Supplemental Material
Pathogenesis and Associations
Supplemental Figure 1: Pathogenesis of MAC
Supplemental References
1
Pathogenesis and Associations
The pathophysiological mechanisms attributing to the formation of MAC are not fully
understood. Previous autopsy histologic and clinicopathologic studies have shed light on the
pathogenesis of MAC and contemporary large size imaging studies that examined the association
between MAC and other disease entities such as atherosclerosis and CKD, further enhanced our
knowledge and enabled a better understanding of this process and its clinical importance
(Central Illustration). Although MAC was first considered a passive degenerative, age-related
process (1, 2), accumulating evidence now points toward a tightly regulated process with
features similar to both medial and atherosclerotic cardiovascular calcification (3).
Degenerative, age-related process
Sell et al. described calcification of the mitral annulus as a chronic, age-related degenerative,
noninflammatory process in the fibrous support structure of the mitral valve (2). They examined
200 mitral annulus specimens from necropsied patients aged 1 day to 96 years. In the first decade
of life the mitral annulus was composed of parallel thin collagen fibers and few elastic fibers.
From the 2nd to 5th decades, the collagen fibers appeared thicker, denser with gradually decreased
parallel orientation. Elastic fibers number slightly increased and lipid flecks started to
accumulate between the collagen fibers. Small foci of calcification were first visible at the 5th
decade and were situated in zones of lipid deposition. After the 5th decade, disorientation in
collagen fibers further increased and deposits of lipid and calcium increased in size
(Supplemental Figure 1) (2). Histologic examination of several massively calcified mitral
valves revealed large amorphous globules of calcified material separated by dense fibrous bands
of varying thickness. Arounlangsy et al. evaluated the histopathology of the early stages of MAC
2
and found that microscopic calcification and lipid-deposition in the mitral annulus were common
finding in elderly autopsy cases without evident of macroscopic MAC (4).
Kanjanauthai et al., evaluated 6,814 CT scans of participants enrolled in the Multi-Ethnic
Study of Atherosclerosis (MESA) (5). The overall prevalence of MAC was 9% and multivariable
analysis found increased age to be independently associated with MAC in all ethnicities (OR 3.6
per 10 years; 95% CI: 3.2 to4). Similar findings were also found in other large studies in which
echocardiography examinations or CT scans were used to diagnose MAC (6–8). Interestingly, in
an analysis of 40 necropsy patients aged 90 years or over, Waller and Roberts found MAC to be
prevalent in 47% (9).
Atherosclerosis
After examining at necropsy more than 300 patients with MAC, Roberts described the calcified
deposits to be most commonly grossly located between the undersurface of the mural
endocardium of the LV wall in apposition to the posterior mitral leaflet. This leaflet has a Cshaped circumferential attachment to the annulus and therefore extensive MAC usually has Cshape appearance, sparing the anterior mitral annulus, which is substantially less commonly
involved (10,11). Based on the pathological features seen in these specimens (e.g., finding foam
cell in early mitral annular lesions) and on the strong association he observed between the coexistence of MAC and cardiovascular risk factors, Roberts suggested that MAC and vascular
atherosclerosis are both a different form of the same disease (10). He also noted the close
resemblance between MAC and aortic valve calcification resulting in aortic stenosis.
