JACC: CARDIOVASCULAR IMAGING VOL. 9, NO. 11, 2016

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PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jcmg.2016.09.001

STATE-OF-THE-ART PAPERS Severe Mitral Annular Calcification Multimodality Imaging for Therapeutic Strategies and Interventions

Mackram F. Eleid, MD, Thomas A. Foley, MD, Sameh M. Said, MD, Sorin V. Pislaru, MD, PHD, Charanjit S. Rihal, MD, MBA

ABSTRACT

Mitral annular calcification (MAC) is a chronic degenerative process associated with advanced age and conditions predisposing to left ventricular hypertrophy. Assessment of mitral valve disease in patients with severe MAC can be a challenge. When severe MAC results in mitral stenosis or regurgitation, multimodality imaging with 2-dimensional, 3-dimensional, and Doppler and cardiac computed tomography angiography can delineate the severity and pathoanatomic features to help guide therapeutic strategies. New approaches using computer-assisted simulation of transcatheter valves and novel percutaneous and surgical techniques are being used to devise effective alternative strategies to conventional mitral in this high-risk group of patients. (J Am Coll Cardiol Img 2016;9:1318–37) © 2016 by the American College of Cardiology Foundation.

itral annular calcification (MAC) is a being investigated, offering hope for this challenging M chronic degenerative process that, when group of patients. severe, can result in mitral stenosis (MS) and/or mitral regurgitation (MR). The prevalence of PATHOPHYSIOLOGY OF MAC significant MS due to severe MAC is increasing in the developed world due to the growing population MAC is a result of slowly progressive calcification of ofelderlypatientsandriskfactorssuchashyperten- the fibrous mitral annulus (Figure 1) (1). The estimated sive and radiation disease. Treatment options prevalence of MAC is 10%, with the posterior annulus for severe MAC are limited. With no specificmedical being more commonly affected than the anterior therapy for MAC, treatment is symptomatic. Balloon annulus (1).MACthatresultsinanelevationinthe valvuloplasty is not suitable for MS due to MAC and mean transmitral gradient is relatively rare, occurring mitral valve surgery is associated with excessive in 0.2% of patients undergoing transthoracic echo- morbidity and mortality in patients with extensive cardiography, with prevalence increasing to 2.5% in annular calcification. Additionally, the complex anat- patients >90 years of age (2,3). omy of the mitral apparatus and challenging left ven- Risk factors for MAC include advanced age, female tricular (LV) geometry in patients with severe MAC sex, chronic kidney disease, and conditions predis- pose unique challenges to minimally invasive mitral posing to LV hypertrophy including and valve implantation using transcatheter devices. aortic stenosis (4). Prior chest irradiation, most Recent advances in multimodality commonly as a treatment for Hodgkin’s lymphoma, is and novel percutaneous and surgical techniques are another cause of MAC, often in combination with

From the Department of Cardiovascular Diseases and Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received June 27, 2016; revised manuscript received August 29, 2016, accepted September 1, 2016. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1319 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

aortic valve disease and restrictive cardiomyopathy. can be gathered by 2-dimensional (2D) imag- ABBREVIATIONS MAC appears to be a multifactorial condition result- ing, the en face atrial and ventricular views AND ACRONYMS ing from a varying combination of abnormal calcium of the mitral valve at 3-dimensional (3D) CTA = computed tomography and phosphorus metabolism (5), increased mitral imaging provides the best information for angiography valve hemodynamic stress (6), and atherosclerotic topographical description of the mitral valve, LV = left ventricular processes (7–10). Although MAC is typically confined and was a key development for the growing LVOT = left ventricular fl to the mitral annulus and the base of the lea ets, in number of percutaneous interventions. outflow tract fi some cases MS can occur when calci cation extends Direct visualization of the extent and MAC = mitral annular further into the leaflets, particularly the anterior magnitude of MAC with 3D imaging is a use- calcification leaflet, resulting in restricted mobility (9). An impor- ful adjunct to understand the severity of MS MR = mitral regurgitation tant distinction compared to rheumatic MS is that in and for determination of therapeutic options. MS = mitral stenosis fl MS due to MAC, there is lack of mitral lea et Whenever MS is suspected on the 2D/3D PISA = proximal isovelocity commissural fusion (Figure 2). images, careful quantitation of disease surface area

