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Prevalence and Natural History of Mitral Annulus Calcification and Related Valve Dysfunction

      Abstract

      Objective

      To evaluate the prevalence and natural history of mitral annulus calcification (MAC) and associated mitral valve dysfunction (MVD) in patients undergoing clinically indicated echocardiography.

      Methods

      A retrospective review was conducted of all adults who underwent echocardiography in 2015. Mitral valve dysfunction was defined as mitral regurgitation or mitral stenosis (MS) of moderate or greater severity. All-cause mortality during 3.0 (0.4 to 4.2) years of follow-up was compared between groups stratified according to the presence of MAC or MVD.

      Results

      Of 24,414 evaluated patients, 5502 (23%) had MAC. Patients with MAC were older (75±10 years vs 60±16 years; P<.001) and more frequently had MVD (MS: 6.6% vs 0.5% [P<.001]; mitral regurgitation without MS: 9.5% vs 6.1% [P<.001]). Associated with MS in patients with MAC were aortic valve dysfunction, female sex, chest irradiation, renal dysfunction, and coronary artery disease. Kaplan-Meier 1-year survival was 76% in MAC+/MVD+, 87% in MAC+/MVD−, 86% in MAC−/MVD+, and 92% in MAC−/MVD−. Adjusted for age, diabetes, renal dysfunction, cancer, chest irradiation, ejection fraction below 50%, aortic stenosis, tricuspid regurgitation, and pulmonary hypertension, MAC was associated with higher mortality during follow-up (adjusted hazard ratio, 1.40; 95% CI, 1.31 to 1.49; P<.001); MVD was associated with even higher mortality in patients with MAC (adjusted hazard ratio, 1.79; 95% CI, 1.58 to 2.01; P<.001). There was no significant interaction between MAC and MVD for mortality (P=.10).

      Conclusion

      In a large cohort of adults undergoing echocardiography, the prevalence of MAC was 23%. Mitral valve dysfunction was more than twice as prevalent in patients with MAC. Adjusted mortality was increased in patients with MAC and worse with both MAC and MVD.

      Abbreviations and Acronyms:

      AS (aortic stenosis), AVR (aortic valve replacement), eGFR (estimated glomerular filtration rate), HR (hazard ratio), LVEF (left ventricular ejection fraction), LVOTO (left ventricular outflow tract obstruction), MAC (mitral annulus calcification), MR (mitral regurgitation), MS (mitral stenosis), MVA (mitral valve area), MVD (mitral valve dysfunction), TTE (transthoracic echocardiography)
      Mitral annulus calcification (MAC) is a chronic degenerative process in the fibrous base of the mitral valve with an estimated prevalence of 8% to 27% in the general adult population.
      • Nestico P.F.
      • Depace N.L.
      • Morganroth J.
      • Kotler M.N.
      • Ross J.
      Mitral annular calcification: clinical, pathophysiology, and echocardiographic review.
      • Kanjanauthai S.
      • Nasir K.
      • Katz R.
      • et al.
      Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA).
      • Fox C.S.
      • Vasan R.S.
      • Parise H.
      • et al.
      Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
      • Kohsaka S.
      • Jin Z.
      • Rundek T.
      • et al.
      Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study.
      Previous studies have reported a significant relationship between MAC and risk factors for atherosclerosis.
      • Kanjanauthai S.
      • Nasir K.
      • Katz R.
      • et al.
      Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA).
      ,
      • Kohsaka S.
      • Jin Z.
      • Rundek T.
      • et al.
      Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study.
      • Adler Y.
      • Fink N.
      • Spector D.
      • Wiser I.
      • Sagie A.
      Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system.
      • Allison M.A.
      • Cheung P.
      • Criqui M.H.
      • Langer R.D.
      • Wright C.M.
      Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis.
      • Atar S.
      • Jeon D.S.
      • Luo H.
      • Siegel R.J.
      Mitral annular calcification: a marker of severe coronary artery disease in patients under 65 years old.
      In addition, the presence of MAC is associated with cardiovascular diseases and events and all-cause death.
      • Fox C.S.
      • Vasan R.S.
      • Parise H.
      • et al.
      Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
      However, there are few data regarding ventricular and valvular function in patients with MAC, and the clinical implications of MAC are uncertain without this information.
      The association between MAC and mitral valve dysfunction (MVD) is of great importance because the presence of MAC affects treatment considerations for MVD. Mitral valve surgery in patients with MAC is associated with high risk because of advanced age, common presence of multiple comorbidities, and technical challenges related to calcium and the necessity of débridement or reconstruction of the mitral annulus.
      • Fusini L.
      • Ghulam Ali S.
      • Tamborini G.
      • et al.
      Prevalence of calcification of the mitral valve annulus in patients undergoing surgical repair of mitral valve prolapse.
      • Tomsic A.
      • Hiemstra Y.L.
      • van Brakel T.J.
      • et al.
      Outcomes of valve repair for degenerative disease in patients with mitral annular calcification.
      • Eleid M.F.
      • Foley T.A.
      • Said S.M.
      • Pislaru S.V.
      • Rihal C.S.
      Severe mitral annular calcification: multimodality imaging for therapeutic strategies and interventions.
      Therefore, surgery for MVD associated with MAC is often delayed until symptoms are severely limiting, or conservative therapy is selected instead. Although the association between MAC and MVD has been previously reported,
      • Nestico P.F.
      • Depace N.L.
      • Morganroth J.
      • Kotler M.N.
      • Ross J.
      Mitral annular calcification: clinical, pathophysiology, and echocardiographic review.
      ,
      • Movahed M.R.
      • Saito Y.
      • Ahmadi-Kashani M.
      • Ebrahimi R.
      Mitral annulus calcification is associated with valvular and cardiac structural abnormalities.
      ,
      • Muddassir S.M.
      • Pressman G.S.
      Mitral annular calcification as a cause of mitral valve gradients.
      the prevalence and natural history of MVD related to MAC remain unclear. Because echocardiography is widely used as a first-line tool for assessment of known or suspected cardiac diseases, it allows the assessment of the natural history of MAC in a large cohort study, providing complementary data to previous studies.
      Thus, this study aimed to assess the clinical characteristics and risk factors of MAC, the prevalence and risk factors of MVD associated with MAC, and the prognostic impact of MAC and related MVD.

