From the Department of Cardiology, The Sheingarten Echocardiography Unit
(Y.A., N.F., D.T., R.F., A.A., J.Y., A.S.), and the Department of Vascular
Surgery (A.K., A.Z.), Rabin Medical Center, Beilinson Campus, Petah Tiqva, and
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Methods—Of the 805 patients in whom the diagnosis of MAC was made
by transthoracic echocardiography
between 1995 and 1997, 133 patients (60 men and 73 women; mean age,
74.3±8 years; range, 47 to 89 years) underwent carotid artery duplex
ultrasound for various indications; the study group comprised these
patients. They were compared with 129 age- and sex-matched patients
without MAC (57 men and 72 women; mean age, 73.6±7 years; range, 61 to
96 years) who underwent carotid artery duplex ultrasound during the
same period for the same indications. MAC was defined as a dense,
localized, highly reflective area at the base of the posterior mitral
leaflet. MAC was considered severe when the thickness of the localized,
highly reflective area was
Results—Compared with the control group, the MAC group
showed a significantly higher prevalence of carotid stenosis of
Conclusions—There is a significant association between the
presence of MAC and carotid artery atherosclerotic disease. MAC may be
an important marker for atherosclerotic disease of the carotid
arteries. This association may explain the high prevalence of stroke in
patients with MAC.
Previous pathological studies22 have claimed that
MAC in the elderly is a form of atherosclerosis and
suggested that coronary atherosclerosis, MAC,
and aortic valve calcium in the elderly have a similar
etiology.23 We recently
demonstrated24 a highly significant association
between the presence of MAC and aortic atheroma, and
Demopoulos et al25 found a very strong
association between the presence of aortic atheroma and
carotid artery atherosclerotic disease. Therefore, the aim of the
present work was to determine whether an association exists between
MAC and carotid artery atherosclerotic disease.
Complete 2-dimensional and Doppler color flow examinations were
performed in all patients with the 2.5-MHz transducer of a
Hewlett-Packard phased array sector scanner (model 77020 A). The
2-dimensional echocardiographic criteria for MAC
included an intense echo-producing structure located at the junction of
the atrioventricular groove and posterior mitral valve
leaflet on the parasternal long axis and apical 4-chamber views or an
intense echo-dense structure located posterior to the posterior mitral
valve leaflet on the parasternal short-axis
view.11 MAC was considered severe when the
thickness of the intense echo-producing structure was
All studies were recorded on super-VHS tape and evaluated
independently by 2 cardiologists with expertise in
echocardiography. In case of disagreement, a third
examiner was consulted. The observers who made the diagnosis of MAC
were blinded to the presence or absence of carotid artery
atherosclerotic disease.
Carotid artery duplex ultrasonography was performed (ATL-HDI 3000,
Siatel) with the patient in the supine position, head slightly
rotated to the side. Imaging was begun in the transverse plane at the
most proximal level obtainable in the common carotid artery (CCA).
After the CCA was scanned, the subclavian artery was identified in its
long axis by sliding the transducer inferiorly and angling
it slightly underneath the clavicle. The transducer was then advanced
cephalad toward the carotid bifurcation to identify the internal (ICA)
and external carotid arteries. During imaging of the carotid vessels in
the transverse orientation, the most stenotic area was
carefully evaluated and measured for the percent area/diameter
stenosis and/or residual lumen diameter.
Sagittal images were obtained next. Imaging was begun with the proximal
CCA. The transducer was aligned so that the CCA appeared in a
horizontal position on the screen, without either end angled up or
down. This allowed for the best acoustic reflection from the vessel.
The transducer was then moved in a cranial fashion to image the
bifurcation.
Carotid artery stenosis (CCA and ICA) was graded as follows:
0%, 20%, 40%, 60%, 80%, and 100%.26
Bilateral carotid artery stenosis was defined as the presence
of carotid artery disease in both right and left carotid arteries
(either CCA or ICA) above a specific limit of stenosis for both
sides (for example, right CCA and left ICA with stenosis of
Atherosclerosis risk factors considered in this study
were diabetes mellitus, hypertension,
hypercholesterolemia, and history of smoking.
Diabetes mellitus was defined as hyperglycemia requiring previous or
ongoing pharmacological therapy. Hypertension was defined as either
systolic or diastolic elevation of blood pressure
(>140/90 mm Hg) or the need for ongoing antihypertensive
pharmacological therapy. Hypercholesterolemia
was defined as a total cholesterol level of >200 mg/dL.
