Mitral Annular Calcification 

Updated: Mar 06, 2017
Author: Saurabh Sharma, MD, FACC, FACP; Chief Editor: David J Maron, MD, FACC, FAHA 



Calcification of various cardiovascular structures is associated with aging, chronic kidney disease, and following radiation therapy.[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.[3] Dewitzky presented detailed pathologic descriptions of 36 cases and demonstrated the close resemblance to a similar process that had been described in the aortic valve in 1904 by Monckeberg.[4]  Yater and Cornell in 1935 histopathologically demonstrated extension of a calcific mass into the Bundle of His leading to heart block.[5] 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.[6, 7] However, evidence of previous disease was often absent; 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.[8, 9] Interestingly, MAC has been proposed as a visible barometer of the burden of atherosclerotic disease.[10, 11] Mitral annular calcification is a growing problem in the elderly. It causes mitral stenosis and regurgitation, which are hard to treat.[12] Furthermore, studies have suggested that the presence of MAC is independently associated with a higher incidence of cardiovascular disease (CVD) and cardiovascular death and stroke.[11, 13, 14]


Mitral annular calcification (MAC) and atherosclerosis are strongly associated. Early pathologic studies suggest that MAC and calcific aortic stenosis may be a part of the spectrum of atherosclerosis.[6, 7] 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.[15] 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, conditions that increase annular stress (eg, mitral valve prolapse), and genetic abnormalities of the fibrous skeleton (eg, Marfan and Hurler syndromes).[15, 16, 17]

Previously thought to reflect a passive process, recent research has demonstrated that cardiac valve calcification is actively regulated and potentially modifiable.[18, 19, 20] 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.[21]

Studies have shown that the prevalence of MAC in patients with end-stage renal disease is higher than in age-matched control subjects.[22, 23, 24, 25] The calcium-phosphate product correlates directly with the prevalence of MAC.[26] 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.[16]

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.[27, 28, 29]


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%.[13] A study by Allison et al of middle-aged and elderly patients seen in a ”preventive health” clinic found a prevalence of 8%.[9] Other studies have shown lower prevalence rates, especially those including asymptomatic patients free of clinical coronary heart disease.[30]

Age-, sex-, and race-related demographics

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).[1] 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%.[1] Notably, in the Framingham Heart Study, MAC was not found in those younger than 40 years.[30] 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.[9]

Conflicting evidence exists regarding the occurrence of MAC between males and females. Although the Framingham Heart Study found that 72% of subjects with MAC were female,[13] the study by Allison et al observed a trend towards lower prevalence of MAC in women versus men (difference not statistically significant).[9] 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).[31] 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.[32]

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%.[33] The prevalence in a cohort of ARIC patients that included only black individuals (mean age, 59 y) was 4.9%.[31] According to data from the MESA cohort of patients aged 45-84 years, the prevalence of MAC was highest in white persons (12%), followed by Hispanic patients (10%) and then black patients (7%); it was lowest in Chinese subjects (5%).[32] Racial differences were not only observed in MAC but also in other valvular calcifications in a prior study.[34]


Mitral annular calcification (MAC) is associated with cardiovascular disease (CVD), but there is no evidence that risk factor control influences progression of MAC.

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 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%.[13]

In the Atherosclerosis Risk in Communities (ARIC) substudy restricted to black patients, MAC was associated with incident CVD events, defined as fatal coronary event, hospitalized myocardial infarction, or cardiac procedure.[31]

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.[35]

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.[33]


Complications of MAC include the following:

  • Stroke (associated with MAC but, in most cases, probably not directly caused by it)

  • Myocardial infarction (associated with MAC but probably not directly caused by it)

  • Atherosclerosis (associated with MAC but probably not directly caused by it)

  • Mitral regurgitation

  • Mitral stenosis

  • Arrhythmias (conduction disease may be associated with cardiac calcification generally)

  • Infective endocarditis




Patients with mitral annular calcification (MAC) may have multiple associated comorbidities. The comorbidities with the strongest association with MAC are described below. Patients with MAC may present with physical signs of any of these comorbid conditions.


The association of MAC and stroke was initially proposed by Rytand and Lipsitch in 1946.[36] One of the first observational studies on the subject was a prospective study in 1989 by Nair et al, in which patients with MAC were found to be at increased risk for stroke.[37] In 1992, Benjamin et al presented a prospective study from the Framingham group; 1159 subjects were studied and followed for an average of 8 years. After adjusting for known risk factors for cerebrovascular events, subjects with MAC still had a higher risk of stroke. Moreover, the multivariate analysis showed that for every additional millimeter of MAC width, the relative risk of stroke increased by approximately 25%.[38]

However, it remains uncertain whether the increased risk for stroke is caused by MAC itself or merely through its relationship with risk factors for cerebrovascular disease.[38, 39] MAC has been associated with carotid stenosis, aortic atheroma, markers of inflammation, and other biomarkers. Although embolic events in MAC patients might be due to calcific material that dislodges from the annulus, the more common scenario is that of associated conditions that are the direct cause of stroke. Further, the association between MAC and stroke is not present in all studies. The Strong Heart Study found that MAC was associated with an increased stroke risk,[40] whereas the Boston Area Anticoagulation Trial for Atrial Fibrillation[41] and the Cardiovascular Health Study[42] did not.


