Background
Severe mitral annular calcification causing degenerative mitral stenosis (DMS) is increasingly encountered in patients undergoing mitral and aortic valve interventions. However, its clinical profile and natural history and the factors affecting survival remain poorly characterized. The goal of this study was to characterize the factors affecting survival in patients with DMS.
Methods
An institutional echocardiographic database was searched for patients with DMS, defined as severe mitral annular calcification without commissural fusion and a mean transmitral diastolic gradient of ≥2 mm Hg. This resulted in a cohort of 1,004 patients. Survival was analyzed as a function of clinical, pharmacologic, and echocardiographic variables.
Results
The patient characteristics were as follows: mean age, 73 ± 14 years; 73% women; coronary artery disease in 49%; and diabetes mellitus in 50%. The 1- and 5-year survival rates were 78% and 47%, respectively, and were slightly worse with higher DMS grades ( P = .02). Risk factors for higher mortality included greater age ( P < .0001), atrial fibrillation ( P = .0009), renal insufficiency ( P = .004), mitral regurgitation ( P < .0001), tricuspid regurgitation ( P < .0001), elevated right atrial pressure ( P < .0001), concomitant aortic stenosis ( P = .02), and low serum albumin level ( P < .0001). Adjusted for propensity scores, use of renin-angiotensin system blockers ( P = .02) or statins ( P = .04) was associated with better survival, and use of digoxin was associated with higher mortality ( P = .007).
Conclusions
Prognosis in patients with DMS is poor, being worse in the aged and those with renal insufficiency, atrial fibrillation, and other concomitant valvular lesions. Renin-angiotensin system blockers and statins may confer a survival benefit, and digoxin use may be associated with higher mortality in these patients.
Mitral annular calcification (MAC) is a marker for atrial fibrillation, atherosclerosis, and higher stroke risk. However, calcific or degenerative mitral stenosis (DMS) resulting from severe MAC continues to be an ill-defined disease process with frequent occurrence in the aging population. It is being increasingly encountered in elderly patients undergoing mitral and aortic valve interventions. However, outcomes and factors affecting outcomes in patients with DMS are not well known. Observational studies have suggested multiple potential targets to modify the disease process in calcific aortic stenosis, which shares pathogenetic mechanisms with DMS. We investigated the clinical associations and outcome determinants in a large cohort of well-characterized patients with DMS.
Methods
Patient Population
This retrospective cohort study was conducted at a large university medical center. The study was approved by the institutional review board, which waived the requirement to obtain patient consent. The echocardiographic database was electronically searched for the period from June 1995 to June 2011 for patients with DMS (this is a searchable field in our database) or mitral stenosis plus severe MAC and mean mitral valve gradient ≥2 mm Hg. Those classified as having rheumatic mitral stenosis and those noted to have commissural fusion were not included. Diagnosis of severe MAC in our laboratory was based on modified Framingham criteria of echodense structure with associated acoustic shadowing, at the junction of the atrioventricular groove and the anterior and posterior mitral leaflet with a thickness of ≥5 mm on M-mode or two-dimensional echocardiography. The severity of MAC was qualitatively assessed in the parasternal long-axis view, the parasternal short-axis view at the mitral valve level, and the apical two- or four-chamber view, as marked echodensity with extension into the anterior or posterior leaflets. Commissural fusion was assessed in the parasternal short-axis view at the mitral valve level. Although our categorization of MAC was created before the Multi-Ethnic Study of Atherosclerosis, it was fairly similar. Duplicate records were removed, yielding a cohort of 1,004 patients. Comprehensive chart reviews were performed, and clinical, echocardiographic, and pharmacologic data were compiled. Mortality data were compiled primarily through the use of the Social Security Death Index, supplemented by chart review.