Significant smoking history was defined as 10 or more pack-years of
cigarette use.
Statistical Analysis
Severe MAC was found in 48 study patients (32 women and 16 men; mean
age, 75±8 years; range, 50 to 87 years) (see Table 2
Indications for Carotid Artery Duplex Ultrasound
Mitral Annulus Calcification and Carotid Artery Disease
Univariate analysis was performed. In the MAC
subgroup, MAC (P=0.006) and age (P=0.03) were the
only significant predictors for carotid artery stenosis of
Association Between Mitral Annulus Calcification and
Stroke
Mitral Annulus Calcification and Atherosclerosis
Experimentally induced systemic arterial
atherosclerosis is also associated with the deposition
of fatty plaques on the aortic surface of the aortic valve cusps and
the ventricular surface of the posterior mitral
leaflet.22 These findings suggest that
coronary atherosclerosis, MAC, and aortic valve
calcium in the elderly have a similar etiology: as the fatty plaques
grow, their nutritional needs fail to be fulfilled, and they degenerate
into calcific deposits. Roberts,23 in an
editorial on the senile cardiac calcification syndrome, claimed that
because calcific deposits in the mitral annular area are observed only
in a population that develops significant coronary
atherosclerosis, it is reasonable to assume that MAC in
the elderly is a form of atherosclerosis.
Carotid Artery Atherosclerotic Disease and Stroke
In the present study, we found a significant association between
the presence of MAC and carotid artery atherosclerotic disease
(stenosis of
Conclusions and Clinical Implications
Received February 19, 1998;
revision received June 3, 1998;
accepted June 3, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Association Between Mitral Annulus Calcification and Carotid Atherosclerotic Disease
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—It has been
established that mitral annulus calcification (MAC) is an independent
predictor of stroke, though a causative relationship was not proved,
and that carotid artery atherosclerotic disease is also associated with
stroke. The aim of this study was to determine whether there is an
association between the presence of MAC and carotid artery
atherosclerotic disease. 
5 mm on 2-dimensional
echocardiography in the 4-chamber view. Carotid
artery stenosis was graded as follows: 0%, 20%, 40%, 60%,
80%, and 100%. 40% (45% versus 29%, P=0.006), which was associated
with 2-vessel disease (23% versus 10%, P=0.006) and
bilateral carotid artery atherosclerotic disease (21% versus 10%,
P=0.011). Severe MAC was found in 48 patients. More
significant differences were found for the severe MAC subgroup (for
carotid stenosis of 40%) in rates of carotid artery
atherosclerotic disease (58% versus 29%, P=0.001), and
2-vessel disease (31% versus 10%, P=0.001), in
addition to bilateral carotid artery stenosis (27% versus
10%, P=0.004) and even bilateral proximal internal
carotid artery stenosis (21% versus 8%,
P=0.015). Furthermore, significant carotid artery
atherosclerotic disease (stenosis of 60%) was significantly
more common in the severe MAC subgroup than in the controls (42%
versus 26%, P<0.05) and was associated with higher
rates of 2-vessel disease (19% versus 7%, P=0.02)
and bilateral carotid artery stenosis (17% versus 7%,
P=0.05). On multivariate
analysis, MAC and age but not traditional risk factors were the
only independent predictors of carotid atherosclerotic disease
(P=0.007 and P=0.04, respectively).
Key Words: carotid artery diseases • mitral annulus calcification • stroke
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Mitral annulus
calcification (MAC) is a chronic, noninflammatory, degenerative process
of the fibrous support structure of the mitral
valve.1 2 It occurs more often in women and the
elderly.3 MAC has been found to play a role in
left atrial enlargement, left ventricular enlargement,
atrial fibrillation, conduction defects, mitral
regurgitation, mitral stenosis, hypertrophic
cardiomyopathy, and bacterial
endocarditis.4 5 6 7 8 9 10 11 Its association with stroke
has been suspected1 2 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 since the 1946 report
of Rytand and Lipsitch.5 However, whether
MAC contributes causally to the risk of stroke or is merely a marker of
increased risk because of its association with other precursors of
stroke remains unclear.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Between 1995 and 1997 our laboratory made a diagnosis of MAC by
transthoracic echocardiography in 805
patients. Of these, 133 (73 women and 60 men; age range, 47 to 89
years; mean, 74.3±8 years) underwent carotid artery duplex ultrasound
for various indications. This group was compared with 129 age- and
sex-matched patients (72 women and 57 men; age range, 61 to 96 years;
mean, 73.6±7 years) without MAC who underwent carotid artery duplex
ultrasound during the same period. Patients with rheumatic
valvular disease, cardiomyopathy, or
prosthetic valves were excluded. 5 mm
measured by 2-dimensional echocardiography in the
4-chamber view. Forty-eight patients were found to have severe MAC (32
women and 16 men; age range, 50 to 87 years; mean, 75±8 years). 40%); disease 2-vessel disease was defined as bilateral disease or
disease involving both the CCA and the ICA on the same side above a
specific limit of stenosis for all vessels.
