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Prevalence of Calcification of the Mitral Valve Annulus in Patients Undergoing Surgical Repair of Mitral Valve Prolapse
Prevalence of Calcification of the Mitral Valve Annulus in Patients Undergoing Surgical Repair of Mitral Valve Prolapse Laura Fusini, MSa,*, Sarah Ghulam Ali, MDa, Gloria Tamborini, MDa, Manuela Muratori, MDa, Paola Gripari, MDa, Francesco Maffessanti, PhDa, Fabrizio Celeste, MDa, Marco Guglielmo, MDa, Claudia Cefalù, MDa, Francesco Alamanni, MDa,b, Marco Zanobini, MDa, and Mauro Pepi, MDa Factors correlating to mitral annulus calcification (MAC) include risk factors predisposing to atherosclerosis. In patients with mitral valve (MV) prolapse (MVP), other anatomic or mechanical factors have been supposed to facilitate MAC. The aims of this study were, in patients with MVP undergoing MV repair, (1) to describe the prevalence and characteristics of MAC, (2) to correlate MAC with clinical risk factors, coronary involvement, and aortic valve disease, and (3) to describe prevalence, site, and extension of MAC in fibroelastic deficiency (FED) versus Barlow’s disease (BD) and correlate MAC to surgical outcomes (repair vs replacement). In 410 consecutive patients with MVP suitable for surgical MV repair, detailed clinical and echocardiographic data were collected to characterize MAC in BD and FED. MAC was found in 99 patients (24%). Age, female gender, coronary artery disease, and cardiovascular risk factors were correlated with MAC. MAC was equally distributed in FED and BD groups despite patients with FED being older with more cardiovascular risk factors. The most common localization of MAC was annular involvement adjacent to P2 (75%), P1 (31%), and P3 (35%). The presence of MAC affected surgical outcomes in both groups (8% patients with MAC underwent replacement after a first attempt of repair vs 3% without MAC). MAC is a common finding in patients undergoing MV repair, and several clinical characteristics correlate with MAC either in FED or BD. In conclusion, despite very high percentage of repairability, MAC influences surgical outcomes and very detailed echo evaluation is advocated. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:1867e1873) Mitral annulus calcification (MAC) is one of the more frequent abnormalities of the heart.1e3 Factors predisposing to MAC include age, hypertension, diabetes mellitus, hypercholesterolemia, chronic renal insufficiency, prolapsing mitral valve (MV), and other congenital and acquired diseases.4e8 The frequent occurrence of factors predisposing to atherosclerosis in patients with MAC supports a common etiologic basis for both MAC and atherosclerosis.9,10 In patients with MV prolapse (MVP), several anatomic or mechanical factors have been supposed to facilitate MAC. Specifically, an extensive calcification of the MV annulus is encountered either in elderly subjects with a fibroelastic deficiency (FED) of the MV or in younger adults with Barlow’s disease (BD).11 MV repair has become preferential to replacement in MVP.12 However, the operation in patients with MAC remains a challenge for the surgeon,13 because, both in patients with FED and patients with BD, an annuloplasty ring should be inserted to stabilize the annulus and the suture line with obvious technical implications in MAC cases. The aims of this study are threefold: (1) to a Centro Cardiologico Monzino IRCCS, Milan, Italy and bCardiovascular Section, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Manuscript received January 15, 2014; revised manuscript received and accepted March 6, 2014. See page 1873 for disclosure information. *Corresponding author: Tel: (þ39) 02 58002011; fax: (þ39) 02 58002287. E-mail address: [email protected] (L. Fusini).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.03.013
describe in detail the prevalence and anatomic characteristics (echocardiography) of MAC in a large consecutive series of patients undergoing MV repair for degenerative MVP, (2) to correlate MAC with clinical risk factors, coronary involvement, and coexisting aortic valve disease, and (3) to describe prevalence, site, and extension of MAC in patients with FED or BD and correlate echocardiographic findings to surgical outcomes (repair vs replacement). Methods This is a retrospective analysis including 410 consecutive patients with MVP who underwent MV surgery in our hospital from January 2008 to June 2012. All patients have an established diagnosis of severe mitral regurgitation (MR) due to degenerative MVP evaluated by 2-dimensional transthoracic echocardiography (TTE) and were suitable for surgical MV repair.14,15 Exclusion criteria were (1) association of MV stenosis, (2) previous or active endocarditis, and (3) history of coronary artery disease (CAD), previous myocardial ischemia or infarction, bypass graft surgery, or coronary stent implantation. The local ethics committee approved the study. Informed consent was obtained from all patients. Detailed baseline demographic and clinical data were collected. Current smoking was defined as self-report of 1 cigarettes in the past 30 days. Hyperglycemia requiring previous or ongoing pharmacologic therapy was considered as diabetes. High blood pressure was described as either www.ajconline.org
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Figure 1. Examples of patients with MVP without and with calcification in short-axis (A and C) and 4-chamber (B and D) views, respectively. LA ¼ left atrium; LV ¼ left ventricle.