Clinical Variables
Hypertension was defined as blood pressure > 140/90 mm Hg or a history of hypertension and the use of antihypertensive medications. Diabetes mellitus was defined as fasting blood glucose ≥ 126 mg/dL or being on a regimen of antidiabetic medications. Renal insufficiency was defined as serum creatinine ≥ 2 mg/dL. Also, the stage of renal dysfunction (chronic kidney disease [CKD] stages 1–5) was determined on the basis of glomerular filtration rate, calculated using the Cockcroft-Gault equation. Coronary artery disease was deemed to be present if any of the following were present: a history of angina pectoris, myocardial infarction, positive stress test results, angiographic evidence of coronary artery disease, coronary intervention, coronary artery bypass surgery, or presence of significant Q waves on the surface electrocardiogram.
Pharmacologic Data
Pharmacotherapy at the time of echocardiography was recorded. This was broadly categorized as using or not using aspirin, β-blockers, calcium channel blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), digoxin, and statins.
Echocardiographic Data
All patients had previously interpreted two-dimensional echocardiographic examinations by a level III–trained echocardiographer according to standard guidelines. Left ventricular (LV) ejection fraction was assessed either by planimetry or visually and entered into a database at the time of the examination.
There are no standard criteria for grading DMS, because the pressure half-time method–derived valve area is not validated for DMS. Hence, it was graded on the basis of mean transmitral gradient (MG) as mild or grade 1 for MG 2 to 5 mm Hg, moderate or grade 2 for MG 6 to 8 mm Hg, and severe or grade 3 for MG ≥ 9 mm Hg, somewhat arbitrarily. Also, because of significant acoustic shadowing, mitral valve area assessment by planimetry was not performed in these patients. Figure 1 shows representative images of different grades of DMS.
Aortic stenosis in our laboratory was defined by a mean transaortic Doppler gradient > 15 mm Hg or a peak transaortic velocity > 2 m/sec, and severity was graded as mild (MG 15–25 mm Hg or V2 2–2.9 m/sec), moderate (MG 25–40 mm Hg or V2 3–3.9 m/sec), or severe (MG > 40 mm Hg or V2 > 4 m/sec).
Mitral regurgitation was graded qualitatively by color Doppler flow mapping. Mitral regurgitation severity was assessed by vena contracta width and jet area in multiple views and by related hemodynamic consequences, by the interpreting echocardiographer in accordance with American Society of Echocardiography guidelines. Similarly, tricuspid regurgitation was also graded qualitatively by Doppler color flow imaging.
Right atrial pressure was estimated from the diameter of inferior vena cava from the subcostal view. High right atrial pressure was defined as inferior vena cava diameter > 2.1 cm and <50% variation during inspiration.
Mortality Data
The end point of the study was death due to any cause. Mortality data were obtained from the National Death Index, supplemented by chart review.
Statistical Analysis
The data were imported into StatView version 5.01 (SAS Institute, Cary, NC) for statistical analysis. Group comparisons were made using Student’s t test for continuous variables and the χ 2 test for categorical variables. Survival analysis was performed using various statistical tools, such as Kaplan-Meier analysis and Cox regression models, as discussed later in the “Results” section. In view of nonrandomized assignment of various pharmacologic agents, we performed propensity score analysis to reduce the effect of treatment bias. The effect of a particular therapy on survival was analyzed by adjusting for the propensity score for a particular therapy developed by logistic regression analysis of the variables predicting that treatment. Then the survival analysis by Cox regression analysis was adjusted for the propensity score to reduce the effect of treatment bias. Separate propensity scores were developed for different pharmacologic agents. Propensity score analysis has been shown to reduce bias by about 85%. P value < .05 were considered to indicate statistical significance.
