1184 EXPERIMENTAL AND THERAPEUTIC MEDICINE 11: 1184-1188, 2016

Pathophysiology of valvular heart disease (Review)

1
Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine; 2Department of Cardiology,
Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University;
3
Department of Cardiology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou, Jiangsu 221009, P.R. China

Received November 9, 2015; Accepted February 5, 2016

DOI: 10.3892/etm.2016.3048

Abstract. Valvular heart disease (VHD) is caused by either review, highlights the current understanding of the biology
damage or defect in one of the four heart valves, aortic, of VHD, with particular reference to molecular and cellular
mitral, tricuspid or pulmonary. Defects in these valves can be aspects of its regulation. Current clinical questions and the
congenital or acquired. Age, gender, tobacco use, hypercho- development of new strategies to treat various forms of VHD
lesterolemia, hypertension, and type II diabetes contribute to medically were addressed.
the risk of disease. VHD is an escalating health issue with a
prevalence of 2.5% in the United States alone. Considering
the likely increase of the aging population worldwide, Contents
the incidence of acquired VHD is expected to increase.
Technological advances are instrumental in identifying 1. Introduction
congenital heart defects in infants, thereby adding to the 2. Structure of cardiac valve and pathogenesis of CAVD
growing VHD population. Almost one‑third of elderly indi- 3. Histopathology of CAVD
viduals have echocardiographic or radiological evidence of 4. Inflammation and activation of CAVD pathogenesis
calcific aortic valve (CAV) sclerosis, an early and subclinical 5. Genetics of CAVD
form of CAV disease (CAVD). Of individuals ages >60, 6. Treatment choices and biomarkers
~2% suffer from disease progression to its most severe form,
calcific aortic stenosis. Surgical intervention is therefore 1. Introduction
required in these patients as no effective pharmacotherapies
exist. Valvular calcium load and valve biomineralization are Valvular heart disease (VHD) is a major health problem
orchestrated by the concerted action of diverse cell‑depen- afflicting the elderly in particular, with a prevalence of 2.5%
dent mechanisms. Signaling pathways important in skeletal in the United States. VHD occurs due to congenital defects or
morphogenesis are also involved in the regulation of cardiac because of acquired pathology (1). Calcific aortic valve disease
valve morphogenesis, CAVD and the pathobiology of cardio- (CAVD) is initiated as aortic valve sclerosis (AVSc), which is
vascular calcification. CAVD usually occurs without any a mild thickening of the valve, to aortic valve stenosis (AVS),
obvious symptoms in early stages over a long period of time which results in severe impairment of the valve motion. CAVD
and symptoms are identified at advanced stages of the disease, is increasingly present in the aging population, reaching
leading to a high rate of mortality. Aortic valve replacement epidemic proportions, with approximately one third of indi-
is the only primary treatment of choice. Biomarkers such as viduals aged >65 years, showing sub‑clinical evidence of
asymmetric dimethylarginine, fetuin‑A, calcium phosphate CAVD, in the form of aortic sclerosis (2). As a large proportion
product, natriuretic peptides and osteopontin have been useful of the worldwide population is becoming aged, the preva-
in improving outcomes among various disease states. This lence of acquired forms of VHD is expected to rise (3). Age,
gender, tobacco use, hypercholesterolemia, rheumatic heart
disease and hypertension constitute significant risk factors of
acquired CAVD. Congenital CAVD primarily results from the
Correspondence to: Dr Peiying Zhang, Department of Cardiology, disturbed expression of genes that are involved in normal heart
Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of valve development. Congenital valve abnormalities comprise
Medical College of Southeast University, 199 South Jiefang Road, almost 50% of the cases of congenital heart defects (CHD) (4).
Xuzhou, Jiangsu 221009, P.R. China Advances in the identification of these defects and in the asso-
E‑mail: zpying58@126.com
ciated care for infants suffering from CHDs is on the rise, thus
Key words: valvular heart disease, calcific aortic valve disease, increasing the net incidence and burden of congenital valve
aortic valve stenosis, congenital heart disease, endothelial cells, diseases (4). Type II diabetes is considered an important risk
biomineralization, calcification factor for native CAVD (5). The pathogenesis of congenital
and acquired CAVD is likely due to the interplay of genetic
and environmental influences, even though the precise mecha-
nisms are not known.
 ZENG et al: PATHOPHYSIOLOGY OF VALVULAR HEART DISEASE 1185

Figure 1. Pathogenic pathways involved in calcific aortic valve disease. Mechanical stress or injury on the aortic valve along with other atherosclerotic risk
factors causes valvular endothelial dysfunction. This leads to lipid deposition in the subendothelium where they are oxidized and factors such as oxidized
low‑density lipoprotein (oxLDL) are formed. Inflammatory cells such as monocytes, infiltrate the valve tissue and form foam cells by phagocytosis of the lipids.
Inflammatory cytokines are released which promote remodeling of the extracellular matrix. Fibroblasts transdifferentiate into valvular myofibroblasts with an
osteoblast‑like phenotype, and cause calcification. Biomarkers are associated with different stages of CAVD and can be useful in following the pathogenesis of
the disease. TNFα, tumor necrosis factor α; TGF‑β, transforming growth factor‑β; IL‑1β, interleukin‑1β; MMP, matrix metalloproteases; ECM, extracellular
matrix; ADMA, asymmetric dimethylaminoarginine; tPA, tissue plasminogen activator; CRP, C‑reactive protein; CaxP, calcium phosphate product.