There is now growing evidence that that development of MAC, like calcific aortic
stenosis and vascular atherosclerosis, may be initiated by endothelial injury at foci of increased
mechanical stress (3,12). The combination of increased stress along with the resulting
3
inflammation are the primary stimulus for valvular calcification. These calcifying foci initially
have macrophage and T-cell infiltrates in response to endothelial injury. Bone morphogenetic
protein-2 and -4 are then expressed by myofibroblasts and preosteoblasts adjacent to these
lymphocytic infiltrates and contribute to both mineralization and local induction of inflammation
(3). Focal calcific deposits in regions of microinjury and lipoprotein accumulation may then
coalesce over time into the dense, fibrotic, rigid band macroscopically evident as MAC. Cardiac
valves express markers of osteoblastic differentiation and calcify in a manner similar to normal
osteogenesis, with lamellar bone evident in the majority of pathological specimens examined
(12). This is also considered a hallmark of atherosclerotic calcification (3). It should be
highlighted, that understanding the mechanism of valvular calcification is based mainly on
multiple cell culture and histopathological studies that were performed on aortic valve specimens
(3,12–16). An atherosclerosis-like process involving basement membrane disruption, lipid
deposition, inflammatory cell infiltration, and cytokine release trigger valve myofibroblast
activation and differentiation into an osteoblast-like cell type (13,15). Osteoblasts subsequently
coordinate calcification of the valve as part of a highly regulated process akin to skeletal bone
formation, with expression of many mediators, such as osteocalcin, alkaline phosphatase and
bone morphogenetic protein-2 (13). Further studies are needed to better understand the
similarities between aortic valve calcification and the development of MAC.
Many studies have shown a strong association between MAC and cardiovascular risk
factors (e.g., hypertension, diabetes, dyslipidemia, and smoking) (5,7,17–21). In addition, a
strong correlation was found between MAC and calcium accumulation in the thoracic and
abdominal aorta and in the carotid arteries (8). A strong correlation was also demonstrated
between MAC and aortic atheroma, carotid atherosclerotic disease, peripheral artery disease, and
4
CAD (6,22–25). These studies further support the hypothesis that calcification of the mitral
annulus is strongly associated to the pathogenesis of atherosclerosis.
Boon et al.(7) compared 657 patients diagnosed with MAC using echocardiography to
568 controls. Multivariable regression analysis found hypertension (OR:2.72), diabetes mellitus
(OR-2.49), and dyslipidemia (OR:2.86) to be associated with MAC. In an analysis of 5,895
participants of the Multi-Ethnic Study of Atherosclerosis, MAC was diagnosed using CT in 534
patients (9%) (19). Diabetes mellitus, hypertension, dyslipidemia, and smoking were all found to
be significant predictors of incident MAC. Another support to the atherosclerotic pathogenesis of
MAC is derived from the association between MAC and increased levels of endothelin-1,
interleukin-6 , C-reactive protein and decreased levels of nitric oxide and fetuin-A (19,26–29).
Hypothyroidism is also associated with increased risk of atherosclerosis and was found also to be
associated with MAC in men (30). Moreover, Molad et al. reported high prevalence of MAC
(20%) among 107 relatively young patients (mean age 45.9±14.7 years) with systemic lupus
erythematosus (31). There was also high prevalence of premature CVD among these patients
suggesting a common pathophysiologic mechanism between MAC and atherosclerosis.
Conditions with increased mitral valve stress
Degenerative calcification of the mitral annular area is accelerated by conditions that increase
mitral valve stress – hypertension, aortic stenosis, and hypertrophic cardiomyopathy (32–34). In
these conditions LV peak systolic pressure and therefore mitral valve closing pressure are
increased resulting in excess annular tension and subsequently annulus degeneration. A recent
support for this association was found by Elmariah et al. who demonstrated a strong correlation
between left ventricular hypertrophy and the prevalence, severity, and incidence of MAC (35).
Calcification of the mitral annulus is also associated with excess tension encountered in disorders
5
of mitral valve motion – mitral valve prolapse (MVP) and mitral valve replacement (32,36–38).
Because of its more perpendicular position to the vector of the LV outflow force and greater
annular attachment, the posterior mitral leaflet is subjected to more of the mitral stresses than the
anterior leaflet (39).
The association between hypertensive CVD and MAC is well established (7,8,32).
Allison et al. (8) examined 1,242 CT scans and found hypertension to be prevalent in 49% of the
patients with MAC compared to 24% of the patients without MAC (p < 0.01). Surprisingly,
although the subjects in the MAC group of the Multi-Ethnic Study of Atherosclerosis had higher
prevalence of hypertension, multivariable analysis failed to demonstrate this connection (5).
