The prevalence of mitral annular calcification (MAC) and related valvular disease is increasing as the population ages. The prevalence of MAC varies from 5 to 42%. The age of study participants and the imaging modality used for MAC detection account for the wide variance ^[1][2][3][1,2,3]. Two population-based studies reported a prevalence of 2.2% and 6.6% for MAC-related mitral stenosis (MS) and 11.9% and 9.5% for significant MAC-related mitral regurgitation (MR) ^[4][5][4,5]. Among patients with mitral valve disease (MVD), patients with MAC-related MVD have the lowest survival rates. The one-year survival rate post-diagnosis is 76% in patients with MAC-related MVD and 86% in patients with other MVD [5].

The development of MAC is viewed as a degenerative aging process. However, besides aging, the following mechanisms contribute to the development and progression of MAC [6]:

• Atherosclerotic process: There is a well-established correlation between MAC and vascular diseases, such as coronary artery disease ^[7][8][7,8], carotid artery disease, and strokes ^[1][2][1,2]. Hence, MAC and atherosclerosis may share common mechanisms.
• Calcium phosphate metabolism: A dysregulated calcium phosphate metabolism in patients with chronic kidney disease may result in calcium deposition, contributing to MAC [9].
• Mechanical stress: Increased stress on the mitral annulus, mitral valve (MV), and MV apparatus is often due to left ventricular (LV) hypertrophy (LVH) and elevated LV pressure. Elderly patients with MAC commonly exhibit abnormal LV diastolic function, left atrial enlargement, and compromised left atrium (LA) reservoir strain, thereby highlighting the high prevalence of MAC in patients with heart failure and preserved ejection fraction (HFpEF) [10].
• Inflammation: There is growing evidence linking MAC to inflammatory processes, as illustrated by elevated inflammatory markers in patients with MAC [11]. Imaging with F18-fluorodeoxyglucose (FDG) reveals increased FDG uptake in patients with MAC [12].

Epicardial adipose tissue secretes inflammatory mediators and cytokines [13]. Likely due to heightened inflammation, the thickness of epicardial adipose tissue is an independent predictor of the severity of MAC [14].

2. MAC Natural History

Over a 10-year follow-up, 22 and 4% of patients with mild MAC progressed to severe MAC and MAC-related MVD, respectively ^[15][22]. Among the patients with moderate MAC, 71 and 23% progressed to severe MAC and MAC-related MVD, respectively ^[15][22]. Within 18–36 months of the initial diagnosis, nearly one-third of patients with MAC progress, as evidenced by a rising trans-mitral mean pressure gradient and MAC angle in the parasternal shortaxis view by 2D TTE ^[16][23]. Patients with progressive MAC had smaller LV end systolic dimensions and higher ejection fraction, systolic blood pressure and pulse pressure than those with stable MAC ^[16][23]. Over a median follow-up of 39.2 months, patients with progressive MAC had worse clinical outcomes than patients with stable MAC ^[16][23]. Control of hemodynamic stress and comorbidities may delay progression of MAC. Rarely, MAC evolves into a caseous form. While the relationship between caseous MAC and MVD remains unclear, it introduces challenges to procedural planning for transcatheter valve interventions, coupled with an increased risk of stroke ^[17][24].

3. MAC Assessment and Grading

Two-dimensional (2D) echocardiography is the core imaging modality to detail MAC and assess MAC amount and impact on MV function. The thickness of calcifications from the leading edge of the anterior annulus to the trailing edge of the posterior leaflet and the extent of circumferential calcification helps us to appraise the amount of MAC ^[2][18][2,25]. Two-dimensional echocardiography has notable limitations for MAC assessment and grading. It cannot distinguish between fibrosis and calcification, and MAC can cast shadows that obscure underlying structures. Transesophageal echocardiography (TEE), particularly with three-dimensional imaging, offers a superior assessment over transthoracic echocardiography (TTE) due to enhanced visualization ^[19][26]. Three-dimensional (3D) TEE is as accurate as multidetector computed tomography (MDCT) in assessing mitral valve geometry ^[20][27], but MDCT is superior for MAC assessment ^[21][28]. However, 3D TEE with maximum intensity projection enhances calcification evaluation by making the calcified spots more irregular/prominent and providing the echocardiographer with improved insights into calcification characteristics ^[22][23][29,30]. MDCT has a high spatial resolution that enables MAC grading. Offering a superior visualization of MAC, MDCT provides a comprehensive evaluation of MAC and supports a novel grading system based on the circumference and thickness of MAC as well as the involvement of leaflets and trigones ^[24][31]. The novel grading system may predict the risk of valve embolization during transcatheter valve replacement procedures. In fact, the Heart Valve Collaboratory ^[19][26] integrated the MDCT score into clinical, echocardiographic, and anatomical data to refine the assessment of patient suitability for potential interventions.

