Prevalence of submitral (anular) calcium and its correlates in a general population-based sample (the Framingham study)

VALVULAR HEART DISEASE

Its

Prevalence of Submitral (Anular) Calcium and Correlates in a General Population-BasedSample (The Framingham Study) DANIEL D. SAVAGE,

MD, PhD, ROBERT J. GARRISON, MS,

WILLIAM P. CASTELLI, MD, PATRICIA M. McNAMARA,

BA,

SANDRA J. ANDERSON, BS, RN, WILLIAM B. KANNEL, MD, MPH, and MANNING FEINLEIB, MD, Dr PH

To obtain epidemiologic information on submitral calcium, 2,069 subjects in the original Framingham Study cohort (mean age 70 f 7 years) and 3,625 of the offsprlng of the cohort and their spouses (mean age 44 f 10 years) with adequate echocardiograms were evaluated. Submitral calcium was detected In 162 (2.8% ) of the 5,694 subjects; >90% of the subjects with such calcium came from the 40% of

the study group >!i9 years of age. Women were more than twice as likely to have such calcium as men. Age In both sexes, systolic blood pressure in men, and obesity in women were significantly and independently associated wlth submttral calcium. There was a 12-fold excess of atria1 flbrlllation In subjects with (20 of 162,12%) compared with those without (53 of 5,532, 1%) submltral calcium.

Although reports of the clinical consequences of submitral calcium date back to the early 19OOs,relatively scant attention has been given to this pathologic finding until recently. Increased use of echocardiography has helped rekindle interest in such calcium not only because it is often found on routine echocardiography, but also because it can be confused with other echocardiographic findings such as mitral stenosis and pericardial effusion.l12 D’Cruz et al3 have suggested that echo-dense bands posterior to the anterior mitral leaflet (previously called mitral anular calcium) should be called posterior submitral calcium, because this pattern often represents calcium in the posterior submitral angle (between the posterior leaflet and left ventricular [LV] wall and not necessarily the anulus). Some reports have suggested that such calcium may be an important cause of mitral

regurgitation and other types of cardiac dysfunction such as dysrhythmias.4-7 Clinical reports have usually not included control groups to help ascertain whether findings associated with submitral calcium were simply due to the fact that most subjects with such calcium are elderly and thus are more likely to have various disorders. Despite the potential importance of this apparently common problem, virtually no epidemiologic information is available regarding it. Routine echocardiography used in the prospective Framingham Study has permitted prevalence estimates and assessment of associations of submitral calcium in a population-based sample. Methods Study population: At the time of this report, 2,291 of the original Framingham cohort (biennial examination 16) and 3,664 offspring (examination 2) of the original cohort (and offspring spouses) had been studied by M-mode echocardiography. Detailed accounts of the sampling procedure for these populations and the clinical methods employed have been reported elsewhere .sl” Echocardiograms of adequate quality to assess the presence or absence of submitral calcium were obtained in 1,250 women and 819 men in the cohort group (mean age 70 f 7 years [standard deviation], range 59 to 90). Such echocardiograms were obtained in 1,869 women and 1,756 men in the offspring-spouse group (mean age 44 f 10 years, range 17 to 77). Quetelet’s index (weight in kilograms

From the Framingham Heart Study, Epidemiology and Biometry Program, the National Heart, Lung, and Blood institute, Framingham, Massachusetts; the Biometrics Research Branch, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and Evans Research Foundation, Boston University School of Medicine, Boston, Massachusetts. This study was supported in part by contracts NOI-W-92922 and NOl-HV-52971 from the National Institutes of Health, Bethesda, Maryland. Manuscript received December 15, 1982; revised manuscript received January 24, 1983, accepted January 26, 1983. Address for reprints: Daniel D. Savage, MD, Framingham Heart Study, 118 Lincoln Street, Framingham, Massachusetts 01701.

1375

1376

SUBMITRALCALCIUM

25

r

25

MALES

‘;

N=2575

tt: 520

20

z I 2 I!

15

15

9

N= (699)

(567)

(507)

(735)

(446)

(165)

N- (590)

(551)

(490)

(589)