systolic or diastolic elevation of blood pressure (>140/ 90 mm Hg) or ongoing antihypertensive treatment. Hypercholesterolemia was defined as total cholesterol level of >200 mg/dl or a value <200 mg/dl in association with hypolipidemic therapy. The presence of CAD was evaluated by preoperative coronary angiography. The surgical approach for MV repair varied according to MV morphology and to the surgeon’s choice. However, the procedure was completed with annular ring implantation in all patients. The surgical repair was considered successful in the absence of significant residual MR (more than mild), stenosis (mean diastolic MV gradient >6 mm Hg), and/or systolic anterior motion of the anterior leaflet evaluated by intraoperative transesophageal echocardiography. MV replacement was performed only in case of unsuccessful repair. A complete presurgical TTE was performed in all patients using a Philips iE33 or a GE Vivid 7 ultrasound system equipped with S5 or M4S probes, respectively (Philips Medical Systems, Andover, Massachusetts, or GE Healthcare, Horten, Norway). All images were digitally acquired and stored for off-line analysis and included standard 2-dimensional, color, and pulse- and continuous-wave Doppler acquisitions.15e17 MR was defined as severe when the effective regurgitant orifice area was 0.4 cm2 estimated by proximal isovelocity surface area and/or in presence of vena contracta width >7 mm or of chordal rupture associated with flail leaflets.18 MVP diagnosis was based on 2and 3-dimensional TTE.19,20 To assess MV anatomy, we
used Carpentier’s widely recognized nomenclature that divides the posterior leaflet into 3 scallops: lateral (P1), middle (P2), and medial (P3), and the anterior leaflet into 3 segments: lateral (A1), middle (A2), and medial (A3).21 The anterolateral and posteromedial commissures were also evaluated. All segments were classified as normal, prolapsing (3 mm beyond the annulus plane), or flail. The presence of ruptured chordae was annotated. MAC was defined as an intense echo-producing structure with stone shadow, usually localized at the posterior mitral annulus, sometimes involving the whole annulus, the base of 1 MV scallops, chordae, and ventricular endocardium (Figure 1). To assign the localization of each calcification involving the annulus, the leaflets, or the commissures, we used the conventional Carpentier’s nomenclature as described previously. Patients were divided into 2 subgroups based on the 2 main phenotypes of degenerative MVP, which are BD and FED. BD is characterized by severe myxomatous degeneration of the leaflets with excess thickened tissue, billowing and/or prolapse of multiple segments of the valve, elongated and thickened, fused, or calcified chordae, and highly dilated annulus. Conversely, the diagnosis of FED is established in case of normal or even thinner leaflets because of impaired production of connective tissue that affects also the chordae tendineae, no billowing, a single prolapsing segment (usually P2) frequently associated with chordal rupture, and slight annular dilation. In the intermediate forms in which the sole prolapsed area presented some
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Table 1 Baseline clinical and transthoracic echocardiographic characteristics of the study population and comparison between patients with and without mitral annulus calcification Variable
Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
Overall (n ¼ 410)
Mitral Annular Calcium Yes (n ¼ 99)
No (n ¼ 311)
62 13 274 (67) 1.81 0.19 224 (55) 22 (5) 265 (65) 43 (11) 87 (21)
68 10 51 (51) 1.75 0.18 67 (68) 8 (8) 75 (76) 16 (16) 32 (32)
60 13 223 (72) 1.82 0.18 157 (51) 14 (4) 190 (61) 27 (9) 55 (18)
323 (79) 50 (12) 20 (5) 17 (4) 76 19 27 9 65 7 18 (4) 38 12 36 5 40 5 0.10 0.07
67 (68) 18 (18) 6 (6) 8 (8) 73 16 27 9 64 8 13 (13) 40 12 35 5 39 5 0.11 0.07
256 (82) 32 (10) 14 (5) 9 (3) 77 20 27 10 65 7 5 (2) 37 12 36 5 41 5 0.10 0.07
p Value
<0.001 <0.001 <0.001 0.003 0.169 0.008 0.031 0.002 0.011
0.025 0.421 0.386 <0.001 0.013 0.023 0.041 0.306
Data are presented as mean SD or n (%).
degree of myxomatous involvement, the size of the mitral annulus was also taken into consideration.11 All images were independently evaluated by 2 experienced cardiologists blinded to clinical data. Conflict was resolved by involving a third expert in the decision. Continuous variables are presented as mean SD and categorical variables as frequency and relevant percentage. The data distribution normality of continuous variables was assessed using the Kolmogorov-Smirnov test. Continuous variables were compared using the unpaired Student t test or Mann-Whitney U test, and for categorical variables, the chisquare test or Fisher’s exact test was used, as appropriate, both for comparison between patients with and without MAC and between BD and FED groups. Differences were considered statistically significant at p <0.05. Significant variables in univariate analysis were included in a multivariate logistic regression analysis with stepwise method for the identification of independent variables predicting MAC. Goodness of fit was assessed using the Hosmer and Lemeshow test, in which a p value of <0.05 indicated a lack of fit of the model. Statistical analyses were conducted using SPSS, version 20.0 (SPSS Inc., Chicago, Illinois). Results This study included 410 patients with severe MR due to MVP undergoing MV repair in our institution from January 2008 to June 2012. The mean age of this cohort was 62 13 year and 274 patients (67%) were male (Table 1). Female patients were significantly older than male patients (64 12 vs 61 12 years, p ¼ 0.020). Prevalence of MAC was 24% and was higher in female patients (35% in women vs 19% in men, p <0.001). The most common site of MAC was
Figure 2. Surgical view of MV showing different distribution of calcifications in mitral annulus (bold number and percentage indicated by arrows) and leaflets (percentage in the middle of each scallop) in patients with MAC. A1, A2, and A3: segments of the anterior leaflets. P1, P2, and P3: scallops of the posterior leaflet. ALC ¼ anterolateral commissure; PMC ¼ posteromedial commissure.
annular involvement adjacent to P2 (75.8%), P1 (31.3%), and P3 (35.4%; Figure 2). Involvement of anterior annulus or leaflets was very uncommon. In 17 of 99 patients (17%)
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Table 2 Baseline clinical and transthoracic echocardiographic characteristics of the study population and comparison between patients with Barlow’s disease (BD) and fibroelastic deficiency (FED) Variable Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Mitral annular calcium Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
Overall (n ¼ 410)
BD (n ¼ 317)
FED (n ¼ 93)
p Value
62 13 274 (67) 1.81 0.19 224 (55) 22 (5) 265 (65) 43 (11) 87 (21)
60 13 205 (65) 1.80 0.18 161 (51) 13 (4) 206 (65) 36 (11) 55 (17)
68 9 69 (74) 1.83 0.19 63 (68) 9 (10) 59 (63) 7 (7) 32 (34)
<0.001 0.086 0.143 0.004 0.036 0.784 0.289 <0.001 0.002
323 (79) 50 (12) 20 (5) 17 (4) 76 19 27 9 65 7 18 (4) 99 (24) 38 12 36 5 40 5 0.10 0.07
262 (83) 33 (10) 10 (3) 12 (4) 79 19 28 10 65 7 12 (4) 72 (23) 37 12 37 5 41 5 0.10 0.07
61 (66) 17 (18) 10 (31) 5 (16) 68 15 25 8 63 8 6 (6) 27 (29) 38 11 34 5 38 5 0.11 0.06
<0.001 0.016 0.034 0.260 0.211 0.283 <0.001 <0.001 0.513
Data are presented as mean SD or n (%).
