Clinical manifestations and diagnosis of mitral annular calcification

INTRODUCTION — 

Mitral annular calcification (MAC) is a chronic, progressive process involving the fibrous annulus of the mitral valve. MAC tends to be more prominent with aging, although other underlying processes, such as atherosclerosis, altered mineral metabolism, or increased mechanical stress, promote development of MAC.

MAC is most commonly asymptomatic, found incidentally on cardiac imaging studies, and without hemodynamic effect. In advanced cases, MAC may cause significant obstruction of left ventricular (LV) inflow and symptomatic mitral stenosis. MAC is also associated with atherosclerotic cardiovascular disease and arrhythmias.

The clinical manifestations (including associated conditions) and diagnosis of MAC are discussed here. Management and prognosis in patients with MAC are discussed separately. (See "Management and prognosis of mitral annular calcification".)

ANATOMY AND PATHOLOGY — 

The mitral valve (MV) annulus has a complex three-dimensional "saddle" shape with the nadirs of the annulus located medially and laterally. At the base of the LV, the annulus is composed of a C-shaped segment of fibrous skeleton. The MV leaflets are suspended from the mitral annulus, which provides structural support to the valve apparatus along the medial, posterior, and lateral aspects of the valve. Anteriorly, the midsection of the anterior mitral leaflet is in fibrous continuity with the posterior aortic root via the intervalvular fibrosa, without intervening annular tissue. In systole, normal mitral annular contraction is along the anteroposterior plane, resulting in folding along the mediolateral plane with a reduction in annular cross-sectional area, facilitating leaflet coaptation [1,2].

Mitral annular calcification — MAC is characterized by calcium deposition along and beneath the MV annulus [3]. Early MAC generally follows the C-shaped fibrous skeleton of the mitral annulus, relatively sparing the base of the anterior mitral leaflet.

In advanced cases, calcification may extend to the basal LV myocardial segments and mitral subvalvular apparatus. Concomitant mitral regurgitation may occur due to restricted leaflet motion from the leaflet base and extension of MAC beneath the posterior mitral leaflet, altering the systolic coaptation. Three-dimensional echocardiography shows a relative loss of annular systolic motion, resulting in a larger, flatter annulus in systole [4].

MAC is readily seen by echocardiography, appearing as a bright echodense region adjacent to the posterior atrioventricular (AV) groove (image 1A and image 1B). Echocardiographic features of MAC are described below. (See 'Identification of mitral annular calcification' below.)

●Rheumatic mitral stenosis (MS) is characterized by commissural fusion, relatively less annular involvement, and a more funnel shaped mitral diastolic geometry at the leaflet tips. Leaflet pliability is relatively preserved with inflow obstruction at the leaflet tips due to commissural fusion.

●Progressive MAC may lead to calcific MS, where calcification extends from the annulus and base of the leaflets onto the leaflets, causing leaflet thickening and restriction of mitral inflow with relative sparing of the leaflet tips, resulting in a more tunnel-shaped orifice [5]. With MAC, there is relative sparing of the mitral leaflet commissures, unlike rheumatic MS.

Caseous calcification — Caseous calcification of the mitral annulus is a rare (less than 1 percent) variant of MAC that appears as a smooth, round periannular mass [6-8]. Echocardiographic features are described below. (See 'Caseous calcification' below.)

PATHOPHYSIOLOGY — 

Data on the pathophysiology of MAC are limited. Initially thought to be a passive, degenerative process, MAC is now understood to be a more active process, akin to atherosclerosis and calcific aortic valve disease [9,10]. There is a strong association between atherosclerotic risk factors and valve calcification [11,12]. (See 'Clinical manifestations' below.)