Although the incidence of VHD is high, therapeutic valves and any derangements in these morphological units
approaches for this disease are limited. The only available can have detrimental effects on the complicated structures
primary clinical approach for valve repair or replacement is of valves that open and close approximately 100,000 times
surgery as the primary treatment (6,7). In fact, aortic valve daily in order to maintain proper directionality of blood flow
replacement is the second most frequent cardiac surgery through the heart chambers (11). The protective endothelium
following coronary artery bypass grafting (8). CAVD advances over the surface of the valve leaflets is formed by the VECs,
to calcific aortic stenosis (CAS), which is the most severe form which communicate with VICs in the underlying layer and
of the disease. It is extremely debilitating affecting as many regulate their response to alterations in the blood flow (10).
as 2% of individuals >60 years of age, requiring surgery to Genetic or acquired/environmental causes that disrupt the
preclude death, once the symptoms become evident (9). normal organization and composition of the ECM and commu-
CAVD is mainly diagnosed by clinical examination, echocar- nication between VECs and VICs alter valve mechanics and
diography and cardiac catheterization. There are also many interfere with the valve leaflet function, culminating in heart
potential biomarkers that provide clinically useful information failure (11).
regarding the extent, severity, progression and prognosis of
CAVD (8). 3. Histopathology of CAVD

2. Structure of cardiac valve and pathogenesis of CAVD The histopathologic heterogeneity of CAVD indicates the
involvement of diverse cell‑dependent mechanisms that
The atrioventricular valves (mitral and tricuspid) and the regulate calcium load on the valve leaflets (12), as well as
semilunar valves (aortic and pulmonic) are two types of the participation of different cell types, including interstitial
mature heart valves. These valves consist of an outer layer cells, endothelial cells and cardiac chondrocytes, in valve
of valve endothelial cells (VECs) surrounding three layers biomineralization (13) (Fig. 1). Histopathologic studies (12)
of extracellular matrix each with specialized function and demonstrated the presence of calcified nodules composed
interspersed with valve interstitial cells (VICs) (10). Changes of amorphous calcium phosphate, without any organization
in the functionality and localization of matrix components into specific histological structures. In these affected valves,
potentially lead to VHD, since the proper organization of similar to atherosclerosis, there are signs of inflammation and
extracellular matrix (ECM) is essential in maintaining overall bone morphogenetic protein‑2 expression (12). Additionally,
valve morphology and normal valve function. The three layers woven and lamellar bone with osteoblast matrix production
of ECM, consisting of collagens, proteoglycans and elastin, and vascularization has been identified in calcifying native
collectively contribute to the biomechanical support for the aortic valves (14). During the pathogenesis of CAVD, one of
1186 EXPERIMENTAL AND THERAPEUTIC MEDICINE 11: 1184-1188, 2016

Figure 2. Crosstalk between the Notch and Wnt signaling pathways in calcific aortic valve disease. Notch 1 signaling, which represses BMP2 and Runx2 expres-
sion and impedes β‑catenin stabilization and signaling, is useful in the prevention of valvular calcification. In calcific aortic valve disease, elevated levels of
Wnt3a activate the coreceptor complex formed by Frizzled and Lrp5/6, leading to the stabilization of β‑catenin and promoting the osteogenic transition of valve
interstitial cells and valvular calcification. BMP, bone morphogenetic protein; NICD, Notch intracellular domain; Runx2, runt‑related transcription factor 2.