Results
Baseline Patient Characteristics
Baseline patient characteristics are shown in Table 1 . The mean age was 73 ± 14 years, 73% were women, 59% were Caucasian, and 21% were Hispanic. Coronary artery disease was present in 49%, diabetes mellitus in 50%, and chronic renal insufficiency in 37%. The prevalence rates of stages 1, 2, 3, 4, and 5 CKD were 12%, 19%, 36%, 20%, and 13%, respectively. The mean mitral diastolic gradient was 4.1 ± 1.7 mm Hg, and the mean grade of mitral stenosis severity was 1.2 ± 0.5 on a scale of 0 to 3. DMS was mild in 78%, moderate in 14%, and severe in 8% of the patients. The mean heart rate for the entire group was 75 ± 13 beats/min, with no difference among those with mild, moderate, or severe DMS. None of the subjects had a resting heart rate > 100 beats/min.
| Variable | Value |
|---|---|
| Age (years) | 73 ± 14 |
| Female gender | 73% |
| Heart rate (beats/min) | 75 ± 13 |
| Hypertension | 85% |
| Diabetes mellitus | 50% |
| Coronary artery disease | 49% |
| History of percutaneous intervention | 11% |
| History of coronary bypass surgery | 21% |
| History of aortic valve replacement | 14% |
| Atrial fibrillation | 28% |
| Chronic renal insufficiency | 37% |
| Dialysis | 24% |
| Current smoker | 9% |
| Smoking history | 39% |
| Statin use | 44% |
| β-blocker use | 56% |
| Calcium channel blocker use | 38% |
| ACE inhibitor/ARB use | 49% |
| Aspirin use | 42% |
| Digoxin use | 10% |
| Serum calcium level (mmol/L) | 2.2 ± 0.23 |
| Serum creatinine level (mg/dL) | 2.16 ± 2.3 |
| Serum phosphorus level (mmol/L) | 1.26 ± 0.54 |
| Serum albumin level (g/dL) | 3.38 ± 0.8 |
| LV ejection fraction (%) | 65 ± 14 |
| MG (mm Hg) | 4.1 ± 1.7 |
| LV end-diastolic dimension (cm) | 4.7 ± 2.3 |
| LV end-systolic dimension (cm) | 2.9 ± 0.8 |
| LV posterior wall thickness (cm) | 1.2 ± 0.2 |
| Ventricular septal thickness (cm) | 1.3 ± 0.3 |
| Left atrial dimension (cm) | 4.5 ± 0.8 |
| 3 or 4+ mitral regurgitation | 13% |
| 3 or 4+ tricuspid regurgitation | 8% |
| Moderate or severe aortic stenosis | 9% |
| Increased right atrial pressure | 45% |
| Pulmonary artery systolic pressure ≥ 40 mm Hg | 63% |
| Pulmonary artery systolic pressure ≥ 60 mm Hg | 9% |
| Peak aortic velocity (m/sec) | 2.2 ± 1.1 |
| Tricuspid regurgitation velocity (m/sec) | 2.9 ± 1.3 |
Survival Patterns and Effect of DMS Severity
Over a mean follow-up period of 3.5 ± 2.8 years, there were 549 deaths, with 1-, 5-, and 10-year survival rates of 78%, 47%, and 25%, respectively. Higher DMS grades were associated with lower 1- and 5-year survival ( P = .02). Survival as a function stenosis severity is shown in Figure 2 .
Clinical Variables Associated with Survival
Univariate clinical associations of poor survival included greater age ( P < .0001), atrial fibrillation ( P = .0009), and renal insufficiency ( P = .004) ( Figures 3A and 3B ). Figure 3C shows survival of patients with DMS as a function of CKD stage. The 5-year mortality rates for CKD stages 1 to 5 were 32%, 44%, 48%, 78%, and 45%, respectively ( P < .0001). The patients with stage 5 CKD were all on dialysis, which may explain better survival compared with those with stage 4 disease. These were independent clinical factors associated with survival after adjusting for gender, race, smoking, diabetes mellitus, and coronary artery disease. Race, smoking, diabetes mellitus, and coronary artery disease were not associated with survival.