Figure 3. Surgical view of MV showing different distribution of calcifications in mitral annulus (bold number and percentage indicated by arrows) and leaflets (percentage in the middle of each scallop) between patients with BD (left) and FED (right). A1, A2, and A3: segments of the anterior leaflets. P1, P2, and P3: scallops of the posterior leaflet. ALC ¼ anterolateral commissure; PMC ¼ posteromedial commissure.
the calcium involved the chordae tendineae and in 18 (18%) the posterior-basal left ventricular endocardium. Surgical inspection confirmed echocardiographic findings in all patients with MAC. Hypertension, dyslipidemia, and positive smoking history were significantly more frequent in patients with MAC. Slightly greater prevalence of CAD was found in patients with MAC compared with patients without MAC, with higher rates of severe CAD. Percentage of aortic valve calcification was higher in patients with MAC. Concomitant coronary bypass grafting was performed in 19 patients (19%) with MAC and 42 (14%) without MAC (p ¼ 0.166). The logistic regression analysis revealed that
independent predictors of MAC were age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05 to 1.10, p <0.001), smoking (OR 3.06, 95% CI 1.44 to 6.52, p ¼ 0.004), female gender (OR 2.17, 95% CI 1.32 to 3.57, p ¼ 0.002), and dyslipidemia (OR 1.86, 95% CI 1.06 to 3.26, p ¼ 0.029). The model displayed satisfactory goodness of fit (p ¼ 0.27). The presence and extent of calcium on MV apparatus influences repair feasibility. Indeed, MV replacement was achieved in 8 patients (8%) with MAC and 9 (3%) without MAC (p ¼ 0.038). No intra- and/or peri-operative death was observed. The presence of MAC was always confirmed by surgical inspection. Concerning morphologic classification,
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Table 3 Comparison of clinical and echocardiographic characteristics of the study population between patients with and without mitral annulus calcification (MAC) grouped by etiology of mitral valve prolapse Variable
Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
BD (n ¼ 317)
p Value
MAC (n ¼ 72)
No MAC (n ¼ 245)
67 10 34 (47) 1.74 0.18 45 (63) 4 (6) 53 (74) 13 (18) 19 (26)
58 13 171 (70) 1.81 0.18 116 (47) 9 (4) 153 (63) 23 (9) 36 (15)
53 (74) 13 (18) 1 (1) 5 (7) 75 16 27 9 64 7 9 (12) 39 12 35 5 40 5 0.11 0.07
209 (85) 20 (8) 9 (4) 7 (3) 80 20 28 10 65 7 3 (1) 37 12 37 5 41 5 0.10 0.07
<0.001 0.001 0.001 0.024 0.479 0.081 0.042 0.021 0.023
0.017 0.508 0.242 <0.001 0.040 0.010 0.042 0.142
FED (n ¼ 93) MAC (n ¼ 27)
No MAC (n ¼ 66)
72 9 17 (63) 1.78 0.18 22 (81) 4 (15) 22 (81) 3 (11) 13 (48)
67 9 52 (79) 1.86 0.19 41 (62) 5 (8) 37 (56) 4 (6) 19 (29)
14 (52) 5 (18.5) 5 (18.5) 3 (11) 68 14 25 9 63 9 4 (15) 40 13 35 5 38 5 0.10 0.06
47 (71) 12 (18) 5 (8) 2 (3) 68 15 25 8 63 8 2 (3) 37 9 34 5 38 5 0.10 0.06
p Value
0.010 0.113 0.072 0.070 0.284 0.021 0.410 0.074 0.135
0.790 0.738 0.995 0.057 0.181 0.708 0.802 0.584
Data are presented as mean SD or n (%).
Figure 4. Flowchart showing the number and percentage of patients with and without MAC and the relative surgical outcome in patients with BD and FED.
317 patients (77%) had BD and 93 (23%) had FED. Slightly, but not significantly, higher percentage of MAC was present in the FED group. Patients with FED were older, with greater prevalence of hypertension, diabetes mellitus, and CAD. Patients with BD were characterized by greater anteroposterior and mediolateral diameters. The prevalence of MV and aortic valve calcification was similar in BD and in FED groups (Table 2). Figure 3 describes the localization of the calcifications adjacent to MV scallops in BD and FED. MV replacement was performed in 10 patients (4%) with BD and 7 (8%) with FED (p ¼ 0.076). Patients with and without MAC grouped by BD and FED are compared in Table 3 for clinical characteristics and echocardiographic findings. The localization of MVP involved the posterior leaflet in 279 patients (68%), the anterior leaflet in 50 (12%), and both MV leaflets in 81 (20%). Ruptured chordae was diagnosed in 268 patients (65%). Figure 4 is a
flowchart showing surgical outcomes (repair vs replacement) according to BD and FED classification and presence or absence of MAC. Discussion Main findings of this study are (1) in patients undergoing MV repair for MVP, MAC is a relatively common finding (24%) with typical morphologic characteristics; (2) age, female gender, cardiovascular risk factors, and CAD (particularly 3-vessel disease) correlate with the presence of MAC; (3) MAC was equally distributed in FED and BD groups despite patients with FED being older with more cardiovascular risk factors; and (4) the presence of MAC in both groups affects surgical outcomes. To our knowledge, this is the first study describing the prevalence, echocardiographic site, and characteristics of
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MAC in a large series of consecutive MVP candidates for repair and correlating MAC with clinical findings, risk factors, CAD, and aortic valve diseases. In several reported series of autopsies, the prevalence of MAC was found to be 8.5%.8 In the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, MAC was found by cardiac computed tomography in 9% of cases and its prevalence was highest in Caucasians (12%).5 In our consecutive series of Caucasian patients with MVP, MAC was found by echocardiography in 24% of cases. According to the MESA data,5 we found that several atherosclerotic risk factors were also associated with MAC in patients undergoing MV repair. Female gender, hypertension, dyslipidemia, and smoking were correlated with the presence of MAC. Moreover, coronary artery involvement (particularly 3-vessel disease) is slightly greater in MAC cases. Female gender was clearly associated with MAC independently of age in accordance with previous studies not specifically dedicated to MVP. Despite the slightly higher mean age of the FED group, MAC was equally distributed in FED and BD groups. We may postulate that in BD there is anticipation in terms of age of presentation of MAC because of the well-known association among MV degeneration (including MAC), BD, and Marfan syndrome. We based our data on TTE because it is the standard technique not only to evaluate MR severity and hemodynamic consequences of a degenerated MV but also to define in detail the localization of MAC with a very high spatial and temporal resolution. Echocardiography is probably not an ideal method for detection of valvular calcification because of its relatively low specificity in distinguishing between calcification and dense collagen, whereas cardiac computed tomography defines the presence of calcium with a very high specificity, but the method has limitations in the description of localization of MAC. In our series, surgical inspection confirmed echocardiographic findings in all patients with MAC. Moreover, in accordance with computed tomography data from the MESA study,5 our echocardiographic data in patients with MVP fit well with the atherosclerotic theory of MAC and with the role of gender, age, and cardiovascular risk factors in facilitating the onset of