INTRODUCTION — Mitral annular calcification (MAC) is a chronic process involving the fibrous annulus of the mitral valve. It is most commonly an incidental finding, more prominent with aging, although other underlying processes, such as atherosclerosis, altered mineral metabolism, or increased mechanical stress, promote development of MAC. In advanced cases, MAC may be significant, causing significant obstruction of left ventricular inflow and symptomatic mitral stenosis. Cohort studies have demonstrated an association of MAC with atherosclerotic disease and adverse cardiovascular events, including stroke and increased mortality. Additionally, there is an association of MAC with arrhythmia, including atrial fibrillation and conduction system disease.
The prognosis and management of MAC-related disorders are discussed here. The pathophysiology, clinical manifestations, and diagnosis of MAC are discussed separately. (See "Clinical manifestations and diagnosis of mitral annular calcification".)
PROGNOSIS — The presence of MAC is associated with adverse cardiovascular events including stroke and mortality, which may be largely due to concurrent cardiovascular disease (CVD) given the strong association between atherosclerotic risk factors and MAC. Complications of MAC that may influence prognosis in some patients include mitral valve disease (regurgitation or stenosis) and conduction system disease. (See "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Pathophysiology' and "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Associated conditions'.)
Scant data are available for the natural history of progression in patients with MAC. In a study of the progression of MAC in 254 patients, the transmitral gradient increased at a rate of 0.8±2.4 mmHg per year. Overall progression was faster in patients with a lower initial transmitral gradient [1].
In a single-center study of patients with severe MAC, 1004 patients with a diastolic mean gradient >2 mmHg were identified. Prognosis in these patients was poor, with one- and five-year survival rates of 78 and 47 percent, respectively, once identified. Factors associated with higher risk included MAC in older patients, chronic renal insufficiency, or other concurrent valve lesions, such as mitral regurgitation (MR), tricuspid regurgitation, and aortic stenosis [2].
A pooled cohort including the Atherosclerosis Risk in Communities (ARIC) cohort and the Cardiovascular Health Study (CHS) cohort evaluated echocardiographic predictors of sudden cardiac death (SCD) [3]. During a median follow-up time of 7.3 and 13.1 years, 44 ARIC participants and 275 CHS participants, respectively, suffered SCD. In the meta-analysis, the predictors for SCD were decreased ejection fraction, MAC, higher left ventricular (LV) mass and left atrial volume, and higher mitral early to late filling (E/A) ratio, with presence of MAC conferring a twofold higher risk of SCD in a multivariate model. Although the mechanism is not well understood, the risk may be related to concurrent atherosclerotic risk factors. Additionally, MAC is associated with abnormalities in the conduction system, which may have contributed to SCD episodes.
Mortality and cardiovascular outcomes — MAC, similar to other forms of cardiac calcification (such as aortic valve sclerosis), is associated with adverse cardiovascular outcomes, including myocardial infarction (MI), heart failure (HF), and death in various populations [4-9].
●In 16 years of follow-up of 1197 subjects in the Framingham Heart Study, the presence of MAC was associated with an increased risk of incident cardiovascular disease (including MI, coronary insufficiency, HF, and nonhemorrhagic stroke; hazard ratio [HR] 1.5, 95% CI 1.1-2.0), CVD death (HR 1.6, 95% CI 1.1-2.3), and all-cause death (HR 1.3, 95% CI 1.0-1.6), after multivariable adjustment [5]. The risks of incident CVD, CVD death, and all-cause death increased by approximately 10 percent for each 1 mm increase in MAC thickness.
●At mean 6.6-year follow-up of 3782 subjects in the Cardiovascular Health Study, MAC, aortic annular calcification, and aortic sclerosis were each associated with increased risk of adverse outcomes [9]. Of the three, MAC was most strongly associated with HF events (adjusted HR 1.7, 95% CI 1.4-2.2). MAC was also associated with cardiovascular death (HR 1.3, 95% CI 1.1-1.6) and all-cause death (HR 1.8, 95% CI 1.3-2.5).
