Management and prognosis of mitral annular calcification

INTRODUCTION — Mitral annular calcification (MAC) is a chronic progressive condition involving the fibrous annulus of the mitral valve. There is higher prevalence of MAC in older adults, females, and adults with chronic kidney disease. MAC is a common incidental finding on imaging studies, such as radiography and echocardiography. In a subset of cases, MAC is a cause of mitral valve dysfunction (stenosis, regurgitation, or both) [1].

The prognosis and management of MAC-related disorders are discussed here. The pathophysiology, prevalence, clinical manifestations, and diagnosis of MAC are discussed separately. (See "Clinical manifestations and diagnosis of mitral annular calcification".)

MEDICAL MANAGEMENT — MAC is most commonly an incidental finding requiring no specific treatment other than assessment and modification of cardiovascular risk factors. There is no established therapy to prevent progression of MAC. The most important intervention for most patients with MAC is evaluation and treatment of standard cardiovascular risk factors. (See 'Risk factor modification' below.)

Patients with MAC-related symptomatic mitral valve dysfunction (stenosis and/or regurgitation) are treated medically and may require mitral valve intervention, as discussed below. (See 'Mitral valve intervention' below and 'Heart failure management' below.)

Risk factor modification — MAC is strongly associated with atherosclerotic disease and adverse cardiovascular outcomes. Thus, presence of MAC should heighten clinical concern for concomitant coronary and atherosclerotic disease and serve as an opportunity to address potentially 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".)

There is no established therapy for the prevention of MAC. The potential impact of risk factor modification on progression of MAC has not been evaluated. Studies on statin or angiotensin converting enzyme inhibitor therapy to prevent progression of calcific 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'.)

Heart failure management — Patients with MAC commonly have concurrent heart failure (HF) with preserved ejection fraction (HFpEF) related to left ventricular (LV) diastolic dysfunction and, therefore, require evaluation and management for HFpEF including diuretic therapy, as described separately. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

In patients with significant inflow obstruction from MAC, pharmacologic therapy also includes use of agents such as beta blockers or calcium channel blockers to slow heart rate and lengthen diastolic filling duration [1].

Mitral valve intervention for MAC-related symptomatic mitral valve dysfunction (mitral stenosis and/or mitral regurgitation) is discussed below. (See 'Mitral valve intervention' below.)

Antithrombotic therapy — Standard indications for antithrombotic therapy apply to patients with MAC. For patients with MAC, the available data do not support antithrombotic prophylaxis for stroke independent of treatment of concurrent conditions that warrant prophylaxis. For example, patients with MAC and atrial fibrillation (AF) (calculator 1) are treated with antithrombotic therapy according to standard recommendations for AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "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".)

Endocarditis prophylaxis — Although endocarditis on or adjacent to MAC has been reported (see "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Endocarditis'), the presence of MAC with or without associated native mitral disease is not included among the lesions with high risk of adverse endocarditis outcomes for which endocarditis prophylaxis is indicated. Prior endocarditis, a prosthetic mitral valve, or a prosthetic mitral ring are among the conditions or devices for which endocarditis prophylaxis is indicated. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures", section on 'Which patients?'.)

MITRAL VALVE INTERVENTION

When to refer — Patients with severe mitral stenosis (MS) or mitral regurgitation (MR) due to MAC and severe symptoms (New York Heart Association [NYHA] class III or IV) refractory to medical therapy should be referred to a multidisciplinary heart valve team at a comprehensive valve center for individualized integrated clinical and imaging assessment. Multimodality imaging includes transthoracic echocardiography, transesophageal echocardiography, and computed tomography (CT) to assess valvular anatomy, quantitate the severity of stenosis and regurgitation, and evaluate LV function. Imaging data are then integrated with patient symptoms, comorbidities, and patient goals to weigh the potential benefits and risks of mitral valve intervention (surgical or transcatheter) [1]. Indications for intervention for MS or MR due to MAC are the same as for other causes of mitral valve dysfunction. However, procedure risk is higher and benefit is less certain. Valve intervention is considered only after discussion of the high procedural risk by the heart valve team and consideration of the individual patient's preferences and values [2]. (See "Clinical manifestations and diagnosis of mitral annular calcification", section on 'Diagnostic evaluation'.)

Comorbidities (such as HF with preserved ejection fraction) may limit the clinical benefit from successful valve intervention and also increase procedural risk [1]. Prior mediastinal (particularly mantle) radiation increases the risk of development of MAC and is associated with increased operative mortality with mitral valve surgery [3].