MAC. Another novelty of this study concerns a detailed description of MAC in this large population with MVP. The most common localization of MAC was annular involvement adjacent to P2 (75%), P1 (31%), and P3 (35%). Involvement of anterior annulus was very uncommon. Carpentier22 studied 68 patients with extensive MAC undergoing MV surgery and showed that, circumferentially, the calcification process involved at least 1/3 of the posterior annulus in 88% of the patients and the whole posterior annulus in 10%, and the calcification extended to the attachment of the anterior leaflet in 1.5%. Thus, our data by TTE agree with surgical findings by others. The pathophysiology of MAC is a subject of controversy. The most common hypothesis is progressive degeneration of the annulus throughout life, but a preexisting MV disease may also facilitate MAC. In fact, the calcification may be due to a preexisting valvular disease, usually a degenerative valvular disease with leaflet billowing, leaflet prolapse, and excess tissue. It has been proposed that both excessive tension from excess tissue and mechanical factors play a role through
excess blood pressure and excess tension on the leaflets eliciting biochemical changes in the annulus.22 Our data not only confirmed a clear correlation between MAC and atherosclerotic risk factors but also showed that most patients had MAC in the region adjacent to the prolapsing scallops. These observations are also supported by our data on FED and BD. In fact, despite different age of presentation and surgical indication, the 2 groups have similar percentage of MAC. Excess tension, excess tissue leaflets tension, and increased fragility may anticipate the deposition of calcium in BD versus FED, although the predominant risk factors for MAC are similar in all cases. d’Alessandro et al23 showed that, although BD can occur in young adults, the annulus calcification is a slowly evolving process and the average age of patients with BD in their series was 60 years. In contrast, FED preferentially develops in the elderly, and patients’ age in this group was 73 years. Accordingly, our mean age of surgical repair was 60 and 68 years in BD and FED, respectively. We also found that MV annulus diameters are larger in BD versus FED.24,25 It has been suggested that in normal MV annulus, the nonplanar saddle-shape is important for reducing mechanical stress on mitral leaflets and chordae tendineae imposed by left ventricular pressure. Flattening of the annular saddle-shape is associated with progressive leaflet billowing and increased frequencies of chordal rupture due to stress to MV leaflets,26 and this phenomenon is always associated with mitral annulus dilation. The third main result of our study concerns immediate surgical outcomes as related to MAC in patients with FED and BD. MVP is nowadays the most common cause of surgical MR in industrialized countries, and MV repair emerged as treatment of choice in patients with MVP allowing the preservation of left ventricular geometry and function while increasing long-term survival. However, optimal timing for MV repair is considered, even in asymptomatic patients, when the likelihood of a successful repair is high at a low operative risk. Not only immediate results but also durability strongly depends on MV anatomy and complexity of surgical procedures,12 and 3-dimensional echocardiography may preoperatively assess the need for simple or complex surgical techniques. MAC has been considered in all surgical series as one of the main risk factors for MV repair affecting both immediate and longterm results. Although nowadays the rate of repairability has markedly increased, extension of MAC, type of MVP, and leaflet tissue characteristics (amount of leaflet tissue available for reconstruction) may influence the feasibility of valve repair. In our study, intraoperative conversion to MV replacement was performed in 8% of patients with MAC and in 3% without MAC. Therefore, in our series MVP repairability was 97% in patients without MAC and 92% in patients with MAC, confirming the importance of MAC in determining surgical outcomes. By selection, we consider only cases without previous or active endocarditis and history of CAD, and this may have determined a very high rate of repairability. Interestingly, MAC affected the surgical results independently on the etiology of MVP: despite higher rate of MV replacement in FED (7% in FED vs 3% in BD), FED and BD groups with MAC had similar rates of replacement.
Valvular Heart Disease/MAC in Mitral Valve Prolapse Patients
There are limitations to this study. Patients were divided into 2 subgroups based on the 2 main phenotypes of degenerative MVP, which are BD and FED. This classification, although widely accepted, is an oversimplification of the disease, and very recent data demonstrate new concepts on the histology of MV leaflets and chordae in patients undergoing MV repair.27 Annular calcium was diagnosed by TTE; however, in cases with suboptimal transthoracic windows transesophageal echocardiography may better visualize MV apparatus anatomy. In our series, we found an excellent correspondence between TTE data and surgical inspection. Therefore, this limitation does not detract much from our conclusions. Disclosures The authors have no conflicts of interest to disclose. 1. Roberts WC, Ko JM. Some observations on mitral and aortic valve disease. Proc (Bayl Univ Med Cent) 2008;21:282e299. 2. Roberts WC. Morphologic features of the normal and abnormal mitral valve. Am J Cardiol 1983;51:1005e1028. 3. Roberts WC, Perloff JK. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972;77:939e975. 4. Koulaouzidis G, Nicoll R, Macarthur T, Jenkins PJ, Henein MY. Coronary artery calcification correlates with the presence and severity of valve calcification. Int J Cardiol 2013;168:5263e5266. 5. Kanjanauthai S, Nasir K, Katz R, Rivera JJ, Takasu J, Blumenthal RS, Eng J, Budoff MJ. Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2010;213:558e562. 6. Boon A, Cheriex E, Lodder J, Kessels F. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve. Heart 1997;78:472e474. 7. Fulkerson PK, Beaver BM, Auseon JC, Graber HL. Calcification of the mitral annulus: etiology, clinical associations, complications and therapy. Am J Med 1979;66:967e977. 8. Pomerance A. Pathological and clinical study of calcification of the mitral valve ring. J Clin Pathol 1970;23:354e361. 9. Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system. Atherosclerosis 2001;155:1e8. 10. Adler Y, Herz I, Vaturi M, Fusman R, Shohat-Zabarski R, Fink N, Porter A, Shapira Y, Assali A, Sagie A. Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 1998;82:1183e1186. 11. Anyanwu AC, Adams DH. Etiologic classification of degenerative mitral valve disease: Barlow’s disease and fibroelastic deficiency. Semin Thorac Cardiovasc Surg 2007;19:90e96. 12. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e1ee142. 13. Chan V, Ruel M, Hynes M, Chaudry S, Mesana TG. Impact of mitral annular calcification on early and late outcomes following mitral valve repair of myxomatous degeneration. Interact Cardiovasc Thorac Surg 2013;17:120e125.