●At mean 4.8-year follow-up of 2409 African American participants in the Atherosclerosis Risk in Communities cohort, MAC was independently associated with increased coronary heart disease events (hospitalized MI, fatal coronary event; adjusted HR 2.3, 95% CI 1.1-4.9) [4].
●Among 1955 subjects 40 years or older without prior MI or ischemic stroke followed for mean duration of 7.4 years in the Northern Manhattan Study, MAC was associated with increased risk of MI (adjusted HR 1.75, 95% CI 1.13-2.69) and vascular death (adjusted HR 1.53, 95% CI 1.09-2.15) but not ischemic stroke after adjusting for cardiovascular risk factors [6]. There was an association between MAC severity and these outcomes.
●In the Belgrade Atrial Fibrillation Study of 1056 subjects with nonvalvular atrial fibrillation (AF), subjects with MAC were more likely to be older, female, and to have a dilated left atrium, reduced LV ejection fraction, permanent AF, hypertension, and/or diabetes mellitus [7]. MAC was associated with increased cardiovascular morbidity and mortality and all-cause mortality.
Stroke — MAC is associated with increased risk of ischemic stroke although studies are conflicting as to whether MAC is an independent predictor of stroke. MAC was identified as an independent risk factor for incident stroke in some large population studies (including the Framingham Heart Study [10] and the Strong Heart Study [11]) but not in others (such as the Cardiovascular Health Study [12] and the Northern Manhattan Study [6]).
During an eight-year follow-up of 1159 subjects from the Framingham cohort, MAC was associated with a relative risk of stroke of 2.10 (CI 1.24-3.57) after multivariable adjustment [10]. By contrast, a study of the 5888 subjects in the Cardiovascular Health Study cohort found that MAC was associated with increased risk of incident stroke but did not remain predictive of stroke after adjustment for risk factors [12].
In a subset of the Cardiovascular Health Study cohort, 2680 participants without history of stroke or transient ischemic attack underwent brain magnetic resonance imaging and echocardiography [13]. The presence of annular or valvular calcification (MAC, aortic annular calcification, or aortic valve sclerosis) was significantly associated with higher prevalence of clinically silent brain infarcts in models adjusting for cerebrovascular risk factors (risk ratio 1.24, 95% CI 1.05-1.47). Although the presence of MAC was associated with brain infarcts in minimally adjusted models, MAC was not associated with brain infarcts in the more fully adjusted model.
Potential causes of stroke in patients with MAC include concurrent AF and vascular atherosclerotic disease, which are both associated with MAC. It is unclear whether or how often MAC itself may be a source of thromboembolism, although case reports have reported a rare finding of thrombus adherent to MAC [14]. Calcific emboli have occasionally been identified in patients with MAC; these may arise from concurrent vascular disease or possibly from MAC itself [15,16].
MANAGEMENT — There is no established therapy for the prevention or treatment of MAC. Rather, treatment strategies for patients with MAC target associated conditions commonly present and include atherosclerotic risk factor modification, arrhythmia management, and antithrombotic medications in patients with transient ischemic attack (TIA) or embolic stroke. Presence of MAC does not modify treatment recommendations or alter the intensity of therapies for associated conditions.
Mitral valve (MV) surgery is only rarely indicated for MAC, most commonly due to symptomatic severe functional mitral stenosis (MS). Of note, the presence of severe MAC in any patient undergoing MV surgery is associated with high operative morbidity and mortality, with potential complications including atrioventricular (AV) disruption, ventricular rupture, and left circumflex artery injury. Patients with severe MAC are often older adults with significant comorbidity. For patients with significant mitral inflow obstruction, medical therapy is aimed at symptomatic improvement with heart rate control and diuretic therapy to treat symptoms of heart failure.