MAC is thought to be initiated by endothelial disruption at foci of increased mechanical stress at the junction between the mitral valve (MV) annulus and ventricular myocardium. Focal accumulation of oxidized lipids serves as a nidus for chronic inflammatory cell infiltrates including T lymphocytes and macrophages, as well as activated mast cells that promote extracellular matrix remodeling [13,14]. Dystrophic calcification refers to focal calcific deposits in regions of microinjury and lipoprotein accumulation that coalesce over time into the dense, fibrotic, rigid band macroscopically evident as MAC. Conditions that increase mitral annular stress, such as higher LV systolic pressure (aortic stenosis or systemic hypertension) or higher leaflet tension (MV prolapse), are also associated with MAC [15,16].

MAC may also result from metastatic calcification in systemic disorders associated with increased circulating calcium and phosphate. Among patients with end-stage renal disease, MAC is associated with an elevated calcium-phosphate product [17,18]. Increased serum phosphate is also associated with aortic valve calcification, aortic annular calcification, and MAC [19].

MAC is associated with systemic markers of inflammation [20]. In a report from the Cardiovascular Health Study, of 5888 participants, 3585 participants had inflammatory, lipid, and mineral biomarker data measured within five years of echocardiography available. Fibroblast growth factor (FGF-23) was positively associated with MAC with a relative risk (RR) of 1.040 (95% CI 1.004-1.078), and fetuin A, a multifunctional glycoprotein that inhibits dystrophic calcification, was negatively associated with an RR of 0.989 (95% CI 0.911-0.989) [21]. While other studies have similarly demonstrated the inverse association of MAC with serum fetuin A [22,23], the association between MAC and systemic inflammatory markers may reflect shared risk factors. In a report from the Framingham Heart Study, while valvular calcification was associated with elevated levels of inflammatory markers, the association was no longer significant after adjusting for other cardiovascular disease risk factors [20]. Imaging data support an inflammatory component for MAC, with demonstrated uptake of ¹⁸F-fluorodeoxyglucose on positron emission tomography testing, a marker of inflammation and increased calcification activity [24].

Other contributing factors for earlier development of MAC (in adolescence or young adulthood) include connective tissue abnormalities and genetic abnormalities of the fibrous skeleton, such as Marfan syndrome [25,26], and systemic disease associated with chronic inflammation, such as systemic lupus erythematosus [27]. In an investigation of the potential genetic contribution to valve calcification, genome-wide associations with MAC (detected by computed tomography scanning) were identified among 3795 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Two single nucleotide polymorphisms, rs17659543 and rs13415097, near IL1F9, a proinflammatory gene, reached significance (p<1.5x1^0-8) for MAC, but the findings could not be reliably replicated in independent cohorts. Genomewide associations with aortic valve calcification in this study were stronger, with results replicated in independent cohorts [28].

EPIDEMIOLOGY

General — Given that calcification of the mitral annulus without significant mitral inflow obstruction is asymptomatic, overall prevalence of MAC in the general population is underestimated. Prevalence and severity of MAC increases with age [29-33]. In cohorts with mean age in the range of 50 to 60 years, reported prevalence of MAC was 3 to 9 percent [15,29,30,34,35]. In the multiethnic Northern Manhattan study cohort of 1955 subjects (with an older mean age of 68 years) without prior myocardial infarction or ischemic stroke, MAC was identified in 27 percent [36]. In two population-based studies of older patients, mean ages of 70 and 76 years, respectively, the prevalence of MAC was 14 percent by M-mode echocardiography and 42 percent by two-dimensional echocardiography [32,33]. The EuroHeart Survey was a prospective study of 5000 patients with moderate to severe valvular heart disease that showed that among age groups 60 to 70 years, 70 to 80 years, and over 80 years, MAC accounted for 10, 30, and 60 percent of mitral stenosis (MS) cases, respectively [37].

A higher prevalence of MAC among females was identified in the following studies. A single center study of 1004 patients with severe MAC and mean diastolic gradient over 2 mmHg reported baseline characteristics of older age (mean 73 years) with female preponderance (73 percent) [38]. In a retrospective study of the natural history of severe calcific MS (mitral valve area <1.5 cm²) that included 200 patients, patients with severe MS were older (mean age 78 years) and predominantly female (82 percent). Only 120 (60 percent) were symptomatic at baseline, with 20 patients (10 percent) developing symptoms during the 2.8-year follow-up period [39].