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14. Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation. Lancet 2009;373:1382e1394. 15. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ, American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777e802. 16. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e1463. 17. Pepi M, Tamborini G, Galli C, Barbier P, Doria E, Berti M, Guazzi M, Fiorentini C. A new formula for echo-Doppler estimation of right ventricular systolic pressure. J Am Soc Echocardiogr 1994;7:20e26. 18. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvardsen T, Pierard LA, Badano L, Zamorano JL, Scientific Document Committee of the European Association of Cardiovascular Imaging. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611e644. 19. Tamborini G, Muratori M, Maltagliati A, Galli CA, Naliato M, Zanobini M, Alamanni F, Salvi L, Sisillo E, Fiorentini C, Pepi M. Pre-operative transthoracic real-time three-dimensional echocardiography in patients undergoing mitral valve repair: accuracy in cases with simple vs. complex prolapse lesions. Eur J Echocardiogr 2010;11:778e785. 20. Pepi M, Tamborini G, Maltagliati A, Galli CA, Sisillo E, Salvi L, Naliato M, Porqueddu M, Parolari A, Zanobini M, Alamanni F. Headto-head comparison of two- and three-dimensional transthoracic and transesophageal echocardiography in the localization of mitral valve prolapse. J Am Coll Cardiol 2006;48:2524e2530. 21. Carpentier A. Cardiac valve surgery—the “French correction”. J Thorac Cardiovasc Surg 1983;86:323e337. 22. Carpentier AF, Pellerin M, Fuzellier JF, Relland JY. Extensive calcification of the mitral valve annulus: pathology and surgical management. J Thorac Cardiovasc Surg 1996;111:718e730. 23. d’Alessandro C, Vistarini N, Aubert S, Jault F, Acar C, Pavie A, Gandjbakhch I. Mitral annulus calcification: determinants of repair feasibility, early and late surgical outcome. Eur J Cardiothorac Surg 2007;32:596e603. 24. Chandra S, Salgo IS, Sugeng L, Weinert L, Tsang W, Takeuchi M, Spencer KT, O’Connor A, Cardinale M, Settlemier S, Mor-Avi V, Lang RM. Characterization of degenerative mitral valve disease using morphologic analysis of real-time three-dimensional echocardiographic images: objective insight into complexity and planning of mitral valve repair. Circ Cardiovasc Imaging 2011;4:24e32. 25. Maffessanti F, Marsan NA, Tamborini G, Sugeng L, Caiani EG, Gripari P, Alamanni F, Jeevanandam V, Lang RM, Pepi M. Quantitative analysis of mitral valve apparatus in mitral valve prolapse before and after annuloplasty: a three-dimensional intraoperative transesophageal study. J Am Soc Echocardiogr 2011;24:405e413. 26. Lee AP, Hsiung MC, Salgo IS, Fang F, Xie JM, Zhang YC, Lin QS, Looi JL, Wan S, Wong RH, Underwood MJ, Sun JP, Yin WH, Wei J, Tsai SK, Yu CM. Quantitative analysis of mitral valve morphology in mitral valve prolapse with real-time 3-dimensional echocardiography: importance of annular saddle shape in the pathogenesis of mitral regurgitation. Circulation 2013;127:832e841. 27. Roberts WC, Vowels TJ, Ko JM, Hebeler RF Jr. Gross and histologic features of excised portions of posterior mitral leaflet in patients having operative repair of mitral valve prolapse and comments on the concept of missing (¼ruptured) chordae tendineae. J Am Coll Cardiol 2013 [Epub ahead of print].
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.03.013
describe in detail the prevalence and anatomic characteristics (echocardiography) of MAC in a large consecutive series of patients undergoing MV repair for degenerative MVP, (2) to correlate MAC with clinical risk factors, coronary involvement, and coexisting aortic valve disease, and (3) to describe prevalence, site, and extension of MAC in patients with FED or BD and correlate echocardiographic findings to surgical outcomes (repair vs replacement). Methods This is a retrospective analysis including 410 consecutive patients with MVP who underwent MV surgery in our hospital from January 2008 to June 2012. All patients have an established diagnosis of severe mitral regurgitation (MR) due to degenerative MVP evaluated by 2-dimensional transthoracic echocardiography (TTE) and were suitable for surgical MV repair.14,15 Exclusion criteria were (1) association of MV stenosis, (2) previous or active endocarditis, and (3) history of coronary artery disease (CAD), previous myocardial ischemia or infarction, bypass graft surgery, or coronary stent implantation. The local ethics committee approved the study. Informed consent was obtained from all patients. Detailed baseline demographic and clinical data were collected. Current smoking was defined as self-report of 1 cigarettes in the past 30 days. Hyperglycemia requiring previous or ongoing pharmacologic therapy was considered as diabetes. High blood pressure was described as either www.ajconline.org
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Figure 1. Examples of patients with MVP without and with calcification in short-axis (A and C) and 4-chamber (B and D) views, respectively. LA ¼ left atrium; LV ¼ left ventricle.
