid valveHeritable disorders of connective tissue (Marfan

syndrome, Ehlers-Danlos syndrome, polycystickidney annuloaortic ectasia, floppy aortic valve,aortic valve prolapse, sinus of Valsalva aneurysm)

Rheumatic feverSyphilisAortitis (Takayasu)Ankylosing spondylitis

Prosthetic valve malfunctionIdiopathic aortic root dilatationAcute aortic regurgitation

Infective endocarditisAcute aortic dissectionTraumaProsthetic valve malfunction

Aortic stenosisBicuspid aortic valveCoarctation of the aortaCalcific stenosis (possibly partly atherosclerotic)Prosthetic valve (malfunctioning or patient prosthesis

mismatch)



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resulting from pulmonary hypertension secondary toleft-sided heart disease rather than from intrinsic valvestructural abnormality (degenerative). Surgical repair oftricuspid regurgitation was commonly avoided in thepast, based on the incorrect assumption that correction ofthe underlying left-sided problem would largely resolve

the tricuspid regurgitation without subsequent major se-quelae. However, recent studies suggest that an aggressivesurgical approach is needed for many patients becausewith increasing survival when left-sided disease is surgi-cally resolved, the long-term sequelae of untreated tricus-pid regurgitation become more apparent [1, 2, 58, 59].

Multivalvular Abnormalities and Current Common

Etiologies

We have presented many different etiologies of VHD.

Certain types are rare and are seldom seen in clinicalpractice. In practice, patients also often have more thanone valve affected (multivalvular heart disease). The mostcommon causes of VHD and multivalvular heart diseaseseen today are shown in table 4 [1, 2].

Vulnerable Plaque and the Vulnerable Valve

Until recently, aortic sclerosis, aortic stenosis and mi-tral annular calcification seen mostly in the elderly werethought to result from degeneration caused by mechani-cal trauma and the biological response to such injury overthe years. However, there is now strong evidence to sug-gest that the same risk factors responsible for the patho-genesis of atherosclerosis are responsible for valve calci-fication and stenosis (aortic sclerosis and stenosis and mi-tral annular calcification).

The possible role of inflammation in degenerativevalve disease characterized by valve calcification was ini-tially emphasized more than 4 decades ago. One earlystudy described valves with mitral annular ring calcifica-tion. The overall incidence of mitral annular calcification

in patients older than 50 years of age was 8.5% [60]. Aor-tic valve calcification was present in more than 30% ofthose patients. Microscopic examination demonstratednonspecific inflammatory changes adjacent to calcium inabout haft of the cases in both sexes. This study [60] wasone of the first to suggest that inflammation may play arole in valvular calcification. More recently, epidemiolog-ic studies have suggested that the modifiable risk factorsfor atherosclerosis such as smoking, hyperlipidemia, arte-

Table 3. Etiology of tricuspid and pulmonic valve disease

A. Tricuspid valve diseaseChronic tricuspid regurgitation

Cardiomyopathy (ischemic and nonischemic)Pulmonary arterial hypertensionHeritable connective tissue disordersEnd-stage renal disease

Postcardiac transplantationCongenital (Ebstein anomaly)Carcinoid heart diseasePacemaker or defibrillator leadsPharmacologic agents

Acute tricuspid regurgitationInfective endocarditisRupture chordae tendineaeRight ventricular infarctionTrauma

Tricuspid stenosisCongenitalRheumaticCarcinoid heart disease

B. Pulmonic valve diseaseChronic pulmonary regurgitation

CongenitalPulmonary annular dilatation

Acute pulmonary regurgitationInfective endocarditisTrauma

Pulmonic stenosisCongenitalRheumaticCarcinoid heart disease


Table 4. Most common causes of VHD and multivalvular abnor-malities today

A. Most common causes of VHDAortic stenosis-sclerosis in the elderlyFMV/MVPBicuspid aortic valveAssociated with other diseases (cardiomyopathy and

end-stage renal disease)Postinterventional therapyInfective endocarditisConnective tissue disordersAtrial fibrillation

B. Most common causes of multivalvular abnormalitiesMitral regurgitation plus tricuspid regurgitation

CardiomyopathyHeritable connective tissue disorders

Mitral regurgitation plus aortic regurgitationHeritable connective tissue disorders