Atherosclerotic disease has a tendency to initiate in areas with decreased shear stress or increased turbulence of blood flow, both of which are present at the attachment points of the aortic and mitral leaflets to their annuli. In animal studies, induced atherosclerosis produces plaque formation in the posterior leaflet of the mitral valve.[43] Clinical studies have observed an association between MAC and risk factors for atherosclerosis.[44] The association between MAC and atherosclerosis has been found in different vascular beds: the coronary tree,[45] the aorta,[46] and the carotid arteries.[47] Thus, it seems feasible that MAC and atherosclerosis represent two facets of the same disease.[48, 49]

MAC is a predictor of coronary artery disease.[50] Moreover, its presence has been related to vulnerable plaque[51] and a greater burden of coronary disease (more than 1 vessel involved).[52]

MAC is also associated with coronary artery calcium (CAC), a marker of coronary atherosclerosis. In one study, the presence of any MAC had a sensitivity and specificity of 71% and 56%, respectively, for detecting CAC above 400; positive (PPV) and negative predictive values (NPV) were 45% and 79%, respectively.[53]  When using the parameter of CAC over 100, the sensitivity was 65% and specificity was 57%, with a PPV of 59% and an NPV of 63%.

Chronic kidney disease

In a community-based sample from the Framingham Heart Study, MAC was more common in patients with chronic kidney disease (CKD) versus patients with normal kidney function.[54] Furthermore, participants with CKD were 50% more likely to have at least one calcified valve. This relationship was attenuated by adjustment for cardiovascular risk factors, suggesting that shared risk factors partially mediate the increased prevalence. In another study of patients with severe MAC, nearly 60% had clinically significant CKD. The authors suggested that severe MAC on echocardiography should alert the physician to the likely presence not only of atherosclerosis but also CKD.[54]

Among dialysis patients, prevalence rates for MAC are 4-5 times higher than in the general population.[55] Moreover, calcium-phosphorus product and parathyroid hormone levels are higher in patients with MAC.[56, 57, 58] For CKD and dialysis patients, some[59, 60] but not all studies[61, 62] have found that MAC correlates with higher total and cardiovascular mortality. In addition, MAC serves as a marker for left ventricular systolic dysfunction in these patients, with or without end-stage renal disease.[63, 64]

Mitral regurgitation

Mitral regurgitation is a hemodynamic abnormality commonly associated with MAC, with a prevalence of up to 63%.[65] Calcium infiltration of the base of the posterior leaflet reduces leaflet mobility, increases traction on the chordae, and elevates the leaflets, which facilitates chordal elongation or rupture, causing secondary mitral regurgitation.[66] Another proposed mechanism is failure of the calcified annulus to contract at the end of diastole.[67] MAC has been reported to lead to regurgitation severe enough to require surgery in some cases.[66]

Mitral stenosis

Mitral stenosis is a rare complication of MAC.[68, 69] However, MAC can occasionally cause mitral stenosis severe enough to warrant valve replacement.[6] The pathophysiology is thought to be an absence of normal annular dilatation during diastole, resulting in functional mitral stenosis.[70] Alternatively, decreased mobility of the valve when annular calcium limits leaflet excursion, particularly of the anterior leaflet, may be responsible.[71]


MAC is associated with a high frequency of conduction defects, including atrioventricular block, bundle branch block, and intraventricular conduction delay, especially in more severe cases.[3, 72] MAC is also associated with symptomatic bradyarrhythmias requiring pacemaker implantation.[73, 74] This is likely secondary to infiltration of calcium into the conduction system.