systolic or diastolic elevation of blood pressure (>140/ 90 mm Hg) or ongoing antihypertensive treatment. Hypercholesterolemia was defined as total cholesterol level of >200 mg/dl or a value <200 mg/dl in association with hypolipidemic therapy. The presence of CAD was evaluated by preoperative coronary angiography. The surgical approach for MV repair varied according to MV morphology and to the surgeon’s choice. However, the procedure was completed with annular ring implantation in all patients. The surgical repair was considered successful in the absence of significant residual MR (more than mild), stenosis (mean diastolic MV gradient >6 mm Hg), and/or systolic anterior motion of the anterior leaflet evaluated by intraoperative transesophageal echocardiography. MV replacement was performed only in case of unsuccessful repair. A complete presurgical TTE was performed in all patients using a Philips iE33 or a GE Vivid 7 ultrasound system equipped with S5 or M4S probes, respectively (Philips Medical Systems, Andover, Massachusetts, or GE Healthcare, Horten, Norway). All images were digitally acquired and stored for off-line analysis and included standard 2-dimensional, color, and pulse- and continuous-wave Doppler acquisitions.15e17 MR was defined as severe when the effective regurgitant orifice area was 0.4 cm2 estimated by proximal isovelocity surface area and/or in presence of vena contracta width >7 mm or of chordal rupture associated with flail leaflets.18 MVP diagnosis was based on 2and 3-dimensional TTE.19,20 To assess MV anatomy, we
used Carpentier’s widely recognized nomenclature that divides the posterior leaflet into 3 scallops: lateral (P1), middle (P2), and medial (P3), and the anterior leaflet into 3 segments: lateral (A1), middle (A2), and medial (A3).21 The anterolateral and posteromedial commissures were also evaluated. All segments were classified as normal, prolapsing (3 mm beyond the annulus plane), or flail. The presence of ruptured chordae was annotated. MAC was defined as an intense echo-producing structure with stone shadow, usually localized at the posterior mitral annulus, sometimes involving the whole annulus, the base of 1 MV scallops, chordae, and ventricular endocardium (Figure 1). To assign the localization of each calcification involving the annulus, the leaflets, or the commissures, we used the conventional Carpentier’s nomenclature as described previously. Patients were divided into 2 subgroups based on the 2 main phenotypes of degenerative MVP, which are BD and FED. BD is characterized by severe myxomatous degeneration of the leaflets with excess thickened tissue, billowing and/or prolapse of multiple segments of the valve, elongated and thickened, fused, or calcified chordae, and highly dilated annulus. Conversely, the diagnosis of FED is established in case of normal or even thinner leaflets because of impaired production of connective tissue that affects also the chordae tendineae, no billowing, a single prolapsing segment (usually P2) frequently associated with chordal rupture, and slight annular dilation. In the intermediate forms in which the sole prolapsed area presented some
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Table 1 Baseline clinical and transthoracic echocardiographic characteristics of the study population and comparison between patients with and without mitral annulus calcification Variable
Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
Overall (n ¼ 410)
Mitral Annular Calcium Yes (n ¼ 99)
No (n ¼ 311)
62 13 274 (67) 1.81 0.19 224 (55) 22 (5) 265 (65) 43 (11) 87 (21)
68 10 51 (51) 1.75 0.18 67 (68) 8 (8) 75 (76) 16 (16) 32 (32)
60 13 223 (72) 1.82 0.18 157 (51) 14 (4) 190 (61) 27 (9) 55 (18)
323 (79) 50 (12) 20 (5) 17 (4) 76 19 27 9 65 7 18 (4) 38 12 36 5 40 5 0.10 0.07
67 (68) 18 (18) 6 (6) 8 (8) 73 16 27 9 64 8 13 (13) 40 12 35 5 39 5 0.11 0.07
256 (82) 32 (10) 14 (5) 9 (3) 77 20 27 10 65 7 5 (2) 37 12 36 5 41 5 0.10 0.07
p Value
<0.001 <0.001 <0.001 0.003 0.169 0.008 0.031 0.002 0.011
0.025 0.421 0.386 <0.001 0.013 0.023 0.041 0.306
Data are presented as mean SD or n (%).
degree of myxomatous involvement, the size of the mitral annulus was also taken into consideration.11 All images were independently evaluated by 2 experienced cardiologists blinded to clinical data. Conflict was resolved by involving a third expert in the decision. Continuous variables are presented as mean SD and categorical variables as frequency and relevant percentage. The data distribution normality of continuous variables was assessed using the Kolmogorov-Smirnov test. Continuous variables were compared using the unpaired Student t test or Mann-Whitney U test, and for categorical variables, the chisquare test or Fisher’s exact test was used, as appropriate, both for comparison between patients with and without MAC and between BD and FED groups. Differences were considered statistically significant at p <0.05. Significant variables in univariate analysis were included in a multivariate logistic regression analysis with stepwise method for the identification of independent variables predicting MAC. Goodness of fit was assessed using the Hosmer and Lemeshow test, in which a p value of <0.05 indicated a lack of fit of the model. Statistical analyses were conducted using SPSS, version 20.0 (SPSS Inc., Chicago, Illinois). Results This study included 410 patients with severe MR due to MVP undergoing MV repair in our institution from January 2008 to June 2012. The mean age of this cohort was 62 13 year and 274 patients (67%) were male (Table 1). Female patients were significantly older than male patients (64 12 vs 61 12 years, p ¼ 0.020). Prevalence of MAC was 24% and was higher in female patients (35% in women vs 19% in men, p <0.001). The most common site of MAC was
Figure 2. Surgical view of MV showing different distribution of calcifications in mitral annulus (bold number and percentage indicated by arrows) and leaflets (percentage in the middle of each scallop) in patients with MAC. A1, A2, and A3: segments of the anterior leaflets. P1, P2, and P3: scallops of the posterior leaflet. ALC ¼ anterolateral commissure; PMC ¼ posteromedial commissure.
annular involvement adjacent to P2 (75.8%), P1 (31.3%), and P3 (35.4%; Figure 2). Involvement of anterior annulus or leaflets was very uncommon. In 17 of 99 patients (17%)
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Table 2 Baseline clinical and transthoracic echocardiographic characteristics of the study population and comparison between patients with Barlow’s disease (BD) and fibroelastic deficiency (FED) Variable Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Mitral annular calcium Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
Overall (n ¼ 410)
BD (n ¼ 317)
FED (n ¼ 93)
p Value
62 13 274 (67) 1.81 0.19 224 (55) 22 (5) 265 (65) 43 (11) 87 (21)
60 13 205 (65) 1.80 0.18 161 (51) 13 (4) 206 (65) 36 (11) 55 (17)
68 9 69 (74) 1.83 0.19 63 (68) 9 (10) 59 (63) 7 (7) 32 (34)
<0.001 0.086 0.143 0.004 0.036 0.784 0.289 <0.001 0.002
323 (79) 50 (12) 20 (5) 17 (4) 76 19 27 9 65 7 18 (4) 99 (24) 38 12 36 5 40 5 0.10 0.07
262 (83) 33 (10) 10 (3) 12 (4) 79 19 28 10 65 7 12 (4) 72 (23) 37 12 37 5 41 5 0.10 0.07
61 (66) 17 (18) 10 (31) 5 (16) 68 15 25 8 63 8 6 (6) 27 (29) 38 11 34 5 38 5 0.11 0.06
<0.001 0.016 0.034 0.260 0.211 0.283 <0.001 <0.001 0.513
Data are presented as mean SD or n (%).