Mitral stenosis plus aortic stenosisRheumatic

Mitral stenosis plus tricuspid stenosis or regurgitationRheumatic



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rial hypertension and metabolic syndrome also constituterisk markers (though not necessarily risk factors modifi-able with reduction of valve disease) for developing aorticsclerosis and stenosis. C-reactive protein, an index of in-flammation, is abnormal in both patients with aortic ste-nosis and atherosclerosis. Moreover, aortic sclerosis with

a normal functioning aortic valve is associated with a rel-atively high incidence of cardiovascular events, suggest-ing that the same underlying mechanisms may be in-volved in the development of atherosclerosis and aorticsclerosis [44, 45]. Hypercholesterolemia in experimentalanimal models produces atherosclerotic lesions in theaortic valve similar to those seen in atherosclerosis. Allthis information supports the hypothesis that aortic scle-rosis or stenosis in the elderly is not a simple degenera-tive process related to aging, but an active metabolic phe-nomenon, possible genetically determined. The initialevent in aortic sclerosis or stenosis is quite plausibly en-

dothelial damage due to high mechanical stress and lowshear stress. If so, then lipids could be expected to pene-trate the damaged endothelium, with oxidation of low-density lipoproteins, initiating an inflammatory process.T cells could then be expected to accumulate, releasingproinflammatory proteins as in atherosclerosis. In fact,monocytes, mast cells and CD3-positive leukocytes withvarious degrees of expression are seen in stenotic aorticvalves. Inflammatory activity stimulates angiogenesis;consistent with this observation, vascular endothelialgrowth factor (VEGF) is present in stenotic aortic valves.Small fragile vessels develop in areas of inflammation;rupture of these vessels results in intraleaflet hemorrhage,most likely accelerating the progression of the disease [61,62]. During the development of aortic stenosis, fibroustissue is formed and fibroblast like-cells, referred to asvalve interstitial cells, accumulate. Some of these cellsapparently undergo a transformation into myofibroblaststhat ultimately differentiate into osteoblasts, which arebelieved to promote calcification and bone formation.Some research suggests that osteopontin and osteocalcinare involved in this process [6365]. Thus, even thoughthe metabolic pathways differ from those involved in ath-

erosclerosis, the genesis may be similar.Inflammation in patients with aortic stenosis has beendemonstrated using positron emission tomography [66,67]. Consistent with the presence of an active process, ahigher temperature was detected in the leaflets of aorticvalves obtained during valve replacement from patientswith aortic stenosis, but not in the leaflets of patients withaortic insufficiency [68]. The metabolic syndrome wasalso found to predict aortic stenosis progression with a

relatively prominent impact in younger patients and in

those treated with statins [69].Calcific VHD is seen more in the left than in the right

heart. Thus, it appears that, in addition to other risk fac-tors, pressure plays an important role in disease develop-ment. Experimental animal models have demonstratedthat hypercholesterolemia results in the development ofatherosclerosis in the aortic and mitral, but not in the pul-monic and tricuspid valves. Studies in humans haveshown that the aortic valve expresses an osteoblastic phe-notype and the mitral valve a chondrogenic phenotype.The pressure on the left-atrial side of the mitral valve ismuch lower compared to the pressure on the ventricularside of the aortic valve. The high pressure in the aorticvalve results in bone formation while the lower pressurein the mitral valve produces cartilage. The slightly higherpressure in the mitral annulus compared to the mitralvalve leaflets results in bone formation and mitral annularcalcification [61, 64]. Toll-like receptors, which are over-expressed in atherosclerosis, are also overexpressed in theinterstitial cells of aortic valves and much less in pulmon-ic valves.

Other studies have suggested that cardiovascular cal-cification is inversely related to bone tissue mineral den-

sity. Diseases of mineral metabolism such as osteoporo-sis, chronic renal failure and Pagets disease are associat-ed with a relatively high incidence of aortic stenosis andvascular calcification (fig. 4). Epidemiologic studies alsosuggest that higher serum phosphate levels within thenormal range are associated with valvular and annular(mitral and aortic) calcification in older adults. Thus,phosphorus may be a novel risk factor for calcific aorticstenosis [70, 71].

Fig. 4. Relationship between cardiovascular calcification and lossof bone mineral.


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In summary, the initial event in the development ofatherosclerosis and aortic stenosis appears to be endo-thelial damage due to high mechanical and low shearstress. During the development of atherosclerosis, mac-rophages, T cells, foam cells and vascular smooth musclecells are accumulated. In aortic stenosis, the cells that ac-

cumulate include macrophages, T cells, valve interstitialcells, myoblasts and osteoblasts. Experimental and em-pirical clinical observation suggests that during the pro-gression of aortic stenosis, inflammation, fibrosis andcalcification are prominent; during the progression ofatherosclerosis, inflammation, lipid deposition, plaquerupture due to lipid rich pool and thrombosis prevail.These differences may explain why statins are not effec-tive in the late stages of aortic stenosis [72]. In atheroscle-rosis, statins may stabilize plaques and prevent rupture,while in aortic stenosis statins cannot prevent fibrosisand bone formation.

However, given the apparent similarities in some ofthe underlying processes, it remains unclear why manypatients with risk factors and coronary artery disease donot develop aortic stenosis. Studies have suggested thateven in the normal trileaflet aortic valve, the size of thethree leaflets may vary slightly (i.e. one leaflet may be alittle smaller than the other two). This minor anatomicvariation may be a factor predisposing to aortic stenosis[2]. Further, it appears that there is a genetic predisposi-tion to aortic calcification and aortic stenosis. Thus, forexample, recent data indicate that variations in the geneencoding lipoprotein(a), leading to variations inlipoprotein(a) levels, is associated with aortic valve calci-fication and aortic stenosis [73]. Better understanding ofthe underlying anatomic, pathophysiologic and molecu-lar mechanisms will assist in the management and even-tual prevention of aortic stenosis.

