Mitral Annular Calcification as a Cause of Mitral Stenosis
Introduction
The mitral annulus is a ring-like fibrous structure by which the leaflets of the mitral valve attach to the myocardium. Over time, noninflammatory degenerative changes, referred to as mitral annular calcification (MAC), may develop. MAC is a process involving calcium and lipid deposition and may interfere with the normal functioning of the mitral apparatus.1,2 Although MAC has been frequently reported as a cause of mitral regurgitation,2,3 usually of no clinical significance, it has rarely been described as a cause of clinically significant mitral stenosis. We report two symptomatic patients who presented with congestive heart failure caused by mitral stenosis secondary to advanced MAC and provide a review of the literature concerning this clinical entity.
Case Presentations
Patient 1
An 82-year-old woman with a history of hypertension developed acute coronary heart disease. Cardiac catheterization demonstrated significant multivessel coronary artery disease and left main coronary artery disease for which she underwent urgent coronary artery bypass graft (CABG) surgery. MAC was incidentally found at that time. The patient did well after CABG surgery with no recurrence of symptoms. She had normal cardiac functional capacity for several years. Seven years after CABG surgery, the patient presented to the emergency department because of gradual-onset dyspnea on exertion for several days. She reported no chest pain or palpitations and she did not have ankle swelling. Physical examination revealed fine crackles at the bases of both lungs, an accentuated S1, a grade 2/6 systolic murmur over the left lower sternal border, and an early diastolic sound followed by an early diastolic rumble best appreciated at the apex of the left ventricle. The electrocardiogram was unremarkable. A transthoracic echocardiogram (TTE) revealed mild, left ventricular concentric hypertrophy without segmental wall motion abnormality and an ejection fraction of 60%. The patient’s left atrium was mildly dilated. The mitral valve annulus was severely calcified with both anterior and posterior leaflet involvement (Figure 1A). While the mitral orifice was stenotic, the movement of leaflet tips was not restricted. There was a 12.5-mm Hg maximum diastolic resting pressure gradient across the mitral valve (Figure 1B) with a valve area of 0.97 cm2. The patient’s right atrium and right ventricle appeared normal. Moderate mitral and mild aortic regurgitations were seen on color Doppler flow mapping.
Parasternal long-axis echocardiogram of patient 1 showing advanced annulus calcification (A), which resulted in mitral stenosis as documented by the recorded transmitral Doppler flow gradients of 12.5 mm Hg (B). The patient was treated with furosemide 40 mg daily. Her symptoms subsided within 5 days and then she was discharged. Outpatient follow-up within 1 week demonstrated a resolution of symptoms and no evidence of congestive heart failure. Cardiac examination revealed the presystolic component of the diastolic rumble. Furosemide was discontinued and the patient remained asymptomatic on a low-sodium diet.
Patient 2
An 85-year-old woman with hypertension presented to the emergency department because of recurrent episodes of chest pain. A TTE demonstrated an ejection fraction of 65%, mild pulmonary arterial hypertension (35 mm Hg), moderate MAC with leaflet involvement, and mitral regurgitation. Cardiac catheterization did not reveal significant coronary artery disease. The patient’s chest pain subsided spontaneously and she was discharged. Approximately 6 years later, she started to have episodes of exertional dyspnea which became more frequent within a few months. The patient was admitted to the hospital because of those symptoms. Physical examination was significant for a grade 3/6 holosystolic murmur that was best heard at the left lower sternal border radiating to the left axilla. A diastolic rumble was audible at the apex; however, an opening snap was not appreciated. Findings from the lung examination were unremarkable. A cardiac stress test was negative for ischemia. A repeat echocardiogram revealed an ejection fraction of approximately 60% and extensive calcification of the mitral annulus which was also involving the leaflets of the valve and causing severe mitral stenosis (Figure 2); the tips were preserved. The echocardiogram also confirmed a moderate mitral regurgitation with mildly elevated pulmonary artery pressure (35 mm Hg).
Apical four-chamber view of patient 2’s heart. Note the heavy calcifications at both the anterior and posterior aspects of the mitral annulus (arrows). Despite being treated with intravenous furosemide 40 mg twice a day, the patient’s condition did not improve and she remained in heart failure. While repeat cardiac catheterization did not reveal significant coronary artery disease, the hemodynamic study of the left ventricle demonstrated a diastolic resting mean pressure gradient of 11 mm Hg across the mitral valve, with a valve area of 0.87 cm2. The patient had a bioprosthetic mitral valve replacement which dramatically improved her symptoms. There was no clinical evidence of congestive heart failure on follow-up examination 2 weeks after discharge. The pathology report of the excised annulus and valve demonstrated degenerative changes of the leaflets with extensive calcification of the annulus.