AGE DECADE IN YEARS

divided by height in meters raised to the second power) was used as a measure of obesity. Evidence of overt cardiac disease was considered present if there were Framingham criteria for coronary disease, congestive heart failure, hypertensive heart disease, valvular heart disease (such as rheumatic heart disease), or miscellaneous “other” heart disease (such as cardiomyopathy) . lo Echocardiographic methods: M-mode echocardiograms were performed with the subject in the partial left lateral decubitus position with the head of the bed elevated 30°. Standard techniques were employed with the transducer preferentially in the fourth intercostal space parasternally.ll Spatial orientation was aided by the use of 2-dimensional (2-D) echocardiography in >90% of studies. Recordings were made using an Aerotech 2.25 MHz focused transducer, a Hoffrel201 echocardiograph interfaced with a Honeywell 1856 line scan recorder, and a Jason thermographic printer. A Hoffrel mechanical sector scanner was used for the 2-D echocardiograms. The criterion for posterior submitral calcium was the presence of an echo-dense band located immediately behind the posterior mitral leaflet (and often obscuring it). This band usually showed less motion than the endocardium of the LV posterior wall. LV wall thickness, LV internal dimensions, and left atrial dimension were measured using previously described echocardiographic methods.12 Such measures were considered abnormal if they were greater than the published 95% confidence limits adjusted for age and body size.12 Statistical analyses: Where appropriate, Student’s t test, the chi-square test, or Fisher’s exact test were used to assess statistical significance. To assess the relation of submitral calcium to known risk factors for cardiac disease, univariate and multivariate logistic regression analyses were used. The regression analyses were performed using a maximum likelihood estimation and testing procedure described by Walker and Duncan.13 Each estimated -regression coefficient was tested against the alternate hypothesis that a particular partial coefficient was zero. A test outcome indicated whether the independent variable in question made a statistically significant contribution to the prediction of the dependent variable. The dependent variable used in the multivariate analyses was the presence of posterior submitral calcium, while the independent variables were age, Quetelet’s index, systolic blood pressure, blood sugar, cigarette use, and serum high- and low-density lipoprotein cholesterol levels. These independent

(2751

(80)

FIGURE 1. Prevalence of submitral calcium in Framingham subjects by age and sex.

variables, except for age, which was current, were measured 8 years before echocardiography was performed.

Results Prevalence and association with known cardiovascular risk factors: Posterior submitral calcium was found in 162 (2.8%) of the 5,694 subjects (Fig. 1). Of the subjects with such calcium, 95% came from the 40% of the study group aged >59 years. No subject aged <45 years had submitral calcium. Women were more than twice (119 of 3,119, or 3.8%) as likely to have such calcium as men (43 of 2,575, or 1.7%), but the excess only became significant at >70 years of age when the prevalence became substantial (Fig. 1). Cardiovascular risk factors in subjects with and without submitral calcium are compared in Table I. The results of multivariate analysis to assess the independent correlates of submitral calcium are summarized in Table II. Echocardiographic associations: Subjects with submitral calcium were significantly more likely to have increased LV wall thickness (3-fold excess), LV dilatation (2-fold excess), left atria1 enlargement (3-fold excess), aortic valve calcium (5-fold excess), and reduced aortic valve leaflet motion (4-fold excess) by echocardiography. These findings remained true for age- and body size-adjusted and sex-specific comparisons of subjects with and without submitral calcium. Only 1 of the 289 subjects with mitral valve prolapse had submitral calcium. None of the 5 subjects with prosthetic mitral valves had submitral calcium.

Associations with heart murmurs, dysrhythmias, and conduction abnormalities: The significant as-

sociations of submitral calcium with heart murmurs and atria1 fibrillation (AF) are summarized in Table III. Age-decade and sex-specific comparisons indicated a 3- to 16-fold greater occurrence of submitral calcium in subjects with AF. Four of the 12 subjects,&h AF who had no overt evidence of cardiac or syst&nic disease (that is, “lone AF”) had submitral calcium~determined by echocardiography. Prolonged P-R intervals (>0.20 second), atrioventricular (second- or third-degree) block, bundle branch block, and artificial pacemakers

May 1, 1983

TABLE I

1377

Cardiovascular Risk Factors In Framlngham Cohort Subjects With and Without Submitral Calcium Women

Men Average Cases (n = 26)

Parameter Age Vr) Systolic blood pressure (mm Hg) Quetelet’s index (kg/m*) Cigarette use ( % ) Blood sugar (mgllO0 ml) LDL cholesterol (mg/ 100 ml) HDL cholesterol (mg/l 00 ml)

73’ 152+ 28

SD

Average Noncases (n = 623)

SD

Average Cases (n = 69)

SD

Average Noncases (n = 847)

2;

70 139

2:

77+ 150+

22:

70 139

2:

3

27

3

28+

5

26

4

26 114 142 46

. .

12’

29 40 12

36 43 17

1;: 155 59

..’ z: 16

1:: 142 47

Cases significantly different from noncases: SD = standard deviation.