      Methods

      The Mayo Clinic Institutional Review Board approved the study, and research authorization was obtained from all included patients. We retrospectively investigated adults in whom MAC was identified by transthoracic echocardiography (TTE) performed between January 1 and December 31, 2015, at Mayo Clinic, Rochester, Minnesota. Transthoracic echocardiography was performed according to clinical judgment of the attending provider. In general, about half of our referrals for echocardiography come from providers other than those of the Department of Cardiovascular Medicine. In patients who underwent multiple echocardiographic evaluations, the first electrocardiogram was used. Mitral annulus calcification was defined as the presence of dense calcium deposits at the base of the mitral leaflets between the left atrium and ventricle as identified on parasternal long- or short-axis or apical 4-, 3-, or 2-chamber views by an experienced level 3 trained echocardiographer. Patients without MAC who were identified by TTE during the same study period were selected as a control to compare characteristics and outcomes with those with MAC. Patients with prior surgical or transcatheter mitral valve intervention (repair or replacement), congenital heart disease, cardiac transplant, or cardiac assist device were excluded from both groups.
      Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2. History of chest irradiation was assessed on the basis of review of medical records; underlying diseases included cancers of the breast, lung, esophagus, or mediastinum and lymphoma. Frailty was assessed with the Rockwood Clinical Frailty Score based on disability for daily living activities obtained by questionnaires. It was considered present if the grade was mild or higher. Data of disability for daily living activities and smoking were obtained by questionnaires 3 months before and after the index TTE, which are distributed to all patients at their first visit. Patients’ comorbidities and International Classification of Diseases codes were recorded prospectively at baseline by the patient’s care provider at our institution. Baseline demographic, echocardiographic, and outcome data were extracted from the electronic medical record.

      Echocardiography

      Comprehensive TTE including assessment of valvular diseases was performed using commercially available ultrasound systems according to established guidelines.
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      • Baumgartner H.
      • Hung J.
      • Bermejo J.
      • et al.
      Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice [erratum appears in J Am Soc Echocardiogr. 2009;22(5):442].
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      Valvular heart diseases were considered present if the severity was moderate or greater. Mitral valve dysfunction was defined as mitral regurgitation (MR) or mitral stenosis (MS). Aortic valve dysfunction was defined as aortic regurgitation or aortic stenosis (AS). Mitral regurgitation was evaluated using a multiparametric integrative approach according to the current guidelines.
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      Mitral stenosis was evaluated predominantly by mitral valve area (MVA) using the continuity equation and graded as moderate (MVA >1.5 to 2.0 cm2) and severe (MVA ≤1.5 cm2).
      • Baumgartner H.
      • Hung J.
      • Bermejo J.
      • et al.
      Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice [erratum appears in J Am Soc Echocardiogr. 2009;22(5):442].
      ,
      • Otto C.M.
      • Nishimura R.A.
      • Bonow R.O.
      • et al.
      2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
      ,
      • Kato N.
      • Padang R.
      • Pislaru C.
      • et al.
      Hemodynamics and prognostic impact of concomitant mitral stenosis in patients undergoing surgical or transcatheter aortic valve replacement for aortic stenosis.
      If patients had aortic regurgitation or MR or if stroke volume by Doppler echocardiography was missing because of left ventricular outflow tract obstruction (LVOTO), the planimetry method was used whenever available. Other findings, such as the deposition of calcium, the mobility of mitral leaflets, and the transmitral gradient, were observed to confirm the presence of MS. Mitral gradient was classified into 3 groups (<5 mm Hg, 5 to 10 mm Hg, and >10 mm Hg) to assess clinical outcomes. Patients in whom mitral gradient was missing were included in mitral gradient of less than 5 mm Hg. In our laboratory, continuous wave Doppler is typically obtained in patients with evidence of aliasing or significantly elevated pulsed wave Doppler velocities across the mitral valve or left ventricular outflow tract. Left ventricular outflow tract obstruction was defined as an instantaneous peak Doppler left ventricular outflow tract pressure gradient of 30 mm Hg or more at rest or during physiologic provocation, such as Valsalva maneuver, amyl nitrite, or exercise.
      • Elliott P.M.
      • Anastasakis A.
      • Borger M.A.
      • et al.
      2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
      Right ventricular systolic dysfunction was defined as right ventricular fractional area change of less than 35%, S′ below 9.5 cm/s, or tricuspid annular plane systolic excursion of less than 17 mm.
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      Reliability in the classification of presence or absence of MAC was assessed by investigators (N.K. and P.A.P.) in 100 randomly selected patients in each of 3 groups: with MAC, without MAC or MVD, and without MAC with MVD. Among patients with MAC, severity was estimated as mild (1 or 2 focal areas of calcification), severe (extensive or bulky calcification involving anterior and posterior portions of the annulus, sometimes extending into the mitral valve), and moderate (intermediate between mild and severe). In 40 randomly selected patients, agreement in assessing severity was performed by 2 investigators (J.M.A. and P.A.P.) and reported as a weighted κ estimate.

      Follow-up and Clinical Outcome

      The primary end point was all-cause death. All patients were observed until death or last contact. To assess mortality without mitral valve intervention in this natural history study, for both patients with and without MAC, patients were censored at the date of mitral valve intervention. The timing of clinical follow-up varied according to the treating physician’s decision. The decision to perform mitral valve intervention was at the discretion of the patients’ treating cardiologists and cardiovascular surgeons along with the patient.

      Statistical Analyses

      Continuous data are expressed as mean ± standard deviation or median (interquartile range) and categorical data as frequency or percentage. Groups were compared using Pearson χ2 or 2-sample t-test as appropriate. Logistic regression analysis was used to assess variables associated with MAC or MVD related to MAC; variables with a P value of less than .05 in univariate analysis were included as candidate variables for the multivariable model. Variables that were missing in 20% or more of the cohort were excluded from the multivariable analyses; these included smoking and frailty. The final multivariable model was then created using backward elimination until only variables with a P value of less than .05 remained. Clinical variables of interest were left in the model. The area under the curve and 95% CI are reported as a measure of discrimination. Survival analysis was performed by the Kaplan-Meier method. In these analyses, patients with mitral valve intervention were censored at the time of intervention. Adjusted Kaplan-Meier plots were created using the method of direct adjustment. Cox proportional hazards modeling was used to identify independent predictors for all-cause mortality, and the final models were created in the same way as in the logistic regression analysis. The survival C statistic was used to measure discrimination of multivariable mortality models. To better control for differences between those with and those without MAC, propensity score matching for patients’ characteristics was used. A logistic regression model for MAC was created, and the predicted probabilities from this model were used to match patients by a greedy matching algorithm. Analyses were then repeated within the matched sets. A 2-sided P value of less than .05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute).