Medical therapy — Medical therapy for patients with MAC includes risk factor modification. Standard recommendations for antithrombotic therapy and arrhythmia management apply to patients with MAC.
Risk factor modification — MAC is strongly associated with atherosclerotic disease and adverse cardiovascular outcomes, as noted above. Thus, the presence of MAC should serve as a warning of potential concomitant coronary and atherosclerotic disease and as a reminder to address potential modifiable cardiovascular risk factors (such as hypertension and dyslipidemia). Cardiovascular risk factors should be evaluated and treated according to standard recommendations. (See "Overview of established risk factors for cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)
The potential impact of risk factor modification on MAC itself has not been evaluated. Studies on statin or angiotensin converting enzyme inhibitor therapy to prevent progression of calcific aortic valvular heart disease have been inconclusive and are discussed separately. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Prevention of disease progression'.)
Antithrombotic therapy — As noted above, MAC is associated with ischemic stroke; this association was independent of other cardiovascular risk factors in some studies but not others. Scant data are available to support specific antithrombotic recommendations in patients with MAC.
Given the paucity of evidence for stroke or other thromboembolic prophylaxis for patients with MAC, we suggest that patients with MAC with ischemic stroke, TIA, or systemic embolic event be treated as other patients according to standard guidelines. This approach is largely consistent with the 2012 American College of Chest Physicians (ACCP) guideline recommendations [17]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Overview of secondary prevention of ischemic stroke".)
However, we disagree with one recommendation in the discussion of MAC in the 2012 ACCP guidelines. These guidelines suggest consideration of valve replacement for patients with MAC who have recurrent thromboembolic events despite antithrombotic therapy or evidence of multiple calcific emboli. Given the lack of evidence of efficacy of such an approach as well as the substantial risks of valve replacement, we recommend against MV replacement as a treatment for thromboembolic events or calcific emboli in patients with MAC.
For patients with MAC and atrial fibrillation (AF), we suggest treatment according to standard recommendations for antithrombotic therapy for AF with risk stratification based on the conventional risk factors assessed in the CHADS2 score (table 1) (calculator 1). (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
Arrhythmia therapy — Arrhythmias associated with MAC such as AF and symptomatic bradyarrhythmias should be managed according to standard recommendations for these disorders. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Permanent cardiac pacing: Overview of devices and indications" and 'Antithrombotic therapy' above.)
Endocarditis prophylaxis — Although endocarditis on or adjacent to MAC has been reported (see "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Endocarditis'), MAC with or without associated native mitral disease is NOT an indication for prophylaxis [18]. Prior endocarditis, a prosthetic MV, or a prosthetic mitral ring are among the indications for endocarditis prophylaxis. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)
Mitral valve intervention
Mitral valve surgery — Symptomatic severe MS or severe mitral regurgitation (MR) is an indication for MV intervention [18]. (See "Rheumatic mitral stenosis: Overview of management" and "Indications for intervention for chronic severe primary mitral regurgitation".)
Severe MAC rarely causes symptomatic severe calcific MS. In these patients, only valve replacement can relieve the obstruction since percutaneous MV balloon valvuloplasty (which treats commissural fusion in patients with rheumatic valve disease) is not effective to treat MAC.
MAC is occasionally associated with significant MR, which may be caused either by coexistent MV disease (eg, myxomatous degeneration) or by MAC itself. (See "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Mitral regurgitation'.)
However, the presence of severe MAC complicates MV surgery and is associated with high operative mortality and morbidity rates [19-22]. Surgical approaches for mitral disease associated with MAC include MV repair following decalcification of the mitral annulus with annular reconstruction and valve replacement. Complications of MV surgery include AV disruption, ventricular rupture, and left circumflex artery injury. It is necessary to avoid sewing a prosthetic MV to a calcium bar to avoid paravalvular leak and valve dehiscence [19]. In surgical series at specialized centers employing a combination of mitral procedures, the operative mortality ranged from 9 to 14 percent with five-year survival ranging from 79 to 73 percent. Thus, management of symptomatic mitral disease associated with MAC requires careful assessment of the potential risks and benefits of MV surgery.
