European Heart Journal Advance Access published online on April 28, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn172
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Association of mitral annular calcification and aortic valve morphology: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study
1 Cardiology Division, Department of Cardiac Sciences, St Boniface General Hospital, Rm Y3010, 409 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6
2 Institute of Cardiovascular Sciences, Cardiology Division, Department of Cardiac Sciences, St Boniface General Hospital, Winnipeg, Manitoba, Canada
3 Department of Radiology, St. Boniface General Hospital, Winnipeg, Manitoba, Canada
4 Clinical Research Unit, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
5 Victoria Heart Institute Foundation, Victoria, British Columbia, Canada
6 Hopital Laval, Sainte-Foy, Quebec, Canada
7 Peter Lougheed Centre, Calgary, Alberta, Canada
8 Vancouver General Hospital, Vancouver, British Columbia, Canada
9 Cambridge Cardiac Care Centre, Cambridge, Ontario, Canada
10 Sunnybrook HSC, Toronto, Ontario, Canada
11 McMaster University, Hamilton, Ontario, Canada
12 University of Ottawa Heart Institute, Ontario, Canada
Received 21 December 2007; revised 6 March 2008; accepted 7 April 2008.
* Corresponding author. Tel: +1 204 237 2023, Fax: +1 204 233 2157, Email: djassal{at}sbgh.mb.ca
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Abstract |
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Aims: Mitral annular calcification (MAC) is characterized by calcium and lipid deposition in the annular fibrosa of the mitral valve. Although individuals with MAC are at increased risk of cardiovascular events, little is known about the significance of this finding in patients with concurrent aortic stenosis (AS). The aim of this study was to describe the association of baseline MAC and aortic valve morphology in asymptomatic patients enrolled in the ASTRONOMER study, a multicentre study to assess the effect of Rosuvastatin on the progression of AS.
Methods and results: At baseline, transthoracic echocardiography was performed with two-dimensional and Doppler imaging following a standardized protocol. Echo measurements including left ventricular (LV) dimensions and aortic root dimensions were obtained according to the ASE recommendations. MAC was identified by bright echoes at the base of the mitral leaflets or annulus on 2D imaging, and aortic valve calcification by visualization of bright echoes on the aortic valve leaflets. The degree of calcification was semi-quantitated from absent to severe. The study population included 219 patients (57 ± 14 years; 129 males), divided into two pre-specified categories; bicuspid (n = 133) and tricuspid (n = 86) aortic valves. Baseline LV dimensions, aortic valve haemodynamics, and cholesterol profiles were similar between the two groups at baseline. Individuals with tricuspid aortic valves were older, more hypertensive, with higher degrees of MAC and AV calcification (P < 0.001). The higher degree of MAC persisted in patients with tricuspid AV after adjustment for age and systolic blood pressure (P = 0.004).
Conclusion: In patients with asymptomatic mild to moderate AS, MAC is more prevalent in those individuals with tricuspid AV, independent of age, and systolic blood pressure. Whether the degree of MAC may be a surrogate for atherosclerosis, and predict the subset of patients who will respond to statin therapy in preventing the progression of AS, remains to be determined.
Key Words: Mitral annular calcification • Aortic valve calcification • Aortic stenosis
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Background |
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Atherosclerosis is a systemic inflammatory process with a predilection for certain anatomic locations of increased turbulent blood flow and mechanical stress.1,2 Aside from arterial branch points and vascular areas, the attachment points of the mitral and aortic valves to their respective annuli may serve as a nidus for the development of atherosclerosis. Calcium deposition occurs in these areas of atherosclerotic lipid accumulation, leading to the development of mitral annular calcification (MAC).3
Recent studies have demonstrated a significant relationship between the presence of cardiovascular risk factors and the degree of annular calcification. Individuals with MAC have a higher prevalence of coronary artery disease, arrhythmias, cerebrovascular disease, and increased cardiovascular mortality.4–6 Consistent with the hypothesis that annular calcification and atherosclerosis share a similar pathophysiologic process, multiple studies have also demonstrated a clear association between the degree of MAC and the presence of aortic atheroma, increased carotid intima-media thickness, and peripheral arterial atherosclerotic disease.4,7,8 Although valvular heart disease, in particular aortic stenosis (AS), is a highly active process with a number of regulated pathways similar to atherosclerosis,9 little is known about the significance of MAC in this clinical setting.