      Results

      Clinical and Echocardiographic Characteristics

      Of 24,414 evaluated patients, 5502 (23%) had MAC. Patients with MAC were older than those without MAC (75±10 years vs 60±16 years; P<.01), and prevalence increased with age (Table 1). Forty-six percent of patients with MAC were women compared with 43% of those without (P<.01; Table 2); MVD was observed in 881 (16%) of patients with MAC. Among patients with MAC, those with MVD were more often women compared with those without MVD (54% vs 44%; P<.01) and more frequently frail (52% vs 44%; P<.01). Characteristics are compared in patients with MVD with and without MAC in Supplemental Table 1 (available online at http://www.mayoclinicproceedings.org).
      Table 1Prevalence of MAC According to Age
      MAC, mitral annulus calcification.
      ,
      Values are reported as number (percentage). Cochran-Armitage trend P<.001.
      Age (y)MAC (n=5502)No MAC (n=18,912)
      <4979 (1.8)4291 (98.2)
      50-59345 (8.2)3849 (91.8)
      60-691030 (17.3)4907 (82.7)
      70-792066 (33.9)4024 (64.1)
      80-891662 (49.7)1680 (50.3)
      ≥90320 (66.5)161 (33.5)
      a MAC, mitral annulus calcification.
      b Values are reported as number (percentage). Cochran-Armitage trend P<.001.
      Table 2Clinical and Echocardiographic Characteristics
      eGFR, estimated glomerular filtration rate; MAC, mitral annulus calcification; MVD, mitral valve dysfunction; LVOTO, left ventricular outflow tract obstruction.
      ,
      Data are presented as mean ± standard deviation or number (percentage). The number of available data is expressed for those variables in which some data were missing.
      MAC (n=5502 [23%])No MAC (n=18,912 [77%])P
      MAC vs no MAC.
      MAC
      MVD (n=881 [16%])No MVD (n=4621 [84%])P
      MVD vs no MVD.
      Clinical variables
       Age, y75±1060±16<.00176±1175±10<.001
       Female sex2525 (46)8143 (43)<.001476 (54)2049 (44)<.001
       Body mass index, kg/m2 (n=24,366)30±729±7<.00129±731±7<.001
       Smoking (n=18,636)2252 (56)6832 (47)<.001332 (51)1920 (56).01
       Frailty (n=18,303)1803 (46)4269 (30)<.001329 (52)1474 (44)<.001
       Atrial fibrillation2442 (44)4862 (26)<.001472 (54)1970 (43)<.001
       Permanent pacemaker907 (16)1892 (10)<.001197 (22)710 (15)<.001
       Hypertension4365 (79)9790 (52)<.001666 (76)3699 (80).003
       Diabetes mellitus2177 (40)3920 (21)<.001321 (36)1856 (40).04
       Dyslipidemia3905 (71)9080 (48)<.001594 (67)3311 (72).01
       eGFR, mL/min per 1.73 m259±2376±25<.00154±2460±23<.001
       eGFR <60 mL/min per 1.73 m22724 (50)4806 (25)<.001530 (60)2194 (48)<.001
       Dialysis262 (4.8)414 (2.2)<.00166 (7.5)196 (4.2)<.001
       Cancer2176 (40)5723 (30)<.001308 (35)1868 (40).002
       Chest irradiation258 (4.7)536 (2.8)<.00160 (6.8)198 (4.3).002
       Cerebrovascular diseases1409 (26)1960 (10)<.001243 (28)1166 (25).14
       Peripheral artery diseases1072 (19)1357 (7.2)<.001197 (22)875 (19).02
       Coronary artery diseases2060 (37)3356 (18).006366 (42)1694 (37).006
       Prior coronary artery bypass graft1075 (20)1397 (7.4)<.001195 (22)880 (19).03
       Prior aortic valve replacement817 (15)680 (3.6)<.001165 (19)652 (14)<.001
       Surgical652 (12)645 (3.4)<.001122 (14)530 (11).045
       Transcatheter165 (3.0)35 (0.2)<.00143 (4.9)122 (2.6)<.001
      Echocardiographic variables
       Left ventricular ejection fraction, % (n=24,363)58±1359±11<.00155±1558±12<.001
       Left ventricular ejection fraction <50% (n=24,363)1125 (21)2789 (15)<.001274 (31)851 (18)<.001
       Left ventricular mass index, g/m2 (n=22,544)108±3298±31<.001119±39106±30<.001
       Left atrial volume index, mL/m2 (n=18,723)45±1735±14<.00158±2342±14<.001
       Right ventricular systolic pressure, mm Hg (n=20,153)40±1433±12<.00147±1638±13<.001
       Right ventricular systolic pressure ≥60 mm Hg (n=20,153)430 (9.0)582 (3.8)<.001147 (18)283 (7.1)<.001
       Right ventricular dysfunction (n=22,356)1201 (24)1911 (11)<.001285 (36)916 (22)<.001
       Aortic stenosis732 (13)411 (2.2)<.001158 (18)574 (12)<.001
       Aortic regurgitation110 (2.0)326 (1.7).1733 (3.7)77 (1.7)<.001
       Tricuspid regurgitation854 (16)1199 (6.3)<.001290 (33)564 (12)<.001
       LVOTO190 (3.5)411 (2.2)<.00155 (6.2)135 (2.9)<.001
      a eGFR, estimated glomerular filtration rate; MAC, mitral annulus calcification; MVD, mitral valve dysfunction; LVOTO, left ventricular outflow tract obstruction.
      b Data are presented as mean ± standard deviation or number (percentage). The number of available data is expressed for those variables in which some data were missing.
      c MAC vs no MAC.
      d MVD vs no MVD.
      Of 100 with MAC coded in the database, all were confirmed. We also reviewed 200 without MAC coded, including 100 with and 100 without MVD. Mitral annulus calcification was missed in 7 of those without MVD and in 17 with MVD; however, in none of the patients in the latter group was MAC the major mechanism of MVD. The overall database accuracy was 92% (88% to 95%) with κ of 0.83 (0.77 to 0.89), indicating strong agreement.

