Sage Journals: Discover world-class research

Abstract

Mitral annular calcification (MAC) is an inflammatory process that shares characteristics with atherosclerosis and results in calcium deposition in the fibrous ring supporting the mitral valve. It is commonly encountered at older ages and in people with chronic kidney disease. MAC is an important prognostic marker of adverse cardiovascular events and atrial fibrillation, as well as cardiovascular and non-cardiovascular death. When severe it can cause valvular dysfunction including mitral stenosis and/or regurgitation. Aside from effects on mitral valve function, MAC is associated with abnormal compliance of both the left atrium and left ventricle. It is also associated with disruption of normal left ventricular vortex formation and increased energy losses. In combination, these factors may help explain the symptoms of dyspnea and exercise intolerance frequently seen in MAC patients.

Graphical abstract

This is a visual representation of the abstract.

Keywords

mitral annular calcification cardiovascular outcomes anatomic distribution hemodynamic effects

Key points

 Mitral annular calcification (MAC) is a common, age-related degenerative process involving the fibrous mitral annulus, often detected incidentally.

MAC is associated with aortic stenosis, atherosclerosis, chronic kidney disease, atrial fibrillation, hypertension, and prior chest irradiation.

MAC independently predicts stroke, cardiovascular events, and all-cause mortality in population-based longitudinal studies.

By altering annular and leaflet mechanics, MAC can cause mitral stenosis, regurgitation, or mixed valvular dysfunction.

 MAC is often associated with altered diastolic function due to reduced atrial and ventricular compliance.

Introduction

Calcification of the mitral annulus is commonly observed in clinical practice. It is typically diagnosed through echocardiography or computed tomography (CT) imaging of the heart but may also be detected via fluoroscopy or cardiac magnetic resonance imaging. Its presence holds prognostic significance, in addition to its effects on valvular structure and function. This review will explore the prevalence and clinical associations of mitral annular calcification (MAC), as well as its impact on cardiac physiology. Furthermore, the current limitations and challenges in quantifying these effects are discussed.

Prevalence and Associated Conditions

MAC is a chronic degenerative condition affecting the fibrous support structure of the mitral valve.^1,2 MAC is often clinically silent and typically identified incidentally during echocardiography. It appears as an echo-dense, shelf-like structure giving the annulus an irregular, lumpy appearance associated with acoustic shadowing (Videos 1–3). The earliest description of this condition was tied to its clinical implications. In 1908, Bonninger reported a case of complete heart block associated with extensive calcification of the mitral annulus.³ Subsequently, in 1910, Dewitzky was the first to formally recognize calcific disease of the mitral annulus as a distinct clinical entity.⁴ He provided a detailed pathological description of 36 cases and compared this lesion to the aortic valve calcification described by Mönckeberg in 1904.⁵ Dewitsky also noted a now well-established observation: the posterior portion of the annulus is more frequently and extensively involved than the anterior segment.

Autopsy studies in the mid-twentieth century identified MAC in approximately 10% of cases.^6,7 More recent clinical investigations have reported a prevalence ranging from 8% to 42%, depending on patient age and diagnostic method employed.^8–11 The largest study to date, which examined echocardiograms in nearly 25,000 patients, found a prevalence of 23%.¹² Data from the Framingham Heart Study as early as 1983 found more than 90% of individuals with MAC were older than 59 years, highlighting a clear age-dependent risk.¹³ Kanjanauthai et al, using 6814 CT scans from participants in the Multi-Ethnic Study of Atherosclerosis (MESA), confirmed that age was independently associated with MAC.¹⁴ Given this association, it is not surprising that MAC often coexists with aortic stenosis.¹⁵ Conversely, up to half of the patients undergoing transcatheter aortic valve replacement (TAVR) also have MAC.¹⁶

The prevalence of MAC is notably higher in certain associated conditions:

Atherosclerosis

There is a strong association between MAC and atherosclerosis which suggests shared pathophysiological mechanisms.¹⁷ Numerous studies have observed associations between MAC, cardiovascular risk factors, and conditions such as aortic atheroma, carotid atherosclerosis, peripheral artery disease, and coronary artery disease (CAD).^18–20 This will be expanded on below. Pathological evidence further supports this link, with foam cells (a hallmark of atherosclerosis) identified in early mitral annular lesions.²¹ Because of these associations it has been suggested that MAC is a marker for underlying atherosclerotic disease^22,23 (Video 4). Notably, these MAC-associated conditions are often encompassed within the clinical phenotype of metabolic syndrome, which is itself associated with an increased risk of MAC.²⁴

Chronic Kidney Disease and Abnormal Calcium–Phosphorus Metabolism

Valvular calcifications are 4 to 10 times more common in patients with chronic kidney disease (CKD) versus those with normal renal function.²⁵ In a community-based sample the Framingham Heart Study found that CKD patients had 60% increased odds of MAC after multivariable adjustment when compared with non-CKD patients.²⁶ While this relationship is partly explained by the increased prevalence of risk factors in CKD, mounting evidence suggests the involvement of abnormal calcium–phosphorus metabolism, electrolyte imbalance, chronic inflammation, and a distinct lipid profile.²⁷

Clinical Conditions with Increased Mitral Valve Stress and Tension

MAC is also associated with conditions that increase stress on the mitral valve,²⁸ such as hypertension, aortic stenosis, and hypertrophic cardiomyopathy (HCM).^29,30 These conditions lead to elevated left ventricular systolic pressure, higher mitral valve closing pressures, and increased annular stress which may promote MAC.¹ The strong association between left ventricular hypertrophy and prevalence, severity, and even incidence of MAC supports this hypothesis.³¹ Additionally, disorders of mitral valve motion, such as mitral valve prolapse, also appear to promote annular calcification. Again, excess stress exerted on the annulus, this time through the valve and chordal apparatus, appears to be involved.^32,33

Chest Irradiation

Radiation to the chest has been associated with MAC, particularly in cases involving the aorto-mitral curtain.^34–36 Many of these patients have had “mantle” radiation in treatment of Hodgkin's lymphoma. In a study of 112 patients with MAC-related mitral stenosis (MS) undergoing invasive hemodynamic assessment, one-third had a history of thoracic radiation.³⁷

Atrial Fibrillation

There is a strong association between MAC and atrial fibrillation. The Framingham study, using M-mode echocardiography, observed a 1.6-fold increased incidence of atrial fibrillation in those with MAC over a 16-year follow-up period.³⁸ The MESA study confirmed this association in a multi-ethnic cohort where the hazard ratio for incident atrial fibrillation was 1.9 for the MAC group over 8.5 years of follow-up.³⁹ The same MESA investigators also observed that MAC progression was an independent predictor of incident atrial fibrillation.⁴⁰ Recently, MAC has been associated with recurrence of atrial fibrillation following catheter ablation.⁴¹ The disruption of atrioventricular coupling and associated increased left ventricular filling pressure that occur with atrial fibrillation may, in turn, promote progression of annular calcification.^39,42

Prognostic Value as a Marker of Cardiovascular Risk

Over the past decade academic interest in the detection and grading of MAC has focused on the planning and optimization of interventional or surgical mitral valve procedures, particularly as the use of these procedures has increased. Thus, younger cardiologists may not be aware that MAC was initially investigated and later validated as an important marker of cardiovascular (CV) disease and adverse outcomes. Here we discuss the association of MAC with CAD, stroke, cardiovascular mortality and all-cause mortality.

The landmark historical literature on MAC as a risk-stratification variable primarily involves the detection and grading of MAC using echocardiography. More recently the routine availability of CT imaging (ECG-triggered cardiac CT or standard chest CT) has produced significant longitudinal CT studies with sufficiently long follow-up to assess incidence of CV diseases and hard outcomes reliably.

Studies investigating MAC as a risk marker for CAD or adverse outcomes should ideally account for the fact that MAC shares many risk factors with atherosclerosis, particularly age. Therefore, a longitudinal design with rigorous multivariate analysis is essential to demonstrate an independent association between MAC and CAD, cardiovascular events, and mortality. Moreover, the most effective clinical setting to determine whether MAC is truly associated with cardiovascular disease and/or outcomes is through prospective cohort studies, rather than retrospective studies of patients with clinically driven echocardiograms, which may introduce selection bias.