In a large single-center study of 11,605 patients (mean age 73±10 years) with MAC, at 10-year follow-up, patients with mild or moderate MAC progressed to severe MAC in 33 percent of the cohort, and 10 percent progressed to calcific mitral valve disease (severe MAC with involvement of the leaflets and subvalvular apparatus) [40].

Kidney disease — In patients with altered mineral metabolism, MAC is more prominent with accelerated progression. In patients with end-stage kidney disease, prevalence of aortic valve and mitral annular calcification is reported in the range of 35 to 50 percent despite a relatively young age range (mean age of 50 to 60 years old) [17,18,41]. MAC is more common among those dialyzed for a longer period of time [17] and is associated with coronary artery disease, atherosclerotic vascular disease, and mortality [18,41].

Among 3929 subjects (mean age 74±5 years, 60 percent women) in the Cardiovascular Health Study, moderate kidney disease (estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m²) was significantly associated with MAC (odds ratio [OR] 1.54) but not with aortic annular calcification or aortic valve sclerosis. Cystatin C levels (another marker of renal insufficiency) were also associated with MAC (OR 1.12) [42].

In an analysis from the MESA study, of 6785 participants, MAC was present in 8 percent of participants with eGFR ≥60 mL/min/1.73 m² (mean age 62 years) but increased to 20 percent of participants with a lower eGFR <60 mL/min/1.73 m² (mean age 70 years). In adjusted analyses, eGFR <60 mL/min/1.73 m² was associated with MAC among subjects with diabetes but not among those without diabetes [43]. From the Framingham Heart Study, of 3047 participants, 284 participants (9.3 percent) had valve/annular calcification. Of these, 20 percent had chronic renal insufficiency compared with just 7 percent in those without valve calcification. After adjustment for atherosclerotic risk factors, those with chronic renal insufficiency had a 60 percent increased likelihood of MAC (OR 1.6, 95% CI 1.03-2.5) [44].

CLINICAL MANIFESTATIONS

Mitral valve disease — MAC is typically asymptomatic, identified as an incidental finding in patients undergoing diagnostic imaging such as chest radiography, chest computed tomography, fluoroscopy, or echocardiography [45,46]. In most clinical cases, MAC has little or no hemodynamic impact on LV inflow or mitral valve (MV) function. However, extensive calcification may cause calcific mitral stenosis (MS), mitral regurgitation (MR) due to leaflet malcoaptation, or both (mixed disease) [47-49].

●Mitral stenosis – In severe cases, MAC leads to calcific MS with hemodynamically significant obstruction of LV inflow at the mitral annular level, impairment of diastolic annular motion, and restriction of MV leaflet motion [48].

●Mitral regurgitation – MAC may lead to annular rigidity, preventing normal systolic annular contraction [48]. Leaflet thickening and restricted motion may lead to systolic leaflet malcoaptation resulting in MR. In a review of 24,380 echocardiograms, MAC was present in 11.7 percent of patients with MR and in 4.3 percent without MR [29].

ASSOCIATED CONDITIONS

Aortic valve disease — Given the similarities in pathologic appearance and clinical associations between MAC and aortic sclerosis, it is not surprising that patients with MAC often have concurrent calcification of the aortic valve annulus, aortic valve leaflets, and aortic root [50]. MAC is a risk factor for hemodynamic progression of calcific aortic valve disease [9]. In patient cohorts from transcatheter aortic valve implantation (TAVI) studies in which cardiac computed tomography (cardiac CT) is obtained during the pre-TAVI procedure evaluation, MAC is highly prevalent. In a single-center cohort of 346 patients referred for TAVI and screened with cardiac CT, 174 (50 percent) had MAC [51]. Of these, significant inflow obstruction (moderate or greater severity stenosis) was present in 34 percent of patients. In a cohort of 761 patients referred for TAVI, 49.3 percent had coexistent MAC [52]. Moderate MAC was present in 72 patients (9.5 percent), and severe MAC was present in 72 patients (9.5 percent).