      Variables Associated With the Presence of MAC

      Univariate and multivariable analyses for the association with the presence of MAC are listed in Table 3. Notably, AS was associated with a 4-fold increase in the odds of presence of MAC. Prior aortic valve replacement (AVR) and LVOTO were associated with a 3-fold and 2-fold increase in the odds, respectively. Mitral stenosis was associated with the presence of MAC, but MR was not.
      Table 3Variables Associated With the Presence of Mitral Annulus Calcification
      UnivariateMultivariable AUC=0.830 (0.824-0.836)
      OR95% CIPOR95% CIP
      Age, per 5 years1.541.52-1.56<.0011.411.39-1.44<.001
      Female sex1.121.06-1.19<.0011.531.42-1.65<.001
      Body mass index, per kg/m21.021.02-1.02<.001
      Hypertension3.583.33-3.84<.0011.391.28-1.52<.001
      Diabetes mellitus2.502.35-2.67<.0011.541.43-1.67<.001
      Dyslipidemia2.652.48-2.83<.001
      eGFR <60 mL/min per 1.73 m22.882.71-3.06<.0011.151.07-1.24<.001
      Dialysis2.231.91-2.62<.001
      Chest irradiation1.691.45-1.96<.0011.581.32-1.89<.001
      Cerebrovascular diseases2.982.76-3.21<.0011.211.10-1.33<.001
      Peripheral artery diseases3.132.87-3.41<.0011.261.14-1.41<.001
      Coronary artery diseases2.772.60-2.96<.0011.321.21-1.43<.001
      Prior aortic valve replacement4.684.20-5.20<.0013.312.92-3.75<.001
      Echocardiographic variables
       Left ventricular ejection fraction <50%1.491.38-1.61<.0010.910.83-1.01.07
       Left ventricular mass index, per 10 g/m21.111.09-1.12<.0011.071.05-1.08<.001
       Mitral stenosis13.110.5-16.3<.0016.925.33-8.98<.001
       Mitral regurgitation1.761.59-1.96<.0011.020.90-1.16.73
       Aortic stenosis6.916.10-7.83<.0014.173.61-4.80<.001
       Aortic regurgitation1.160.94-1.45.17
       LVOTO1.611.35-1.92<.0012.191.77-2.70<.001
      AUC, area under the curve; eGFR, estimated glomerular filtration rate; LVOTO, left ventricular outflow tract obstruction; OR, odds ratio.

      Prevalence of MVD Related to MAC

      Mitral valve dysfunction was more frequent in patients with MAC than in those without (Figure 1A ; MVD: 16% vs 6.6% [P<.001]; MS regardless of MR: 6.6% vs 0.5% [P<.001]; MR: 9.5% vs 6.1% [P<.001]). Of patients with MS, mean MVA was 1.6±0.3 cm2 and 1.5±0.4 cm2 (P<.001) in patients with and without MAC, and transmitral gradient was 5.8±3.1 mm Hg and 7.9±4.9 mm Hg (P<.001), respectively.
      Figure thumbnail gr1
      Figure 1The prevalence of mitral annulus calcification (MAC) and valve diseases. A, The prevalence of MAC and mitral valve dysfunction (MVD) is shown. B, In patients with MVD, the percentages of aortic valve dysfunction including aortic stenosis (AS), aortic regurgitation (AR), left ventricular outflow tract obstruction (LVOTO), and prior aortic valve replacement (AVR) are shown. The percentages shown in the figure include some patients who have more than 1 aortic valve disease and are thus shown in multiple groups. In patients with MAC and mitral stenosis (MS), AS and AR coexisted in 3%, AS and LVOTO in 0.3%, and LVOTO and prior AVR in 0.8%. In patients with MAC and mitral regurgitation (MR), AS and AR coexisted in 0.4%, AS and LVOTO in 1.0%, and LVOTO and prior AVR in 0.4%. In patients with MVD without MAC, AS and AR coexisted in 0.2%, and LVOTO and prior AVR in 0.1%. MSR, mitral stenosis and regurgitation.
      Combined mitral and aortic valve dysfunction was more frequent in patients with MAC compared with those without (44% vs 16%; P<.001). Notably, aortic valve dysfunction was more frequent in patients with MS related to MAC than in those with MR (60% vs 33% [P<.001]; Figure 1B).

      Risk Factors for MVD in Patients With MAC

      After multivariable adjustment, AS and prior AVR were associated with a 4-fold increase in the odds of presence of MS in patients with MAC (Figure 2A ; odds ratio, 4.03 [95% CI, 3.05 to 5.33; P<.01] for AS; odds ratio, 3.67 [95% CI, 2.78 to 4.83; P<.01] for prior AVR). Female sex, LVOTO, chest irradiation, eGFR, and coronary artery disease were also associated with the presence of MS.
      Figure thumbnail gr2
      Figure 2Risk factors for mitral valve dysfunction related to mitral annulus calcification. Odds ratios (ORs) of risk factors for mitral stenosis (A) and mitral regurgitation (B) in patients with mitral annulus calcification are shown. The same variables as in were assessed in the univariate model. AVR, aortic valve replacement; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; LVM, left ventricular mass; LVOTO, left ventricular outflow tract obstruction.
      Reduced left ventricular ejection fraction (LVEF), LVOTO, eGFR, female sex, left ventricular mass index, and age were associated with the presence of MR (Figure 2B).