The aim of the current study was to examine the effect of valve morphology on MAC and aortic valve calcification (AVC) in patients with mild to moderate AS.
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Methods |
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Patient population
Between 2002 and 2005, 272 patients from 23 Canadian centres with mild to moderate AS were recruited for the ASTRONOMER study, a multicentre randomized trial to evaluate the effects of Rosuvastatin on the progression of AS.10 Patients between 18 and 82 years of age with mild to moderate AS defined by peak Doppler aortic valve velocity 2.5–4.0 m/s were included. For the purpose of the current substudy, the population was divided into two categories; bicuspid and tricuspid aortic valves. After exclusion of 53 patients with undetermined number of aortic valve leaflets, the final cohort consisted of 219 individuals; 133 with bicuspid AV and 96 with tricuspid AV. The study protocol was approved by the institutional review boards at the various participating centres.
Plasma lipids
Fasting blood samples were drawn to obtain complete lipid profile, which included total cholesterol, triglycerides, LDL-C, and HDL-C, using automated techniques standardized with the Canadian reference laboratory.
Echocardiography
Parasternal and apical views were obtained using standard echocardiographic systems and multifrequency transducers with tissue Doppler capability. Standard two-dimensional images, M-mode, and spectral and colour Doppler were performed. Determination of aortic valvular calcification, aortic valve morphology (bicuspid vs. tricupsid), and MAC were performed at each local site of the ASTRONOMER trial, using the baseline echocardiogram. The echocardiographic criteria for these features were prospectively defined and reviewed with the investigators prior to the launch of the study.
Aortic root dimensions, left atrial and left ventricular cavity dimensions, and LV ejection fraction were determined from two-dimensional images according to established criteria including the modified Simpson’s method.11 Aortic valve morphology and the presence of concomitant stenotic disease were determined using continuous wave Doppler and the continuity equation.
MAC was defined as a dense highly reflective area at the base of the posterior mitral leaflet in the parasternal short-axis view. Mild MAC involvement affected one-third or less of the annulus; moderate involvement was between one-third and two-third of the annulus; and severe involvement exceeded two-third of the annulus (Figure 1). The presence of significant mitral stenosis (mitral valve area <1.5 cm2) was an exclusion criteria of the ASTRONOMER study.10
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AVC relied on visualization of bright echoes at the base of the aortic valve leaflets. Mild AVC was scored as small isolated spots; moderately calcified included multiple larger spots; and heavily calcified involved extensive thickening and calcification of all cusps (Figure 2).
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Statistics
The data are summarized as mean ± SD or number (percent). Fisher’s exact test was used to compare the distribution of sex between the aortic valve morphology groups. Other baseline characteristics and baseline echocardiographic findings were compared using Student’s t-test. Weighted kappa statistics were performed to assess inter-observer and intra-observer agreement rates for the determination of aortic valvular and MAC. Ordinal regression models assuming proportional odds were fit to examine the relationship between AVC and MAC with valve morphology. Subsequently, age and systolic blood pressure were simultaneously added to the models to account for their potential confounding effect in the relationships. A two-sided P-value of <0.05 was deemed statistically significant.
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Results |
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Baseline characteristics
The total population for this substudy included 219 patients (129 males) with a mean age of 57 ± 14 years. Overall, the patients demonstrated moderate AS with a peak gradient of 40 ± 11 mm Hg and AV of 1.2 ± 0.5 cm2. The patients were divided into two pre-specified categories: bicuspid AV (n = 133) and tricuspid AV (n = 86). Baseline patient characteristics are shown in Table 1 for both groups. Patients with tricuspid AV were older and more hypertensive when compared with bicuspid AV (P < 0.001). There were no differences in other patient demographics including sex, body habitus, and cholesterol profile.