Figure 3. Surgical view of MV showing different distribution of calcifications in mitral annulus (bold number and percentage indicated by arrows) and leaflets (percentage in the middle of each scallop) between patients with BD (left) and FED (right). A1, A2, and A3: segments of the anterior leaflets. P1, P2, and P3: scallops of the posterior leaflet. ALC ¼ anterolateral commissure; PMC ¼ posteromedial commissure.
the calcium involved the chordae tendineae and in 18 (18%) the posterior-basal left ventricular endocardium. Surgical inspection confirmed echocardiographic findings in all patients with MAC. Hypertension, dyslipidemia, and positive smoking history were significantly more frequent in patients with MAC. Slightly greater prevalence of CAD was found in patients with MAC compared with patients without MAC, with higher rates of severe CAD. Percentage of aortic valve calcification was higher in patients with MAC. Concomitant coronary bypass grafting was performed in 19 patients (19%) with MAC and 42 (14%) without MAC (p ¼ 0.166). The logistic regression analysis revealed that
independent predictors of MAC were age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05 to 1.10, p <0.001), smoking (OR 3.06, 95% CI 1.44 to 6.52, p ¼ 0.004), female gender (OR 2.17, 95% CI 1.32 to 3.57, p ¼ 0.002), and dyslipidemia (OR 1.86, 95% CI 1.06 to 3.26, p ¼ 0.029). The model displayed satisfactory goodness of fit (p ¼ 0.27). The presence and extent of calcium on MV apparatus influences repair feasibility. Indeed, MV replacement was achieved in 8 patients (8%) with MAC and 9 (3%) without MAC (p ¼ 0.038). No intra- and/or peri-operative death was observed. The presence of MAC was always confirmed by surgical inspection. Concerning morphologic classification,
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Table 3 Comparison of clinical and echocardiographic characteristics of the study population between patients with and without mitral annulus calcification (MAC) grouped by etiology of mitral valve prolapse Variable
Age (yrs) Men Body surface area (m2) Hypertension Diabetes mellitus Dyslipidemia Smoker Coronary artery disease No. of coronary arteries involved 0 1 2 3 End-diastolic volume index (ml/m2) End-systolic volume index (ml/m2) Ejection fraction (%) Aortic valve calcification Pulmonary artery systolic pressure (mm Hg) Annulus anteroposterior diameter (mm) Annulus mediolateral diameter (mm) Eccentricity
BD (n ¼ 317)
p Value
MAC (n ¼ 72)
No MAC (n ¼ 245)
67 10 34 (47) 1.74 0.18 45 (63) 4 (6) 53 (74) 13 (18) 19 (26)
58 13 171 (70) 1.81 0.18 116 (47) 9 (4) 153 (63) 23 (9) 36 (15)
53 (74) 13 (18) 1 (1) 5 (7) 75 16 27 9 64 7 9 (12) 39 12 35 5 40 5 0.11 0.07
209 (85) 20 (8) 9 (4) 7 (3) 80 20 28 10 65 7 3 (1) 37 12 37 5 41 5 0.10 0.07
<0.001 0.001 0.001 0.024 0.479 0.081 0.042 0.021 0.023
0.017 0.508 0.242 <0.001 0.040 0.010 0.042 0.142
FED (n ¼ 93) MAC (n ¼ 27)
No MAC (n ¼ 66)
72 9 17 (63) 1.78 0.18 22 (81) 4 (15) 22 (81) 3 (11) 13 (48)
67 9 52 (79) 1.86 0.19 41 (62) 5 (8) 37 (56) 4 (6) 19 (29)
14 (52) 5 (18.5) 5 (18.5) 3 (11) 68 14 25 9 63 9 4 (15) 40 13 35 5 38 5 0.10 0.06
47 (71) 12 (18) 5 (8) 2 (3) 68 15 25 8 63 8 2 (3) 37 9 34 5 38 5 0.10 0.06
p Value
0.010 0.113 0.072 0.070 0.284 0.021 0.410 0.074 0.135
0.790 0.738 0.995 0.057 0.181 0.708 0.802 0.584
Data are presented as mean SD or n (%).
Figure 4. Flowchart showing the number and percentage of patients with and without MAC and the relative surgical outcome in patients with BD and FED.
317 patients (77%) had BD and 93 (23%) had FED. Slightly, but not significantly, higher percentage of MAC was present in the FED group. Patients with FED were older, with greater prevalence of hypertension, diabetes mellitus, and CAD. Patients with BD were characterized by greater anteroposterior and mediolateral diameters. The prevalence of MV and aortic valve calcification was similar in BD and in FED groups (Table 2). Figure 3 describes the localization of the calcifications adjacent to MV scallops in BD and FED. MV replacement was performed in 10 patients (4%) with BD and 7 (8%) with FED (p ¼ 0.076). Patients with and without MAC grouped by BD and FED are compared in Table 3 for clinical characteristics and echocardiographic findings. The localization of MVP involved the posterior leaflet in 279 patients (68%), the anterior leaflet in 50 (12%), and both MV leaflets in 81 (20%). Ruptured chordae was diagnosed in 268 patients (65%). Figure 4 is a
flowchart showing surgical outcomes (repair vs replacement) according to BD and FED classification and presence or absence of MAC. Discussion Main findings of this study are (1) in patients undergoing MV repair for MVP, MAC is a relatively common finding (24%) with typical morphologic characteristics; (2) age, female gender, cardiovascular risk factors, and CAD (particularly 3-vessel disease) correlate with the presence of MAC; (3) MAC was equally distributed in FED and BD groups despite patients with FED being older with more cardiovascular risk factors; and (4) the presence of MAC in both groups affects surgical outcomes. To our knowledge, this is the first study describing the prevalence, echocardiographic site, and characteristics of
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MAC in a large series of consecutive MVP candidates for repair and correlating MAC with clinical findings, risk factors, CAD, and aortic valve diseases. In several reported series of autopsies, the prevalence of MAC was found to be 8.5%.8 In the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, MAC was found by cardiac computed tomography in 9% of cases and its prevalence was highest in Caucasians (12%).5 In our consecutive series of Caucasian patients with MVP, MAC was found by echocardiography in 24% of cases. According to the MESA data,5 we found that several atherosclerotic risk factors were also associated with MAC in patients undergoing MV repair. Female gender, hypertension, dyslipidemia, and smoking were correlated with the presence of MAC. Moreover, coronary artery involvement (particularly 3-vessel disease) is slightly greater in MAC cases. Female gender was clearly associated with MAC independently of age in accordance with previous studies not specifically dedicated to MVP. Despite the slightly higher mean age of the FED group, MAC was equally distributed in FED and BD groups. We may postulate that in BD there is anticipation in terms of age of presentation of MAC because of the well-known association among MV degeneration (including MAC), BD, and Marfan syndrome. We based our data on TTE because it is the standard technique not only to evaluate MR severity and hemodynamic consequences of a degenerated MV but also to define in detail the localization of MAC with a very high spatial and temporal resolution. Echocardiography is probably not an ideal method for detection of valvular calcification because of its relatively low specificity in distinguishing between calcification and dense collagen, whereas cardiac computed tomography defines the presence of calcium with a very high specificity, but the method has limitations in the description of localization of MAC. In our series, surgical inspection confirmed echocardiographic findings in all patients with MAC. Moreover, in accordance with computed tomography data from the MESA study,5 our echocardiographic data in patients with