      All-Cause Mortality Without Mitral Valve Intervention

      During median follow-up of 3.0 (0.4 to 4.2) years, 352 of 881 patients with MAC+/MVD+, 1405 of 4621 with MAC+/MVD−, 255 of 1255 with MAC−/MVD+, and 2512 of 17,657 with MAC−/MVD− died without intervention. Mitral valve intervention was performed in 141, 26, 348, and 49, respectively (who subsequently developed an indication for intervention). Kaplan-Meier survival without mitral valve intervention at 1 year was 76%, 87%, 86%, and 92%, respectively (log-rank P<.001). As outlined in Table 4, age, diabetes, eGFR below 60 mL/min per 1.73 m2, cancer, a history of chest irradiation, LVEF below 50%, right ventricular systolic pressure of 60 mm Hg or higher, and tricuspid regurgitation were independently associated with all-cause mortality in the overall cohort. Adjusted for these variables, MAC was independently associated with higher mortality compared with the absence of MAC (Figure 3A ; adjusted hazard ratio [HR], 1.40; 95% CI, 1.31 to 1.49; P<.001). Combined MAC and MVD was associated with the highest mortality (Figure 3B). MAC+/MVD+ was associated with 1.5-fold higher mortality than MAC−/MVD+ (adjusted HR, 1.57; 95% CI, 1.34 to 1.85; P<.001). No significant interaction between MAC and MVD for mortality was observed (P=.10); this result was similar between MAC and MS (P=.18) and MAC and MR (P=.32). Among patients with MAC, severe MVD and moderate MVD were associated with higher mortality compared with the absence of MVD (Figure 3C; adjusted HR, 1.47 [95% CI, 1.17 to 1.86; P=.001] for severe MVD; adjusted HR, 1.29 [95% CI, 1.13 to 1.47; P<.001] for moderate MVD). There was no significant mortality difference in patients with MS (with or without MR) compared with those with only MR (age- and sex-adjusted HR, 0.92; 95% CI, 0.75 to 1.14; P=.45).
      Table 4Variables Associated With All-Cause Mortality in Overall Cohort
      eGFR, estimated glomerular filtration rate; HR, hazard ratio; LVOTO, left ventricular outflow tract obstruction; MAC, mitral annulus calcification; MVD, mitral valve dysfunction.
      UnivariateMultivariable

      C statistic=0.701 (0.693-0.709)
      HR95% CIPHR95% CIP
      Age, per 5 years1.231.21-1.24<.0011.121.10-1.13<.001
      Male sex1.171.11-1.25<.001
      Body mass index, per kg/m20.990.98-0.99<.001
      Atrial fibrillation1.751.65-1.85<.001
      Permanent pacemaker1.381.27-1.49<.001
      Hypertension1.811.69-1.93<.001
      Diabetes mellitus1.871.76-1.98<.0011.321.24-1.40<.001
      Dyslipidemia1.151.08-1.22<.001
      eGFR <60 mL/min per 1.73 m22.632.48-2.79<.0011.631.53-1.74<.001
      Dialysis2.842.54-3.18<.001
      Cancer1.711.61-1.81<.0011.271.20-1.36<.001
      Chest irradiation1.621.43-1.84<.0011.411.24-1.61<.001
      Cerebrovascular diseases1.791.67-1.92<.001
      Peripheral artery diseases2.061.91-2.21<.001
      Coronary artery diseases1.861.75-1.98<.001
      Prior coronary artery bypass graft1.791.66-1.94<.001
      Prior aortic valve replacement1.281.15-1.42<.001
      Echocardiographic variables
       Left ventricular ejection fraction <50%2.061.93-2.20<.0011.581.48-1.69<.001
       Left ventricular mass index, per 10 g/m21.071.07-1.08<.001
       Right ventricular systolic pressure ≥60 mm Hg3.393.08-3.73<.0012.151.94-2.38<.001
      Right ventricular dysfunction2.111.97-2.27<.001
      MAC+/MVD+3.943.52-4.40<.0011.791.58-2.01<.001
      MAC+/MVD−2.232.09-2.38<.0011.361.26-1.45<.001
      MAC−/MVD+2.001.76-2.27<.0011.140.99-1.30.06
      MAC−/MVD−1.00Reference1.00Reference
      Aortic stenosis1.731.56-1.92<.0011.050.94-1.18.38
      Aortic regurgitation0.880.69-1.12.29
      Tricuspid regurgitation2.612.42-2.82<.0011.351.24-1.47<.001
      LVOTO0.610.47-0.80<.001
      a eGFR, estimated glomerular filtration rate; HR, hazard ratio; LVOTO, left ventricular outflow tract obstruction; MAC, mitral annulus calcification; MVD, mitral valve dysfunction.
      Figure thumbnail gr3
      Figure 3Outcomes of mitral annulus calcification (MAC) and associated mitral valve dysfunction (MVD). All-cause mortality according to presence of MAC (A), further stratified according to MVD (B). All-cause mortality according to severity of MVD in patients with MAC (C). All-cause mortality was compared according to presence of MAC or MVD in propensity score–matched cohort (D). The Kaplan-Meier curves were adjusted for age, diabetes, estimated glomerular filtration rate below 60 mL/min per 1.73 m2, cancer, history of chest irradiation, left ventricular ejection fraction below 50%, right ventricular systolic pressure of 60 mm Hg or higher, aortic stenosis, and tricuspid regurgitation.

      Impact of MAC Severity and Mitral Gradient on Clinical Outcomes

      Severity of MAC was graded as mild in 581 (11%), moderate in 1395 (25%), severe in 3524 (64%), and indeterminate in 2. In the 40 patients in whom MAC severity was graded by 2 observers, 33 (82.5%) were in exact agreement and 7 differed by 1 category (weighted κ=0.76 [0.60 to 0.93]). The prevalence of MVD by severity of MAC was 9% in mild MAC, 21% in moderate MAC, and 46% in severe MAC (P<.001). Severe MAC and moderate MAC were associated with higher mortality compared with mild MAC, independent of MVD (adjusted HR, 1.54 [95% CI, 1.33 to 1.78; P=.001] for severe MAC; adjusted HR, 1.37 [95% CI, 1.23 to 1.52; P<.001] for moderate MAC).
      The impact of mitral gradient on outcomes was assessed in all patients with and without MAC. When mitral gradient was included in the multivariable model in Table 4, patients with mitral gradient above 10 mm Hg and 5 to 10 mm Hg had higher mortality compared with those with mitral gradient below 5 mm Hg (adjusted HR, 1.96 [95% CI, 1.10 to 3.48; P=.02] for mitral gradient >10 mm Hg; adjusted HR, 1.24 [95% CI, 1.05 to 1.48; P=.01] for mitral gradient of 5 to 10 mm Hg). Among patients with MAC, results were similar (adjusted HR, 1.80 [95% CI, 0.89 to 3.64; P=.10] for mitral gradient >10 mm Hg; adjusted HR, 1.26 [95% CI, 1.12 to 1.63; P=.001] for mitral gradient of 5 to 10 mm Hg).