Fortunately, at the beginning of the current century several large-scale longitudinal community-based studies were published, which included assessment of MAC in their imaging protocols. These studies also collected data on many other known and potential cardiovascular risk factors allowing investigation of possible independent associations of MAC with incident CV diseases, CV mortality, and all-cause mortality.

The Cardiovascular Health Study (CHS) and the Framingham Heart Study were the first such large cohort studies with long-term follow-up.^43–45 They established a clear independent association of MAC with incident coronary heart disease (CHS study) as well as all-cause mortality and CV mortality (Framingham Heart Study).

Coronary events, defined as fatal coronary events, hospitalized myocardial infarction or coronary procedures, were also assessed in a substudy of the Atherosclerosis Risk in Communities (ARIC) study.⁴⁶ Here MAC was observed to be independently associated with this combined coronary endpoint. More recently, in 2010, the Study of Health in Pomerania (SHIP) confirmed that MAC was associated with all-cause and cardiovascular mortality.⁴⁷ OxVALVE (Oxford Valvular Heart Disease) is another contemporary echocardiography screening study, initially designed to detect the presence and severity of valvular disease in individuals over 65 years of age. This large study also confirmed the independent association between MAC and its severity with mortality.⁴⁸

Several multisite echocardiographic cardiovascular calcium scores have been proposed which typically include MAC and additional sites of potential calcification, such as the papillary muscles, ascending/thoracic aorta and aortic valve. These scores provide incremental value in ascertaining clinical CAD risk, and risk of CV events and mortality.^49,50 They have been tested in primary prevention samples and in patients undergoing echocardiography for various clinical indications, including those undergoing stress echocardiography for suspected CAD.⁵¹ Interestingly, there is also evidence that such global calcium scores are significantly associated with coronary calcium.^52,53

Determining the presence of MAC using echocardiography is based on visual features and thus inexact. It is not always possible to distinguish calcium from sclerotic changes. In addition the severity and extent of MAC is semiquantitative and lacks precision; studies have used various definitions and classifications, and this also represents a drawback of echocardiographic assessment of MAC. These limitations don’t exist for CT determination of presence and severity of MAC. Multisite cardiac calcium scores can be utilized with SPECT-CT techniques⁵⁴ and ungated chest CT, as well as cardiac CT. In this way routine studies ordered for other indications can provide additional “free” information about cardiovascular risk.

A recent paper from the MESA study, a community-based study of individuals without CV disease at baseline who underwent CT, confirmed that MAC is a predictor of long-term stroke risk, even after accounting for the presence of atrial fibrillation/flutter. There is also a concept that MAC is a marker of biological age. In another recent paper using the MESA database MAC was independently associated with a higher incidence of all-cause, cardiovascular, and non-cardiovascular mortality.⁵⁵ MAC subjects also had a significantly higher risk of developing dementia.

It should be mentioned as well that MAC can serve as a nidus for endocarditis.^56,57 In such cases it appears that S. aureus infections are usually present. On occasion, very large vegetations can form (Figure 1, Video 5). Annular complications, including perforation, can also occur and mortality rates are high.

Figure 1.

The top portion of the image is a 2D still frame from a TEE 4-chamber view. There is a large vegetation originating from the atrial surface of the calcified mitral annulus. The bottom portion of the image is a 3D still frame from the same study, looking onto the mitral valve from the left atrium. The aortic valve is at 12 o’clock and the atrial septum is at 5 o’clock. See also Video 5. Reproduced with permission from Ref.⁵⁶

MAC is a significant and robust prognostic marker regarding CAD, stroke, and mortality, both due to cardiovascular causes and non-cardiovascular causes. Information about the presence and severity of MAC, along with more global cardiac calcium scores, is readily available on clinically driven echocardiograms and CT scans. Awareness of the prognostic importance of these findings can aid the clinician in routine diagnosis and risk assessment of patients.

Anatomic Distribution and Effects on Valve Geometry

The anatomical distribution and severity of MAC can vary widely among individuals, as can its hemodynamic effects. Traditionally, semiquantitative echocardiographic scoring systems have been employed to assess severity of MAC. These mostly involve the extent of annular involvement, thickness of the calcification, and effects on valve leaflet motion.^58–60 More recently, improved imaging techniques, particularly involving cardiac CT, have led to more detailed reporting of anatomical and hemodynamic characteristics of MAC.⁶¹ With the rise of catheter based structural procedures it has become essential to have more precise assessment of MAC. The system devised by Guerrero et al⁶² appears to be gaining generalized acceptance in this regard (Table 1).

Table 1.

Proposed Grading System for Mitral Annular Calcification (MAC) Severity (Adapted From References ⁶² and ⁷⁴).

Severity of MAC	Transthoracic echocardiography	TEE and/or cardiac CT
Mild	<180° MAC circumference	MAC score ≤3
Moderate	180°-270° MAC circumference	MAC score 4-6
Severe	≥270° MAC circumference or ventricular wall calcification	MAC score ≥7 or ventricular wall calcification, or calcium volume >1000 mm³
MAC score
Annular calcium thickness	<5 mm 5-9.99 mm ≥10 mm	1 2 3
Calcium distribution	<180°	1
	180°-270°	2
	≥270°	3
Trigone calcification	None	0
	Anterolateral	1
	Posteromedial	1
	Both trigones	2
Mitral leaflet calcification	NoneAnterior leafletPosterior leafletBoth leaflets	0112

CT = computed tomography; TEE = transesophageal echocardiography.

Variation by Sex

Most studies have observed a female predominance in patients with MAC.^14,63,64 According to the MESA, the prevalence of MAC was higher in women than in men across all ethnic groups.¹⁴ In addition, a previous pathologic study found that women tended to have more extensive calcium deposits as compared to men.⁶⁵ More recently, a positron emission tomography study, using ¹⁸F-sodium fluoride (as a marker of calcification activity) found that MAC activity was closely associated with female sex.⁸ While MAC has been suggested to have a shared etiology with atherosclerosis,²¹ these gender differences are not well explained by the traditional paradigm of atherosclerosis.^14,20 Thus, other causal factors have been proposed including inflammation, mechanical stress and differences in calcium metabolism.^8,66–69 (Figure 2).

Figure 2.

Clinical and Anatomic Differences Between Men and Women with Mitral Annular Calcification.

It has been observed that MAC in elderly women is associated with severe bone loss due to post-menopausal osteoporosis.⁶⁶ Bone mineral density has also been associated with increased incidence and progression of MAC in both men and women,⁷⁰ though osteoporosis is more common in women. Additionally, the higher prevalence and more extensive nature of MAC in women could be associated with hemodynamic mechanisms. A recent study involving 537 MAC patients found that women had a higher frequency of moderate-severe MAC than men and were more likely to have mitral regurgitation.⁶⁷ In this study, risk factors for moderate-severe MAC differed significantly between women and men. While end-stage renal disease was a risk in both men and women, conditions that increase left ventricular afterload, such as uncontrolled hypertension or obstructive HCM, were independently associated with moderate-severe MAC only in women. Thus, mechanical stress associated with increased afterload and a relatively small ventricle may contribute to MAC in women.

Women with MAC had more mitral regurgitation than men. Significant MS (≥5 mm Hg) occurred in approximately 10% of both sexes but was independently associated with death only in women. Another study involving 3523 patients with extensive MAC and a mitral valve gradient greater >3 mm Hg showed similar findings.⁶⁸ In this study, using a large echocardiographic database, women significantly outnumbered men, accounting for 67% of subjects. Compared to men, women were significantly older and had fewer cardiovascular comorbidities. Women had higher transmitral gradients, more frequent concentric hypertrophy, and more frequent mitral regurgitation. In a separate study of 287 patients with severe calcific mitral stenosis associated with MAC, two-thirds of the patients were female, with this female predominance becoming particularly pronounced after age 50.⁶⁹ Furthermore, women exhibited a worse prognosis compared to men. By contrast, in a longitudinal study of MAC patients, factors such as widened pulse pressure, high ejection fraction, and the structural and functional severity of MAC at baseline were independent predictors of progression while female sex was not.⁷¹

Posterior Annulus Versus Interannular Fibrosa

The normal mitral annulus has a saddle shape and is typically divided into anterior and posterior segments. The anterior annulus extends between the left and right fibrous trigones and is anatomically connected to the aortic annulus.^1,29 The posterior annulus makes up the rest of the annular perimeter. As mentioned above MAC more commonly affects the posterior annulus than the anterior annulus.^65,72,73 As the disease progresses, it can also involve the anterior annulus, or interannular fibrosa, the fibrous tissue between the anterior mitral leaflet and aortic valve.⁷⁴ Anterior annular involvement appears to be more common in cases of radiation-induced heart disease³⁴ but can also be present with other etiologies. When MAC is limited to the posterior annulus and non-severe, it usually does not cause functional abnormalities. More extensive MAC, particularly when it involves the anterior annulus, is often associated with functional abnormalities (see below). In the era of transcatheter mitral valve replacement, CT-scoring of MAC has prognostic value and is important for procedure planning⁶² (Table 1). A key element of the CT MAC score is trigone involvement. Notably, the severity of MAC can help predict risk of valve embolization after transcatheter mitral valve replacement.