Diastolic dysfunction — MAC is associated with reduced early- and late-diastolic annular velocities [53]. Reduction in mitral annular motion in patients with MAC may be due to diastolic dysfunction associated with LV hypertrophy, which is associated with MAC [29]. (See 'Interference with evaluation of concurrent conditions' below.)

Arrhythmias

Conduction system disease and bradyarrhythmias — MAC is associated with a high prevalence of conduction system disease (including AV block, bundle branch block, and intraventricular conduction delay) [47,54]. MAC is also associated with an increased rate of symptomatic bradyarrhythmias (due to sinus arrest or conduction system disease) requiring permanent pacemaker implantation [55]. In a single-center study of patients referred for TAVI, of 761 patients referred for TAVI, severe MAC was an independent predictor of need for new permanent pacer placement following TAVI procedure (odds ratio 2.83, 95% CI 1.08-7.47). There were 70 patients (11.6 percent) who required new pacemaker placement post-TAVI among the 606 patients that did not have a pacemaker prior to TAVI [52]. (See "Permanent cardiac pacing: Overview of devices and indications".)

The association between MAC and conduction disease may be due to direct extension of calcific deposits to the region of the AV node and His bundle. In a small study, conduction abnormalities (AV block), bundle branch block, or intraventricular conduction delay were more common in patients with MAC near the conduction system (53 percent) than in those with MAC further from the conduction system (26 percent) [56]. However, prevalence of conduction disturbances remote from MAC (eg, sinoatrial dysfunction) suggests that diffuse degenerative conduction system disease is also present [55].

Atrial fibrillation — There is an association between MAC and atrial fibrillation (AF) [35,57,58]. A report from the Framingham Heart Study with 16 years of follow-up of 1126 subjects found that MAC was an independent predictor of incident AF (adjusted hazard ratio 1.6, 95% CI 1.1-2.2) [58]. Among 6641 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), there was a strong association between MAC and AF, with higher risk for development of AF in patients who had progression of MAC severity across several evaluations [59,60].

Atherosclerotic cardiovascular disease — Cohort studies have demonstrated an association of MAC with atherosclerotic disease (of the coronary arteries, aorta, carotid arteries and peripheral arteries) and adverse cardiovascular events, including stroke and mortality [15,61-64].

MAC is associated with coronary artery disease as detected by radionuclide myocardial perfusion imaging [65], coronary CT [34,66], or invasive coronary angiography [67-69]. In a population of 2465 patients with mean age 69 years who underwent coronary angiography for suspected coronary artery disease, the presence of MAC was associated with increased prevalence of >70 percent coronary artery stenosis (80 percent in those with MAC versus 69 percent in those without MAC) [69]. In addition, significant three vessel disease was more common in patients with severe MAC (47 percent) and in those with mild to moderate MAC (35 percent) than in those with no MAC (30 percent).

Similarly, in the MESA population of 6814 subjects undergoing coronary CT scans, coronary artery calcification was present in 3398 (50 percent of the study cohort). After taking into account demographics and other risk factors, the prevalence ratio of MAC in those with mild coronary artery calcification (1 to 99) was 2.13 (95% CI 1.69-2.69) but increased to 7.57 (95% CI 5.95-9.62) for coronary artery calcification >400. This association weakened but persisted after adjustment for age, sex, and other traditional cardiovascular risk factors, suggesting that MAC presence is an indicator of atherosclerotic burden [34].