Numerical values are reported as mean±SD or as a proportion of
the sample size. Comparisons between the study and control groups were
made with the 
2 test for categorical data and
Student's t test for continuous data.
Multivariate analysis was used to identify
predictors for carotid artery disease. The following variables were
entered into the model: age, sex, MAC, diabetes mellitus, hypertension,
hypercholesterolemia, and history of smoking.
The univariate correlation coefficients for these
variables were determined and then entered into a
multivariate model for prediction of carotid artery
atherosclerotic disease with use of the RS1 Statistical
Package (Bolt, Beranek, and Newman, 1997). Forward stepping was
used, with the F to enter and F to remove any variable selected so
that the corresponding significance level (outer tail area) was <0.05;
no variables were forced into the model.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patient Characteristics
The MAC group included 133 patients (73 women and 60 men; mean
age, 74.3±8 years; range, 47 to 89 years) (see Table 1
).
The control group included 129 age- and sex-matched patients (72 women
and 57 men; mean age, 73.6±7 years; range, 61 to 96 years). There were
no intergroup differences in
hypercholesterolemia and positive smoking
history. Diabetes mellitus and hypertension were significantly more
frequent in the MAC patients (30% versus 8%, P=0.001, and
66% versus 53%, P=0.03, respectively).
View this table:
[in a new window]
Table 1. Clinical Characteristics of MAC Subjects and
Controls ). There were no
differences between this subgroup and the control group in age and sex
distribution or in hypercholesterolemia and
positive smoking history. Diabetes mellitus and hypertension were also
more frequent in the severe MAC patients (31% versus 8%,
P=0.001, and 77% versus 53%, P=0.003,
respectively).
View this table:
[in a new window]
Table 2. Clinical Characteristics of Severe MAC Subjects
and Controls
There were no significant differences between the MAC and control
groups regarding indications for referral for carotid duplex
ultrasound: stroke, 67 patients (50.3%) versus 58 (45%); carotid
bruit or screening before cardiac surgery, 66 patients (49.7%) versus
71 (55%). This was also true when the severe MAC subgroup was compared
with the controls: stroke, 24 patients (50%); carotid bruit or
screening before cardiac surgery, 24 patients (50%).
Carotid artery stenosis of 40% was found in 37 of the
129 patients without MAC (29%) compared with 60 of the 133 with MAC
(45%, P=0.006) and in 28 of the 48 patients with severe MAC
(58%, P=0.001) (see Tables 3 and 4). A significant difference
was also found for the presence of carotid artery stenosis of
60% between the controls (26%) and the severe MAC subgroup (42%,
P<0.05). Disease 2-vessel disease with carotid artery
stenosis of 40% was found in 13 control patients (10%)
compared with 30 MAC patients (23%, P=0.006) and 15 severe
MAC patients (31%, P=0.001). The differences in the rate of
disease 2-vessel disease with significant stenosis of 60%
between the severe MAC patients (19%) and the control patients (7%)
was also significant (P=0.02). Bilateral carotid artery
disease with stenosis of 40% was found in 13 control
patients (10%) compared with 28 MAC patients (21%, P=0.01)
and 13 severe MAC patients (27%, P=0.004). Bilateral
carotid artery disease with stenosis of 60% was found in 9
controls (7%) and 8 severe MAC patients (17%, P=0.05).
Bilateral proximal ICA stenosis of 40% was also found
significantly more often in the severe MAC subgroup compared with the
control group (21% versus 8%, P=0.015). No carotid artery
atherosclerotic disease was significantly more common in the controls
compared with both the MAC group and the severe MAC subgroup (66%
versus 46%, P=0.001, and 66% versus 35%,
P=0.001), respectively.
View this table:
[in a new window]
Table 3. Prevalence and Characteristics of Carotid Artery
Atherosclerotic Disease in Patients With and Without MAC
View this table:
[in a new window]
Table 4. Prevalence and Characteristics of Carotid Artery
Atherosclerotic Disease in Patients With and Without Severe MAC 40%. Multivariate analysis also identified
MAC (P=0.007) and age (P=0.04) as the only
independent predictors for carotid artery stenosis of 40%.