Atrial fibrillation

Data from the Framingham cohort show that MAC is associated with an increased risk of incident atrial fibrillation, even when adjusted for atrial size.[75] Nair et al found a similar association.[76] This is not surprising given that MAC is more prevalent in elderly people and that MAC, atherosclerosis, and atrial fibrillation all share common risk factors. The mechanisms by which MAC is predisposed to incident atrial fibrillation are likely multifactorial, but they appear to be partially mediated through left atrial enlargement.[77]  MAC may also interrupt the interatrial and intra-atrial conduction processes, leading to conduction system and atrial conduction defects, thus resulting in atrial fibrillation.[78]


Infective endocarditis is a possible complication of MAC.[79] One prospective study of 976 elderly patients demonstrated a higher incidence of infective endocarditis in patients with MAC (3% vs 1%).[80]  In a study by Pressman et al, MAC has also been shown as a nidus for infection, especially with Staphylococcus aureus.[81]

Aortic valve disease

In a retrospective study among 24,380 patients, Movahed et al found that MAC was present in 15% of patients with aortic stenosis, compared with only 6% of patients without aortic stenosis.[82] In another study that included 219 patients with a mean age of 57 years, MAC was strongly associated with aortic valve calcification.[83] MAC has also been found to be associated with more severe aortic stenosis in a study by Michel et al.[84]



Diagnostic Considerations

Mitral annular calcification (MAC) often takes unusual configurations, which can raise concerns about neoplasm, abscess, or thrombus. In general, any prominent echo-bright abnormality in the posterior annulus region is likely to be MAC. Tumor, infection, and clot are distinctly unusual in this location.

Caseous annular calcification is an unusual form of MAC in which there is a prominent mass in the annulus with a liquid or gelatinous center. At surgery, the contents have been described as having the texture of gruel or toothpaste. Caseous MAC has an estimated prevalence of approximately 0.6% of all cases of MAC.[85]  At times MAC can also be mobile or produce mobile projections, which can embolize and be a source of stroke.

Differential Diagnoses



Approach Considerations

Imaging studies

Mitral annular calcification (MAC) is usually an incidental finding on cardiac imaging. With transthoracic echocardiography, on the parasternal or apical views, MAC is identified as an echodense band or mass in the atrioventricular groove. MAC is seen all the way through systole and diastole, distinguishable from the posterior mitral valve leaflet.[86] Although most commonly affecting the posterior annulus, it can occasionally involve the anterior annulus, or interannular fibrosa, as noted in the video below.

Transesophageal two-dimensional echocardiography. Mitral annular calcification is especially prominent in the anterior annulus (interannular fibrosa). A mobile element extends from the calcified anterior annulus into the aortic outflow tract.

Calcification can extend from the annulus onto the leaflets, limiting their mobility. It is not unusual to find the posterior leaflet encased in calcium and completely immobilized. This usually has no physiologic consequences. However, calcification extending onto the anterior leaflet and limiting its mobility may be associated with transmitral gradients.[68] Caseous calcification is less echodense than typical MAC; a central echolucent zone is usually present and acoustic shadowing is generally absent.

Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) scanning have also been used in the evaluation of MAC[87] and can be particularly helpful in differentiating caseous MAC, cardiac tumor, and thrombus when poor quality images are seen on echocardiography.[88, 89]

Histologic Findings

Biopsy is never needed for the diagnosis of mitral annular calcification (MAC). In its most characteristic configuration, it forms a semilunar deposit of calcium within the annulus fibrosus, with limited extension to the leaflet tissue. This is different from the calcification seen in rheumatic valvular disease, which usually involves the commissures and the leaflet tissue with only late extension to the annulus.

Carpentier et al studied pathologic specimens of 68 patients (mean age, 62 y) with extensive MAC and significant mitral regurgitation. They found calcification of at least one third of the posterior annulus in 88% of cases, with calcification of the entire posterior annulus in 10%.[66] Calcium formation was generally encapsulated in a fibrous sheath. However, fibrous encapsulation was not found in areas of myocardium infiltrated by the calcific process. Beyond the limits of the calcification, the remaining annulus fibrosus usually displayed fissures and zones of dehiscence. These defects were filled with lipoid substances, platelets, and red blood cell aggregates. In caseous MAC in particular, the histopathologic findings are characterized by central liquefaction necrosis and scattered calcifications that are predominantly located in the peripheral regions.[27]


In general, no standard grading system by echocardiography is recognized. Many studies have classified the severity of mitral annular calcification (MAC) by measuring its thickness on M-mode echocardiography at the point of greatest width. Thickness greater than 1 mm but less than 4 mm has been considered mild to moderate, whereas thickness greater than 4 mm has been considered severe. MAC greater than 4 mm has been found to be an independent predictor of myocardial infarction and valvular disease.[33]

Other investigators have graded the severity of MAC by dividing the posterior annulus in thirds and adding up the number of thirds involved. Still others have looked at annular calcification in the context of overall cardiac calcification, using semiquantitative systems to grade calcification in the aortic and mitral valves, aortic root, and submitral apparatus, as well as the mitral annulus.[25, 83]



Approach Considerations

The presence of asymptomatic mitral annular calcification (MAC) does not require specific medical therapy. Because of the association between MAC and atherosclerosis, valvular disease, stroke, and other vascular diseases, appropriate medical management of concomitant cardiovascular risk factors is recommended.[90]