Endocarditis

MAC at or near nidus of infection — Case reports and published series have described infective endocarditis involving the mitral valve (MV) in patients with MAC. Endocarditis lesions have included MV leaflet vegetations, paravalvular abscess, and, less commonly, vegetations adherent to MAC [70]. These observational studies suggest that MAC endocarditis is associated with greater comorbidity (eg, diabetes mellitus and cancer) and poor clinical outcome with high in-hospital mortality [70]. A single-center retrospective review of echocardiographic studies in 56 patients with native MV endocarditis identified Staphylococcus aureus as the culprit in 28 patients and streptococcal species in 17 patients. When S. aureus was the infecting organism, the vegetation was adherent to MAC in 57 percent of cases. By contrast, streptococcal infections more predominantly affected the valve leaflets, suggesting that MAC may act as a nidus for infection, particularly for S. aureus infections [71]. The presence of MAC may obscure echocardiographic detection of adjacent abscess cavities due to acoustic shadowing of the ultrasound beam distal to the calcium. (See 'MAC may obscure an abscess' below.)

Limited data suggest a poor prognosis among patients with MAC undergoing surgery for MV infective endocarditis. In one series of 24 patients with MAC and endocarditis (18 with acute and 6 with healed endocarditis) undergoing mitral surgery, in-hospital mortality was 29 percent, with all early deaths occurring in patients operated on during the acute infection event [72]. Frequent comorbidities (eg, chronic kidney disease, cancer, coronary disease) contribute to poor outcomes.

MAC may obscure an abscess — The presence of MAC can interfere with echocardiographic identification of abscesses in the region of the calcified posterior mitral annulus. In a transesophageal echocardiography (TEE) study of 115 patients with definite infective endocarditis who underwent cardiac surgery, 38 percent had an abscess detected at surgery [73]. TEE detected an abscess in 48 percent of those with an abscess. The majority (61 percent) of missed abscesses were localized to the posterior mitral annulus, which was frequently calcified.

Tricuspid annular calcification — Tricuspid annular calcification (TAC) is much less common than MAC and does not typically progress to hemodynamically significant obstruction of right ventricular inflow. TAC has been reported in patients with chronic kidney disease [74] and in patients with pulmonic stenosis. Like MAC, a variant of TAC with caseous calcification has been reported (image 2) [6]. (See 'Caseous calcification' above.)

DIAGNOSTIC EVALUATION — 

The diagnostic evaluation includes identification and characterization of MAC and identification and characterization of mitral stenosis (MS) and mitral regurgitation (MR) and associated conditions.

Approach to diagnosis — Echocardiography is the primary imaging modality for identification and characterization of MAC and associated mitral valve (MV) disease. For symptomatic patients with severe MAC for whom the severity of MS is uncertain, cardiac catheterization with hemodynamic assessment can be helpful [49].

Echocardiography — Echocardiography enables identification of MAC, evaluation of MV anatomy and valve hemodynamics (including assessment for MR), evaluation of biventricular function, estimation of pulmonary pressures, and identification of concurrent valve and cardiac conditions [75]. In a retrospective echocardiography study of 24,380 echocardiographic examinations, MAC was independently associated with the presence of LV hypertrophy, MR, tricuspid regurgitation, aortic stenosis, left atrial (LA) enlargement, and reversed early to late filling (E/A) ratio [29].

Identification of mitral annular calcification — MAC is visualized by echocardiography as an echodense, irregular shelf-like structure involving the MV annulus adjacent to the posterior AV groove with associated acoustic shadowing (image 1A-B). MAC is most commonly an incidental finding on echocardiographic imaging and is characteristically identified on parasternal and apical views of the left heart with acoustic shadowing of structures distal to the calcification.

Although MV leaflets and chordae tendineae are generally not involved, in more advanced cases, calcification may progressively accumulate in the subvalvular region beneath the posterior leaflet with encroachment onto the leaflet and into the basal LV myocardial segments. Relative to echocardiography, cardiac CT provides superior definition of the extent and severity of calcification in MAC and is often utilized for procedural planning for both surgical and percutaneous interventions for severe MAC cases.

Severity of MAC is typically reported qualitatively based upon integrated echocardiographic and cardiac CT features, with calcification of less than one-half (180°) of the annulus graded as "mild," one-half to three-quarters (180 to 270°) graded as "moderate," and greater than three-quarters (270°) graded as "severe" [5,49,75-77]. The thickness of the calcific band may also be measured via cardiac CT. (See "Management and prognosis of mitral annular calcification", section on 'Prognosis'.)