      All-Cause Mortality in Propensity Score–Matched Cohort

      Because there were significant differences in most clinical characteristics in patients with and without MAC, we further adjusted for clinical characteristics to assess the prognostic impact of MAC in itself (Table 5). Propensity score matching was used to match 4754 pairs of patients with and without MAC. Mitral stenosis was present in 5% of patients with MAC and in 1% of those without MAC (absolute standardized difference, 0.232). Mitral regurgitation was present in 10% and 12%, respectively (absolute standardized difference, 0.068). Similar to the analysis in the overall cohort (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org), MAC was independently associated with higher mortality compared with the absence of MAC (HR, 1.34 [95% CI, 1.23 to 1.44; P<.01] after adjustment for age, diabetes, eGFR <60 mL/min per 1.73 m2, cancer, history of chest irradiation, LVEF <50%, right ventricular systolic pressure ≥60 mm Hg, and tricuspid regurgitation). Combined MAC with MVD was associated with the highest mortality (Figure 3D; adjusted HR, 1.82 [95% CI, 1.58 to 2.11; P<.01] for MAC+/MVD+, 1.31 [1.20 to 1.43; P<.01] for MAC+/MVD−, and 1.25 [1.06 to 1.47; P<.01] for MAC−/MVD+ compared with MAC−/MVD−).
      Table 5Characteristics of Patients in Propensity Score–Matched Cohort
      ASD, absolute standardized difference; eGFR, estimated glomerular filtration rate; MAC, mitral annulus calcification.
      ,
      Data are presented as mean ± standard deviation or number (percentage).
      MAC (n=4754)No MAC (n=4754)ASD
      Clinical variables
       Age, y74±1074±100.025
       Female sex2122 (45)2066 (43)0.024
       Body mass index, kg/m230±730±70.014
       Atrial fibrillation2002 (42)1992 (42)0.004
       Permanent pacemaker733 (15)761 (16)0.016
       Hypertension3683 (77)3716 (78)0.017
       Diabetes mellitus1787 (38)1808 (38)0.009
       Dyslipidemia3297 (69)3335 (70)0.017
       eGFR <60 mL/min per 1.73 m22238 (47)2238 (47)<0.001
       Dialysis211 (4)175 (4)0.038
       Cancer1660 (35)1741 (37)0.036
       Chest irradiation213 (4)206 (4)0.007
       Cerebrovascular diseases1075 (23)979 (21)0.049
       Peripheral artery diseases803 (17)726 (15)0.044
       Coronary artery diseases1651 (35)1593 (34)0.026
       Prior coronary artery bypass graft838 (18)785 (17)0.030
       Prior aortic valve replacement536 (11)463 (10)0.050
      Echocardiographic variables
       Left ventricular ejection fraction, %58±1357±130.026
       Left ventricular mass index, g/m2107±32108±330.015
       Left atrial volume index, mL/m243±1543±180.024
       Right ventricular systolic pressure, mm Hg39±1339±140.039
       Right ventricular dysfunction940 (22)891 (21)0.026
       Aortic stenosis442 (9)335 (7)0.082
       Aortic regurgitation90 (2)101 (2)0.015
       Tricuspid regurgitation668 (14)652 (14)0.010
       Left ventricular outflow tract obstruction159 (3)155 (3)0.005
      a ASD, absolute standardized difference; eGFR, estimated glomerular filtration rate; MAC, mitral annulus calcification.
      b Data are presented as mean ± standard deviation or number (percentage).