Interestingly, a study from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort determined that while several cardiovascular risk factors predicted incident MAC, the severity of MAC at the time of first detection was the primary predictor of MAC progression.[91] This would suggest that while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression.[91] Indeed, the potential regression of MAC with medical therapy has not been examined, but studies done with aortic valve calcification have shown no regression despite treatment with angiotensin-converting enzyme (ACE) inhibitors and statins.[92, 93]

MAC has also been associated with chronic kidney disease (CKD), and its presence on echocardiography should alert the physician to the possible presence of decreased renal function.[54, 55]

No endocarditis prophylaxis is indicated in patients with isolated MAC.[90]

According to the 2008 American College of Chest Physicians guidelines for valvular and structural heart disease, antithrombotic therapy with aspirin is recommended in patients with MAC but without atrial fibrillation who have experienced systemic embolism, ischemic stroke, or transient ischemic attack.[93] For recurrent events despite aspirin therapy, anticoagulation with a vitamin K antagonist is suggested (target international normalized ratio, 2.5; range, 2-3). In patients with MAC who have a single embolus documented to be calcific, data are not sufficient to recommend either for or against antithrombotic therapy.

Patients with isolated MAC do not require hospitalization. However, these patients are at increased risk for major cardiovascular events (eg, stroke, myocardial infarction). Given the strong association with atherosclerosis, cardiovascular risk factor modification (eg, hypertension, hyperlipidemia) and appropriate follow-up is important.

Surgical Care for MAC

No surgical treatment is indicated for mitral annular calcification (MAC), unless correction of concomitant mitral regurgitation or mitral stenosis is needed. In fact, severe MAC makes valve surgery more difficult. Risks and benefits of surgery must be carefully assessed in patients with significant MAC, as increased surgical mortality has been observed in these patients. For those patients with documented calcific emboli or repeated thromboembolism despite anticoagulation, valve replacement may be considered.

Mitral valve replacement in the setting of severe MAC can cause complications such as left ventricular rupture. MacVaugh et al reported unusual complications during mitral valve replacement in the presence of calcification of the annulus in 1971.[94] In the perioperative period, patients developed acute posterior myocardial infarction, ventricular aneurysm, or hemorrhage from the left ventricle. Spencer et al reported that debridement of the calcified mitral annulus at the time of valve replacement led to left ventricular rupture in 3 cases.[95]

Impact of MAC in Transcatheter Aortic Valve Replacement

A 2016 report showed that mitral annular calcificaiton (MAC) has prognostic implications in Transcatheter Aortic Valve Replacement (TAVR).[96] Of 761 patients studied, 49.3% had MAC. Severe MAC was found to be an independent strong predictor of overall mortality following TAVR and cardiovascular mortality, as well as an independent strong predictor of new permanent pacemaker implantation after TAVR.

Impact of MAC in Transcatheter Mitral Valve Replacement

Severe mitral annular calcification (MAC) has been considered a contraindication for percutaneous mitral valve repair. Manipulation of wires and large balloons during transcatheter mitral valve replacement (TMVR) or repair may cause an increased risk of stroke or myocardial infarction due to a release of calcific debris, resulting in cerebral or coronary emboli. However, this procedure has been used as a less invasive alternative for patients who are deemed to be either very high risk or unsuitable for conventional mitral valve surgery owing to multiple comorbidities, including old age and left ventricular dysfunction.

Case reports have described various approaches to TMVR, such as a transapical approach,[97]  a transseptal approach combined with transapical externalization of the wire,[98]  an open left atrial approach, and an isolated transvenous-transseptal approach.[99] In most of these case reports, patients had circumferential MAC that may have provided adequate anchorage for the prosthesis. Moderate circumferential MAC allows stable anchoring of the prosthesis. In contrast, if the MAC is severe, it poses a risk of annular rupture during valve deployment. If MAC is noncircumferential, it may not provide enough anchorage for the prosthesis, thereby potentially causing a periprosthetic leak or dislodgement due to exposure to high systolic pressure.



Medication Summary

The eighth edition of the American College of Chest Physicians guidelines recommends antithrombotic therapy with aspirin (50-100 mg/day).[93] These guidelines also state that warfarin therapy (target international normalized ratio, 2.5; range, 2-3) may be considered under certain circumstances for long-term stroke prevention.[93] Start with caution, especially in elderly patients and those with hepatic impairment, poor nutrition, congestive failure, severe chronic kidney disease (CKD), or a high risk of bleeding. Treatment of associated cardiovascular conditions should be addressed as per respective guidelines.

Antiplatelet agents

Class Summary

Antiplatelet agents inhibit platelet aggregation by blocking cyclooxygenase and subsequent aggregation.


Class Summary

Anticoagulants reduce the synthesis of active clotting factors and have been reported to be beneficial.