Technical challenges and associated risk of mitral valve intervention vary depending upon the patient's clinical status (including comorbidities and surgical risk) and the extent and distribution of MAC, including the degree of encroachment on adjacent structures (leaflets, aortic mitral curtain, subvalvular structures, LV outflow, and left circumflex coronary artery) [4-8]. Technically challenging mitral valve interventions (surgical or transcatheter) in patients with MAC are associated with high risk of morbidity and mortality, as discussed below [1,8]. (See 'Mitral valve surgery' below and 'Transcatheter intervention' below.)

The most common indication for symptomatic MAC-related mitral valve dysfunction is severe MS. In MS caused by MAC, obstruction of mitral inflow is at the level of the annulus, with decreased diastolic expansion of the annulus and restricted leaflet opening. MAC-related MR may result from annular dilation due to atrial enlargement or poor leaflet coaptation due to displacement of the coaptation zone from posterior mitral valve leaflet calcification and thickening.

Mitral valve surgery — Surgery for MAC-related mitral valve dysfunction is associated with high operative morbidity and mortality rates. Operative mortality rates in small studies have ranged from 6 to 14 percent [8] with higher mortality rates in centers with less than 50 mitral valve procedures per year [9]. Complications of mitral valve surgery in patients with MAC include rupture of the atrioventricular groove, left circumflex coronary artery injury (as the artery is adjacent to the posterior mitral annulus), conduction disturbances, paravalvular regurgitation, and patient-prosthesis mismatch [8]. In patients with MR due to myxomatous mitral valve disease and concurrent MAC, standard surgical approaches may be considered if MAC does not encroach on valve leaflets, subvalvular apparatus, or LV outflow tract (LVOT) [8]. (See "Chronic primary mitral regurgitation: General management" and "Chronic secondary mitral regurgitation: General management and prognosis".)

Repair versus replacement

●Mitral regurgitation – For patients with MAC-related symptomatic severe MR, surgical mitral valve repair when feasible is generally preferred to valve replacement, as repair is associated with superior operative survival rates and postoperative LV function and lower rates of complications [8,10].

●Mitral stenosis or mixed mitral stenosis and mitral regurgitation – Patients with MAC-related symptomatic severe MS or mixed MS and MR generally require mitral valve replacement [11].

Resect or respect approaches — A range of surgical approaches are used for mitral valve repair or replacement MAC-related mitral valve dysfunction [8,11]:

●Resect strategy – The original resect approach involves extensive en bloc resection of annular calcium (with myocardial sparing) with or without annular reconstruction. This approach provides a smooth surface for mitral valve repair or seating of a mitral valve prosthesis to avoid paravalvular leak. However, complete decalcification increases cardiopulmonary bypass time and the risk of bleeding, atrioventricular dehiscence, and left circumflex coronary artery injury. In-hospital mortality following mitral valve repair or replacement with this approach has ranged from 2 to 9 percent [8].

●Respect strategy – Respect strategies seek to work around the annular calcium (or perform targeted annular calcium resection with sparing of the ventricle) to avoid complications associated with annular debridement.

•Valve repair – For mitral valve repair, this strategy may involve an oversized annuloplasty technique with the annuloplasty ring implanted behind the calcium bar or atypical annuloplasty with a partial annuloplasty band placed into the noncalcified part of the annulus; these techniques are combined with standard leaflet and chordal repair techniques.

•Valve replacement – For mitral valve replacement, this strategy involves placing annular sutures around the calcium bar, through the leaflets, or a combination of these approaches. In a retrospective study of 61 patients with severe MAC undergoing surgical mitral valve replacement using the respect approach, in-hospital mortality was 4.9 percent and no paravalvular regurgitation was detected during mean 40 month follow-up [12].

Some centers have used a targeted approach to annular calcium resection. Observational studies using a conservative decalcification approach have reported similar mortality rates for mitral valve replacement in patients with MAC treated with targeted calcium resection as in patients without MAC (1 versus 2 percent in one study [13]; 5 percent in both groups in another study) [8,14].

Alternative approaches — Alternate surgical approaches to mitral valve dysfunction for patients with severe MAC include strategies with only limited resection or nonresection of mitral valve leaflets [8,15].

●Atrial-to-LV conduit – For patients with severe MAC and heavily calcified mitral leaflets, an alternative surgical approach has been described in which the mitral valve is bypassed with a valved conduit from the left atrium to the LV [16,17].

