Background
Mitral annular calcification (MAC) is common in chronic kidney disease. It is associated with cardiovascular events and can cause valvular dysfunction, but it has not been systematically characterized. The aim of this prospective study was to assess the prevalence and distribution of MAC, its effects on leaflet motion, and its association with mitral stenosis and mitral regurgitation (MR) in a hemodialysis population.
Methods
Echocardiograms were obtained in 75 consecutive hemodialysis outpatients. MAC extent and distribution were graded semiquantitatively using two-dimensional and three-dimensional echocardiography. Associations with the presence and severity of mitral stenosis and MR were explored.
Results
The mean age was 60 ± 14 years; 60% were men, and 87% were African American. MAC was present in 64% (moderate to severe in 48%). Calcium extended more than halfway onto the leaflet in 37% and beyond the annulus in 40%. Leaflet motion was restricted in 37%. Mitral stenosis was present in 28%, and the extent of calcification was associated with mean mitral valve gradient ( P < .0001). MR was prevalent (present in 81%) but was severe in none. The severity of MAC was greater in patients with moderate MR than in those with no or mild MR ( P = .04). Three-dimensional analysis suggested an uneven distribution of annular calcium; the middle and lateral anterior segments were less often calcified than the anterior-medial or posterior segments. Calcification in any annular segment was highly associated with restricted motion of the attached leaflet segment.
Conclusions
MAC is common and often extensive in hemodialysis patients. Calcium may be unevenly distributed among the annular segments. When present, annular calcification reduces the angle of leaflet opening and can cause valvular dysfunction.
It is well established that vascular and valvular calcification increase with advancing age. Mitral annular calcification (MAC) is associated with atherosclerotic risk factors, prevalent coronary artery disease, and cardiovascular events. Cardiac calcification is also associated with coronary calcium score by computed tomography and severe conduction disease. Abnormalities of mineral metabolism (calcium and phosphorous) in chronic kidney disease promote the accumulation of calcium in various cardiovascular structures, including the mitral annulus. Conversely, severe MAC has been shown to predict chronic kidney disease.
Cardiac calcification can also impair valve function. Although calcific aortic stenosis is a well-recognized clinical entity, there is less awareness of MAC as a cause of mitral valve dysfunction. MAC can cause mitral stenosis (MS) or mitral regurgitation (MR) and is associated with progressive gradients across the mitral valve. Precisely how annular calcification impairs valve function is poorly understood. Possible mechanisms include (1) distortion of annular shape and motion, (2) restriction of leaflet motion, and (3) impaired function of the subvalvular apparatus.
The primary aim of this study was to systematically examine how calcium is laid down in the mitral annulus and how it affects valve function. We studied a sample of hemodialysis patients because of the high prevalence of MAC in this group.
Methods
A total of 75 unselected outpatients on chronic hemodialysis were recruited between August 2010 and March 2012. The study was approved by the institutional review board at Albert Einstein Medical Center, and informed consent was obtained from all subjects. Patients were ≥18 years of age and had received hemodialysis for ≥6 months before study inclusion. Patients with preexisting mitral valve disease were excluded. Demographic and clinical data were obtained, including age, gender, race, height, weight, smoking history, duration of hemodialysis, and history of diabetes, hypertension, dyslipidemia, stroke, congestive heart failure, or coronary artery disease.
Doppler echocardiography was performed on a nondialysis day to avoid any hemodynamic changes that may occur on the day of dialysis. Standard measurements were made in accordance with American Society of Echocardiography recommendations using a Philips iE33 system (Philips Medical Systems, Andover, MA) and an X3-1 or X5-1 transducer. These included left ventricular ejection fraction (visual estimate), wall thickness, left atrial size (anteroposterior dimension in parasternal long-axis view), and diastolic parameters. MS was graded according to mean transvalvular gradient as absent, mild (mean gradient at rest, 3–4 mm Hg), moderate (mean gradient at rest, 5–10 mm Hg), or severe (mean gradient at rest > 10 mm Hg). Furthermore, mitral valve area was calculated using the continuity equation for those with resting gradients ≥ 5 mm Hg. MR was graded according to color Doppler jet area as absent, mild (<20% of left atrial area), moderate, or severe (>40% of left atrial area). In addition, effective regurgitant orifice area was calculated using the proximal isovelocity surface area (PISA) method in those with measurable PISA radii.