In isolated MAC, valve leaflet motion is preserved, severity must be performed by measuring TEE = transesophageal and ventricular filling occurs unimpeded. However, mitral valve gradient and mitral valve area. echocardiography over time calcific degeneration tends to further This information is critical for further clinical TTE = transthoracic expand into the leaflets resulting in impaired mobility decisions in patient management. echocardiography and geometric distortion. These anatomic changes Mitral valve gradients are estimated from the typically lead to development of both MS and MR. continuous wave (CW) Doppler spectrum obtained Either lesion may be dominant in a given patient, but from apical (TTE) or mid-esophageal (TEE) windows. more commonly there is mixed disease. When MS or We recommend that color Doppler imaging is first MR become severe, heart failure symptoms including performed to assess which imaging view allows for dyspnea and exercise intolerance may ensue. the best alignment of the CW Doppler line of inter- rogation with the direction of mitral inflow. The mean ASSESSMENT OF MS IN SEVERE MAC gradient is derived by integrating the CW velocity spectral envelope, and closely correlates with the Echocardiography is particularly well suited for gradient directly measured at catheterization (11). anatomic and physiological assessment of valvular The mitral gradient cannot be used in isolation for function, and is the cornerstone in assessment of quantitating MS severity because it is highly depen- calcific mitral valve disease. We recommend a sys- dent on factors other than stenotic area, most notably tematic approach to diagnosis, which should include on heart rate, cardiac output, and associated MR (12). assessment of qualitative (visual appearance, calcifi- Mitral valve area by continuity equation is the cation, thickening, leaflet mobility, adequacy of recommended method in the case of calcificMS(12), coaptation) and quantitative parameters (mitral valve but its value is limited in the presence of concomitant area, gradients, indices of regurgitation severity). At aortic and mitral valve regurgitation. Direct planim- the completion of the imaging study, internal con- etry may be challenging in calcific degeneration of the sistency between visual cues, measured parameters, valve (12); 3D technology seems to improve accuracy and clinical findings must be verified. and reproducibility of planimetric measurements. Visual inspection of the entire mitral apparatus Whenever TTE evaluation is inconclusive, we should be systematic. We begin with assessment of recommend additional TEE imaging; 3D-TEE extent of annular calcification (focal vs. circumfer- planimetry of valve area is feasible in the majority of ential), best achieved on short-axis views of the mitral patients (Figure 3). Pressure half-time is influenced by valve (parasternal short-axis at the base on trans- numerous factors beyond MS severity (left atrial and thoracic echocardiography [TTE], or short-axis from ventricular compliance, delayed ventricular relaxa- the gastro-esophageal junction on transesophageal tion, concomitant aortic regurgitation), and has echocardiography [TEE]). If short-axis images are limited utility in estimating mitral valve area in unavailable, inspection of the mitral annulus by elderly patients with calcificMS.Theinflow proximal rotating the imaging plane from the apical (TTE) or isovelocity surface area (PISA) method can also be mid-esophageal windows (TEE) allows systematic used for estimating mitral valve area, but is highly evaluation of circumferential extent. Visual inspec- dependent on operator experience, image quality, tion of the mitral leaflets should describe presence and correct measurement of the PISA radius and and location of degenerative changes, their location angle of leaflet correction. For patients with symp- according to the Carpentier nomenclature, and extent toms that are disproportionate to the resting mitral from base to coaptation line. While all information valve gradient and/or valve area, an exercise or 1320 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

for accurate assessment of the mean transmitral FIGURE 1 Mitral Annular Calcification gradient and also provides valuable insight into the compliance properties of the left and the LV diastolic function. Concomitant measurement of cardiac output with simultaneous right heart cathe- terization will allow for measurement of the mitral valve area using the Gorlin formula. Hemodynamics and loading conditions can be manipulated to assess valve function under conditions of higher heart rates and volume conditions.