Limited data also suggest that rheumatic valve calcifi-cation is not a random passive process, but related to aninflammatory process that is associated with osteoblastformation and osteogenesis [65].

VHD Interrelationships

VHD affects the structure and function of several oth-er organs (fig. 5). Aortic stenosis, aortic regurgitationand mitral regurgitation, through different mechanisms,have an important effect on left-ventricular structureand function. Thickening of left-ventricular walls andconcentric hypertrophy is seen in aortic stenosis; eccen-tric left-ventricular hypertrophy with dilatation is pres-

ent in aortic regurgitation and mitral regurgitation.Myocardial fibrosis, which also determines the naturalhistory of the disease, is also seen. Indeed, during the past

2 decades, it has become clear that fibrosis is not an in-flammatory response due to the injury of myocytes un-der the mechanical stress of valve disease, but is rather aprimary response of myocardial fibroblasts to myocar-dial stress and strain [7477]. In addition, increased oxi-dative stress appears to cause myofibrillar degenerationand lipofuscin accumulation resulting in left-ventricularcontractile dysfunction in mitral regurgitation [78]. Left-or right-atrial dilatation and dysfunction, which are of-ten associated with atrial fibrillation, are present in pa-tients with mitral and tricuspid valve disease (stenosis orregurgitation) [79, 80]. Pulmonary hypertension sec-ondary to increased left-ventricular and/or left-atrialpressure is not uncommon in VHD. Increased venouspressure and peripheral edema are associated with tri-cuspid valve disease (stenosis or regurgitation). Aorticfunction and endothelial function are abnormal in pa-tients with bicuspid aortic valve [17]. Aortic dysfunction(i.e. stiff aorta) may accelerate the natural history of aor-tic regurgitation and mitral regurgitation [81]. As previ-ously noted, aortic sclerosis is directly associated withcoronary events. In patients with FMV/MVP, nerve end-ings in the mitral valve may be stimulated, resulting in

central nervous system responses forming a heart-braininteraction [82]. Altering preload, afterload or other he-modynamic factors may also result in a change in theseverity of VHD [83]. Finally, VHD may result in a dete-rioration of the process underlying the valvular disorder(e.g. cardiomyopathy), which, in turn, impacts negative-ly on valvular function (e.g. mitral regurgitation) [2, 84,85]. Thus, VHD may affect the circulation in a globalfashion.

Fig. 5. Interrelationships of VHD, several organs and underlyingdisease.


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Conclusions

A metamorphosis in the etiology of VHD has occurredover the last 6 decades. The almost complete disappear-ance of rheumatic fever in industrialized countries, in-creased life expectancy and iatrogenic forms of VHD

(postinterventional therapy) are major factors contribut-ing to this metamorphosis. Nonetheless, VHD today con-stitutes an important public health problem.

The most common causes of VHD today are calcificaortic stenosis in the elderly, FMV/MVP associated withmitral regurgitation, bicuspid aortic valve, VHD associat-ed with cardiomyopathy (ischemic and nonischemic),postinterventional therapy (iatrogenic), infective endocar-ditis and VHD in patients with connective tissue disorders.When mitral and tricuspid regurgitation are present, car-diomyopathy or, less often, connective tissue disorders aremost commonly the underlying causes. In contrast, when

mitral stenosis is one of the lesions (e.g. mitral stenosis plusaortic stenosis or mitral stenosis plus tricuspid stenosis)the finding has usually been in South Africa, China or India(where rheumatic fever remains prevalent) and the under-lying etiology is most likely rheumatic fever.

Until recently, it was thought that calcific aortic steno-sis was related only to aging. Recent developments, how-ever, suggest that calcific aortic stenosis and valvular cal-cification in general involves an active inflammatory pro-cess in which anatomic, genetic and other risk factorsassociated with atherosclerosis contribute to the develop-

ment of the disease.VHD may affect the structure and function of severalother organs, such as the cardiac ventricles, atria and thepulmonary circulation, central nervous system function(heart-brain interaction) and aortic function. In turn,aortic function (aortic stiffness) may accelerate the pro-gression of mitral and aortic regurgitation. VHD mayeven result in deterioration of the disease underlying theVHD (e.g. cardiomyopathy), which in turn potentiatesthe valve disease (e.g. mitral regurgitation).

Better understanding of the genetic, anatomic, patho-physiologic and molecular mechanisms responsible for

the development of VHD and the interrelationship ofVHD with other systems/organs will help clinicians opti-mize current management and, eventually, prevent thedevelopment of VHD.

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