Univariate analysis of the severe MAC subgroup
identified MAC (P=0.0001),
hypercholesterolemia (P=0.01), and
age (P=0.014) as the only significant predictors for carotid
artery stenosis of 40%. Similar results were identified in
the multivariate analysis: MAC
(P=0.0002), hypercholesterolemia
(P=0.009), and age (P=0.019) for carotid artery
stenosis of 40%.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The present study is the first to show a strong and
significant association between the presence of MAC and carotid
atherosclerotic disease. Patients with severe MAC had more severe
atherosclerotic disease in the carotid arteries.
Since the report by Rytand and Lipsitch,5
numerous studies have suggested an association between MAC and
stroke.1 2 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 In a 4.4-year follow-up study of
107 MAC patients and an equal number of matched control patients, Nair
et al11 noted a 10% rate of cerebrovascular
events in the first group compared with a 2% rate in the second
(P<0.01). Benjamin et al27 examined
the relationship between MAC and the incidence of stroke in a
population-based study from the Framingham cohort. They concluded that
in the elderly, MAC was associated with a doubled risk of stroke,
independent of traditional risk factors for stroke. Yet, whether such
calcification contributes causally to the risk of stroke or is merely a
marker of increased risk because of its association with other
precursors of stroke remains unknown.
Pathological studies22 have proved that foam
cells representing early atherosclerotic
lesions23 can been found in affected patients
already during adolescence and in the second and third decades of life
on the endothelium of the epicardial coronary
arteries, the ventricular surface of the posterior mitral
leaflet, and the aortic aspects of each of the aortic valve cusps.
Carotid artery atherosclerotic disease has been found with high
prevalence in elderly patients with hypertension,
hyperlipidemia, a history of smoking, and diabetes
mellitus.28 29 30 Its association with
coronary artery disease31 32 33 34 35 and
abdominal aortic aneurysm36 has also been
noted, in addition to a possible link with
stroke.37 A review of hospital and community
stroke registries revealed that 25% to 33% of all ischemic
strokes can be attributed to atherothrombotic disease that affects the
major arteries to the brain in their extracranial and intracranial
courses.38 39 40 41 42 Demopoulos et
al25 also found a very strong association between
the presence of aortic atheromas and carotid artery
disease. Our group recently demonstrated a highly significant
association between the presence of MAC and aortic
atheroma,24 suggesting that this
association may explain the high incidence of stroke in patients with
MAC. 40%, P=0.006), and even association
between the presence of severe MAC and significant carotid artery
atherosclerotic disease (stenosis of 60%,
P<0.05). This supports our previous hypothesis that MAC is
a marker for the systemic atherosclerotic processes that are
responsible for stroke. We also found that MAC eliminated hypertension
and diabetes mellitus, both known to be risk factors for carotid
disease, from the multivariate analysis of
risks for carotid atheromatous disease. A
possible reason for this is that since MAC, carotid artery disease, and
aortic atheroma presumably have a common etiologic basis
(namely, atherosclerosis), they express the summation
of atherosclerotic risk factors such as hypertension and diabetes
mellitus. It is therefore not surprising that MAC is a stronger
predictor of carotid artery atherosclerotic disease than these
individual risk factors. It should be noted that our study design was
not planned to examine the association between MAC and stroke subtypes
believed to be due to atherothrombotic carotid disease; this awaits
further investigation.
MAC can be detected by transthoracic
echocardiography, a simple, noninvasive imaging
method. Using MAC as a marker, we can define a subgroup of patients
with a high prevalence of carotid artery disease. We suspect the
association between MAC and carotid artery disease explains the high
incidence of stroke in MAC patients. A prospective study is mandatory
to prove this hypothesis. The presence of MAC probably indicates a
systemic atherosclerotic process that involves the aorta, aortic valve,
coronary system, and probably the carotid arteries. This
information is important to candidates for cardiac surgery, since this
procedure is associated with an increased risk of stroke in patients
with carotid artery atherosclerotic disease. Carotid artery duplex
ultrasound should be considered in patients with MAC before cardiac
surgery is performed.
Acknowledgments
We thank Sigal Tabachnik and Ida Tzadik for their
assistance in performing and interpreting the duplex carotid
ultrasound examinations.