MAC, particularly when extensive, can encroach on the conduction system and produce conduction disturbances.^75–77 This is because calcific deposits can extend to the atrioventricular node and the bundle of His. Interestingly, a small study that subdivided MAC by location found that AV conduction disturbances were associated with moderate to severe MAC (≥3 mm) but only when it was localized postero-medially in the mitral annulus, which is close to the AV-node and bundle of His.⁷⁸ It has also been suggested that MAC increases the risk of high-grade heart block following TAVR. In a group of 761 patients MAC was reported to be a strong independent predictor of pacemaker implantation post-TAVR.⁷⁹ However, this finding was not confirmed in another study involving 875 subjects.⁸⁰

Effects on Leaflet Function

In isolated MAC (not involving the leaflets), valve motion is maintained, allowing unhindered ventricular filling. However, calcific degeneration often progresses onto the leaflets, leading to reduced mobility and geometric distortion. These anatomic changes commonly result in the development of mitral stenosis and/or regurgitation (discussed below). In a study that performed echocardiographic evaluations on 75 consecutive hemodialysis outpatients to assess the extent of MAC, three-dimensional (3D) analysis revealed an uneven distribution of annular calcium. The middle and lateral anterior segments were less frequently calcified than the antero-medial and posterior segments.⁵⁸

Effects on Annular Function

The annulus possesses a dynamic, non-planar configuration that plays an important role in leaflet coaptation, unloading mitral valve closing forces, and promoting left atrial and left ventricular filling and emptying.²⁹ Recent research involving 3D echocardiography^81–83 has provided insights into normal annular function and the effects of various disease processes. There has also been a study on the shape and function of the annulus using 3D echocardiography in patients with MAC.⁸⁴ This study compared 43 patients with MAC to 36 age- and sex-matched normal controls. Compared to the normal annulus, the anteroposterior diameter was larger in diastole and showed a smaller decrease during systole. Furthermore, the MAC annulus was flatter in diastole versus normal and had a smaller increase in saddle height during systole. The annular flattening and loss of systolic folding along the intercommissural axis might predispose to development of mitral regurgitation. However, these factors are opposed by the reduced motion and stiffening of the leaflets seen in MAC (see below).

Time Course and Determinants of Progression

The progression of valvular disease and its associated factors has long been of interest but remains challenging to understand. This is largely because early disease is often asymptomatic and discovered incidentally, making it difficult to study.⁸⁵ Additionally, factors that drive the initial stages of the disease may differ from those contributing to its progression.

MAC is a dynamic condition with its progression influenced by localized calcification activity and inflammation. Once present the key factors determining progression include the baseline calcium load, ethnic background, and smoking habits.⁸⁶

As is well-known, the factors associated with the incidence of MAC largely overlap with those of atherosclerosis.⁸⁷ However, these factors do not appear to be significant promoters with the exception of smoking. Conversely, ethnicity may affect disease course, with slower progression observed in Black and Hispanic patients.^8,55 Notably, while CKD is a significant risk factor for developing MAC, no association has been found between eGFR levels and MAC progression^8,87 though dialysis patients were excluded in these studies.

In a retrospective study using data from MESA, Elmariah et al observed that baseline severity of calcification was the primary determinant of MAC progression.⁸⁷ Individuals who started with more severe disease experienced more rapid progression. MAC progression was relatively independent of modifiable risk factors, further highlighting the importance of primary prevention. The one apparent exception was smoking cessation, which was associated with attenuated MAC progression and with MAC stabilization/regression. Similar observations have been made in other studies, with the fastest progression observed in patients with the largest baseline burden of MAC.⁸ Cigarette smoking was again identified as a factor influencing progression of MAC.

With regards to inflammation, Massera et al utilized ¹⁸F-sodium fluoride and ¹⁸F-fluorodeoxyglucose (18F-FDG) PET to explore the relationship between calcification activity in the mitral annulus and local inflammatory signals. Increased ¹⁸F-sodium fluoride uptake (a marker of active calcification) in the mitral annulus was closely associated with ¹⁸F-FDG uptake (a marker of active inflammation) highlighting the role of inflammation not only in the development of MAC but also in sustaining the vicious cycle underlying progression of this condition. As to disease triggers the authors hypothesize that the presence of calcium within the mitral annulus increases mechanical stress and injury, thus leading to inflammation and enhanced calcification activity.⁸

Lee et al investigated MAC progression by examining it from both structural and hemodynamic perspectives.⁷¹ Structural progression was defined as an increase in MAC angle (extent of annular calcification expressed as degrees of arc) as measured via echocardiography. Hemodynamic progression was characterized by an increase in the mean Doppler transmitral pressure gradient. The authors found that MAC progression was associated with a wider pulse pressure (systolic – diastolic blood pressure), higher left ventricular ejection fraction, baseline severity of MAC, and its initial hemodynamic severity. Hemodynamic factors, including an increased pulse pressure and elevated ejection fraction, were identified as independent predictors of MAC progression (Figure 3). Pulse pressure serves as a marker of aortic stiffness, vascular aging, and associated comorbidities. An increase in pulse pressure leads to chronic elevation in left ventricular afterload, reduced longitudinal myocardial function, and compensatory enhancements in radial or circumferential contraction. The resultant increase in mechanical stress on the annulus might contribute to endothelial damage, localized oxidative stress, and inflammatory processes, which collectively drive MAC progression.⁷¹

Figure 3.

Factors Associated with Progression of Mitral Annular Calcification.

Hemodynamics—Due to MAC and Interaction with Associated Conditions

When calcific deposits extend onto the base of the mitral leaflet(s) a “bar” or ‘‘shelf’’ of calcium can form that limits leaflet motion and displaces their hinge point towards the left ventricular (LV) apex. When severe, particularly when the anterior leaflet is involved, this can produce valvular stenosis.^58,88 As the population ages MAC has emerged as an important cause of mitral stenosis (MS), accounting for one in eight cases.⁸⁹

Stenosis with Comparisons to Rheumatic Disease

MS due to MAC, often referred to as degenerative mitral stenosis, has a different morphology when compared to rheumatic mitral stenosis. Calcification of the annulus and basal portions of the leaflets in degenerative MS leads to a “tunnel-like” stenosis with the greatest narrowing at the base of the valve (Figure 4, Video 6). This contrasts with rheumatic MS where commissural fusion (absent in degenerative MS) causes the valve to taper towards a narrowed orifice, yielding a characteristic “funnel type stenosis.” In addition, the MAC orifice is crescentic with open commissures while the rheumatic orifice typically has a “fish mouth” appearance bracketed by fused commissures (Figure 5). The tunnel-like stenosis of degenerative MS also produces greater flow convergence distal to the valve, resulting in a smaller contraction coefficient (effective orifice area [at the vena contracta]/anatomic orifice area). This in turn produces a higher transmitral pressure gradient for a given anatomic area and flow rate as compared to the funnel type stenosis of rheumatic MS (which has a higher contraction coefficient).⁹⁰

Figure 4.