●Hybrid approaches – Hybrid procedures with surgical access for transcatheter valve in mitral annular calcification (ViMAC) procedures are discussed below. (See 'ViMAC approaches' below.)

Transcatheter intervention

ViMAC approaches — ViMAC can be performed via a hybrid (surgical and transcatheter) approach or a percutaneous approach:

●Hybrid strategy – Hybrid surgical strategies with transcatheter heart valves use open transatrial or open transapical approaches [8,11,18,19].

•Transatrial approach – Resection of the anterior mitral leaflet via a transatrial approach reduces the risk of LV outflow obstruction compared with transcatheter approaches. This is followed by open transatrial implantation of a transcatheter balloon expandable valve (ViMAC). A modified technique has been described to reduce the risk of paravalvular regurgitation in which pledgeted sutures are placed anteriorly through the aortomitral curtain and through a rim of left atrial tissue around the posterior annulus and a felt cuff sewn to the valve skirt [19].

•Transapical approach – With the transapical approach, a transcatheter heart valve is implanted via access from the LV apex. The anterior mitral leaflet cannot be resected using this approach, so other measures to reduce the risk of LV outflow obstruction (eg, alcohol septal ablation or laceration of the anterior mitral leaflet) may be considered [11].

●Percutaneous approach – Transseptal ViMAC is primarily performed via a percutaneous (femoral vein) route and thus is an alternative for patients with high or prohibitive surgical risk. As with the transapical ViMAC approach, the anterior mitral leaflet cannot be resected, so alternate methods for reducing risk of LV outflow obstruction may be used.

Preprocedure planning includes cardiac CT to evaluate mitral annular calcium burden and anatomy and aid in assessment for potential LVOT obstruction. The risk of LVOT obstruction is higher in patients with smaller left ventricles, a longer or redundant anterior mitral valve leaflet, and smaller aortomitral angle. With a heavily calcified mitral valve, there is increased risk of calcium embolization and stroke during the procedure.

ViMAC outcomes — ViMAC is an alternative for patients with severely symptomatic MAC-related mitral valve dysfunction who are not candidates for conventional mitral valve surgery (including those with high or prohibitive surgical risk), but percutaneous ViMAC is also associated with high risk of morbidity and mortality [8,15,20,21].

Challenges for ViMAC include valve annulus asymmetry with lack of a complete circumferential annulus to anchor the device, raising the risk of transcatheter heart valve (THV) embolism and paravalvular regurgitation, and the risk of displacement of the anterior MV leaflet or protrusion of the valve stent into the LVOT. Hemolysis is a complication of ViMAC procedures with a prevalence of 3.8 percent at 1 year in the Transcatheter Mitral Valve Replacement (TMVR) in MAC Global Registry [22].

A study from 51 sites in the TMVR in MAC Global Registry included 116 patients with severe MAC who were not surgical candidates [22]. Participants had significant comorbidities (mean Society of Thoracic Surgeons score 15.3 percent) and were symptomatic, with 90 percent at NYHA functional class III or IV status. The mean preprocedure mitral valve gradient was 11.5 mmHg. While technical success was achieved in 89 patients (77 percent of cases), with mean immediate postprocedure mitral gradient of 4.37 mmHg, LVOT obstruction with hemodynamic compromise occurred in 13 patients (11.2 percent), and there was significant periprocedural mortality, with 30-day and one-year all-cause mortality of 25 and 54 percent, respectively [22].

A report from the TMVR registry compared results for participants who received TMVR for valve-in-prosthetic-valve (ViV, 322 patients), valve-in-annuloplasty-ring (ViR, 141 patients), and ViMAC (58 patients) [23]. Patients were symptomatic, with 88.5 percent at NYHA functional class III or IV. Of the three groups, overall technical success was lowest in the ViMAC group (62.1 percent) relative to ViV (94.4 percent) and ViR (80.9 percent), largely driven by development of LVOT obstruction for ViMAC (39.7 percent) compared with ViV (2.5 percent) and ViR (5.0 percent). All-cause mortality for ViMAC compared with ViR and ViV was higher at 30 days (34.5 versus 9.9 and 6.2 percent; p<0.001) and one year (62.8 versus 30.6 and 14 percent; p<0.001), respectively.

Given that operative morbidity is high for patients with severe MAC, an already high comorbid risk population, further developments in transcatheter valve protocols and prostheses aim to better predict and mitigate complications, particularly LVOT obstruction, with optimized mitral valve and LV anatomy assessment and ViMAC patient selection.