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Echocardiographic dimensions
The left ventricular dimensions and AV haemodynamics were similar between both the groups (Table 2). While individuals with bicuspid AV had larger ascending aortic root dimensions (P < 0.001), patients with tricuspid AV had larger left atrium diameters and higher degree of AVC (P < 0.001) (Table 3).
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Mitral annular calcification
All 219 patients had complete assessment of MAC (Table 3). Figure 1 illustrates the representative examples of varying severities of MAC. Individuals with tricuspid AV demonstrated higher degree of MAC (n = 39) when compared with bicuspid AV (n = 11) (P < 0.001). The higher degree of MAC in tricuspid AV patients persisted after adjustment for age and systolic blood pressure (P = 0.004).
Agreement
A subset of studies (n = 24) was re-reviewed to determine the inter-observer and intra-observer variation in the grading of AV and MAC. The inter-observer and intra-observer agreement rates for aortic valvular calcification were 92% (
: 0.95; 95% CI: 0.57, 1.00) and 88% (: 0.92; 95% CI: 0.48, 1.00), respectively. The inter-observer and intra-observer agreement rates for MAC were 88% (: 0.97; 95% CI: 0.49, 1.00) and 83% ( 0.56; 95% CI: 0.12, 1.00), respectively.
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Discussion |
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In this observational substudy of the baseline data from the ASTRONOMER trial, we examined the effect of valve morphology on MAC and AVC in patients with asymptomatic mild to moderate AS, and it was discovered that those individuals with tricuspid aortic valves had more extensive MAC and AVC compared to those with bicuspid aortic valves. Furthermore, after adjustment for age and systolic blood pressure, MAC was still over-represented in the group with tricuspid aortic valves. An important question that arose from this study was whether the degree of MAC could act as a surrogate for atherosclerosis to predict a subset of AS patients who would demonstrate a greater response to statin therapy.
Degenerative or calcific AS was initially considered to be a passive process; however, increasingly, it is being discovered that the process is in fact dynamic and highly regulated. From animal studies, histologic analyses of aortic valves have elucidated several similarities between calcific AS and vascular atherosclerosis.9 Specifically, both processes involve basement membrane disruption, macrophage and T-lymphocyte migration, and lipid infiltration.12 There are other factors that play a role in the degenerative process of the valve as well. There is a greater degree of endothelial damage sustained to the aortic side of the aortic valve secondary to chronic exposure to shear forces. Genetic factors are also contributory as the NOTCH1 transcriptional factor regulates aortic valve development.13 Mutations in this gene have been found to produce deleterious effects on the structural development of the valve. Finally, calcification in the valve per se is dependent on proteins produced during the ossification process.14 The RANK ligand made by osteoblasts and T-cells in osteocytes have also been found to be present on calcified valve leaflets.14
The pathophysiologic basis of MAC and AVC essentially represents a process akin to calcific AS, as outlined above. MAC represents a chronic, degenerative, non-inflammatory condition in the fibrous base of the mitral valve apparatus.3 It also involves calcium and lipid deposition, and there is ample evidence in the literature supporting an association between MAC and systemic atherosclerotic disease.9 There are some uncontrolled studies in the literature suggesting that MAC or AVC may be related to AS.15,16 In a retrospective study, Movahed et al.15 noted that MAC was present in 15% of patients with AS compared to only 6% of patients without AS. Similarly, in a large population-based study from the Mayo Clinic, patients with AVC progressed to calcific AS faster.16
