Calcification of various cardiovascular structures is associated with aging. [1, 2] Mitral annular calcification (MAC) is a chronic degenerative process of the mitral valve ring; it was first described in 1908 by Bonninger as associated with complete heart block.  Calcification of the annulus fibrosus of the mitral valve was commonly found in older people at autopsy and was considered to be a sequela of rheumatic heart disease. [4, 5] However, evidence of previous disease was often absent and the lesion is now generally regarded as the end stage of an inflammatory process.
MAC and atherosclerosis share similar risk factors, and the presence of MAC may reflect the intensity and duration of exposure to these risk factors. [6, 7] Interestingly, MAC has been proposed as a visible barometer of the burden of atherosclerotic disease. [8, 9] Furthermore, studies have suggested that the presence of MAC is independently associated with a higher incidence of cardiovascular disease (CVD) and cardiovascular death. [9, 10, 11]
Pathophysiology and Etiology
Mitral annular calcification (MAC) and atherosclerosis are strongly associated. Early pathologic studies suggest that MAC and calcific aortic stenosis may be forms of atherosclerosis. [4, 5] The attachment points of the aortic and mitral valves to their respective annuli are sites of turbulent blood flow, which may induce endothelial injury and increase the risk of developing atherosclerosis. Calcifying valves contain sites of lipid accumulation and exhibit macrophage and T-cell infiltrates, presumably in response to endothelial injury.  Calcification within the mitral annulus has been reported to be accelerated by advanced age, systemic hypertension, hypercholesterolemia, diabetes mellitus, chronic renal failure with secondary hyperparathyroidism, and genetic abnormalities of the fibrous skeleton, such as Marfan and Hurler syndromes. [12, 13, 14]
Previously thought to reflect a passive process, recent research has demonstrated that cardiac valve calcification is actively regulated and potentially modifiable. [15, 16, 17] Moreover, 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. 
Studies have shown that the prevalence of MAC in patients with end-stage renal disease is higher than in age-matched control subjects. [19, 20, 21, 22] The calcium-phosphate product correlates directly with the prevalence of MAC.  Although it was initially believed that high phosphate concentrations trigger vascular calcification simply by exceeding the calcium-phosphate solubility product (causing precipitation), studies have suggested that high phosphate levels induce vascular smooth muscle cells to differentiate into an osteoblastic phenotype. 
Caseous calcification of the mitral valve is a rare form of MAC that typically affects the posterior annulus. The contents of the cavity are composed of a mixture of calcium, fatty acid, and cholesterol, with a ‘‘toothpaste-like’’ texture, and may present as an intracardiac mass or cavity. [24, 25, 26]
The prevalence of mitral annular calcification (MAC) varies significantly among different populations and is also influenced by differences in age and the presence of comorbidities. In the Framingham study with an elderly population, the prevalence of MAC was 14%.  A study by Allison et al of middle-aged and elderly patients seen in a ”preventive health” clinic found a prevalence of 8%.  Other studies have shown lower prevalence rates, especially those including asymptomatic patients free of clinical coronary heart disease. 
In elderly people, the prevalence of MAC is significantly higher, as described in the Cardiovascular Health Study (CHS), a community-based cohort study of elderly individuals (mean age, 76 y).  The prevalence of MAC in this study was 42% and was strongly associated with the presence of cardiovascular disease (CVD). Among patients older than 85 years, the prevalence of MAC was 60%.  Notably, in the Framingham Heart Study, MAC was not found in those younger than 40 years.  In the study by Allison et al, each 10-year increase in age was associated with a 3.7-fold increase in the likelihood of MAC being present. 
Conflicting evidence exists regarding the occurrence of MAC between males and females. While the Framingham Heart Study found that 72% of subjects with MAC were female,  the study by Allison et al observed a trend towards lower prevalence of MAC in women versus men (difference not statistically significant).  The population-based Atherosclerosis Risk in Communities (ARIC) study found a similar overall prevalence of MAC between sexes (4.6% in women and 5.6% in men, with a mean age of 59 y).  The prevalence increased with age; at age 70 years, 10% of women and 15% of men were found to have MAC. The Multi-Ethnic Study of Atherosclerosis (MESA) found a female predominance for MAC, observing a prevalence of 12% in women and 8% in men aged 45-84 years. 
Data on the prevalence of MAC in different racial groups are limited. A cohort that included a majority of Hispanic patients (mean age, 68 y) showed a prevalence of 26%.  The prevalence in a cohort of ARIC patients that included only African Americans (mean age, 59 y) was 4.9%.  According to data from the MESA cohort of patients aged 45-84 years, the prevalence of MAC was highest in whites (12%), followed by Hispanics (10%) and then African Americans (7%), and was lowest in Chinese subjects (5%).  Racial differences were not only observed in MAC but also in other valvular calcifications in a prior study. 
Several studies have looked at associations between the presence of MAC and cardiovascular events. The Framingham Study followed 1197 subjects for 16 years and showed an association between MAC and cardiovascular disease (CVD), CVD death, and all-cause death. Moreover, for each 1 mm increase in MAC, the risk of CVD, CVD death, and all-cause death increased by approximately 10%. 
In the ARIC substudy restricted to African Americans, MAC was associated with incident CVD events, defined as fatal coronary event, hospitalized myocardial infarction, or cardiac procedure. 
Mortality data in patients with MAC and nonvalvular atrial fibrillation was examined in the Belgrade Atrial Fibrillation Study. This prospective study followed 1056 middle-aged subjects for a mean of 9.9 years. Significant associations were found between MAC and all-cause death, CVD death, and the composite endpoint of ischemic stroke, myocardial infarction, and all-cause death. 
In the Northern Manhattan Study of 1955 subjects with a mean follow up of 7.4 years, MAC was associated with an increased risk of myocardial infarction and vascular death but not ischemic stroke. 
Mitral annular calcification (MAC) is associated with cardiovascular disease (CVD), but there is no evidence that risk factor control influences progression of MAC.
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