TABLE II

Volume 5 1

THE AMERICAN JOURNAL OF CARDIOLOGY

l

p
MuMvariate Logistic Regression Standardized Coefficients of Cardiovascular Risk Factors in Framlngham Cohort Subjects With and Without Submitral Calcium

x: 13

:;F 56

+ p
TABLE Ill

Frequency of Atrial Fibrillation and Heart Murmurs in Framingham Cohort Subjects With and Without Submitral Calcium

Regression Coefficients

Parameter

Men In = 649)

Women (n = 916) Finding

ACPWI Systolic blood pressure (mm Hg) Duetelet’s index (kg/m*) Q&Mtt~ . (%) (mg/lOO ml) LM cholesterol (mg/ 100 ml) HDL cholesterol &no/ 100 ml)

0.42’ 0.50+ 0.20

0.40

-0.14 0.08

0.10 0.14

0.00

0.18

0.05

0.06

SD

AF Systolic murmurs Apical holosystolic Basilar crescendo-decrescendo LGrade 3 Diastolic murmurs Apical (mitral) Left sternal border (aortic)

Percent of Subjects With Submitral Calcium Who Had the Finding*

Percent of Subjects Without Submitral Calcium Who Had the Finding

12 (20)+

1 (53)

12 (16)+ 29 (38)+

4 (69) 8 (150)

37 (43)Z .

26 (115)

1.5 (2)9 3 (4Y

0.4 (7) 0.6 (11)

Numbers in parentheses represent absolute numbers of subjects with each finding. Associations of the findings with submitral calcium remained true for age- and sex-specific comparisons. + p <0.0001. + p
i$;zl. P

.

were no more common in subjects without submitral calcium.

with than in those

Discussion This report documents a steep age-dependent gradient of prevalence of submitral calcium in a free-living population-based sample. This is consistent with clinical reports which have only rarely reported submitral calcium in subjects under age 50.4,1p17 The 2-fold excess of submitral calcium in women versus men in the current report is also similar to that reported in clinical studies.**16917 This excess in women is not simply due to women living longer than the men since age-decade specific comparisons in the present study also show this excess. Some controversy exists regarding whether the echo-dense band behind the posterior mitral leaflet always represents calcium.* Joyner et all8 have demonstrated good correlation of the echocardiographic findings with surgery and necropsy findings of calcium even when there was no radiographically demonstrable calcium. Gabor et al2 found excellent correlation be-

echocardiographic and fluoroscopic findings using an image intensifier. The association of submitral calcium with systemic arterial hypertension in the present study has also been noted in clinical studies.2~4~16*1g~20 Systemic hypertension and aortic stenosis (evidence of which was also prominent in the present study) are both associated with increased LV systolic pressure. This increased pressure might be expected to cause increased stress to be transferred to the mitral anulus by way of the mitral valve leaflets, as outlined by Fulkerson et al.* The association of submitral calcium with systolic murmurs is likely to be the result of multiple factors. First, the association with systolic ejection murmurs (especially at the base and in conjunction with aortic valvular calcium and decreased leaflet motion by echocardiography) suggests a link with aortic valvular stenosis. This association has been found in reported tween

1378

SUBMITRAL CALCIUM

clinica12y4and autopsylsJ6 series. Alternatively, aortic valve calcium and submitral calcium may occur in parallel as part of a generalized degenerative process with neither necessarily predisposing in a causal way to the other. The association of submitral calcium with systolic murmurs believed to be mitral in origin suggests another factor which may accelerate such calcium. Abnormal or increased mitral valve motion may result in anular stresses and accelerate degenerative changes there.4 In their clinical series of 80 subjects with submitral calcium, the average age of 11 subjects who also had mitral valve prolapse was > 10 years less than the age of those without prolapse (64 versus 75 years).4 Bulkley et al2l found that in patients with caged-ball mitral valve replacement, progressive submitral calcification could develop within 44 months of mitral valve replacement. Another explanation for mitral murmurs associated with submitral calcium in the present study is that these murmurs may have been caused by the submitral calcium. Pomerancelg found that systolic murmurs were 3 times more common when severe submitral calcium distorted the posterior mitral cusps than when submitral calcium was slight or moderate and without mitral valve distortion. In another report, Pomerance22 reported postmortem findings in 173 patients >7O years who had systolic murmurs. Seventy patients (41%) had submitral calcium as the sole or predominant cardiac lesion. Although several reports2p4*23y24 of submitral calcium have prominently featured conduction abnormalities, these studies have usually not included control groups. One study that did include a large control group revealed that only right bundle branch block was significantly more common in subjects with submitral calcium.14 The lack of a significant association of conduction abnormalities in the present study suggests that selective bias may account for a significant part of the reported association between submitral calcium and conduction abnormalities. In contrast is the strong association of submitral calcium with AF. Of potential significance is the finding of subjects with submitral calcium and no other evidence of cardiac or systemic disease to explain their AF. This suggests that a significant number of patients diagnosed as having lone AF have submitral calcium as a possible origin of the dysrhythmia. Mechanisms for AF might include left atria1 enlargement causing temporal dispersion of refractory periods in atrial tissue which would in turn predispose to reentrant rhythms such as AF. LV inflow obstruction could increase left atrial pressure and lead to left atria1 enIargement.i6 Decreased LV com-