MVP fit well with the atherosclerotic theory of MAC and with the role of gender, age, and cardiovascular risk factors in facilitating the onset of MAC. Another novelty of this study concerns a detailed description of MAC in this large population with MVP. The most common localization of MAC was annular involvement adjacent to P2 (75%), P1 (31%), and P3 (35%). Involvement of anterior annulus was very uncommon. Carpentier22 studied 68 patients with extensive MAC undergoing MV surgery and showed that, circumferentially, the calcification process involved at least 1/3 of the posterior annulus in 88% of the patients and the whole posterior annulus in 10%, and the calcification extended to the attachment of the anterior leaflet in 1.5%. Thus, our data by TTE agree with surgical findings by others. The pathophysiology of MAC is a subject of controversy. The most common hypothesis is progressive degeneration of the annulus throughout life, but a preexisting MV disease may also facilitate MAC. In fact, the calcification may be due to a preexisting valvular disease, usually a degenerative valvular disease with leaflet billowing, leaflet prolapse, and excess tissue. It has been proposed that both excessive tension from excess tissue and mechanical factors play a role through
excess blood pressure and excess tension on the leaflets eliciting biochemical changes in the annulus.22 Our data not only confirmed a clear correlation between MAC and atherosclerotic risk factors but also showed that most patients had MAC in the region adjacent to the prolapsing scallops. These observations are also supported by our data on FED and BD. In fact, despite different age of presentation and surgical indication, the 2 groups have similar percentage of MAC. Excess tension, excess tissue leaflets tension, and increased fragility may anticipate the deposition of calcium in BD versus FED, although the predominant risk factors for MAC are similar in all cases. d’Alessandro et al23 showed that, although BD can occur in young adults, the annulus calcification is a slowly evolving process and the average age of patients with BD in their series was 60 years. In contrast, FED preferentially develops in the elderly, and patients’ age in this group was 73 years. Accordingly, our mean age of surgical repair was 60 and 68 years in BD and FED, respectively. We also found that MV annulus diameters are larger in BD versus FED.24,25 It has been suggested that in normal MV annulus, the nonplanar saddle-shape is important for reducing mechanical stress on mitral leaflets and chordae tendineae imposed by left ventricular pressure. Flattening of the annular saddle-shape is associated with progressive leaflet billowing and increased frequencies of chordal rupture due to stress to MV leaflets,26 and this phenomenon is always associated with mitral annulus dilation. The third main result of our study concerns immediate surgical outcomes as related to MAC in patients with FED and BD. MVP is nowadays the most common cause of surgical MR in industrialized countries, and MV repair emerged as treatment of choice in patients with MVP allowing the preservation of left ventricular geometry and function while increasing long-term survival. However, optimal timing for MV repair is considered, even in asymptomatic patients, when the likelihood of a successful repair is high at a low operative risk. Not only immediate results but also durability strongly depends on MV anatomy and complexity of surgical procedures,12 and 3-dimensional echocardiography may preoperatively assess the need for simple or complex surgical techniques. MAC has been considered in all surgical series as one of the main risk factors for MV repair affecting both immediate and longterm results. Although nowadays the rate of repairability has markedly increased, extension of MAC, type of MVP, and leaflet tissue characteristics (amount of leaflet tissue available for reconstruction) may influence the feasibility of valve repair. In our study, intraoperative conversion to MV replacement was performed in 8% of patients with MAC and in 3% without MAC. Therefore, in our series MVP repairability was 97% in patients without MAC and 92% in patients with MAC, confirming the importance of MAC in determining surgical outcomes. By selection, we consider only cases without previous or active endocarditis and history of CAD, and this may have determined a very high rate of repairability. Interestingly, MAC affected the surgical results independently on the etiology of MVP: despite higher rate of MV replacement in FED (7% in FED vs 3% in BD), FED and BD groups with MAC had similar rates of replacement.
Valvular Heart Disease/MAC in Mitral Valve Prolapse Patients
There are limitations to this study. Patients were divided into 2 subgroups based on the 2 main phenotypes of degenerative MVP, which are BD and FED. This classification, although widely accepted, is an oversimplification of the disease, and very recent data demonstrate new concepts on the histology of MV leaflets and chordae in patients undergoing MV repair.27 Annular calcium was diagnosed by TTE; however, in cases with suboptimal transthoracic windows transesophageal echocardiography may better visualize MV apparatus anatomy. In our series, we found an excellent correspondence between TTE data and surgical inspection. Therefore, this limitation does not detract much from our conclusions. Disclosures The authors have no conflicts of interest to disclose. 1. Roberts WC, Ko JM. Some observations on mitral and aortic valve disease. Proc (Bayl Univ Med Cent) 2008;21:282e299. 2. Roberts WC. Morphologic features of the normal and abnormal mitral valve. Am J Cardiol 1983;51:1005e1028. 3. Roberts WC, Perloff JK. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972;77:939e975. 4. Koulaouzidis G, Nicoll R, Macarthur T, Jenkins PJ, Henein MY. Coronary artery calcification correlates with the presence and severity of valve calcification. Int J Cardiol 2013;168:5263e5266. 5. Kanjanauthai S, Nasir K, Katz R, Rivera JJ, Takasu J, Blumenthal RS, Eng J, Budoff MJ. Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2010;213:558e562. 6. Boon A, Cheriex E, Lodder J, Kessels F. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve. Heart 1997;78:472e474. 7. Fulkerson PK, Beaver BM, Auseon JC, Graber HL. Calcification of the mitral annulus: etiology, clinical associations, complications and therapy. Am J Med 1979;66:967e977. 8. Pomerance A. Pathological and clinical study of calcification of the mitral valve ring. J Clin Pathol 1970;23:354e361. 9. Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system. Atherosclerosis 2001;155:1e8. 10. Adler Y, Herz I, Vaturi M, Fusman R, Shohat-Zabarski R, Fink N, Porter A, Shapira Y, Assali A, Sagie A. Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 1998;82:1183e1186. 11. Anyanwu AC, Adams DH. Etiologic classification of degenerative mitral valve disease: Barlow’s disease and fibroelastic deficiency. Semin Thorac Cardiovasc Surg 2007;19:90e96. 12. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e1ee142. 13. Chan V, Ruel M, Hynes M, Chaudry S, Mesana TG. Impact of mitral annular calcification on early and late outcomes following mitral valve repair of myxomatous degeneration. Interact Cardiovasc Thorac Surg 2013;17:120e125.
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