Parasternal Long-Axis Views of MAC Mitral Stenosis (left) and Rheumatic Mitral Stenosis (right). The blue lines mark the valve leaflets and left atrium, the red dots mark the mitral annulus. Note that the MAC valve has a “tunnel-like” configuration with a short distance from the annulus to the stenotic inlet of the calcium “tunnel.” By contrast the rheumatic leaflets slope more gradually to the stenotic orifice at the leaflet tips creating a “funnel” configuration.

Figure 5.

3D Diastolic Frames Obtained via Transesophageal Echocardiography. The panel on the left shows a MAC valve with prominent calcifications visualized on top of the anterior leaflet. Note the crescentic orifice and open commissures. The panel on the right shows a rheumatic valve with a “fish mouth” orifice bracketed by fused commissures.

In addition, mean gradients are dependent on the pressure difference between the left atrium and left ventricle. Degenerative MS patients are frequently elderly and have multiple comorbidities that can affect compliance of either chamber. Net atrioventricular compliance, along with valve area, determines the transvalvular gradient.⁹¹ Poor left ventricular compliance (and high filling pressure) can result in a reduced transvalvular gradient, while poor left atrial compliance (and high atrial pressure) can increase the transvalvular gradient. Thus, although they have prognostic value, mean gradients may provide an inaccurate picture of the hemodynamic severity of degenerative MS. The cut-offs used to assess rheumatic MS severity have not been validated for degenerative MS and may not be relevant to this disease. Additionally, it should be borne in mind that transvalvular mitral gradients are greatly dependent on heart rate and flow rate across the valve.

Measurement of valve area in patients with severe MAC is challenging. However, with new transcatheter treatments becoming available it is essential to determine valve area accurately. There is no agreed upon method to measure mitral valve area in severe MAC but the pressure half-time technique should not be used.^61,92 The abnormal chamber compliances noted above affect the slope of the Doppler signal making this method inaccurate. The continuity equation can be used in the absence of more than mild left-sided valvular regurgitation and is probably the most useful technique at this time.⁹³ A mitral valve dimensionless index⁹⁴ has also been proposed as a useful tool which eliminates the inaccuracies of left ventricular outflow tract (LVOT) measurement. 3D echocardiography, particularly via transesophageal echocardiography, can be used to directly measure orifice area via multiplanar reconstruction. However, acoustic shadowing from the annular calcium can make this difficult. In addition, the MAC orifice, as opposed to the rheumatic orifice, is non-planar. We have been working on use of virtual reality to directly measure the non-planar orifice in 3D space with encouraging preliminary data (unpublished). On occasion 3D color Doppler and multiplanar reconstruction can be used to measure the orifice area within the calcium tunnel.⁹⁵ This technique is also limited by acoustic shadowing from the annular calcium.

Regurgitation

Mitral regurgitation (MR) occurs through multiple mechanisms: (a) MAC can interfere with the sphincter-like function of the annulus, (b) it can directly restrict leaflet motion thus interfering with coaptation, or (c) it can push the posterior leaflet towards the atrium reducing the area of coaptation.^73,96 Calcification of the chordae tendineae and disruption of normal annular dynamics can also contribute to MR.⁸⁴ The frequency with which significant regurgitation occurs in MAC has not been well studied. In one series of 138 MAC subjects, 22 (16%) were reported to have moderate or severe MR.⁷¹ Another study looked at a group of 56 younger patients with MAC (<age 50) and found moderate or severe MR in 14 (25%).⁹⁷ By contrast in a study of 75 dialysis patients, 64% of whom had MAC, none had severe MR and severity of MAC was not predictive of presence or absence of MR.⁵⁸ Finally, in a large observational study of 24,414 subjects who underwent clinically indicated echocardiography, there was no significant association between presence of MAC and presence of MR.¹²

Recently, a staging system has been proposed which assesses extra-mitral cardiac damage in MAC patients with mitral valve dysfunction.⁹⁸ This is similar in concept to the staging system used for patients with calcific aortic stenosis. In stage 0 there is no extra-mitral cardiac damage. Stage 1 is defined by the presence of left ventricular remodeling with sex-specific thresholds for LV end-systolic and end-diastolic volumes. Stage 2 occurs when there is left atrial remodeling defined as indexed left atrial volume >34 mL/m² and/or the presence of atrial fibrillation. Development of pulmonary hypertension and/or ≥ moderate-severe tricuspid regurgitation denotes the presence of stage 3 disease with the addition of right ventricular dysfunction defining stage 4. Using this system graded relationships were found between higher stages and mortality as well as heart failure hospitalization.

Systolic Anterior Motion (SAM) of the Mitral Valve

SAM of the mitral valve is a characteristic finding in patients with dynamic outflow tract obstruction. While typically found in patients with HCM it is not universally present in this entity, and it can occur in other clinical scenarios.⁹⁹ SAM involves movement of one or both mitral leaflets into the LVOT during systole. If septal contact occurs, particularly if it is prolonged, a pressure gradient develops in the LVOT. In severe cases this gradient can be quite high and can be associated with syncope. Mechanistically, the valve leaflets are “pushed” into the LVOT, although there may be some contribution to SAM by the Venturi effect as the pressure gradient increases.¹⁰⁰

Various anatomic features of the left ventricle, mitral valve, and LVOT predispose patients to the development of SAM. These include protrusion of the septum into the LVOT, elongated mitral leaflets, abnormally positioned papillary muscles, and anterior displacement of the mitral coaptation line towards the interventricular septum. While these features predispose to SAM the resultant outflow tract gradients are dynamic and vary according to hemodynamic conditions such as left ventricular preload, afterload, and inotropic state. A recent paper described a series of patients with severe posterior MAC that appeared to contribute to development of SAM. In these patients the bulky calcium deposits formed in such a way that the mitral coaptation line was displaced anteriorly, effectively narrowing the LVOT and allowing SAM to emerge¹⁰¹ (Video 7). Many of these patients had other anatomic features often associated with SAM including an elongated anterior mitral leaflet and a hyperdynamic LV.

Left Ventricular Diastolic Function

Patients with MAC are often elderly and have many comorbidities. The left ventricle is typically small and hypertrophied while the left atrium is often dilated and may be fibrotic as reflected by reduced atrial strain.¹⁰² Patients with moderate or severe MAC often have reduced tissue Doppler velocities¹⁰³ and it is difficult to accurately assess diastolic function in these patients.¹⁰⁴ Whether the reduced values are due to the annular calcification or reflect true diastolic dysfunction is uncertain. A framework for assessing left ventricular diastolic dysfunction in patients with substantial MAC has been proposed.¹⁰⁵ The authors note that MAC can affect mitral E velocity and annular e′ thus making the E/e′ ratio unreliable in this setting. Their algorithm focuses instead on the E:A ratio and isovolumic relaxation time (IVRT). In an initial cohort of 60 subjects plus a validation cohort of 21 subjects they observed a sensitivity of 85% and specificity of 95% for detecting high LV filling pressure (>12 mm Hg). However, a subsequent study from a different center¹⁰⁶ was unable to demonstrate comparable sensitivity, specificity, and accuracy. Further work needs to be done in this area.

Interpretation of Doppler Gradients in Severe MAC

Patients with severe MAC often have a resting gradient across the mitral valve, and this gradient has prognostic value.^107,108 It should be recognized, however, that the Doppler velocity envelope in these patients may have a configuration that differs from that in rheumatic mitral stenosis (Figure 6). Left atrial compliance in patients with severe MAC is often reduced (ie, the atrium is “stiff”) and this can alter the Doppler signal across the valve. A high peak E-velocity occurs in early diastole due to high left atrial pressure at valve opening. Left atrial pressure then drops quickly as blood leaves the atrium, resulting in a short deceleration time. These effects can potentially increase the transvalvular gradient as determined by the simplified Bernoulli equation¹⁰⁹ but are unrelated to valve obstruction. In a study comparing MAC MS with rheumatic MS we observed that, for similar valve areas, patients with MAC had higher transvalvular gradients than did patients with rheumatic disease.¹¹⁰ While that difference may have been related to higher stroke volume in the MAC patients, effects of differing chamber compliances may also have played a role. In addition, Doppler echocardiography, particularly using the simplified Bernoulli equation, has not been validated in MAC.

Figure 6.