PMBC not indicated — Percutaneous mitral balloon commissurotomy (PMBC) is not effective and is not indicated to treat MAC. PMBC is a treatment for leaflet commissural fusion in selected patients with rheumatic MS. (See "Percutaneous mitral balloon commissurotomy in adults".)

PROGNOSIS — The presence of MAC is associated with adverse cardiovascular events including coronary artery disease, HF, and mortality, which may be largely due to concurrent cardiovascular disease (CVD) given the associations between MAC and atherosclerotic risk factors. (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'.)

MAC progression — Limited data are available for the natural history of MAC progression. A study from the University of Ottowa included 11,605 patients with MAC and at least two echocardiograms performed over a year apart between 2005 and 2019 [24].

●Among patients with initially mild or moderate MAC, 33 percent progressed to severe MAC at 10-year follow-up. Progression to severe MAC was more common in females and in patients with moderate MAC at baseline.

●At 10-year follow-up of all patients, severe MAC associated with mitral valve dysfunction was present in 10 percent, with higher rates in females and in patients with moderate or greater MAC at baseline.

In a study of 1004 patients (mean age 73) with severe mitral annular calcification and a mean transmitral diastolic gradient of ≥2 mmHg, risk factors associated with all-cause mortality included older age, presence of chronic renal insufficiency, AF, and concurrent valve dysfunction (eg, mitral regurgitation, tricuspid regurgitation, and aortic stenosis) [25]. Prognosis was poor, with one- and five-year survival rates of 78 and 47 percent, respectively.

Adverse 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), HF (particularly HF with preserved ejection fraction), and death [26-33].

●Risk of cardiovascular disease

•In 16 years of follow-up for 1197 subjects in the Framingham Heart Study, the presence of MAC was associated with an increased risk of incident CVD (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 [27]. The risk of incident CVD, CVD death, and all-cause death increased by approximately 10 percent for each 1 mm increase in MAC thickness.

•Associations between echocardiographic findings and clinical outcomes (mean follow-up of 6.6 years) were evaluated for 3782 participants in the Cardiovascular Health Study (CHS) [31]. MAC, aortic annular calcification, and aortic sclerosis were each associated with risk of incident HF and mortality [31]. MAC was associated with incident HF events (adjusted HR 1.7, 95% CI 1.4-2.2), CVD death (HR 1.3, 95% CI 1.1-1.6), and all-cause mortality (HR 1.8, 95% CI 1.3-2.5).

•From the Atherosclerosis Risk in Communities study, with mean follow-up of 4.8 years, echocardiograms from 2409 African American participants showed that MAC was independently associated with coronary heart disease events (hospitalized MI, cardiac procedure, or fatal coronary event; adjusted HR 2.3, 95% CI 1.1-4.9) [26].

•Among 1955 subjects 40 years or older without prior MI or ischemic stroke followed for a 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 [28]. MAC was a strong independent risk factor for MI or vascular death, with the highest risk associated with the most severe MAC, greater than 4 mm in thickness.

●Risk of sudden cardiac death – A pooled cohort including 2383 participants from the Atherosclerosis Risk in Communities (ARIC) study and 5366 participants from the CHS was evaluated for echocardiographic predictors of sudden cardiac death (SCD) [34]. During median follow-up times of 7.3 and 13.1 years, respectively, SCD occurred in 44 ARIC participants and 275 CHS participants. Multivariate predictors for SCD included presence of MAC, decreased ejection fraction, higher 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. Additionally, MAC was associated with abnormalities in the conduction system, which was thought to be a potential contributor to SCD events.

●Risk among patients with AF – In the Belgrade Atrial Fibrillation Study, 1056 participants with nonvalvular AF were followed for a mean duration of 10 years. Incidence of MAC was 3.1 percent. 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 diabetes mellitus [29]. In multivariate analyses, MAC was significantly associated with new cardiovascular morbidity (HR 2.4, 95% CI 1.3-4.5), CVD mortality (HR 3.5, 95% CI 1.2-10.4), and all-cause mortality (HR 4.3, 95% CI 1.8-10.0).

Stroke — A causal relationship between MAC and stroke has not been established. Studies are have yielded inconsistent findings as to whether MAC is an independent predictor for ischemic stroke. While MAC was identified as an independent risk factor for incident stroke in some large population studies (including the Framingham Heart Study [35] and the Strong Heart Study [36]), it was not in other studies (such as the CHS [37] and the Northern Manhattan Study [28]).