Footnotes
Reprint requests to Alex Sagie, MD, Department of Cardiology, Echocardiography Unit, Rabin Medical Center (Beilinson Campus), Petah Tiqva, 49100 Israel.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
This article has been cited by other articles:
 |
|
 |
|
  D. S. Jassal, J. W. Tam, K. M. Bhagirath, I. Gaboury, R. A. Sochowski, J. G. Dumesnil, P. J. Giannoccaro, J. Jue, A. S. Pandey, C. D. Joyner, et al. Association of mitral annular calcification and aortic valve morphology: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study Eur. Heart J., June 2, 2008; 29(12): 1542 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nemcsik, K. Farkas, E. Kolossvary, Z. Jarai, J. Egresits, G. Borgulya, I. Kiss, and M. Lengyel Intracardiac Calcification Is a Marker of Generalized Atherosclerosis Angiology, September 1, 2007; 58(4): 413 - 419. [Abstract] [PDF]
|
|
|
|
 |
|
 O. Kluck, M. Berman, A. Stamler, G. Sahar, A. Kogan, E. Porat, and A. Sagie Value of echocardiography for stroke and mortality prediction following coronary artery bypass grafting Interactive CardioVascular and Thoracic Surgery, February 1, 2007; 6(1): 30 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Kizer, D. O. Wiebers, J. P. Whisnant, J. M. Galloway, T. K. Welty, E. T. Lee, L. G. Best, H. E. Resnick, M. J. Roman, and R. B. Devereux Mitral Annular Calcification, Aortic Valve Sclerosis, and Incident Stroke in Adults Free of Clinical Cardiovascular Disease: The Strong Heart Study Stroke, December 1, 2005; 36(12): 2533 - 2537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Makkena, H. Salti, M. Subramaniam, S. Thennapan, R. H. Bonow, F. Caira, R. O. Bonow, T. C. Spelsberg, and N. M. Rajamannan Atorvastatin decreases cellular proliferation and bone matrix expression in the hypercholesterolemic mitral valve J. Am. Coll. Cardiol., February 15, 2005; 45(4): 631 - 633. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y.-M. Wang, S. S.-Y. Ho, M. Wang, E. K.-H. Liu, S. Ho, P. K.-T. Li, S.-F. Lui, and J. E. Sanderson Cardiac Valvular Calcification as a Marker of Atherosclerosis and Arterial Calcification in End-stage Renal Disease Arch Intern Med, February 14, 2005; 165(3): 327 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Acarturk, A. Bozkurt, M. Cayli, and M. Demir Mitral Annular Calcification and Aortic Valve Calcification May Help in Predicting Significant Coronary Artery Disease Angiology, September 1, 2003; 54(5): 561 - 567. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Y.-M. Wang, M. Wang, J. Woo, C. W.-K. Lam, P. K.-T. Li, S.-F. Lui, and J. E. Sanderson Cardiac Valve Calcification as an Important Predictor for All-Cause Mortality and Cardiovascular Mortality in Long-Term Peritoneal Dialysis Patients: A Prospective Study J. Am. Soc. Nephrol., January 1, 2003; 14(1): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Hisar, M. Ileri, E. Yetkin, I. Tandogan, S. Cehreli, R. Atak, K. Senen, and D. Demirkan Aortic Valve Calcification: Its Significance and Limitation as a Marker for Coronary Artery Disease Angiology, March 1, 2002; 53(2): 165 - 169. [Abstract] [PDF]
|
|
|
|
|
|
D. Tanne, A. Shotan, U. Goldbourt, M. Haim, V. Boyko, Y. Adler, L. Mandelzweig, and S. Behar Severity of Angina Pectoris and Risk of Ischemic Stroke Stroke, January 1, 2002; 33(1): 245 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Dincer, C. Ozdol, R. Dandachi, O. Akyurek, Y. Atmaca, M. Kilickap, C. Erol, and D. Oral Predictive Value of Mitral Annular Calcification for the Diagnosis of Coronary Artery Disease in Patients with Dilated Cardiomyopathy Angiology, August 1, 2001; 52(8): 515 - 520. [Abstract] [PDF]
|
|
|
|
|
|
M. Soylu, A. D. Demir, K. Arda, Y. Uzun, and S. Goksel Association Between Mitral Annular Calcification and Carotid Atheroma Angiology, March 1, 2001; 52(3): 201 - 204. [Abstract] [PDF]
|
|
|
|
|
|
A. Boon, J. Lodder, E. Cheriex, F. Kessels, Y. Adler, D. Tanne, and A. Sagie Mitral Annulus Calcification and Carotid Atherosclerotic Disease • Response Stroke, March 1, 1999; 30(3): 693 - 693. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||