ASSESSMENT OF MR IN SEVERE MAC

Beyond qualitative assessment of mitral valve appa- ratus (described in the preceding text), assessment of MR relies on color Doppler imaging and quantitative measurements of regurgitation severity. TTE evalua- tion of presence and extent of MR in calcific degen- erative mitral disease is frequently hampered by the acoustic shadowing of the left atrium. The absence of color Doppler signal in the left atrium does not rule out MR. We recommend a “blind” CW sweep of the left atrium (which sometimes detects the signature MR spectrum), or imaging of the left atrial dome above the MAC (for instance in parasternal short-axis at aortic valve level) may also show presence of regurgitation, and is often an underutilized view. TEE is excellent for detection and quantitation of MR,astheprobeislocatedjustbehindtheleft atrium, with unimpeded views. 3D color Doppler is particularly useful in clarifying number and location of regurgitant jets, critical for planning percutaneous interventions. We find particularly useful the 3D en face view of the mitral valve from the ventricular side; this view allows reliable identification of jet(s) origin, as well as detection of functional and nonfunctional cleft-like indentations in the mitral leaflets (13). We prefer the PISA method for quantitation of MR

(A) Parasternal short-axis at the level of the mitral annulus shows severe mitral severity. The method is robust (14), allows estimation annular calcification (MAC) involving the posterior annulus (arrows). (B) Gated cardiac of anatomic disease severity (effective regurgitant computed tomographic angiography with 3-dimensional (3D) reconstruction shows nearly orifice) and hemodynamic burden (regurgitant vol- circumferential severe MAC in the same patient. ume), and, unlike the continuity method, is not influenced by concomitant presence of aortic regur- gitation. PISA-derived indexes have validated clinical pharmacologic stress hemodynamic echocardio- impact, and are incorporated in all guidelines for graphic study examining the changes in mean management of MR (15,16).AswithMS,internal gradient, valve area, and right ventricular systolic consistency of the echocardiographic report must be pressure with stress can help establish severity of MS. verified for a valid assessment (i.e., When severe MR In cases where the severity of MS is uncertain, a is suspected, are the left and left atrium carefully performed invasive hemodynamic assess- enlarged? Are systolic flow reversals present in the ment with can be useful to pulmonary veins? Are the measured LV outflow tract clarify the severity of MS. Direct measurement of [LVOT] stroke volume, LV end-diastolic volume, and simultaneous left atrial and LV pressure is necessary MR regurgitant volume compatible?). JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1321 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 2 Unique Features of Calcific Mitral Stenosis

The left atrial (A) and left ventricular (B) views show calcific mitral stenosis (MS) is characterized by disease progression from the mitral annulus towards the leaflet tips. Calcific MS usually involves the posterior annulus, but in this patient the intertrigonal and anterior leaflet portions of the valve are also calcified (circumferential disease). Note that leaflet mobility is reduced with restricted opening, but that commissures are not fused. The left atrial (C) and left ventricle (D) views show that, in contrast, rheumatic MS is characterized by inflammatory process that usually involves the leaflet tip and results in commissural fusion.

When MR severity remains unclear or there is evaluate for the presence, location, and extent of discordance between physical examination findings mitral calcificationsaswellastoevaluateother and echocardiography, cardiac catheterization with cardiac and extracardiac structures. left ventriculography is a useful adjunct to either Both noncontrast and contrast-enhanced CT confirm or rule out significant MR (15,17). scans can be used to assess mitral calcifications. Methods have been developed using noncontrast CT COMPUTED TOMOGRAPHIC IMAGING OF MAC scans to quantify the amount of mitral annular calcification (18). Noncontrast examinations, how- Computed tomography (CT) is a versatile noninva- ever, are limited for evaluation of other cardiac sive imaging modality that provides complementary structures. Intravenous contrast is needed to opa- data to echocardiography in the evaluation of the cify the cardiac blood pool so the mitral valve mitral valve and MAC (18–20).Calcification is espe- leaflets and myocardium can be differentiated from cially well seen on CT due to its high x-ray attenu- blood in the cardiac chambers as these structures ation and because of the high spatial resolution of have similar imaging characteristics on noncontrast CT. CT has been shown to have a higher accuracy for examinations (Figure 4). the detection of cardiac calcifications than other For this reason, we perform a retrospectively ECG- imaging modalities (3,21).Mitralcalcifications are gated CT with intravenous contrast for pre- often detected incidentally on CT scans of the chest procedural planning of patients with MAC. ECG or abdomen (19). Dedicated electrocardiogram gating reduces motion artifact from cardiac motion (ECG)–gated cardiac CT scans can be performed to andwithretrospectivegating,multiphasicimages 1322 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