pliance (associated with increased wall thickness) and mitral regurgitation or LV failure (which are associated with LV dilatation), or a combination of these would be expected to contribute to increased left atria1 pressure and left atria1 enlargement. Extension of the degenerative changes associated with submitral calcium into atrial tissue might interrupt atria1 conduction and predispose to AF. Alternatively, increased stress on the mitral apparatus associated with AF might accelerate degenerative changes and lead to submitral calcium. References 1. Hlrschfefd DS, Emifeon BB. Echocardiogram in calcified mitral annulus. Am J Cardfol 1975;38:354-356. 2. Gabor GB, Mohr BD, Gael PC, Cohen B. Echocardiographic and clinical soectrum of mitral anular calcium. Am J Cardiol 1976:38:836-842. 3. d’l%uz I, Panetia F, Cohen H, Gllck G.8ubmitral caldfu~mor sclerosis in elderly patients: m mode and two dimensional echocardiography in “mitral annulus calcium.” Am J Cardiol 1979;44:31-38. 4. Fulkemon PK. Seaver SM. Aussun JC. Graber HL. Cafcificatfon of the mitral annulus. Etloiogy, cllnicai associations, compllcatlons and therapy. Am J f&l 1979:86:967-977. 8. Cohen H, D’Cruz IA, Prabbu I?, Blefa V, Gllck 0. Abnormalities of cardiac conduction in oatients with mitral annulus calcium (abstr). Circulation . 1978;43,54:Suppl ll:ll-136. 8. Bertolalus J. RKlolrl FL. Hutchlns GM. Comolete heart block caused bv calciflc mitral annulus iibrosis. Johns Hopkins Med J 1974;135:i991 203. 7. Lev M. Anatomic basis for atrloventricular block. Am J Med 196437:

. ._ . ._.

749_7An

8. Dawber TR, Meadors GF, Moore FE Jr. Epidemiologic ap roaches to heart disease: the Framinoham Studv. Am J Public Health 19 s 1:41:279-286. 9. Fefnlelb M, Kannel-WB, Oar&n RJ, M&Jam&a PM, C&tot2 WP..The Framingham Offspring Study. Design and preliminary data. Prev Med 1975:4:518-525. 10. Sortie P. Cardiovascular Diseases and Death FollowingMyocardial Infarction and An ina Pectoris: Framingham Study, 20 Year Follow-Up. Washington gZ7U 8 Government Printing Office, 1977:DHEW Publication (NIH)7711. ;fgenbaum

H. Echocardiography. Philadelphia: Lea 8 Febiger, 1972:37,

12. Gardln JM, Henry WL, Savage DD, Ware JH, Burn C, Borer JS. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound 1979; 7:439-447. 13. Walker SH, Duncan DB. Estimation of the probability of an event as a function of several independent variables. Siometrlka 1967;54:187-179. 14. D’Cruz IA, Cohen HC, Prabhu R. Blsla V. Gllck G. Clinical manifestations of mitral annulus calcium, with emphasis on its ecbocardlographic feeties. Am Heart J 1977;94:367-377. 15. Roberts WC, Perloff JK. Mitral valvular disease: a clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972:77:939-975. Sell S. Massive calcium of the mitral annulus: a 18. K&i D, DeSanc&iIk, clinicopathologlcal study of fourteen cases. N Engl J Med 1962;267: 900-909. 17. Schutt CR, Kutler MN, Parry WR, Segal BL. Mitral anular calcification. Clinical and echocardiographic correlations. Arch Intern Med 1977;137: 1143-1150. Joyner CR Jr, Dyrda I, Barrett JS, Reid JM. Preoperative determination 18. of ihe functionai anatomy of the mitral valve (atistr). Circulation 1965; 31.32:Suool ll:ll-120. A. Pathologic and clinical study of calcium of mitral valve ring. is. Po&a&e J Clin Pathol 1970:23:354-361. 20. Simon MA, Lkr SF. Calcification of the mitral valve annulus and its relation to functional valvular disturbance. Am Heart J 1954;48:497-505. 21. Bulkfey BH. Morrow AG, Roberts WC. Calcification of the mitral annulus. A late complication of yalve replacement with caged-ball prosthesis (abe). Am J Cardiol 1973:31:123. 22. Pomerance A. Cardiac pathology and systolic murmurs in the elderly. Br Heart J 1968:30:687-689. 23. R$a&l DA, MfPeftch LS. Clinical aspects of calcium of the mitral annulus fibrosus. Arch Intern Med 1948;78:544-564. 24. Gelll T. Classification of the left annulus fibrosus (230 cases) Acta Med Stand 1950;138 (Suppl239):153-154