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 [35]. In contrast, the CHS cohort of 5888 subjects found that while MAC was a univariate predictor for incident stroke, MAC did not remain predictive of stroke after multivariate adjustment for other risk factors [37].

In a subset of the CHS, 2680 participants without history of stroke or transient ischemic attack underwent brain magnetic resonance imaging and echocardiography [38]. 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 prediction models adjusting for cerebrovascular risk factors (HR 1.24, 95% CI 1.05-1.47). Although the presence of MAC was associated with brain infarcts in minimally adjusted prediction 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. Whether MAC itself is a significant source of thromboembolism is unknown, as only case reports have reported a rare finding of thrombus adherent to MAC [39]. Calcific emboli have occasionally been identified in patients with MAC [40,41].

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

●Medical management – Mitral annular calcification (MAC) is most commonly an incidental finding found on imaging studies. There is no established therapy to prevent progression of MAC.

Patients with MAC with symptomatic mitral valve dysfunction are treated medically and may require mitral valve intervention. (See 'Medical management' above and 'Mitral valve intervention' above.)

•Cardiovascular risk factor evaluation and modification – MAC is strongly associated with atherosclerotic disease and adverse cardiovascular outcomes. The most important intervention for most patients with MAC is evaluation and treatment of standard cardiovascular risk factors. (See 'Prognosis' above and 'Risk factor modification' above.)

•Heart failure – For patients with MAC with symptomatic mitral inflow obstruction, medical therapy is directed at treating heart failure (HF) symptoms with therapies to slow heart rate and lengthen diastolic filling duration and diuretic therapy for volume control, with referral for intervention as indicated. Patients with MAC commonly have concurrent HF with preserved ejection fraction (HFpEF), which is treated as described separately. (See 'Heart failure management' above and "Treatment and prognosis of heart failure with preserved ejection fraction" and 'Mitral valve intervention' above.)

•Treatment of concomitant conditions – The presence of MAC does not modify treatment recommendations for concurrent conditions such as atherosclerotic risk factors or arrhythmias. Standard indications for antithrombotic therapy (for conditions such as atrial fibrillation [AF]) apply to patients with MAC. (See 'Risk factor modification' above and 'Antithrombotic therapy' above and 'Arrhythmia therapy' above.)

●When to refer for mitral valve intervention – Patients with severe symptoms (New York Heart Association [NYHA] class III or IV) due to MAC-related mitral valve dysfunction (stenosis, regurgitation, or both stenosis and regurgitation) refractory to medical therapy should be referred to a multidisciplinary heart valve team at a comprehensive valve center for individualized integrated clinical and imaging assessment of patient symptoms, valvular anatomy, comorbidities, and patient goals to weigh the potential benefits and risks of mitral valve intervention (surgical or transcatheter). Valve intervention is considered only after discussion of the high procedural risk by the heart valve team and consideration of the individual patient's preferences and values. (See 'When to refer' above.)

●Mitral valve surgery – Strategies for mitral valve repair or replacement for MAC-related mitral valve dysfunction include targeted resection of annular calcium and strategies that avoid resection of annular calcium.

Surgery for MAC-related mitral valve dysfunction is associated with high operative morbidity and mortality rates. Complications of mitral valve surgery in patients with MAC include rupture of the atrioventricular groove, left circumflex coronary artery injury (as the artery is adjacent to the posterior mitral annulus), conduction disturbances, paravalvular regurgitation, and patient-prosthesis mismatch.

●Transcatheter intervention (See 'Transcatheter intervention' above.)

•ViMAC approaches – Transcatheter valve in mitral annular calcification (ViMAC) is an alternative for patients who are not candidates for conventional surgical approaches. ViMAC can be performed via surgical access (for transatrial or transapical approaches) or percutaneously (for the transseptal approach). However, morbidity and mortality rates are high with open or percutaneous ViMAC. (See 'ViMAC approaches' above and 'ViMAC outcomes' above.)

•PMBC not indicated – Severe MAC causes obstruction of mitral inflow at the level of the annulus, not the valve leaflets. Therefore, percutaneous mitral balloon commissurotomy (PMBC; which treats leaflet commissural fusion in rheumatic mitral stenosis) is not an effective therapy for MAC.

●Prognosis – The presence of MAC is associated with adverse cardiovascular outcomes including coronary heart disease events, HF, and mortality, which may be largely due to concurrent cardiovascular disease (CVD) given the associations between MAC and atherosclerotic risk factors. A causal relationship between MAC and stroke has not been established. (See 'Prognosis' above.)