Representative Continuous-Wave Doppler Signals from a Subject with Rheumatic Stenosis (left) and Stenosis Due to Mitral Annular Calcification (MAC, right). Note that the MAC patient has an E-wave dominant profile and a shorter deceleration time as compared to the rheumatic patient.

Chamber Compliance, Vortex Formation, and Energy Losses

Calcification causes the annulus to become more rigid and less compliant which reduces the ability of the LA to expand and contract during the cardiac cycle.⁹⁶ Reduced annular compliance also impedes valve opening in diastole, contributing to elevated left atrial pressure.^58,111 This elevated pressure increases the risk of pulmonary congestion and development of pulmonary hypertension over time.¹¹² This might also contribute to the observed increased risk of atrial fibrillation.^39,42

Severe MAC can cause mitral stenosis and/or regurgitation, both of which affect left ventricular filling.^61,113 Mitral stenosis impedes diastolic filling of the LV while regurgitation causes backward blood flow, potentially leading to increased LV filling. Both conditions can disrupt normal flow patterns, resulting in absence of a transmitral vortex and reduced forward stroke volume.^114,115 If the LV becomes hypertrophied in response to increased workload, its compliance may be further reduced, exacerbating the hemodynamic impact.^116,117

Reduced compliance of both the atrium and the ventricle leads to a decrease in overall cardiac efficiency.¹¹⁸ The heart struggles to maintain an adequate stroke volume and may exhibit signs of heart failure, particularly in the presence of hypertension or CAD.

In diastole, when blood flows into the LV, vortex formation facilitates optimal filling, ensuring that the ventricle can expand and accept a proper volume of blood.^119,120 Moreover, the diastolic vortex ring plays a crucial role in facilitating the exchange of flow at the apex, promoting efficient ventricular fluid washout during systole. In the absence of this diastolic vortex ring, apical fluid washout is significantly reduced, which increases the risk of thrombus formation.^121,122

The diastolic vortex also plays a key role in transformation of kinetic energy and momentum transfer. It redirects flow forces while simultaneously facilitating the rotation and movement of blood as the cardiac cycle transitions from diastole to systole.^123,124 During systole, as blood is being ejected from the LV, a well-coordinated vortex forms in the ventricle, aiding in efficient blood propulsion. This vortex helps create smooth laminar flow that minimizes energy loss.^125–127

When MAC stiffens the mitral annulus, it can lead to incomplete or irregular mitral valve opening⁹⁶ which disrupts normal vortex formation.^128,129 The resultant turbulent flow leads to inefficient heart pumping via increased friction and energy dissipation^130,131 (Figure 7). Disruption of vortex flow due to MAC results in higher levels of energy loss, particularly during diastole when the ventricle should be passively filling.¹³² In the absence of a well-formed vortex, there is a greater resistance to blood flow, which forces the heart to expend more energy to achieve the same level of filling and pumping.^133–135 As a result of inefficient filling and increased energy demands, the LV may undergo hypertrophy to compensate for the reduced efficiency.¹³⁶ Over time, this can further reduce LV compliance, creating a cycle of increasing hemodynamic strain.

Figure 7.

Sketch Illustrating Normal Vortex Formation in Diastole as Blood Crosses the Mitral Valve and Enters the Left Ventricle (right). In the setting of severe mitral annular calcification this vortex formation is absent (left).

The combination of disrupted vortex flow, turbulent filling, and increased energy loss likely contribute to limitations in cardiac output and symptoms of dyspnea and exercise intolerance. These changes in myocardial energetics may also help explain associations of MAC with increased risk of arrhythmias, heart failure, and other cardiovascular complications.^137,138

Conclusion

In summary, MAC is a common finding in clinical practice, particularly in the elderly and those with CKD. It serves as an important marker of increased risk for adverse cardiovascular outcomes and mortality. Its presence should thus prompt consideration of aggressive risk factor modification. When annular calcification is extensive, particularly when it migrates onto the valve leaflets, it produces valvular dysfunction. While mitral regurgitation is a common consequence it is typically mild. By contrast, MAC can produce significant, even severe stenosis. Associated abnormalities in compliance of the left atrium and left ventricle, combined with valvular dysfunction, can significantly impact hemodynamics and increase myocardial energy losses.

Supplemental Material

sj-docx-1-hvs-10.1177_30494826251347539 - Supplemental material for Clinical and hemodynamic implications of mitral annular calcification

Supplemental material, sj-docx-1-hvs-10.1177_30494826251347539 for Clinical and hemodynamic implications of mitral annular calcification by Andrea Faggiano, Bianca Rocca, Chi Young Shim, Samer Farhud, Geu-ru Hong, Nicola Gaibazzi, Pompilio Faggiano, Giovanni Benfari, Salima Qamruddin, Arash Kheradvar and Gregg S. Pressman in Journal of the Heart Valve Society

Supplemental Material

Footnotes

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ORCID iDs

Andrea Faggiano

Chi Young Shim

Samer Farhud

Giovanni Benfari

Salima Qamruddin

Arash Kheradvar

Gregg S. Pressman

Supplemental material

Supplemental material for this article is available online.

References

Abramowitz

Jilaihawi

Chakravarty

Mack

Makkar

. Mitral annulus calcification. J Am Coll Cardiol. 2015;66(17):1934–1941.

Nestico

Depace

Morganroth

Kotler

Ross

. Mitral annular calcification: clinical, pathophysiology, and echocardiographic review. Am Heart J. 1984;107(5 Pt 1):989–996.

Bonninger

. Zwei Falle von Herzblock. Dtsch Med Wochenschr. 1908;34:2292.

Dewitzky

. Über den Bau und die Entstehung verschiedener Formen der chronischen Veränderungen in den Hherzklappen. Virchows Arch Pathol Anat Physiol Klin Med. 1910;199(2):273–377.

Mönckeberg

. Der normale histologische bau und die sklerose der aortenklappen. Virchows Arch Pathol Anat Physiol Klin Med. 1904;176(3):472–514.

Fertman

Wolff

. Calcification of the mitral valve. Am Heart J. 1946;31:580–589.

Simon

Liu

. Calcification of the mitral valve annulus and its relation to functional valvular disturbance. Am Heart J. 1954;48(4):497–505.

Massera

Trivieri

Andrews

JPM

, et al. Disease activity in mitral annular calcification. Circ Cardiovasc Imaging. 2019;12(2):e008513.

Allison

Cheung

Criqui

Langer

Wright

. Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis. Circulation. 2006;113(6):861–866.

10.

Kizer

Wiebers

Whisnant

, et al. Mitral annular calcification, aortic valve sclerosis, and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study. Stroke. 2005;36(12):2533–2537.

11.

Okura

Nakada

Nogi

, et al. Prevalence of mitral annular calcification and its association with mitral valvular disease. Echocardiography. 2021;38(11):1907–1912.

12.

Kato

Guerrero

Padang

, et al. Prevalence and natural history of mitral annulus calcification and related valve dysfunction. Mayo Clin Proc. 2022;97(6):1094–1107.

13.

Savage

Garrison

Castelli

, et al. Prevalence of submitral (anular) calcium and its correlates in a general population-based sample (the Framingham Study). Am J Cardiol. 1983;51(8):1375–1378.

14.

Kanjanauthai

Nasir

Katz

, et al. Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2010;213(2):558–562.

15.

Santangelo

Bursi

Faggiano

, et al. The global burden of valvular heart disease: from clinical epidemiology to management. J Clin Med. 2023;12(6):2178.

16.

Abramowitz

Kazuno

Chakravarty

, et al. Concomitant mitral annular calcification and severe aortic stenosis: prevalence, characteristics and outcome following transcatheter aortic valve replacement. Eur Heart J. 2017;38(16):1194–1203.

17.

Faggiano

Dasseni

Gaibazzi

Rossi

Henein

Pressman

. Cardiac calcification as a marker of subclinical atherosclerosis and predictor of cardiovascular events: a review of the evidence. Eur J Prev Cardiol. 2019;26(11):1191–1204.

18.

Adler

Fink

Spector

Wiser

Sagie

. Mitral annulus calcification—a window to diffuse atherosclerosis of the vascular system. Atherosclerosis. 2001;155(1):1–8.

19.

Barasch

Gottdiener

Larsen

Chaves

Newman

Manolio

. Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). Am Heart J. 2006;151(1):39–47.