      Discussion

      This is the first large cohort study to comprehensively investigate clinical characteristics including cardiac function to assess the prevalence and natural history of MAC and associated MVD in patients undergoing clinically indicated echocardiographic evaluation. Our major findings were as follows. In a large adult echocardiographic cohort, MAC was present in 23% and MVD was more than twice as prevalent in patients with MAC as in patients without. Mitral annulus calcification was associated with higher mortality compared with the absence of MAC even after adjustment for clinical characteristics, and MVD related to MAC was associated with even higher mortality. In addition, this study found that certain clinical characteristics in patients with MAC confer a greater likelihood for development of MS, including AS, prior AVR, female sex, LVOTO, history of chest irradiation, renal dysfunction, and coronary artery disease.
      Several studies have reported the prevalence of MAC, but the estimates were variable according to the study population. A prior study evaluating 1955 patients older than 39 years without stroke reported that MAC was observed in 27% from a multiwindow approach using TTE, similar to our findings.
      • Kohsaka S.
      • Jin Z.
      • Rundek T.
      • et al.
      Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study.
      A study evaluating 1197 patients using longitudinal M-mode echocardiography reported that MAC was observed in 14%.
      • Fox C.S.
      • Vasan R.S.
      • Parise H.
      • et al.
      Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
      Kanjanauthai et al
      • Kanjanauthai S.
      • Nasir K.
      • Katz R.
      • et al.
      Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA).
      evaluated the presence of MAC using cardiac computed tomography and found that MAC was present in 9% of 6814 patients without known cardiovascular disease. However, MAC was observed in 35% of patients who had coronary artery disease.
      • Atar S.
      • Jeon D.S.
      • Luo H.
      • Siegel R.J.
      Mitral annular calcification: a marker of severe coronary artery disease in patients under 65 years old.
      This study included all adults undergoing echocardiography for clinical purposes and indicated a higher prevalence of MAC with increasing life expectancy.
      Our study found that patients with MAC more frequently had valvular diseases as well as cardiovascular diseases, and the presence of MAC was associated with 1.3-fold higher mortality even after adjustment for most of these diseases. These results indicate that MAC was not only a marker of cardiovascular and valvular diseases but also a predictor of mortality.
      • Fox C.S.
      • Vasan R.S.
      • Parise H.
      • et al.
      Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
      ,
      • Adler Y.
      • Fink N.
      • Spector D.
      • Wiser I.
      • Sagie A.
      Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system.
      ,
      • Allison M.A.
      • Cheung P.
      • Criqui M.H.
      • Langer R.D.
      • Wright C.M.
      Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis.
      Although MAC is usually an incidental finding, it may predict the progression of cardiovascular or valvular diseases because cardiovascular death has been more frequently seen in patients with MAC than in those without.
      • Fox C.S.
      • Vasan R.S.
      • Parise H.
      • et al.
      Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
      There is also evidence that inflammation may contribute to the pathogenesis of valve calcification, including MAC. Systemic biomarkers of inflammation are elevated in the setting of calcified valves, although this relationship decreases after adjustment for cardiovascular risk factors.
      • Ezeigwe A.
      • Fashanu O.E.
      • Zhao D.
      • et al.
      The novel inflammatory marker GlycA and the prevalence and progression of valvular and thoracic aortic calcification: the Multi-Ethnic Study of Atherosclerosis.
      ,
      • Fox C.S.
      • Guo C.Y.
      • Larson M.G.
      • et al.
      Relations of inflammation and novel risk factors to valvular calcification.
      Systemic inflammation has been related to mortality in the general population and in patients with cancer
      • Möhlenkamp S.
      • Lehmann N.
      • Moebus S.
      • et al.
      Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality.
      ,
      • Fox P.
      • Hudson M.
      • Brown C.
      • et al.
      Markers of systemic inflammation predict survival in patients with advanced renal cell cancer.
      and could potentially play a role in the increased mortality observed in patients with MAC.
      Mitral annulus calcification appears to be an increasingly important cause of MS among patients in developed countries, where the prevalence of MS was more than 10 times higher in patients with MAC than in patients without.
      • Kato N.
      • Padang R.
      • Scott C.G.
      • Guerrero M.
      • Pislaru S.V.
      • Pellikka P.A.
      The natural history of severe calcific mitral stenosis.
      Interestingly, female sex, chest irradiation, and chronic kidney disease were more important risk factors of MS than age in patients with MAC. Notably, AS and prior AVR were strongly associated with the presence of MS, possibly suggesting that a common atherosclerosis-like process affects both valves.
      • Allison M.A.
      • Cheung P.
      • Criqui M.H.
      • Langer R.D.
      • Wright C.M.
      Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis.
      The relationship of calcification in aortic valve, interannular fibrosa, and anterior mitral leaflet reduces its mobility and contributes to development of MS.
      • Muddassir S.M.
      • Pressman G.S.
      Mitral annular calcification as a cause of mitral valve gradients.
      Although the relation between MR and MAC was not seen, the presence of MAC is an important factor in treatment consideration for MR regardless of mechanism. The calcification process, which extends to the mitral leaflets,
      • Movva R.
      • Murthy K.
      • Romero-Corral A.
      • Seetha Rammohan H.R.
      • Fumo P.
      • Pressman G.S.
      Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function.
      affects repairability of the mitral valve. The diagnosis of LVOTO might have clinical significance for management; it often causes MR because of systolic anterior motion of the anterior mitral leaflet, and intervention for MVD sometimes worsens LVOTO, particularly after transcatheter mitral valve replacement.
      • Guerrero M.
      • Urena M.
      • Himbert D.
      • et al.
      1-Year outcomes of transcatheter mitral valve replacement in patients with severe mitral annular calcification.
      The prominent septal bulge sometimes seen in an aging population may contribute to LVOTO.
      Mitral valve dysfunction increased mortality regardless of the presence of MAC, but patients with both MAC and MVD had the highest mortality. Our study also suggested novel challenges in treatment considerations for MVD related to MAC. Frailty, which was associated with higher mortality, was more frequently seen in patients with MAC with MVD than in those without MVD.
      • Clegg A.
      • Young J.
      • Iliffe S.
      • Rikkert M.O.
      • Rockwood K.
      Frailty in elderly people [erratum appears in Lancet. 2013;382(9901):1328].
      Mitral valve dysfunction related to MAC frequently coexisted with comorbidities, including other valve diseases, coronary artery disease, and history of chest irradiation. Multiple procedures and cardiac surgery for patients with prior cardiac surgery or a history of chest irradiation may increase perioperative mortality in addition to heightened risk due to mitral annular débridement and reconstruction.
      • Eleid M.F.
      • Foley T.A.
      • Said S.M.
      • Pislaru S.V.
      • Rihal C.S.
      Severe mitral annular calcification: multimodality imaging for therapeutic strategies and interventions.
      ,
      • Galloway A.C.
      • Grossi E.A.
      • Baumann F.G.
      • et al.
      Multiple valve operation for advanced valvular heart disease: results and risk factors in 513 patients [errtum appears in J Am Coll Cardiol. 1992;19(7):1677-1678].
      ,
      • Wu W.
      • Masri A.
      • Popovic Z.B.
      • et al.
      Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study.
      Future studies are needed to determine optimal therapy for patients with MAC and MVD.

      Clinical Implications

      Mitral annulus calcification was commonly observed in patients undergoing clinically indicated echocardiography, and MVD was more frequently observed in patients with MAC than in those without. Suspicion for valve diseases including MVD should be increased and evaluation carefully performed in patients with MAC. The presence of MAC was independently associated with higher mortality, and MVD related to MAC was associated with even higher mortality, highlighting the clinical importance of detection of MAC. Furthermore, this study identifies a higher risk group of patients with MAC with specific clinical characteristics that are associated with a greater likelihood for development of MVD, including female sex, aortic valve disease, LVOTO, and renal dysfunction. The impact of intervention on MVD associated with MAC should be assessed in future studies.

      Limitations

      This is a single-center retrospective study from a high-volume tertiary referral center in the United States. Comprehensive TTE was performed by multiple credentialed sonographers according to usual clinical practice, and data were reviewed by an experienced level 3 trained echocardiographer before dismissal of the patient from the laboratory. It was possible that MVD severity was not accurately recognized in this TTE-based study because of the difficulty in assessing MVD severity in the presence of MAC. The mechanism of MS or MR was not systemically assessed in this study. Mitral valve area and transmitral gradient were not measured in all patients. However, it would be unlikely that MS of moderate or greater severity was missed in our laboratories as continuous wave Doppler is typically obtained in patients with evidence of aliasing across the mitral valve or significantly elevated pulsed wave Doppler velocities. Left ventricular outflow tract obstruction was not systemically assessed with Valsalva maneuver, amyl nitrite, or exercise. Three-dimensional imaging by echocardiography or cardiac computed tomography to quantify MAC severity was not available. Only all-cause mortality is reported here.
      • Lauer M.S.
      • Blackstone E.H.
      • Young J.B.
      • Topol E.J.
      Cause of death in clinical research: time for a reassessment?.
      The impact of interventions except mitral valve intervention on outcomes could not be removed. Selection bias might exist. Population prevalence cannot be ascertained from this study of patients undergoing clinically indicated echocardiography.

      Conclusion

      In a large cohort of adults undergoing echocardiographic evaluation, MAC was present in 23%. Patients with MAC were twice as likely to have MVD as those without MAC. Patients with MAC had higher all-cause mortality than patients without MAC after adjustment for clinical characteristics. In patients with MVD related to MAC, adjusted mortality was even higher.

      Potential Competing Interests

      Dr Guerrero has served as consultant for Tendyne Holdings and has received research grant support from Abbott Vascular and Edwards Lifesciences . The remaining authors have reported that they have no relationships relevant to the contents of this paper to disclose.