FIGURE 3 Mitral Valve Area in Severe Mitral Annular Calcification

Determining correct mitral valve area in calcific mitral stenosis can be challenging. Whenever 3D echocardiographic images are of good quality we recommend direct planimetry. This can be performed directly on the scanner on carefully selected ventricular en face views of the mitral valve (A), or on multiplanar-reconstructed images of the mitral orifice (C to F); note that cross-section plane is carefully aligned to the leaflet tips in orthogonal views. Pressure half-time (B) usually overestimated valve area due to concomitant diastolic dysfunction that is typically present in this elderly group. MVA ¼ mitral valve area; PHT ¼ pressure half-time; other abbreviation as in Figure 1.

can be generated, allowing motion of the mitral valve The CT is used to determine the precise location leaflets and annulus to be evaluated. Intravenous and extent of MAC. The circumferential arch of cal- contrast is injected at a rate of 4 to 6 ml/s depending cifications is best viewed using multiplanar refor- on patient size and the scan is timed to optimize matting to create a short-axis view of the mitral opacification of the left atrium and ventricle using annulus. Also, CT can be used to determine whether contrast bolus tracking in the ascending . The there are mitral leaflet calcifications, subvalvular scan range includes the entire heart and ascending apparatus calcifications, or myocardial extension of aorta. To optimize image quality throughout the calcification (Figure 4) (19,20).CTisespeciallyuseful entirecardiaccycle,wedonotusedosemodulation. for detecting caseous calcification of the mitral Although this increases radiation dose, patients with annulus, which can be mistaken for an intracardiac significant MAC are usually elderly and the improved tumor, but rather is due to liquefaction of mitral image quality is believed to be necessary for proced- annular calcification. On CT, caseous calcification ure planning. generally appears as a uniform hyperdense mass JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1323 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 4 Caseous Degeneration of Mitral Annular Calcification and Extra-Annular Calcification

Noncontrast computed tomography (CT) (A) and CT angiogram (B) in a patient with caseous degeneration of mitral annular calcification. Note that contrast allows for visualization of adjacent myocardial structures and blood pool. Extra-annular calcification can involve the mitral valve leaflets (C, arrow), subvalvular apparatus, or the myocardium (D, arrow).

FIGURE 5 CT Measurement of Mitral Annular Area

The presence of circumferential annular calcification can be confirmed with reformatted CT images. Abbreviation as in Figure 4. 1324 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

magnetic resonance (CMR) sequences (27).Becauseof FIGURE 6 Aortomitral Angle this, we do not routinely use CMR to evaluate MAC or use CMR for procedure planning. As with CT scans, CMR results have been used to evaluate suspected cases of caseous calcification of the mitral annulus (22,27,28).CMRcanbeusedtoevaluatetheseverity of mitral valve stenosis and regurgitation in cases where echocardiography is nondiagnostic; however, this is not routinely performed in patients with MAC.