It is important to recognize that the degree of MAC or AVC and its relationship to valve morphology (either tricuspid or bicuspid) is a novel concept, and the literature is lacking in this area. There is, however, some evidence that tricuspid aortic valves tend to fare worse. In a surgical series published by Davies et al. in 1996, it was determined that in the 465 adult patients undergoing aortic valve replacement, the sex and age distributions of bicuspid and tricuspid calcific aortic valve stenosis were different.17 The higher rate of insertion of vascular grafts in tricuspid aortic valves in their study may indicate that risk factors for atherosclerosis enhance cusp calcification in this group.17 The authors hypothesized that calcification in bicuspid valves occurs in the fibrous core of the cusp, whereas it occurs on the aortic face of the cusps in tricuspid valves. Furthermore, calcification in tricuspid valves is reminiscent of atherosclerosis in other vascular beds, with an important pathophysiologic role for plasma lipids.9
Given the concept that calcific AS is at least partly related to atherosclerosis, it had been hypothesized that statin therapy may be helpful in slowing the progression of this valvular pathology. However, despite retrospective studies supporting this hypothesis,18,19 prospective randomized trials have had conflicting results in patients with moderate to severe AS.20,21 In the double-blinded, placebo-controlled SALTIRE trial, intensive lipid-lowering with 80 mg of atorvastatin did not stop the progression of calcific AS or produce regression compared to placebo.20 In contrast, in an open-label, prospective study performed by Moura et al.21 in Portugal, treatment of AS with rosuvastatin resulted in significant improvement of echocardiographic measures compared to no treatment. Other more definitive studies are ongoing.10,22
In comparison to tricuspid aortic valves, bicuspid aortic valves are a common congenital cardiac anomaly with a multifactorial genetic inheritance.23 Little data exist on the pathophysiologic comparison of these two populations. Caira et al.24 found evidence of increased low-density lipoprotein receptor-related proteins (Lrp5), osteocalcin, and osteochondrogenic differentiation markers in 23 calcified bicuspid and 27 tricuspid aortic valves. No formal statistical comparison was performed, however, between these two groups. Wallby et al.25 demonstrated the same degree of T lymphocyte infiltration in 12 bicuspid and 17 tricuspid aortic valves at the time of surgery. Larger studies comparing the relative prevalence of MAC and AVC in bicuspid and tricuspid aortic valves are lacking.
There were some important limitations in this study. This study was an observational substudy of a prospectively designed randomized trial of rosuvastatin in patients with asymptomatic mild to moderate aortic stenosis (ASTRONOMER).10 The original sample size was constructed for the purpose of answering the primary question,10 rather than designed to evaluate the relationship between aortic valvular and MAC. Given the subgroup nature of these analyses, the results of the current study have to be interpreted cautiously.26 Due to the relatively small sample size, a type-2 error cannot be excluded in presence of factors that were not found to be significantly related to aortic valve morphology. Additionally, the baseline patients in the ASTRONOMER trial represent a fairly homogenous, Caucasian population, and, therefore, it is difficult to extrapolate the results to other ethnic groups. Only a large multi-national study will be able to address this important question more conclusively. Finally, there is clearly a certain degree of subjectivity involved when assessing for valve calcification via echocardiography.27,28
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Conclusions |
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In conclusion, this observational study demonstrated that in patients with mild to moderate AS, there was more extensive MAC and AVC in patients with tricuspid aortic valves compared with bicuspid aortic valves independent of age and systolic blood pressure. Whether MAC could be utilized as a marker for atherosclerosis and their response to statin therapy in AS patients is presently unknown; however, the results of the upcoming ASTRONOMER trial will likely help elucidate this hypothesis.
Conflict of interest: none declared.
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Dr Davinder S. Jassal holds the Dr F.W. Du Val Clinical Research Professorship. This study was supported by the Canadian Institute of Health Research and AstraZeneca Canada Inc.
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References |
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  M. Pachon and J. Zamorano Mitral annular calcifications and aortic valve stenosis Eur. Heart J., June 2, 2008; 29(12): 1478 - 1480. [Full Text] [PDF]
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