The association between MAC and calcific aortic stenosis was first established in 1954
by Simon and Liu (40), who found stenotic aortic valves in 27% of 59 autopsy specimens of
patients with MAC. In a retrospective study of 24,380 echocardiograms, Movahed et al. (41)
noted that MAC was present in 15% versus 6% of patients with and without aortic stenosis,
respectively. Multivariable analysis further enhanced this association in their study. A recent
study examining CT scans of patients with severe aortic stenosis that underwent aortic valve
replacement showed evidence of MAC in 53% of the patients (42). Aronow et al. (43) found
MAC diagnosed with echocardiography to be present in 13 out of 17 patients (76%) with
hypertrophic cardiomyopathy. Motamed et al. examined necropsy cases of hypertrophic
cardiomyopathy and found 30 cases of MAC among the 100 hypertrophic cardiomyopathy
patients older than 40 years (44).
In a recent report of 410 patients with MVP that underwent surgical mitral valve repair,
MAC was found in 24% (38). Increased incidence of MAC in patients with MVP is thought to
result from dystrophic calcification at sites of annular trauma caused by increased tension
6
exerted by redundant hypermobile leaflets (34,37). Mitral annulus calcium deposits are also
encountered several years after prosthetic mitral valve implantation and is the result of increased
mitral valve stress caused by removal of papillary muscles and chordal support (32,39).
Abnormal calcium-phosphorus metabolism
MAC is a common finding in patients with CKD. It has been found to be associated with reduced
glomerular filtration rate (45–47), with end-stage renal disease (48) and with peritoneal dialysis
and hemodialysis therapies (49–51). Several mechanisms might be responsible for the increased
risk of MAC in patients with renal disease. The association between CKD and MAC may be
partially explained by an increased prevalence and severity of cardiovascular risk factors and of
atherosclerotic disease in these patients (47). Moreover, the high incidence of co-morbidities and
hemodynamic stresses that produce left ventricular pressure and volume overload in patients
with end-stage renal disease also contributes to the high incidence of MAC in these patients (48).
Nonetheless, there is growing evidence that abnormal calcium-phosphorus metabolism observed
in patients with chronic renal failure has a direct role in the pathogenesis of MAC (32,34,48).
As chronic renal failure progresses, there is a progressive decline in the filtration of
phosphate, which results in phosphate retention. This is accompanied by a small decline in the
serum calcium level and compensatory increase in the serum parathyroid hormone level (48). It
is followed by removal of calcium from the bones in an attempt to maintain homeostasis.
Secondary hyperparathyroidism results in an elevated calcium-phosphorus product that when
exceeding solubility in the serum may cause metastatic calcification in the mitral annulus,
producing the characteristic lesion of MAC (52,53). Furthermore, hyperphosphatemia have been
shown to contribute to MAC in patients without CKD (54), and have been shown to induce
7
vascular smooth muscle cells to differentiate into an osteoblastic phenotype that may initiate
matrix mineralization (55).
Jesri et al. examined patients diagnosed with severe MAC by echocardiography. Nearly
60% had CKD defined by a glomerular filtration rate <60 ml/min/1.73m2 with a relative risk of
1.8 versus controls (45). In a sub-study of the Cardiovascular Health Study, MAC diagnosed
with echocardiography was present in 42% of the 3,929 participants. After multivariable
adjustment, glomerular filtration rate <45 ml/min/1.73m2 was significantly associated with
prevalent MAC (46). Interestingly, in this study as well as in others, there was no correlation
between CKD and aortic valve calcification suggesting that derangement of the calcium–
phosphate metabolism may be less important in the development of calcified aortic valve (51). In
a recent report examining MAC in hemodialysis outpatients it was found to be prevalent in 64%
(49).
Congenital metabolic disorders associated with MAC
Marfan Syndrome: Marfan syndrome is a multi-systemic inherited connective tissue disease
that affects the cardiovascular system (56). MAC at age <40 years was considered in the past as a
minor diagnostic criteria for this syndrome (57). Aortic root dilatation and MVP are common
cardiovascular features of this disease (56). It remains unclear whether the mitral annulus
calcifies because of increased mitral stress caused by MVP or due to an intrinsic abnormality of
the connective tissue composing the annulus.