MULTIMODALITY IMAGING TO DETERMINE OPTIMAL TREATMENT STRATEGY

CARDIAC CT FOR PROCEDURAL PLANNING. Cardiac CT has taken on an essential role in planning of structural heart procedures, best demonstrated by its use in planning transcatheter aortic valve replace- ment. As novel procedures are being developed to treat mitral valve disease, including obstruction due to MAC, cardiac CT is becoming an integral tool in the planning these procedures. As with transcatheter planning, CT is an important tool both for assessment of surgical options and transcatheter device selection. Visual analysis of degree of MAC and measurements

A lower aortomitral angle (arrows) is associated with greater risk of left ventricular of the mitral annulus area can be performed with outflow tract obstruction. most standard CT post-processing software. Exten- sion of MAC into extra-annular structures that would increase the risk of surgical debridement can be easily along the mitral annulus surrounded by dense calci- visualized by CT. The presence of circumferential fications (22) (Figure 4). Although it is not routinely annular calcification, needed for optimal device performed, mitral valve planimetry can be used to anchoring of balloon-expandable prostheses, can be calculate a valve area, especially in patients with confirmed with reformatted CT images (Figure 5). limited quality echocardiographic images (23,24). Methods for measuring the mitral annular area in In addition to evaluation of mitral calcifications, patients with annular calcification have been re- CT is used to evaluate other cardiac structures during ported; however, a consensus technique for making the same examination. For patients in whom cardiac annular measurements has not been reached (29–31). surgical procedures are planned, CT angiography is More research is needed to determine the optimal often used to evaluate for , as technique for device sizing and for minimizing CT angiography is a well-established technique for complications. noninvasive evaluation of the coronary arteries (25). Three of the common conditions associated with Cardiac CT can also be used to evaluate the cardiac MAC, advanced age, female sex, and LV hypertrophy, anatomy, cardiac chamber volumes, ejection fraction, often lead to a management conundrum when andwallmotionandcanbeusedtoevaluatefor devising percutaneous treatment strategies owing to intracardiac thrombus (26). In patients with planned a heightened risk of LVOT obstruction in the setting interventional procedures on the mitral valve, CT is of small LV cavities with basal septal hypertrophy and used to evaluate the systemic arterial and venous more acute angulation between the aortic and mitral anatomy. CT is limited in that it does not allow for the valve planes (Figure 6). Furthermore, transcatheter visualization or quantification of mitral regurgitation mitral valve implantations can result in elongation of or transmitral gradients. the outflow tract by displacement of the anterior CARDIAC MAGNETIC RESONANCE OF MAC mitral valve leaflet (32),predisposingtoLVOT obstruction. In the global transcatheter mitral valve Calcifications are difficult to reliably visualize and replacement in native mitral valve disease with accurately quantify with conventional cardiac severe MAC registry, clinically significant LVOT JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1325 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

obstruction occurred in 6 of 64 (9.3%) patients FIGURE 7 ReformattedCTAngiogramforValveSizing undergoing balloon-expandable transcatheter mitral valve implantation (33). The angle between the aortic and mitral valves (termed “aortomitral angle”)may be predictive of LVOT obstruction (Figure 6). In addition to standard post-processing software, specialized software has been developed which can be used to place “virtual” prosthetic valves of various sizes in the mitral valve position. The virtual valve image is overlaid on the volumetric CT images showing relationship to the annular calcification and adjacent structures (Figure 7). Adequacy of valve fit, protrusion into the LVOT, and likelihood of LVOT obstruction can be assessed using these images (Figure 8). The measured LVOT area before and after mitral valve implantation is used to predict risk of obstruction using a formula proposed by Wang et al. (34) ([native LVOT area – neo LVOT area]/native LVOT area), although no specific cutpoint has been identi- fied as of yet (Figure 9). These variables can then be calculated with different relative atrial and ventric- ular valve positions (e.g., 40% atrial 60% ventricular, 50% atrial 50% ventricular, etc.) to determine proce- dural options for an individual patient (34). In addition to use in valve sizing and positioning, CT is useful for planning other aspects of the pro- CT angiogram reformatted in a short-axis view of the mitral annulus with a simulated 29- cedure. CT can also be used to predict optimal fluo- mm valve placed in the mitral position. There is circumferential annular calcification and roscopic angles for device placement. For transapical adequate apposition of the valve. LVOT ¼ left ventricular outflow tract; other abbreviation approaches, ideal rib space and LV access point as in Figure 4. for ideal trajectory can be determined.