Specific measurements of cardiac calcification were made in all subjects. First, we applied a semiquantitative global calcium score ( Table 1 ), which accounts for calcium in the aortic root and valve, the mitral valve and annulus, and the submitral apparatus. This score has been previously shown to correlate with global cardiac calcium as measured by computed tomography. We then separately evaluated the mitral valve leaflets and annulus, noting (1) the presence or absence of annular calcium, (2) the severity of calcification (absent, mild [<5 mm in any direction], moderate to severe [≥5 mm in any direction]), (3) the presence or absence of calcium protruding beyond the normal limits of the annulus, (4) the extension of calcium onto the mitral leaflets (halfway or greater vs less than halfway), and (5) restriction of leaflet motion (none, mild [leaflet excursion near normal], moderate [leaflet tip excursion 5–10 mm from end-systole to end-diastole], or severe [leaflet tip excursion < 5 mm]). Figure 1 and Videos 1 to 4 (available at www.onlinejase.com ) illustrate these various features.
| Feature | Points |
|---|---|
| Posterior mitral annulus (by thirds) | None = 0 |
| One third calcified = 1 | |
| Two thirds calcified = 2 | |
| Three thirds calcified = 3 | |
| Posterior mitral leaflet restriction | No = 0 |
| Yes = 1 | |
| Anterior mitral annular involvement | No = 0 |
| Yes = 1 | |
| Anterior mitral leaflet restriction (<10-mm valve opening on the long-axis view) | No = 0 |
| Yes = 1 | |
| Mitral valve calcification | No = 0 |
| Mild = 1 | |
| More than mild = 2 | |
| Subvalvular mitral apparatus calcification | No = 0 |
| Yes = 1 | |
| Aortic valve calcification | None = 0 |
| Nodule(s) in fewer than three leaflets = 1 | |
| Nodules in three leaflets, nonrestrictive = 2 | |
| Leaflet restriction = 3 | |
| Aortic root calcification | No = 0 |
| Yes = 1 | |
| Total possible score | 13 |
Three-dimensional echocardiography was performed in each patient. Full-volume data sets were acquired from the parasternal position. Slices were then made through the medial, middle, and lateral thirds of the mitral valve using a parasternal short-axis view for guidance ( Figure 2 , Videos 5 to 7 ; available at www.onlinejase.com ). The resultant parasternal long-axis images were used to assess distribution of any calcium deposits and leaflet motion. For each parasternal slice, we recorded (1) the presence or absence of calcium in both the anterior and posterior mitral annulus, (2) the protrusion of calcium beyond the normal limits of the annulus, and (3) the extension of calcium onto the mitral leaflets (halfway or greater vs less than halfway). In addition, the maximal angle of opening between the leaflet and the mitral annulus was recorded for each leaflet in each slice ( Figure 3 ). Finally, tenting area and tenting height were measured in midsystole for each slice ( Figure 4 ).
Statistical Analyses
Data for continuous variables are presented as mean ± SD, and categorical variables are presented as numbers and percentages. Baseline characteristics are presented by the presence or absence of calcium, and the presence or absence of MS and MR. Student’s t tests, χ 2 tests, and odds ratios were used to compare the degrees of MS and MR, the angle of leaflet opening, and tenting height and area by various measures of calcification (extent, protrusion beyond the annulus, and extension onto the leaflets). Correlation coefficients were calculated between calcium deposition (severity) and years on dialysis. Logistic regression analyses were used to identify univariate predictors of leaflet motion, and parsimonious modeling construction (forward, backward, and mixed) was used to identify the best predictors of leaflet motion in multivariate analyses. P values < .05 were considered statistically significant in advance. Statistical analyses were performed using JMP version 9.0 (SAS Institute Inc., Cary, NC).