Discussion
MAC mainly affects elderly women and has no ethnic predilection. In a study published in 1982, Lewandowski and Winsberg4 retrospectively reviewed the M-mode and 2-dimensional echocardiograms of 3254 patients without evidence of rheumatic heart disease who were admitted to their hospital over a 2-year period and estimated the incidence of MAC to be 6.3%. In a study published in 1970, Pomerance1 reported that the overall incidence in patients over age 50 years on autopsy was 8.5%. In a retrospective study published in 2008 by Willens et al,5 echocardiograms of 857 patients between ages 40 and 75 years were reviewed; MAC was a common finding and was detected in 21.1% of the cohort population. In spite of having very similar cellular changes to what is seen in aortic sclerosis4 and sharing common findings with atherosclerosis,1,2,6 MAC is considered an independent process that also differs from the calcification that occurs in rheumatic mitral valve disease.7
The exact pathogenesis is not well understood; however, Shiraki et al8 found significantly higher parathyroid hormone levels in addition to lower vitamin D metabolite levels in patients with MAC as compared with patients without calcification. This has led to speculation that the calcium-metabolism regulating system may play an important role in the pathogenesis of MAC in addition to known mechanical factors.8,9 Patients with MAC usually have no clinical symptoms, but on physical examination the most common sign detected is systolic murmur.10,11 Interestingly, in 1968, Pomerence10 reported MAC as the commonest cardiac abnormality in elderly patients with a systolic murmur. While the exact mechanism of this murmur is not exactly known, it could be related to aortic valve stenosis (since MAC is commonly associated with aortic valve calcification), mitral regurgitation, or a combination of both.10 If it is severe, MAC will form a calcified spur that may lift the posterior leaflet of the mitral valve and cause valvular distortion, which may play a role in mitral incompetence.1,2 In addition, the calcified mitral ring in severe cases of MAC becomes rigid and loses its contractile property. These changes also will result in valvular incompetence; hence, the contractility of the annulus is very important to maintain competent closure of the mitral valve, by significantly reducing the area that needs to be bridged by the mitral leaflets during systole.2,4 However, diastolic rumbles not preceded by opening snaps, as reported in the case patients, have infrequently been described in patients with MAC.
The diastolic murmur found in persons with MAC has been attributed, by some authors, to the flow of the blood over the leaflet which becomes angulated by the calcified lesion.2 MAC has rarely been reported to cause symptomatic mitral stenosis. The prevalence of this complication is not well appreciated. Akram et al12 retrospectively studied the prevalence of annular mitral stenosis in a general population. The authors reviewed 7000 consecutive inpatient and outpatient echocardiograms from a digitally archived database and found that 70 patients had echocardiographic evidence of mitral stenosis. Out of these 70 subjects, 13 (18.5%) had annular mitral stenosis and 57 (81.5%) had rheumatic mitral stenosis. The patients received a diagnosis of annual mitral stenosis if the increased diastolic pressure gradient across the mitral valve was associated with MAC with normal or minimal limitation of leaflet motion and without restriction of the leaflet tips. In the case patients, the physicians made a diagnosis of annular mitral stenosis based on their observation of similar echocardiographic findings as well as the patients’ negative histories of rheumatic heart disease. While in the Akram study, the patients’ symptoms and cardiac functional class were not known, in the case patients, the clinical symptoms were attributed to annular mitral stenosis.12 The Table summarizes the main differences between MAC and rheumatic mitral calcification.
Osterberger et al13 and Hammer et al14 described the hemodynamic changes in patients with severe MAC. Both studies found a diastolic gradient across the mitral valve without actual stenosis of the mitral leaflets. Incomplete relaxation of the annulus during diastole is the main mechanism postulated to explain this pressure difference.13-15 The annulus is a dynamic contractile structure that contributes to the opening of the mitral valve, and hence plays an important role in determining the blood flow during diastole. Tsakiris et al16 reported that, in dogs, the annulus size rapidly decreases at the same time of P-wave deflection on the electrocardiogram, continues decreasing during the whole systole, and then starts to dilate rapidly during the isovolumetric relaxation of the ventricle.16 In their 2002 study, Soeki et al17 reported that subjects with severe MAC had higher mitral inflow velocities because of mitral annular restriction and lower mitral annular velocities due to decreased mitral annular motion and abnormal left ventricular relaxation. They found that the dynamic contractile properties of the annulus are affected by the calcification process, which, presumably, explains their findings with regard to decreased annular motion velocity in severe forms of MAC. In addition to these changes, Muddassir and Pressman18 reported that impaired motion of the anterior mitral leaflet is also an important finding to explain the cause of functional mitral stenosis.
Unfortunately, there is no effective treatment for MAC and there is no established therapy to prevent the occurrence or progression of this aging-related process. However, MAC may act as an alarming sign indicating the presence of other concomitant cardiovascular diseases that may need special attention and management. Atherosclerosis, in particular, is commonly associated with MAC; therefore, the cardiovascular risk factors in patients with atherosclerosis should be carefully evaluated and aggressively modified to reduce the rate of cardiovascular events. In patients who have symptoms of advanced heart failure caused by severe mitral stenosis, mitral valve surgery is the only available option to relieve the obstruction; however, the potential risks and benefits of this intervention should be assessed thoroughly. Mitral valve surgery in this high-risk population has been shown to be associated with high morbidity and mortality. Ventricular rupture, coronary artery injury, atrioventricular disruption, and major bleeding are important fatal complications that may occur during mitral surgery.19,20
Conclusion
The potential of MAC to cause symptomatic obstruction of the mitral valve may not be fully appreciated. As demonstrated in the case patients, persons with MAC may present with symptoms of congestive heart failure secondary to significant obstruction of the mitral valve; however, the leaflet tip movement is frequently preserved. These patients usually have a hemodynamically significant diastolic pressure gradient across the mitral valve with reduced orifice area. Some of these elderly patients may be managed with medical treatment, but in cases of inadequate response, valve replacement would be the last resort to improve symptoms, as was undertaken in patient 2.
The authors report no relevant financial relationships.
Drs. Qaqa, Goldfarb, and Shamoon are from the Department of Cardiology, and Drs. Federici and Suleiman are from the Department of Internal Medicine, Seton Hall University, South Orange, NJ, and St. Michael’s Medical Center, Newark, NJ.
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