FIGURE 8 3DReformattedCTWithTranscatheterValveSimulation

3D reformatted cardiac CT angiogram demonstrating (left) apical long axis view of a patient with severe MAC and 29 mm SAPIEN 3 (third generation balloon expandable valve) valve implanted in the 20% atrial 80% ventricular mitral position. (Right) Surgeon’s transaortic view demonstrating the ventricular aspect of the transcatheter valve protruding into the left ventricular outflow tract. Abbreviations as in Figures 1 and 4. 1326 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

FIGURE 9 CT Measurement of Baseline and Projected Left Ventricular Outflow Tract Area

CT angiogram reformatted to show the LVOT without and with (“Neo-LVOT”) (arrows) a simulated 29-mm valve placed in the mitral position. The LVOT area without the valve is 335 mm2 (top) and with the valve is 53 mm2 (bottom). Predicted percentage of obstruction is 84%. Abbreviations as in Figures 4 and 8.

In patients where a transatrial approach is planned, then integrated along with CT derived data to help extracardiac structures can be evaluated. CT can be predict the risk and anticipated risk of LVOT used for evaluating the adequacy of the systemic obstruction with either surgery or a transcatheter arterial and venous system when needed depending mitral valve implantation. In cases where severe basal on the planned approach. septal hypertrophy is present and there is a high risk of LVOT obstruction with percutaneous mitral valve ECHOCARDIOGRAPHY FOR PROCEDURAL PLANNING. 2D implantation, septal reduction therapy with either and is essential to charac- alcoholseptalablationorsurgicalmyectomywithor terize the LV geometry (LV dimensions and relative without anterior mitral leaflet resection can expand wall thickness), quantify the presence and severity of the LVOT width to facilitate . basal septal hypertrophy, LVOT width, the presence For the transseptal approach, TEE assessment of the of outflow tract obstruction at baseline, systolic mo- interatrial septum is important for planning of the tion of the mitral apparatus, and the length of the most appropriate septal puncture location and anterior mitral valve leaflet. All of these variables are for anticipated difficulty in crossing the septum JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1327 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 10 3D Printing for Procedural Simulation

A 3D printed model was created based on cardiac CTA in a patient with severe MAC. (A) Left ventricular view demonstrating the native LVOT and anterior mitral valve leaflet (AL). (B) Following implantation of a 29-mm third generation balloon expandable stent, displacement of the AL results in severe LVOT obstruction. (C, F) Subsequent resection of the AL restores patency of the LVOT with residual stent frame protruding into LVOT. (D) En face mitral valve view in the same patient with severe MAC. (E) Following third generation balloon expandable stent deployment a large paravalvular defect is present at the medial commissure. Abbreviations as in Figures 1, 3, and 7.

due to fibrosis, prior surgical repair, or lipomatous and route of access to the mitral annulus. In certain hypertrophy. cases, a physical 3D model can be printed using polymers that mimic tissue characteristics and which 3D PRINTING FOR PROCEDURAL SIMULATION. 3D allow actual bench testing of valves into the printed printing has emerged as a fabrication technique in models (Figure 10). This allows direct visual assess- many industries. Medical applications are also rapidly ment of the LVOT and adequacy of fit. As of now, emerging, whether for fabrication of medical devices there are no controlled studies showing the useful- or modeling of anatomy. The heart is an extremely ness of 3D printed models for improving procedure complex organ and it frequently is difficult to un- feasibility or success or improvements in patient derstand the precise 3D anatomy and spatial re- outcomes. lationships using 2D imaging representations. Using specialized software, volumetric medical images (CT, THERAPEUTIC OPTIONS FOR TREATMENT CMR, 3D echocardiography), can be used to create 3D OF SEVERE MAC printed life-size physical models of anatomic struc- tures. There are multiple different 3D printing tech- STANDARD MITRAL VALVE REPLACEMENT. Standard nologies available that vary in material properties, mitral valve replacement in the setting of severe MAC geometries that can be printed, print speed, and print represents a real challenge to the surgeon. Proper cost. These models are used to more intuitively debridement of the annulus with possible recon- visualize the extent of MAC, relationship of MAC and struction is necessary to ensure a well-seated pros- valve leaflets to adjacent structures such as the LVOT, thesis with no periprosthetic regurgitation and serves 1328 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