the earliest events following endothelial cell dysfunction is and neovascularization phases of disease, whereas CD45
the accumulation of lipids and subendothelial matrix at the (+) cells are observed in ossifying and non‑ossifying valve
ventricular surface of the valve with downward displacement segments (23). Circulating myeloid calcifying cells, which are
of the subjacent elastic lamina while plaque‑like subendothe- positive for alkaline phosphatase and osteocalcin are elevated
lial deposits occur on the aortic surface of the valve. It has in type II diabetes patients, and may contribute to the increased
been suggested that VECs via the endothelial‑mesenchymal incidence of CAVD in these patients (24).
transition (EMT), can contribute to calcifying vascular cell
types, in response to stimuli that promote arteriosclerotic 4. Inflammation and activation of CAVD pathogenesis
calcification (15). Athough the contribution of acquired immu-
nity to the progression of CAVD remains to be determined, Inflammation is known to play a significant role in many
recent data indicate that an adaptive immune response is likely types of macrovascular calcification, including CAVD (25).
activated in CAVD as clonally expanded effector‑memory A number of the inflammation‑associated factors, including
T‑cell populations are observed in the valve and in the circula- tumor necrosis factor, interleukin 1‑β, advanced glycosyl-
tion of patients with severe CAS (16) (Fig. 1). ation‑end products, and oxidized low‑density lipoprotein
The earliest amorphous calcium phosphate deposition (oxLDL) cholesterol, activate vascular biomineralization
occurs in a stippled pattern on the fibrosal interface with the and vascular osteogenic signaling processes (26) (Fig. 1).
fibro‑fatty expansion of the valve spongiosa (17) and these Aggravated fibrocalcific responses have been observed in
calcium deposits form readily via epitaxial mineral deposi- CAVD in association with increased levels of oxLDL (27). By
tion on a number of nidi, including cholesterol crystals (18), employing histological studies on human samples and mouse
collagen and fragmented elastin fibers (19). Coexpression of models, it has been demonstrated that reactive oxygen species,
collagen and alkaline phosphatase, which in the elastin‑rich specifically hydrogen peroxide, has a pro‑osteogenic and
environment can trigger mineralization, has been demon- pathogenic role in CAVD and that a number of the enzymatic
strated in CAVD by immunogold electron microscopy (20). mechanisms that counteract oxidative stress are down-
Biomineralization also occurs in the absence of alkaline regulated in valves during the pathogenesis of CAVD (28).
phosphatase, as matrix vesicles contain molecules such as Specifically, hydrogen peroxide has been shown to activate
annexin A5, annexin A6, and phosphatidylserine, which osteogenic Cbfa1/ runt‑related transcription factor 2 (Runx2)
readily bind calcium and nucleate mineral deposition (21) and Msx2/Wnt signaling pathways to promote mineralization
while the absence of inhibitors of mineralization such as and these pathways are activated in calcifying human aortic
pyrophosphate, phosphoosteopontin, and fetuin can further valves (28).
promote the deposition of calcium (22). However, following
the initiation of mineral deposition, circulating osteoprogeni- 5. Genetics of CAVD
tors (COPs) derived from myeloid cell lineage arrive to the site
and play an important role in the subsequent stages of disease Advances in genomic technologies have led to the identifica-
response.T These COP cells most likely originate from the tion of several genes that contribute to the normal development
bone marrow. The presence of type I collagen (+) CD45 (+) and function of the four heart valves and to the identification
COP cells in valves has been detected at the fibroproliferative of many genetic abnormalities in some of these genes in
 ZENG et al: PATHOPHYSIOLOGY OF VALVULAR HEART DISEASE 1187

congenital form of CAVD (29). The most common congenital which occurs during the latter stages of CAVD making this
valve anomalies are bicuspid aortic valve (BAV) and mitral protein a specific biomarker for CAVD (42).
valve prolapse (MVP). BAV is estimated to have a prevalence In conclusion, CAVD and other types of VHDs are reaching
of 1‑2% (30). Normal aortic valve develops until there are three epidemic status in their prevalence in many developed and
cusps, whereas in BAV disease there is a fusion of two of the developing countries. CAVD ranges from AVSc, i.e., mild
leaflets during development, leading to significant morbidity thickening of the valve, to AVS, which is severe impairment
primarily through valve calcification. NOTCH1, a member of the valve motion. Risk factors for acquired valve diseases
of the Notch signaling pathway, was one of the first mutated include age, gender, tobacco use, hypercholesterolemia, hyper-
genes identified in BAV. The Jagged/Notch signaling pathway, tension, and type II diabetes mellitus. Diverse cell‑dependent
which plays an important role in bone formation is also central mechanisms and signaling pathways orchestrate valve
to valve morphogenesis and CAVD. Jagged1 signals from biomineralization with the participation of different cell types
endothelial cells support the Notch1‑mediated EMT necessary including interstitial cells, endothelial cells, cardiac chondro-
for cardiac valve morphogenesis during the development of cytes, and COPs. In addition, several genetic mutations that
heart (31). Heterozygous loss‑of‑function NOTCH1 mutations cause congenital valve diseases have been identified along
segregate with the disease in families with autosomal domi- with specific SNPs associated with CAVD. Despite the many
nant BAV (32). Ex vivo, Notch can suppress Runx2 signaling advances, there is still a lack of pharmacological treatments
and mineralization (Fig. 2) in VICs (33). for the valve diseases and the most widely accepted approach
MVP affects 2‑3% of the population and is manifested by is surgery. Recent advances in the identification of molecular
systolic displacement of a thickened mitral valve leaflet into mechanisms involved in the development and pathogenesis of
the left atrium. This condition is normally observed in adults valvular disease are making a significant impact in our under-
and often associated with the fibromyxomatous degeneration standing of the heart valve disease.
of the leaflets, valve regurgitation, congestive heart failure,
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