      Supplemental Online Material

      References

        • Nestico P.F.
        • Depace N.L.
        • Morganroth J.
        • Kotler M.N.
        • Ross J.
        Mitral annular calcification: clinical, pathophysiology, and echocardiographic review.
        Am Heart J. 1984; 107: 989-996
        • Kanjanauthai S.
        • Nasir K.
        • Katz R.
        • et al.
        Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA).
        Atherosclerosis. 2010; 213: 558-562
        • Fox C.S.
        • Vasan R.S.
        • Parise H.
        • et al.
        Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study.
        Circulation. 2003; 107: 1492-1496
        • Kohsaka S.
        • Jin Z.
        • Rundek T.
        • et al.
        Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study.
        JACC Cardiovasc Imaging. 2008; 1: 617-623
        • Adler Y.
        • Fink N.
        • Spector D.
        • Wiser I.
        • Sagie A.
        Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system.
        Atherosclerosis. 2001; 155: 1-8
        • Allison M.A.
        • Cheung P.
        • Criqui M.H.
        • Langer R.D.
        • Wright C.M.
        Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis.
        Circulation. 2006; 113: 861-866
        • Atar S.
        • Jeon D.S.
        • Luo H.
        • Siegel R.J.
        Mitral annular calcification: a marker of severe coronary artery disease in patients under 65 years old.
        Heart. 2003; 89: 161-164
        • Fusini L.
        • Ghulam Ali S.
        • Tamborini G.
        • et al.
        Prevalence of calcification of the mitral valve annulus in patients undergoing surgical repair of mitral valve prolapse.
        Am J Cardiol. 2014; 113: 1867-1873
        • Tomsic A.
        • Hiemstra Y.L.
        • van Brakel T.J.
        • et al.
        Outcomes of valve repair for degenerative disease in patients with mitral annular calcification.
        Ann Thorac Surg. 2019; 107: 1195-1201
        • Eleid M.F.
        • Foley T.A.
        • Said S.M.
        • Pislaru S.V.
        • Rihal C.S.
        Severe mitral annular calcification: multimodality imaging for therapeutic strategies and interventions.
        JACC Cardiovasc Imaging. 2016; 9: 1318-1337
        • Movahed M.R.
        • Saito Y.
        • Ahmadi-Kashani M.
        • Ebrahimi R.
        Mitral annulus calcification is associated with valvular and cardiac structural abnormalities.
        Cardiovasc Ultrasound. 2007; 5: 14
        • Muddassir S.M.
        • Pressman G.S.
        Mitral annular calcification as a cause of mitral valve gradients.
        Int J Cardiol. 2007; 123: 58-62
        • Lang R.M.
        • Badano L.P.
        • Mor-Avi V.
        • et al.
        Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        J Am Soc Echocardiogr. 2015; 28: 1-39.e14
        • Baumgartner H.
        • Hung J.
        • Bermejo J.
        • et al.
        Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice [erratum appears in J Am Soc Echocardiogr. 2009;22(5):442].
        J Am Soc Echocardiogr. 2009; 22 (quiz 101-102): 1-23
        • Zoghbi W.A.
        • Adams D.
        • Bonow R.O.
        • et al.
        Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
        J Am Soc Echocardiogr. 2017; 30: 303-371
        • Otto C.M.
        • Nishimura R.A.
        • Bonow R.O.
        • et al.
        2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
        Circulation. 2021; 143: e72-e227
        • Kato N.
        • Padang R.
        • Pislaru C.
        • et al.
        Hemodynamics and prognostic impact of concomitant mitral stenosis in patients undergoing surgical or transcatheter aortic valve replacement for aortic stenosis.
        Circulation. 2019; 140: 1251-1260
        • Elliott P.M.
        • Anastasakis A.
        • Borger M.A.
        • et al.
        2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
        Eur Heart J. 2014; 35: 2733-2779
        • Ezeigwe A.
        • Fashanu O.E.
        • Zhao D.
        • et al.
        The novel inflammatory marker GlycA and the prevalence and progression of valvular and thoracic aortic calcification: the Multi-Ethnic Study of Atherosclerosis.
        Atherosclerosis. 2019; 282: 91-99
        • Fox C.S.
        • Guo C.Y.
        • Larson M.G.
        • et al.
        Relations of inflammation and novel risk factors to valvular calcification.
        Am J Cardiol. 2006; 97: 1502-1505
        • Möhlenkamp S.
        • Lehmann N.
        • Moebus S.
        • et al.
        Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality.
        J Am Coll Cardiol. 2011; 57: 1455-1464
        • Fox P.
        • Hudson M.
        • Brown C.
        • et al.
        Markers of systemic inflammation predict survival in patients with advanced renal cell cancer.
        Br J Cancer. 2013; 109: 147-153
        • Kato N.
        • Padang R.
        • Scott C.G.
        • Guerrero M.
        • Pislaru S.V.
        • Pellikka P.A.
        The natural history of severe calcific mitral stenosis.
        J Am Coll Cardiol. 2020; 75: 3048-3057
        • Movva R.
        • Murthy K.
        • Romero-Corral A.
        • Seetha Rammohan H.R.
        • Fumo P.
        • Pressman G.S.
        Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function.
        J Am Soc Echocardiogr. 2013; 26: 1135-1142
        • Guerrero M.
        • Urena M.
        • Himbert D.
        • et al.
        1-Year outcomes of transcatheter mitral valve replacement in patients with severe mitral annular calcification.
        J Am Coll Cardiol. 2018; 71: 1841-1853
        • Clegg A.
        • Young J.
        • Iliffe S.
        • Rikkert M.O.
        • Rockwood K.
        Frailty in elderly people [erratum appears in Lancet. 2013;382(9901):1328].
        Lancet. 2013; 381: 752-762
        • Galloway A.C.
        • Grossi E.A.
        • Baumann F.G.
        • et al.
        Multiple valve operation for advanced valvular heart disease: results and risk factors in 513 patients [errtum appears in J Am Coll Cardiol. 1992;19(7):1677-1678].
        J Am Coll Cardiol. 1992; 19: 725-1678
        • Wu W.
        • Masri A.
        • Popovic Z.B.
        • et al.
        Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study.
        Circulation. 2013; 127: 1476-1485
        • Lauer M.S.
        • Blackstone E.H.
        • Young J.B.
        • Topol E.J.
        Cause of death in clinical research: time for a reassessment?.
        J Am Coll Cardiol. 1999; 34: 618-620