There are several surgical techniques that have FIGURE 11 Surgical Mitral Valve Replacement for Severe MAC been described to overcome the challenges associated with the presence of severe MAC: STANDARD ANNULAR DEBRIDEMENT WITH RECONSTRUCTION. This has been the standard technique in which the annulus is thoroughly debri- ded and all the calcium is removed (35). The calcium bar usually can be separated from the mitral annulus if the dissection is performed in the correct plane. When calcification extends to the underlying myocardium and/or includes one or both mitral leaf- lets as well as the subvalvular apparatus, the risk of debridement increases considerably. Because of these hazards, the decalcification process may not be suit- able to apply for a large number of patients. After debridement and decalcification, the annulus must be reconstructed before placement of the prosthesis. This can be accomplished using either an autologous or a bovine pericardial patch. Local tissue recon- struction can be performed as well using the non- calcified anterior leaflet which can be transposed to the posterior annulus (Figure 11). Despite being the “gold standard” procedure for severe MAC, this technique requires prolonged and aortic cross clamp times which further increases the morbidity of the procedure.

ULTRASONIC PULVERIZATION. Ultrasonic pulveri- zation using the Cavitron Ultrasonic Surgical Aspi- rator device (Integra, Plainsboro, New Jersey) have been used in the presence of calcificationssuchasin cases of constrictive pericarditis (37) and debride- ment of calcificaorticvalveleaflets. Some in- (Top) Intraoperative photo from the surgeon view looking through the left atrium showing vestigators have used this technique for debridement the debrided posterior mitral valve annulus and the mobilized anterior mitral leaflet that of MAC as well (38). will be used for reconstruction. (Bottom) Intraoperative photo of the same patient DEEP PERIANNULAR SUTURE PLACEMENT. showing the pledgeted prosthesis sutures in place through the translocated anterior mitral Placing leaflet. sutures deeply around the calcium bar is another po- tential option for prosthesis anchoring; however, this technique can result in injury of the circumflex coro- nary artery, which is close to the mitral valve annulus, to minimize the risk of particulate embolization. The especially in a left dominant coronary system (39). calcification process involves the posterior third of Furthermore, leaving the calcium bar untouched may the mitral annulus in the majority of patients but it increase the risk of periprosthetic regurgitation. may involve the entire circumference of the annulus INTRA-ATRIAL PROSTHESIS PLACEMENT. Some in approximately 1.5% of cases. On the vertical level, authors suggest intra-atrial placement of the mitral calcification is most commonly limited to the prosthesis (40,41).InthistechniqueaDacroncollaris annulus; however, extension to the leaflet tissues, added to enlarge the circumference of the prosthesis ventricular myocardium, and papillary muscle can sewing ring and then the collar is sutured to the left occur in some cases (35). The Achilles heel of this atrial wall above the mitral annulus. This technique operation is the risk of atrioventricular groove may be more appropriate for cases of severe mitral disruption with subsequent increase in morbidity and valve regurgitation due to the presence of a dilated mortality in addition to the time needed for the annulus but is difficult to accomplish when the main debridement and valve replacement (36). pathology is severe mitral stenosis as a subvalvular JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1329 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 12 Left Atrial-to-Left Ventricular Valved Conduit Technique

(Left) Artist illustration demonstrating left atrial-to-left ventricular valved conduit utilizing a mechanical prosthesis. Notice the direction and the location of the prosthesis in relation to the left ventricular apex. The inflow of the conduit is from the left atrial appendage. (Right) Post-operative CT scan with 3D reconstruction in the same patient showing the location and the direction of the conduit. This patient had previous coronary artery bypass surgery. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved. Abbreviations as in Figures 1 and 4.