Caseous calcification — As noted above, caseous calcification is a rare variant of MAC. On echocardiography, caseous calcification is less echodense than typical MAC, and a central echolucent zone is present. The caseous contents of the mass have a putty-like consistency with microscopic features consistent with liquefaction necrosis with amorphous eosinophilic acellular material surrounded by macrophages and lymphocytes and multiple small calcifications [6].

Limited longitudinal observations indicate that caseous calcification may be a dynamic condition. Caseous calcification may spontaneously resolve [78] or convert to typical MAC, and typical MAC may rarely convert to caseous calcification [7]. Caseous calcification should not be misdiagnosed as a myocardial abscess, tumor, or thrombus.

Hemodynamic assessment for mitral stenosis — Spectral Doppler interrogation of the MV from the apical views of the heart provides hemodynamic data on functional restriction of LV inflow (image 3). The LA to LV diastolic mean pressure gradient is calculated from the transmitral continuous wave Doppler signal, utilizing the simplified Bernoulli equation [79]. Stenosis of the MV with inflow obstruction increases transvalvular flow. Other conditions that increase transvalvular flow, such as increased heart rate or significant MR, will also increase transmitral gradient. Therefore, in addition to severity of inflow obstruction, transmitral gradients depend on length of the diastolic filling period, cardiac output, severity of associated MR (transvalvular flow), and factors which affect hemodynamic load, such as LV diastolic filling pressure and chamber compliance. Severity of anatomic valve obstruction from MAC, as assessed by the transmitral gradient, should account for LV diastolic dysfunction with high LV filling pressures, decreased LA and LV compliance, and MR (increasing the early diastolic gradient, the mitral "E" wave) [5].

A single-center retrospective study of patients with calcific MV disease correlated a "projected" transmitral mean gradient to the MV area (MVA). This study utilized data from 3315 patients to derive a formula for the projected mean gradient, accounting for heart rate, sex, and stroke volume, and validated their formula on an additional 1658 patients. A projected mean gradient >6 mmHg was highly specific for identifying severe stenosis [80].

From a practical standpoint, stenosis severity in MAC is commonly gauged based upon Doppler measures of the mean transmitral gradient, taking into account the effect of hemodynamic loading conditions, heart rate, and transmitral flow on diastolic gradients. A diastolic mean gradient >10 mmHg is consistent with severe stenosis. MAC may decrease mitral annular systolic translation with associated decline in forward stroke volume. Decreased forward stroke volume and decreased LV compliance may confound transmitral gradient assessments, decreasing measured gradients relative to stenosis severity.

MVA estimates in MAC are challenging, but the continuity equation is the most accurate of the methods available for MVA calculation. MVA estimates are more reliable utilizing the continuity equation (in the absence of significant aortic or mitral regurgitation), compared with MVA estimates from valve planimetry or the pressure half-time (PHT) equation [5,75]. For the continuity equation, mitral and LV outflow velocity time integrals (VTIs) are used to calculate volume of flow across the MV relative to forward stroke volume. However, accuracy for calculation of MVA using the continuity equation decreases in the setting of concurrent regurgitant aortic or mitral valve lesions, which affect transvalvular flow, and irregular rhythms, such as AF, due to variability in VTI measurements [75]. MVA <1.5 cm² is consistent with severe stenosis.

None of the methods validated for rheumatic MS have been validated for calcific MS patients.

●Planimetry by two- or three-dimensional imaging is challenging because the flow-limiting area is the irregularly shaped, nonplanar calcified annulus, rather than a simple elliptical diastolic orifice seen with rheumatic disease. Relatively poor image quality due to acoustic shadowing from heavy calcium in MAC hinders planimetry of the tunnel-like orifice.