20.

Boon

Cheriex

Lodder

Kessels

. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve. Heart. 1997;78(5):472–474.

21.

Roberts

. The senile cardiac calcification syndrome. Am J Cardiol. 1986;58(6):572–574.

22.

Carabello

. Aortic sclerosis—a window to the coronary arteries? N Engl J Med. 1999;341(3):193–195.

23.

Faggiano

Santangelo

Carugo

Pressman

Picano

Faggiano

. Cardiovascular calcification as a marker of increased cardiovascular risk and a surrogate for subclinical atherosclerosis: role of echocardiography. J Clin Med. 2021;10(8):1668.

24.

Aksoy

Guler

Kahraman

, et al.

The relationship between mitral annular calcification, metabolic syndrome and thromboembolic risk.

Braz J Cardiovasc Surg. 2019;34(5):535–541.

25.

Tian

Feng

Zhan

, et al. Risk factors for new-onset cardiac valve calcification in patients on maintenance peritoneal dialysis. Cardiorenal Med. 2016;6(2):150–158.

26.

Fox

Larson

Vasan

, et al. Cross-sectional association of kidney function with valvular and annular calcification: the Framingham Heart Study. J Am Soc Nephrol. 2006;17(2):521–527.

27.

Faggiano

Pressman

. MAC in CKD and dialysis patients: pathophysiological doubts and clinical implications. Int J Cardiol. 2019;293:256–257.

28.

Roberts

Perloff

. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med. 1972;77(6):939–975.

29.

Silbiger

. Anatomy, mechanics, and pathophysiology of the mitral annulus. Am Heart J. 2012;164(2):163–176.

30.

Patlolla

Schaff

Nishimura

, et al. Mitral annular calcification in obstructive hypertrophic cardiomyopathy: prevalence and outcomes. Ann Thorac Surg. 2022;114(5):1679–1687.

31.

Elmariah

Delaney

Bluemke

, et al. Associations of LV hypertrophy with prevalent and incident valve calcification: multi-ethnic study of atherosclerosis. JACC Cardiovasc Imaging. 2012;5(8):781–788.

32.

Newcomb

David

Lad

Bobiarski

Armstrong

Maganti

. Mitral valve repair for advanced myxomatous degeneration with posterior displacement of the mitral annulus. J Thorac Cardiovasc Surg. 2008;136(6):1503–1509.

33.

Fusini

Ghulam Ali

Tamborini

, et al. Prevalence of calcification of the mitral valve annulus in patients undergoing surgical repair of mitral valve prolapse. Am J Cardiol. 2014;113(11):1867–1873.

34.

Hering

Faber

Horstkotte

. Echocardiographic features of radiation-associated valvular disease. Am J Cardiol. 2003;92(2):226–230.

35.

Lancellotti

Nkomo

Badano

, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013–1032.

36.

Lee

Hahn

. Valvular heart disease associated with radiation therapy: a contemporary review. Struct Heart. 2023;7(2):100104.

37.

Sabbagh A

Parikh

Ray

, et al. Mitral annulus calcium score in patients with calcific mitral stenosis undergoing invasive hemodynamic assessment. J Am Heart Assoc. 2024;13(3):e030540.

38.

Fox

Parise

Vasan

, et al. Mitral annular calcification is a predictor for incident atrial fibrillation. Atherosclerosis. 2004;173(2):291–294.

39.

O’Neal

Efird

Nazarian

Alonso

Heckbert

Soliman

. Mitral annular calcification and incident atrial fibrillation in the multi-ethnic study of atherosclerosis. Europace. 2015;17(3):358–363.

40.

O’Neal

Efird

Nazarian

, et al. Mitral annular calcification progression and the risk of atrial fibrillation: results from MESA. Eur Heart J Cardiovasc Imaging. 2018;19(3):279–284.

41.

Yao

Zhang

Xue

, et al. Echocardiographic mitral annular calcification is associated with atrial fibrillation recurrence after catheter ablation. Am J Cardiol. 2023;193(193):55–60.

42.

Huang

. Mitral annular calcification is associated with atrial fibrillation and major cardiac adverse events in atrial fibrillation patients: a systematic review and meta-analysis. Medicine (Baltimore). 2019;98(44):e17548.

43.

Gardin

McClelland

Kitzman

, et al. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the cardiovascular health study). Am J Cardiol. 2001;87(9):1051–1057.

44.

Barasch

Gottdiener

Marino Larsen

Chaves

Newman

. Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (the cardiovascular health study). Am J Cardiol. 2006;97(9):1281–1286.

45.

Fox

Vasan

Parise

, et al. Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation. 2003;107(11):1492–1496.

46.

Fox

Harkins

Taylor

, et al. Epidemiology of mitral annular calcification and its predictive value for coronary events in African Americans: the Jackson cohort of the atherosclerotic risk in communities study. Am Heart J. 2004;148(6):979–984.

47.

Volzke

Haring

Lorbeer

, et al. Heart valve sclerosis predicts all-cause and cardiovascular mortality. Atherosclerosis. 2010;209(2):606–610.

48.

Taylor

Ordonez-Mena

Jones

, et al. Survival of people with valvular heart disease in a large, English community-based cohort study. Heart. 2021;107(16):1336–1343.

49.

Gaibazzi

Rigo

Facchetti

, et al. Differential incremental value of ultrasound carotid intima-media thickness, carotid plaque, and cardiac calcium to predict angiographic coronary artery disease across Framingham risk score strata in the APRES multicentre study. Eur Heart J Cardiovasc Imaging. 2016;17(9):991–1000.

50.

Gupta

Romero-Corral

, et al. Cardiac calcifications on echocardiography are associated with mortality and stroke. J Am Soc Echocardiogr. 2016;29(12):1171–1178.

51.

Gaibazzi

Porter

Agricola

, et al. Prognostic value of echocardiographic calcium score in patients with a clinical indication for stress echocardiography. JACC Cardiovasc Imaging. 2015;8(4):389–396.

52.

Pressman

Crudu

Parameswaran-Chandrika

Romero-Corral

Purushottam

Figueredo

. Can total cardiac calcium predict the coronary calcium score? Int J Cardiol. 2011;146(2):202–206.

53.

Gaibazzi

Baldari

Faggiano

, et al. Cardiac calcium score on 2D echo: correlations with cardiac and coronary calcium at multi-detector computed tomography. Cardiovasc Ultrasound. 2014;12:43.

54.

Gaibazzi

Suma

Garibaldi

, et al. Visually assessed coronary and cardiac calcium outperforms perfusion data during scintigraphy in the prediction of adverse outcomes. Int J Cardiol. 2020;312:123–128.

55.

Oni

Boakye

Pressman

, et al. The association of mitral annular calcification with cardiovascular and noncardiovascular outcomes: the multi-ethnic study of atherosclerosis. Am J Cardiol. 2024;225:75–83.

56.

Pressman

Rodriguez-Ziccardi

Gartman

, et al. Mitral annular calcification as a possible nidus for endocarditis: a descriptive series with bacteriological differences noted. J Am Soc Echocardiogr. 2017;30(6):572–578.

57.

Kumar

Samra

Kaur

Ogunnowo

Kocyigit

. Mitral annular calcification related infective endocarditis: a contemporary systematic review. Curr Probl Cardiol. 2023;48(3):101558.

58.

Movva

Murthy

Romero-Corral

Seetha Rammohan

Fumo

Pressman

. Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function. J Am Soc Echocardiogr. 2013;26(10):1135–1142.

59.

Kohsaka

Jin

Rundek

, et al. Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study. JACC Cardiovasc Imaging. 2008;1(5):617–623.

60.

Jassal

Tam

Bhagirath

, 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. 2008;29(12):1542–1547.

61.

Eleid

Foley

Said

Pislaru

Rihal

. Severe mitral annular calcification: multimodality imaging for therapeutic strategies and interventions. JACC Cardiovasc Imaging. 2016;9(11):1318–1337.

62.

Guerrero

Wang

Pursnani

, et al. A cardiac computed tomography-based score to categorize mitral annular calcification severity and predict valve embolization. JACC Cardiovasc Imaging. 2020;13(9):1945–1957.

63.