4. MAC Management

The presence of MAC is surgically challenging. Any amount of MAC increases operative mortality and complications ^[25][59]. Patients with MAC-related MVD confront two major risks: elevated surgical risk attributed to very old age and multiple comorbidities and anatomical risk determined by the amount of MAC. Both risks guide the selection of interventions ^[26][60]. Surgical techniques can be broadly categorized into two groups: MV surgery with MAC resection and annulus reconstruction and MV surgery without MAC resection ^[27][61], also termed as resect vs. respect ^[28][62]. The resection technique carries risks of atrioventricular groove dissociation, LV perforation, and injury to the left circumflex artery. Conversely, the respect approach presents increased risk of paravalvular leak due to suboptimal suture anchoring to the calcified annulus and the tendency to use a smaller valve with the risk of valve prosthesis mismatch ^[27][28][61,62]. In a systematic review ^[29][63], 15 surgical studies reported wide ranges of mortalities at 30 days, 1 year, and 5 years: 0% to 27.3% (median 6.3%), 0–17% (median 15.8%), and 0–68.6% (median 38.8%), respectively. Variances in mortality rates are likely attributable to broad surgical and anatomical risks that may have been underreported in some studies. Whether the minimally invasive surgical approaches ^[30][31][32][64,65,66] can benefit patients with MAC-related MR is unclear. For patients with low surgical risk and anatomically feasible conditions, the surgical option remains the optimal choice for managing degenerative MVD. For patients with very high surgical or anatomical risk, or both, the transcatheter approach is being considered increasingly often. The first case of human transcatheter mitral valve replacement (TMVR) was reported in 2009 by Cheung et al. ^[33][67] using the transapical approach for the valve-in-valve (ViV) TMVR. Commonly, TMVR is performed using a transfemoral transeptal approach with a balloon-expandable valve (SAPIEN valve from Edwards Lifesciences LLC) originally designed for transcatheter aortic valve replacement (TAVR) ^[34][68]. Transapical or direct transatrial approaches have also been used ^[34][68]. The median age was 75 years in a systematic review of 13 studies encompassing 354 patients who underwent transseptal or transapical TMVR ^[29][63]. The technical success rate for transeptal TMVR was 75%, with LV outflow tract (LVOT) obstruction occurring in 11.2%. The median in-hospital, 30-day, and 1-year mortality rates for TMVR in patients with MAC were 16.7%, 22.7%, and 43%, respectively. The mean age was 79 years and the New York Heart Association (NYHA) functional class was III-IV in an early cohort of 12 patients who underwent TMVR for MAC-related MVD ^[35][69]. In total, 67% of patients had mitral stenosis and 25% had mixed MAC-related MVD. One patient developed LVOT obstruction and later died. Three patients displayed valve migration, one with complete embolization to LA requiring bailout surgery and two with slight valve migration resulting in severe paravalvular leak. Survival rates at 30 days and 1 year were 83% and 57%, respectively, with 9 out of 10 surviving patients reporting improved exercise tolerance at 30 days and 3 out of 4 patients reporting improved symptoms at 1 year. Although the survival of patients with MAC was initially poor after TMVR, selection and procedural insights have been gained. Patients with a modest amount of MAC are prone to valve embolization and migration due to insufficient calcium for anchoring. Unexpectedly, a sizeable amount of MAC proved favorable for procedural success. Identification of patients prone to LVOT obstruction helped reduce procedural mortality. The two largest cohorts of TMVR in MAC, the MAC global registry (n = 106) ^[36][70] and STS/ACC/TVT registry (n = 100) ^[37][71], reported LVOT obstructions in 11.2% and 10% of patients, respectively. Strategies were devised to mitigate LVOT obstruction and reduce procedural mortality. The first strategy, reported in the MITRAL trial ^[38][72], involved preemptive alcohol septal ablation 3–4 weeks before TMVR. The strategy was carried out in seven patients who were identified as being at high risk of LVOT obstruction. It was technically successful, and all seven patients survived the 30-day period. The second strategy, tested in a small single-arm trial, included 30 patients with indication for TMVR in MAC or annuloplasty ring. The strategy involved transcatheter intentional laceration of the anterior mitral valve leaflet (LAMPOON) ^[39][73] and resulted in an 87% survival rate at 30 days post-op in patients with MAC. The strategy intended to copycat the anterior leaflet resection during surgical MVR. In patients with MAC, TMVR remains a very high-risk intervention that may benefit highly selected patients who failed optimal medical therapy of co-existent conditions like HFpEF and COPD. Further, TMVR should be performed in experienced centers for patients with favorable anatomy. Experience with transcatheter edge-to-edge repair (TEER) is limited in patients with MAC-related MR, as severe MAC was one of the exclusion criteria in the EVERESTII trial ^[40][74]. Nevertheless, TEER appears safe in selected patients with moderate-to-severe MAC ^{[41][42][43][44]}[75,76,77,78]. Patients with MAC-related MR and mitral valve area < 4cm², calcification extending to the margin of the leaflets and coexisting MS are not candidates for TEER ^[42][76].