Echocardiographic Variables Associated with Survival
Among the echocardiographic variable, lower LV ejection fraction ( P = .0003), larger LV dimension ( P = .02), larger left atrial diameter ( P < .0001), higher transmitral gradient ( P = .005), higher aortic stenosis grade (moderate to severe; mean transaortic gradient > 25 mm Hg) ( P = .02; Figure 4 A), higher grade of mitral or tricuspid regurgitation ( P < .0001; Figures 4B and 4C ), and higher right atrial pressure ( P < .0001; Figure 4 D) were associated with lower survival ( Table 2 ). All these individual variables were independently associated with survival after adjusting for all the clinical variables.
| Variable | 95% CI | χ 2 | P |
|---|---|---|---|
| LV ejection fraction (per 10%) | 0.81–0.90 | 13.2 | .0003 |
| Left atrial diameter (per 5 mm) | 1.79–3.25 | 22.6 | <.0001 |
| LV end-diastolic diameter (per 5 mm) | 1.02–1.33 | 5.1 | .024 |
| LV end-systolic diameter (per 5 mm) | 1.02–1.28 | 5.4 | .02 |
| MG (per mm Hg) | 1.02–1.12 | 7.8 | .005 |
| Mitral regurgitation grade (per 1 grade) | 1.16–1.40 | 26.8 | <.0001 |
| Aortic stenosis grade (per 1 grade) | 1.02–1.21 | 5.4 | .02 |
| Tricuspid regurgitation grade (per 1 grade) | 1.19–1.48 | 25.5 | <.0001 |
| Elevated right atrial pressure | 1.30–1.71 | 33.5 | <.0001 |
| Systolic wall motion abnormality | 1.22–1.78 | 15.8 | <.0001 |
Serum Biochemical Variables Associated with Survival
Among the routine biochemical variables we examined, low serum albumin ( P < .0001; Figure 5 ) and high serum creatinine ( P = .004) were associated with reduced survival by both univariate and multivariate analysis adjusted for the clinical variables.
Pharmacologic Variables Associated with Survival by Propensity Score Analysis
In view of nonrandomized assignment of various pharmacologic agents, we performed propensity score analysis to reduce the effect of treatment bias, as described in the section on statistics. Treatment with an ACE inhibitor or ARB was predicted by the presence of hypertension, diabetes mellitus, and lower LV ejection fraction. Adjusted for the propensity score, Cox regression analysis showed that therapy with an ACE inhibitor or ARB was predictive of better survival (hazard ratio, 0.65; 95% CI, 0.79–0.96; P = .02). In a similar fashion, statin therapy was predicted by the presence of coronary artery disease, diabetes mellitus, hypertension, and lower ejection fraction. Adjusted for propensity score, treatment with a statin was associated with better survival (hazard ratio, 0.81; 95% CI, 0.67–0.99; P = .04). Digoxin therapy was predicted by the presence of atrial fibrillation, greater age, and absence of renal insufficiency and hypertension. The adjusted for propensity score developed from these variables, therapy with digoxin was associated with higher mortality (hazard ratio, 1.51; 95% CI, 1.22–2.04, P = .007). Use of calcium channel blockers, β-blockers, and aspirin had no impact on survival.
Comprehensive Multivariate Model of Survival
A comprehensive multivariate model of survival was constructed to provide approximate contributions of various factors to mortality in a comprehensive fashion. First, we created a stepwise regression model of survival incorporating all the clinical variables, including age, gender, race, current smoking, hypertension, diabetes mellitus, coronary artery disease, renal insufficiency, and atrial fibrillation. Age (χ 2 = 38.1, P < .0001), hypertension (χ 2 = 6.5, P = .011), renal insufficiency (χ 2 = 18.4, P < .0001), and atrial fibrillation (χ 2 = 9.5, P = .002) were significant independent predictors of survival in this model, with a global Wald χ 2 statistic of 70.3. Smoking and diabetes remained in the model, with χ 2 values of 3.5 and 3.4, respectively, adding significantly to the overall model. Adding serum albumin to the model increased the global χ 2 statistic to 137.9, with 78.8 attributable to serum albumin. The final stepwise model adding echocardiographic variables, including DMS grade and MG, yielded a global χ 2 statistic of 165.8. However, DMS grade and MG failed to remain in the final model. Among the pharmacologic variables, only treatment with an ACE inhibitor or ARB added incrementally, resulting in a global χ 2 statistic of 179.0, as shown in Table 3 .