Movahed

Ahmadi-Kashani

Kasravi

Saito

. Increased prevalence of mitral stenosis in women. J Am Soc Echocardiogr. 2006;19(7):911–913.

64.

Labovitz

Nelson

Windhorst

Kennedy

Williams

. Frequency of mitral valve dysfunction from mitral anular calcium as detected by Doppler echocardiography. Am J Cardiol. 1985;55(1):133–137.

65.

Roberts

. Morphologic features of the normal and abnormal mitral valve. Am J Cardiol. 1983;51(6):1005–1028.

66.

Sugihara

Matsuzaki

. The influence of severe bone loss on mitral annular calcification in postmenopausal osteoporosis of elderly Japanese women. Jpn Circ J. 1993;57(1):14–26.

67.

Seo

Jeong

Cho

Hong

Shim

. Sex differences in mitral annular calcification and the clinical implications. Front Cardiovasc Med. 2021;8:736040.

68.

Churchill

Yucel

Bernard

, et al. Sex differences in extensive mitral annular calcification with associated mitral valve dysfunction. Am J Cardiol. 2023;193:83–90.

69.

Saijo

Okushi

Gillinov

, et al. Sex-related differences in outcomes and prognosis of severe calcific mitral stenosis due to mitral annular calcification: a propensity-score matched cohort study. Int J Cardiol. 2025;421:132893.

70.

Massera

Buzkova

Bortnick

, et al. Bone mineral density and long-term progression of aortic valve and mitral annular calcification: the multi-ethnic study of atherosclerosis. Atherosclerosis. 2021;335:126–134.

71.

Lee

Seo

Gwak

, et al. Risk factors and outcomes with progressive mitral annular calcification. J Am Heart Assoc. 2023;12(18):e030620.

72.

Koshkelashvili

Codolosa

Goykhman

Romero-Corral

Pressman

. Distribution of mitral annular and aortic valve calcium as assessed by unenhanced multidetector computed tomography. Am J Cardiol. 2015;116(12):1923–1927.

73.

Massera

Kizer

Dweck

. Mechanisms of mitral annular calcification. Trends Cardiovasc Med. 2020;30(5):289–295.

74.

Guerrero

Grayburn

Smith

II , et al. Diagnosis, classification, and management strategies for mitral annular calcification: a heart valve collaboratory position statement. JACC Cardiovasc Interv. 2023;16(18):2195–2210.

75.

Mainigi

Chebrolu

Romero-Corral

, et al. Prediction of significant conduction disease through noninvasive assessment of cardiac calcification. Echocardiography. 2012;29(9):1017–1021.

76.

Nair

Runco

Everson

, et al. Conduction defects and mitral annulus calcification. Br Heart J. 1980;44(2):162–167.

77.

Ragupathi

Johnson

Greenspon

Frisch

Pavri

. Clinical and electrophysiological characteristics of patients with paroxysmal intra-His block with narrow QRS complexes. Heart Rhythm. 2018;15(9):1372–1377.

78.

Takamoto

Nitta

Taniguchi

. Conduction disturbances associated with mitral anular calcification. Bull Tokyo Med Dent Univ. 1987;34(3):61–68.

79.

Rasmussen

Fredgart

Lindholt

, et al. Mitral annulus calcification and cardiac conduction disturbances: a DANCAVAS sub-study. J Cardiovasc Imaging. 2022;30(1):62–75.

80.

Okuno

Brugger

Asami

, et al. Clinical impact of mitral calcium volume in patients undergoing transcatheter aortic valve implantation. J Cardiovasc Comput Tomogr. 2021;15(4):356–365.

81.

Watanabe

Ogasawara

Yamaura

, et al. Quantitation of mitral valve tenting in ischemic mitral regurgitation by transthoracic real-time three-dimensional echocardiography. J Am Coll Cardiol. 2005;45(5):763–769.

82.

Henry

Cotella

Mor-Avi

, et al. Three-Dimensional transthoracic static and dynamic normative values of the mitral valve apparatus: results from the multicenter world alliance societies of echocardiography study. J Am Soc Echocardiogr. 2022;35(7):738–751.e1.

83.

van Wijngaarden

Kamperidis

Regeer

, et al. Three-dimensional assessment of mitral valve annulus dynamics and impact on quantification of mitral regurgitation. Eur Heart J Cardiovasc Imaging. 2018;19(2):176–184.

84.

Pressman

Movva

Topilsky

, et al. Mitral annular dynamics in mitral annular calcification: a three-dimensional imaging study. J Am Soc Echocardiogr. 2015;28(7):786–794.

85.

Goody

Hosen

Christmann

, et al. Aortic valve stenosis: from basic mechanisms to novel therapeutic targets. Arterioscler Thromb Vasc Biol. 2020;40(4):885–900.

86.

Chehab

Roberts-Thomson

Bivona

, et al. Management of patients with severe mitral annular calcification: JACC state-of-the-art review. J Am Coll Cardiol. 2022;80(7):722–738.

87.

Elmariah

Budoff

Delaney

, et al. Risk factors associated with the incidence and progression of mitral annulus calcification: the multi-ethnic study of atherosclerosis. Am Heart J. 2013;166(5):904–912.

88.

Muddassir

Pressman

. Mitral annular calcification as a cause of mitral valve gradients. Int J Cardiol. 2007;123(1):58–62.

89.

Iung

Baron

Butchart

, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on valvular heart disease. Eur Heart J. 2003;24(13):1231–1243.

90.

Gilon

Cape

Handschumacher

, et al. Insights from three-dimensional echocardiographic laser stereolithography. Effect of leaflet funnel geometry on the coefficient of orifice contraction, pressure loss, and the Gorlin formula in mitral stenosis. Circulation. 1996;94(3):452–459.

91.

Thomas

Newell

Choong

Weyman

. Physical and physiological determinants of transmitral velocity: numerical analysis. Am J Physiol. 1991;260(5 Pt 2):H1718–H1731.

92.

Miranda

Sabbagh

Jain

Pellikka

Nishimura

. Inaccuracy of pressure half-time method for valve area in mitral stenosis related to annular calcification. Am J Cardiol. 2024;230:1–2.

93.

Baumgartner

Hung

Bermejo

, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr. 2009;22(1):1–23. quiz 101–2.

94.

Oktay

Riehl

Kachur

, et al. Dimensionless index of the mitral valve for evaluation of degenerative mitral stenosis. Echocardiography. 2020;37(10):1533–1542.

95.

Chu

Levine

Chua

, et al. Assessing mitral valve area and orifice geometry in calcific mitral stenosis: a new solution by real-time three-dimensional echocardiography. J Am Soc Echocardiogr. 2008;21(9):1006–1009.

96.

Churchill

Yucel

Deferm

Levine

Hung

Bertrand

. Mitral valve dysfunction in patients with annular calcification: JACC review topic of the week. J Am Coll Cardiol. 2022;80(7):739–751.

97.

Weissler-Snir

Weisenberg

Natanzon

et al. Clinical and echocardiographic features of mitral annular calcium in patients aged </=50 years. Am J Cardiol 2015;116(9):1447–1450.

98.

Al-Abcha

Abbasi

El-Am

, et al. Staging extramitral cardiac damage in mitral annular calcification with mitral valve dysfunction. JACC Cardiovasc Interv. 2024;17(13):1577–1590.

99.

Raut

Maheshwari

Swain

. Awareness of ‘systolic anterior motion’ in different conditions. Clin Med Insights Cardiol. 2018;12:1179546817751921.

100.

Silbiger

. Abnormalities of the mitral apparatus in hypertrophic cardiomyopathy: echocardiographic, pathophysiologic, and surgical insights. J Am Soc Echocardiogr. 2016;29(7):622–639.

101.

Friend

Wiener

Murthy

Peterson

Al-Sudani

Pressman

. Systolic anterior motion of the mitral valve in the presence of annular calcification. J Am Soc Echocardiogr. 2023;36(4):421–427.

102.

Qamruddin

Pressman

. Determining severity of mitral stenosis due to annular calcification. Am J Cardiol. 2020;125(1):161–162.

103.

Codolosa

Koshkelashvili

Alnabelsi

Goykhman

Romero-Corral

Pressman

. Effect of mitral annular calcium on left ventricular diastolic parameters. Am J Cardiol. 2016;117(5):847–852.