Hurler syndrome: Calcification of the mitral annulus has been reported in children with Hurler
syndrome (58). Abnormal fibroblasts and accelerated collagen degeneration may cause early
MAC appearance in these patients (32).
Sex Related Differences
8
Contrary to the atherosclerosis paradigm, several studies have found that female sex is associated
with an increased risk of developing MAC.(5,7,19,25,59). Based on his systematic pathologic
evaluation of 200 patients with MAC, Roberts concluded that although MAC of any degree
appear to occur with similar frequency in men and women, the larger deposits are more frequent
in women (11). It has been suggested that MAC in elderly women can be attributed to ectopic
calcium deposits related to the severe bone loss caused by postmenopausal osteoporosis (59,60).
Further support that osteoporosis contributes to the mechanism of MAC in elderly women was
demonstrated by Elmariah et al. in a sub-study of the diverse Multi-Ethnic Study of
Atherosclerosis cohort (61). Multivariable analysis revealed bisphosphonate use to be associated
with a lower prevalence of cardiovascular calcification in women ≥65 years of age.
Caseous calcification of the mitral annulus (CCMA):
CCMA also known as liquefaction necrosis of MAC is an atypical rare variant of MAC (less
than 1%) (62,63). It is characterized echocardiographically by an echo-dense outer shell and by
an inner echo-lucent core devoid of flow on color Doppler imaging. Echocardiographic studies
have shown that CCMA is often dynamic, and interval examinations may demonstrate
spontaneous resolution or progression. The inner core of the lesion is filled with material of
toothpaste-like consistency, the byproduct of liquefaction necrosis (63). Histologic examination
reveals sterile, amorphous acellular eosinophilic material with macrophage and lymphocyte
infiltration (62). The clinical course of CCMA is generally benign; however, hemodynamically
significant mitral valve stenosis or regurgitation may occur secondary to mass effect (63).
Although rarely, ulcerative erosion with peripheral or cerebral embolization and endocarditis
have also been described and should prompt operative intervention (62). Cardiac magnetic
9
resonance imaging is important in the evaluation of CCMA and can be particularly helpful in
differentiating this entity from cardiac tumor or thrombus (62).
10
Supplemental Figure 1: Pathogenesis of MAC
Degenerative process: During the first years of life the mitral annulus is composed of parallel
thin collagen fibers and few elastic fibers. From the 2nd to 5th decades, the collagen fibers
appeared thicker, denser with gradually decreased parallel orientation. Lipid flecks start to
accumulate between the collagen fibers. Small foci of calcification are first visible at the 5th
decade and are situated in zones of lipid deposition. After the 5th decade, disorientation in
collagen fibers further increased and deposits of lipid and calcium increases in size.
11
Atherosclerosis: Endothelial injury at foci of increased mechanical stress results in macrophage
and T-cell infiltrates. BMP-2 and 4 are then expressed by myofibroblasts and preosteoblasts
adjacent to these infiltrates and contribute to both mineralization and local induction of
inflammation. Focal calcific deposits in regions of microinjury and lipoprotein accumulation
may then coalesce over time into the dense, fibrotic, rigid band macroscopically evident as
MAC. Increased mitral valve stress: Conditions that cause LVH result in increased LV peak
systolic pressure and MV closing pressure followed by excess annular tension and subsequently
accelerated annulus calcification. Abnormal calcium-phosphorus metabolism: As GFR
decreases, there is a progressive decline in the filtration of phosphate, which results in phosphate
retention. This is accompanied by a small decline in the serum calcium level and compensatory
increase in the serum parathyroid hormone level. It is followed by the removal of calcium from
the bone in an attempt to maintain homeostasis. Secondary hyperparathyroidism results in an
elevated calcium-phosphorus product that when exceeding solubility in the serum may cause
metastatic calcification in the mitral annulus. BMP = Bone morphogenetic protein; Ca = calcium;
GFR = glomerular filtration rate; LV = left ventricle; LVH = left ventricular hypertrophy; MV =
mitral valve; p = phosphate; PTH = parathyroid hormone
12
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