●Calculation of MVA via the empirically derived Hatle equation (MVA = 220/PHT) was based on a rheumatic MS model and is not accurate for MVA estimation in calcific MS. PHT is the duration of time for the peak diastolic pressure gradient to decrease by half, derived from the continuous wave Doppler transmitral signal. However, PHT decreases in the setting of tachycardia and LV compliance, conditions which are frequently present in patients with MAC [81], and therefore tends to overestimate MVA calculation [82].

●The proximal isovelocity surface area (PISA) method for calculating MVA is technically challenging to apply to calcific MS, given difficulty in measuring leaflet angles due to the bulky annular calcification.

Evaluation of mitral regurgitation — Color Doppler imaging can aid in evaluating the mechanism and severity of concurrent MR, although transthoracic images of MR jets in the LA are frequently suboptimal due to acoustic shadowing (image 4). The impact of such shadowing may be reduced by acquiring multiple views of the valve on transthoracic echocardiography, although in some cases TEE (in which the LA is closer to the transducer and therefore not obscured by MAC) may be helpful to better visualize the extent of regurgitation. (See "Echocardiographic evaluation of the mitral valve" and "Transesophageal echocardiography in the evaluation of mitral valve disease".)

Interference with evaluation of concurrent conditions — MAC can interfere with echocardiographic evaluation of MR (see 'Evaluation of mitral regurgitation' above), detection of MV abscess (see 'MAC may obscure an abscess' above), interpretation of tissue Doppler velocities, and evaluation of other adjacent structures. (See 'Evaluation of mitral regurgitation' above and 'MAC may obscure an abscess' above.)

Decreased LA compliance due to chronic congestion and concurrent LV diastolic dysfunction impact the spectral Doppler inflow tracings in patients with MAC. Early mitral inflow velocity (E) may be increased in the setting of significant MR, increased mitral inflow gradient, and decreased ventricular compliance [75]. Therefore, the E/e' ratio is not accurate as an index of filling pressures in patients with heavy MAC [83]. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)

In a study of 50 patients with MAC in which 26 patients had mild MAC and 24 patients had moderate or severe MAC, there was weak correlation (r = 0.42) between the E/e' ratio and LV filling pressure [84]. This study proposed a clinical algorithm utilizing mitral early to late filling (E/A) ratio and isovolumic relaxation time for prediction of higher LV filling pressure. A validation of the algorithm in a separate cohort yielded diagnostic accuracy of 94 percent. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)

Cardiac catheterization — For symptomatic patients with severe MAC for whom the severity of MS is uncertain, cardiac catheterization with hemodynamic assessment may be helpful [49]. The study should include simultaneous direct measurement of LA and LV pressures to measure the mean transmitral gradient as well as concomitant measurement of cardiac output with right heart catheterization to measure the MVA using the Gorlin formula, as discussed separately. (See "Hemodynamics of valvular disorders as measured by cardiac catheterization", section on 'Mitral stenosis' and "Rheumatic mitral stenosis: Clinical manifestations and diagnosis", section on 'Cardiac catheterization'.)

Cardiac computed tomography — Cardiac CT is an effective, noninvasive diagnostic test for cardiac calcification (atherosclerotic disease, valve calcification, aortic atherosclerosis). High spatial resolution of cardiac CT allows for accurate identification of the severity and extent of calcification. Cardiac CT scans are gated to the electrocardiogram to decrease artifact due to cardiac motion, improving image quality. Although both contrast and noncontrast cardiac CT studies can assess the extent of mitral calcification, contrast is needed to evaluate cardiac structures, such as MV leaflet calcification, involvement of the subvalvular apparatus, or extension of calcification to the myocardium. Cardiac CT imaging also allows for anatomic assessment of other cardiac structures, including coronary arteries and the aorta, but does not allow for hemodynamic assessment of valve function [49,77].

Cardiac CT is increasingly utilized in preprocedure planning to evaluate mitral annular calcium burden and anatomy. For patients under evaluation for percutaneous transcatheter valve interventions, preprocedure cardiac CT may aid in assessment for potential LV outflow tract (LVOT) obstruction created by protrusion of the valve and displaced anterior MV leaflet into the LVOT. Risk of LVOT obstruction is higher in patients with a small LV, longer or redundant anterior MV leaflet, and small aortomitral angle.