104.

Nagueh

Smiseth

Appleton

, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Eardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–314.

105.

Abudiab

Chebrolu

Schutt

Nagueh

Zoghbi

. Doppler echocardiography for the estimation of LV filling pressure in patients with mitral annular calcification. JACC Cardiovasc Imaging. 2017;10(12):1411–1420.

106.

Haines

Dickey

Chambers

Ogunsua

Aurigemma

. Evaluating a decision tool for diagnosing diastolic dysfunction and estimation of left ventricular filling pressures in the presence of mitral annular calcium. Echocardiography. 2020;37(11):1757–1765.

107.

Pasca

Dang

Tyagi

Pai

. Survival in patients with degenerative mitral stenosis: results from a large retrospective cohort study. J Am Soc Echocardiogr. 2016;29(5):461–469.

108.

Bertrand

Churchill

Yucel

, et al. Prognostic importance of the transmitral pressure gradient in mitral annular calcification with associated mitral valve dysfunction. Eur Heart J. 2020;41(45):4321–4328.

109.

Reddy

YNV

Murgo

Nishimura

. Complexity of defining severe “stenosis” from mitral annular calcification. Circulation. 2019;140(7):523–525.

110.

Pressman

Ranjan

Park

Shim

Hong

. Degenerative mitral stenosis versus rheumatic mitral stenosis. Am J Cardiol. 2020;125(10):1536–1542.

111.

Zoghbi

Levine

Flachskampf

, et al. Atrial functional mitral regurgitation: a JACC: cardiovascular imaging expert panel viewpoint. JACC Cardiovasc Imaging. 2022;15(11):1870–1882.

112.

Guazzi

Borlaug

. Pulmonary hypertension due to left heart disease. Circulation. 2012;126(8):975–990.

113.

Museedi

Le Jemtel

. Mitral annular calcification-related valvular disease: a challenging entity. J Clin Med. 2024;13(3):896.

114.

Akins

Travis

Yoganathan

. Energy loss for evaluating heart valve performance. J Thorac Cardiovasc Surg. 2008;136(4):820–833.

115.

Morisawa

Falahatpisheh

Avenatti

Little

Kheradvar

. Intraventricular vortex interaction between transmitral flow and paravalvular leak. Sci Rep. 2018;8(1):15657.

116.

Carabello

. The pathophysiology of afterload mismatch and ventricular hypertrophy. Structural Heart. 2021;5(5):446–456.

117.

Katholi

Couri

. Left ventricular hypertrophy: major risk factor in patients with hypertension: update and practical clinical applications. Int J Hypertens. 2011;2011:495349.

118.

Rossi

Gheorghiade

Triposkiadis

Solomon

Pieske

Butler

. Left atrium in heart failure with preserved ejection fraction: structure, function, and significance. Circ Heart Fail. 2014;7(6):1042–1049.

119.

Kheradvar

Gharib

. On mitral valve dynamics and its connection to early diastolic flow. Ann Biomed Eng. 2009;37(1):1–13.

120.

Kheradvar

Assadi

Falahatpisheh

Sengupta

. Assessment of transmitral vortex formation in patients with diastolic dysfunction. J Am Soc Echocardiogr. 2012;25(2):220–227.

121.

Son

Park

Choi

, et al. Abnormal left ventricular vortex flow patterns in association with left ventricular apical thrombus formation in patients with anterior myocardial infarction: a quantitative analysis by contrast echocardiography. Circ J. 2012;76(11):2640–2646.

122.

Vasudevan

Low

AJJ

Annamalai

, et al. Role of diastolic vortices in flow and energy dynamics during systolic ejection. J Biomech. 2019;90:50–57.

123.

Falahatpisheh

Pahlevan

Kheradvar

. Effect of the mitral valve’s anterior leaflet on axisymmetry of transmitral vortex ring. Ann Biomed Eng. 2015;43(10):2349–2360.

124.

Kheradvar

Rickers

Morisawa

Kim

Hong

Pedrizzetti

. Diagnostic and prognostic significance of cardiovascular vortex formation. J Cardiol. 2019;74(5):403–411.

125.

Hong

Pedrizzetti

Tonti

, et al. Characterization and quantification of vortex flow in the human left ventricle by contrast echocardiography using vector particle image velocimetry. JACC Cardiovasc Imaging. 2008;1(6):705–717.

126.

Chan

JSK

Lau

DHH

Fan

Lee

. Age-related changes in left ventricular Vortex Formation and Flow Energetics. J Clin Med. 2021;10(16):3619.

127.

Abe

Caracciolo

Kheradvar

, et al. Contrast echocardiography for assessing left ventricular vortex strength in heart failure: a prospective cohort study. Eur Heart J Cardiovasc Imaging. 2013;14(11):1049–1060.

128.

Gharib

Rambod

Kheradvar

Sahn

Dabiri

. Optimal vortex formation as an index of cardiac health. Proc Natl Acad Sci U S A. 2006;103(16):6305–6308.

129.

Ambhore

Ngiam

Chew

NWS

, et al. Optimal vortex formation time index in mitral valve stenosis. Int J Cardiovasc Imaging. 2021;37(5):1595–1600.

130.

Van Hemelrijck

Taramasso

Gulmez

Maisano

Mestres

. Mitral annular calcification: challenges and future perspectives. Indian J Thorac Cardiovasc Surg. 2020;36(4):397–403.

131.

Faludi

Szulik

D'Hooge

, et al. Left ventricular flow patterns in healthy subjects and patients with prosthetic mitral valves: an in vivo study using echocardiographic particle image velocimetry. J Thorac Cardiovasc Surg. 2010;139(6):1501–1510.

132.

Elbaz

van der Geest

Calkoen

, et al. Assessment of viscous energy loss and the association with three-dimensional vortex ring formation in left ventricular inflow: in vivo evaluation using four-dimensional flow MRI. Magn Reson Med. 2017;77(2):794–805.

133.

Sengupta

Narula

Chandrashekhar

. The dynamic vortex of a beating heart: wring out the old and ring in the new!. J Am Coll Cardiol. 2014;64(16):1722–1724.

134.

Agafonov

Talygin

Bockeria

Gorodkov

. The hydrodynamics of a swirling blood flow in the left heart and aorta. Acta Naturae. 2021;13(4):4–16.

135.

Kheradvar

Pedrizzetti

. Vortex formation in the cardiovascular system. Springer-Verlag; 2012.

136.

Jameel

Zhang

. Myocardial energetics in left ventricular hypertrophy. Curr Cardiol Rev. 2009;5(3):243–250.

137.

Dai

Chen

Johnson

Szeto

Rabinovitch

. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012;16(12):1492–1526.

138.

Kato

Arimura

Shiga

Kuwano

Sugihara

Miura

. Association between mitral annulus calcification and subtypes of heart failure rehospitalization. Cardiol J. 2023;30(2):256–265.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB

Clinical and Hemodynamic Implications of Mitral Annular Calcification

Abstract

Keywords

Key points

Introduction

Prevalence and Associated Conditions

Atherosclerosis

Chronic Kidney Disease and Abnormal Calcium–Phosphorus Metabolism

Clinical Conditions with Increased Mitral Valve Stress and Tension

Chest Irradiation

Atrial Fibrillation

Prognostic Value as a Marker of Cardiovascular Risk

Anatomic Distribution and Effects on Valve Geometry

Variation by Sex

Posterior Annulus Versus Interannular Fibrosa

Effects on Leaflet Function

Effects on Annular Function

Time Course and Determinants of Progression

Hemodynamics—Due to MAC and Interaction with Associated Conditions

Stenosis with Comparisons to Rheumatic Disease

Regurgitation

Systolic Anterior Motion (SAM) of the Mitral Valve

Left Ventricular Diastolic Function

Interpretation of Doppler Gradients in Severe MAC

Chamber Compliance, Vortex Formation, and Energy Losses

Conclusion

Supplemental Material

sj-docx-1-hvs-10.1177_30494826251347539 - Supplemental material for Clinical and hemodynamic implications of mitral annular calcification

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Footnotes

Funding

Declaration of conflicting interests

ORCID iDs

Supplemental material

References

Supplementary Material