Investigational transcatheter intervention — Given the high surgical morbidity in patients with MAC, newer, experimental valve replacement procedures including transcatheter valve options are emerging [23,24]. Historically, severe MAC had been considered a contraindication for percutaneous valve repair given challenges in placing a transcatheter prosthesis with an asymmetric valve annulus, lack of a complete circumferential annulus to anchor the device, and potential displacement of the anterior MV leaflet into the left ventricular (LV) outflow tract, raising the risk of paravalvular regurgitation. With a heavy calcium burden, there is also increased risk of calcium embolization and stroke during the procedure.
Limited data are available on transcatheter intervention for severe MAC, and studies comparing outcomes with valve surgery are lacking. In a multicenter (32 centers) registry of 64 patients who underwent compassionate use, transcatheter MV implantation for severe MAC, technical success was achieved in 46 patients (72 percent of cases), with mean postprocedure mitral gradient of 4±2.2 mmHg, and at most, only mild paravalvular regurgitation [25]. However, six patients developed LV tract obstruction with hemodynamic compromise, and there was significant periprocedural mortality, with 30-day all-cause mortality of 29.7 percent (12.5 percent cardiovascular and 17.2 percent noncardiac) in this high-risk cohort. Similarly, a 30-day mortality rate of 22 percent was seen among 12 patients with severe MAC treated with transcatheter MV implantation in a later series [26].
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
●The presence of mitral annular calcification (MAC) is associated with adverse cardiovascular events including stroke and mortality, which may be largely due to concurrent cardiovascular disease given the strong association between atherosclerotic risk factors and MAC. Complications of MAC that may influence prognosis in some patients include mitral valve (MV) disease (regurgitation or stenosis) and conduction system disease. (See 'Prognosis' above and "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Pathophysiology' and "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Associated conditions'.)
●There is no established therapy for the prevention or treatment of MAC. Rather, treatment strategies target associated conditions and include atherosclerotic risk factor modification, arrhythmia management, and antithrombotic medications in patients with transient ischemic attack (TIA) or embolic stroke. (See 'Management' above.)
●Patients with MAC should undergo evaluation for potentially modifiable cardiovascular risk factors, such as hypertension and dyslipidemia. (See 'Risk factor modification' above and "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Clinical manifestations'.)
●MAC is associated with atrial fibrillation (AF); data to support specific recommendations for patients with this combination of disorders are lacking. For patients with MAC with AF, we suggest following standard antithrombotic recommendations for AF (Grade 2C). (See 'Antithrombotic therapy' above.)
●MAC is associated with stroke, although data to support specific antithrombotic therapy in patients with MAC are lacking. For patients with MAC with stroke, TIA, or systemic embolic events, we suggest following standard antithrombotic recommendations for these conditions (Grade 2C). (See 'Antithrombotic therapy' above.)
●Symptomatic severe mitral stenosis (MS) or severe mitral regurgitation is an indication for MV intervention. Severe MAC rarely causes symptomatic severe calcific MS. In these patients, only valve replacement can relieve the obstruction since percutaneous MV balloon valvuloplasty (which treats commissural fusion in patients with rheumatic valve disease) is not effective to treat MAC. (See 'Mitral valve surgery' above and "Rheumatic mitral stenosis: Overview of management" and "Indications for intervention for chronic severe primary mitral regurgitation".)
●When MV surgery is indicated in patients with MAC, a careful assessment of potential risks and benefits should be performed since patients with MAC face high rates of operative morbidity and mortality. Transcatheter MV implantation procedures for patients with severe MAC are under investigation and have not been directly compared with valve surgery. (See 'Mitral valve surgery' above and 'Investigational transcatheter intervention' above.)