Cardiovascular magnetic resonance — Cardiovascular magnetic resonance (CMR) is not generally used to detect MAC, as calcium is hypointense relative to myocardium [46], but CMR may be helpful in evaluating caseous calcification [8,49]. On CMR, caseous calcification appears as a well-defined mass with a hyperintense center and hypointense rim on T1-weighted fast spin-echo imaging or T1-weighted spoiled gradient-echo imaging [8]. On T2-weighted imaging, caseous calcification appears as a mass without central signal and with a high intensity ring [8].

Differential diagnosis — While MAC is generally recognized by its characteristic density, location, and shape on echocardiography and cardiac CT, unusual variants are sometimes confused with other lesions. Characteristic features of MAC (including caseous calcification) on echocardiography, cardiac CT, and CMR as described above distinguish MAC from myocardial abscess, tumor, or thrombus or lipomatosis of the AV groove. (See 'Caseous calcification' above and "Cardiac tumors".)

MAC is differentiated from other causes of calcific MV disease, such as radiation valve disease. Mediastinal radiation therapy is a treatment for malignancies such as breast cancer and Hodgkin lymphoma and is delivered anteriorly to posteriorly in patients. In contrast to MAC, which tends to involve the posterior mitral annulus, radiation valve disease is more likely to involve the aortic and MV and surrounding structures such as the aorto-mitral curtain, anterior MV annulus, and subvalvular apparatus. Patients with radiation valve disease typically present after a lengthy latency period (10 to 20 years) following exposure. Severity of valve involvement is associated with radiation dose [85]. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Mitral annular calcification (MAC) is caused by an active process similar to atherosclerosis and calcific aortic valve disease. There is a strong association between MAC and atherosclerotic risk factors and valve calcification. (See 'Pathophysiology' above.)

●Epidemiology – The prevalence and severity of MAC increase with age. MAC is particularly common in patients with end-stage kidney disease. (See 'Epidemiology' above.)

●Clinical manifestations – MAC is generally an incidental finding associated with aging, although it is occasionally prominent enough to cause calcific mitral stenosis (MS), mitral regurgitation (MR), or both (mixed disease). (See 'Clinical manifestations' above.)

●Associated conditions – MAC is associated with a number of conditions including calcific aortic valve disease, diastolic dysfunction, conduction system disease, atrial fibrillation (AF), and atherosclerotic cardiovascular disease. (See 'Associated conditions' above.)

●Identifying endocarditis – Patients with MAC with endocarditis have vegetations on the mitral valve (MV) leaflets and, less commonly, vegetations adherent to MAC, as well as paravalvular abscesses in the region of MAC. The presence of MAC can interfere with identification of an abscess near the posterior mitral annulus. (See 'Endocarditis' above.)

●Diagnostic evaluation – Echocardiography is the primary imaging modality for identification and characterization of MAC and associated MV disease. For patients undergoing evaluation for MV replacement, cardiac computed tomography (cardiac CT) is an imaging modality that allows for detailed assessment of the extent and location of calcification. (See 'Diagnostic evaluation' above.)

●Determining the severity of calcific MS (See 'Hemodynamic assessment for mitral stenosis' above.)

•Mean gradient – To describe the severity of calcific MS, clinicians commonly use Doppler measures of the diastolic mean transmitral gradient. A diastolic mean gradient >10 mmHg is consistent with severe stenosis, but measurement is affected by hemodynamic loading conditions, heart rate, and transmitral flow.

•MVA – MV area (MVA) estimation in patients with MAC is challenging; pressure half-time calculation of MVA in patients with MAC tends to overestimate valve area, and planimetry of orifice area is rarely possible. In the absence of significant mitral or aortic regurgitation or arrhythmia, MVA calculation using the continuity equation is the preferred method for MVA calculation. MVA <1.5 cm² is consistent with severe stenosis.