Results
Baseline Characteristics
Baseline characteristics are displayed in Table 2 . The mean age of the group was 60 ± 14 years; 60% were men, and 87% were African American. Annular calcium was present in 22 of 30 women (73%) and 26 of 45 men (58%). Among those with annular calcification, age was significantly greater, as was the number of years on hemodialysis. This group also had a greater prevalence of prior stroke and heart failure. History of stroke was greater among those with any degree of MS, and MS was more prevalent among ever smokers than never smokers. Other associations are more difficult to explain, such as less diabetes and less dyslipidemia among those with moderate MR compared with those with no or mild MR.
| Variable | All patients | Calcium absent ( n = 27) | Calcium present ( n = 48) | P | MS absent ( n = 54) | MS present ( n = 21) | P | MR none or mild ( n = 64) | MR moderate ( n = 11) | P |
|---|---|---|---|---|---|---|---|---|---|---|
| Age (y) | 60 ± 14 | 55 ± 13 | 63 ± 13 | .01 | 61 ± 14 | 59 ± 12 | NS | 60 ± 14 | 63 ± 15 | NS |
| Men | 45 (60%) | 19 (70%) | 26 (54%) | NS | 32 (59%) | 13 (62%) | NS | 39 (61%) | 6 (55%) | NS |
| Race | ||||||||||
| Black | 65 (87%) | 26 (96%) | 39 (81%) | NS | 50 (93%) | 15 (71%) | .03 | 55 (86%) | 10 (91%) | NS |
| White | 7 (9%) | 1 (4%) | 6 (13%) | 2 (4%) | 5 (24%) | 7 (11%) | 0 | |||
| Hispanic | 3 (4%) | 0 | 3 (6%) | 2 (4%) | 1 (5%) | 2 (3)% | 1 (9%) | |||
| Ever smokers | 21 (28%) | 5 (18%) | 16 (33%) | NS | 11 (20%) | 10 (48%) | .01 | 16 (25%) | 5 (45%) | NS |
| Diabetes | 42 (57%) | 15 (56%) | 27 (57%) | NS | 28 (52%) | 14 (70%) | NS | 39 (62%) | 3 (27%) | .04 |
| History of stroke | 14 (19%) | 2 (7%) | 12 (26%) | .05 | 7 (13%) | 7 (35%) | .03 | 10 (16%) | 4 (36%) | NS |
| Dyslipidemia | 36 (48%) | 14 (53%) | 22 (46%) | NS | 28 (52%) | 8 (38%) | NS | 34 (53%) | 2 (18%) | .04 |
| Hypertension | 70 (92%) | 25 (93%) | 45 (94%) | NS | 52 (96%) | 18 (86%) | NS | 59 (92%) | 11 (100%) | NS |
| History of congestive heart failure | 25 (34%) | 5 (19%) | 20 (43%) | .03 | 15 (28%) | 10 (50%) | .07 | 21 (33%) | 4 (36%) | NS |
| Coronary artery disease | 27 (37%) | 7 (26%) | 20 (43%) | NS | 17 (31%) | 10 (53%) | NS | 22 (35%) | 5 (45%) | NS |
| Total cholesterol | 152 ± 47 | 157 ± 40 | 149 ± 52 | NS | 151 ± 51 | 155 ± 36 | NS | 157 ± 48 | 130 ± 39 | NS |
| Low-density lipoprotein | 81 ± 39 | 88 ± 36 | 76 ± 42 | NS | 81 ± 42 | 79 ± 30 | NS | 85 ± 42 | 64 ± 22 | NS |
| High-density lipoprotein | 46 ± 14 | 48 ± 19 | 45 ± 10 | NS | 46 ± 16 | 47 ± 10 | NS | 48 ± 15 | 38 ± 7 | .02 |
| Triglycerides | 124 ± 67 | 122 ± 61 | 125 ± 72 | NS | 123 ± 62 | 128 ± 84 | NS | 125 ± 67 | 119 ± 68 | NS |
| Ejection fraction | 58 ± 12 | 59 ± 13 | 58 ± 12 | NS | 60 ± 14 | 56 ± 8 | NS | 59 ± 12 | 54 ± 13 | NS |
| Years on dialysis | 3.9 ± 2.5 | 2.3 ± 1.8 | 5.3 ± 2.2 | <.0001 | 3.2 ± 2.1 | 5.7 ± 2.7 | .008 | 3.8 ± 2.6 | 4.2 ± 1.6 | NS |
| Body mass index (kg/m 2 ) | 28 ± 7.2 | 27 ± 7.1 | 28 ± 7.3 | NS | 28 ± 7.9 | 27 ± 5.3 | NS | 28 ± 7.7 | 27 ± 3.7 | NS |
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