level of obstruction will persist after placement of the of the severely calcified mitral annulus. Importantly, prosthesis. This approach may also be associated with this technique cannot be used as a stand-alone an increased risk of left atrial dissection and bleeding treatment for patients with significant MR due to due to the presence of a left atrial segment below the MAC,asthebypassisonlyatreatmentforMS. prosthesis that will be under LV pressure. Theleftatrialsideoftheconduitcanbesewn either to the left atrial appendage or the left atriot- LEFT ATRIAL–TO–LEFT VENTRICULAR APICAL omy incision site. Both bioprostheses and mechanical CONDUIT (MITRAL VALVE BYPASS). The concept of valves can be in the conduit depending on the patient mitral valve bypass using a valved conduit from the age and related comorbidities (Figure 12). Our pref- left atrium to the LV apex is not new and has been erence is to connect the inflow of the conduit to the previously reported as a treatment for congenital left atrial appendage and place the valve as close to mitral valve stenosis (42,43). For treatment of the LV apex as possible (44). This approach allows the severe MS due to MAC, mitral valve bypass is an conduit to take the shortest pathway, minimizing experimental therapy that avoids direct manipulation thehighpressurezonebetweentheLVapexandthe

TABLE 1 Proposed Mitral Annular Calcification Grading System

MAC Grade Annular Calcification Extra-Annular Calcification Therapeutic Options Grade 1 (Mild) Focal noncontiguous calcification limited None Standard mitral valve replacement to <180 total annular circumference Medical therapy alone Grade 2 (Moderate) Dense continuous calcification limited Posterior and/or anterior leaflet Standard mitral valve replacement to <270 total annular circumference calcification may be present (ifnoanteriorleaflet involvement) Transcatheter mitral valve replace- ment with dedicated devices LA-LV conduit (if < moderate MR) Medical therapy alone Grade 3 (Severe) Dense continuous calcification extending Posterior and/or anterior leaflet Transcatheter mitral valve replace- past the commissures into anterior calcification may be present. ment with balloon-expandable or annulus or complete circumferential Papillary muscle or ventricular dedicated devices MAC ($270 calcification arc) myocardial calcification may LA-LV conduit (if < moderate MR) be present Medical therapy alone

LA ¼ left atrial; LV ¼ left ventricular; MAC ¼ mitral annular calcification; MR ¼ mitral regurgitation. 1330 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

FIGURE 13 MAC Grading

Short-axis parasternal transthoracic echocardiography images (left) and CT angiography images (right) in corresponding patients are shown. (Top) Grade 1 (mild) MAC is characterized by scattered noncontiguous calcification limited to <180 total annular circumference (arrows). (Middle) Grade 2 (moderate) MAC is composed of dense continuous calcification limited to <270 total annular circumference (arrows). (Bottom) Grade 3 (severe) MAC is defined as dense continuous calcification extending past the commissures into anterior annulus or complete circumferential MAC ($270 calcification arc [arrows]). Abbreviations as in Figures 1 and 5. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1331 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 14 Paravalvular Leak Closure After Transatrial SAPIEN Implantation for Severe MAC

(Left) A patient with severe posteromedial paravalvular leak following transatrial third generation balloon expandable valve implantation underwent mitral paravalvular leak closure via antegrade transseptal approach. (Right) Two Amplatzer vascular plug II devices are visualized posterior to the third generation balloon expandable valve prosthesis.

prosthesis. In those patients where the left atrial mitral position. In the largest multicenter experience appendage is too friable or has been ligated or of first generation balloon expandable valve implan- removed in prior surgery, the inflow of the conduit tation in 64 patients with severe MAC, technical can be from the left atriotomy incision site. success was achieved in 72% of cases, with a 30-day Using a valved conduit to bypass severe MAC is all-cause mortality rate of 29.7% (33).Inthisearly a new indication for the technique that has experience including multiple access routes (trans- been performed in a small number of patients. As such, atrial 15.6%, transapical 43.8%, and transseptal in long-term outcomes are lacking; however, it seems to 40.6%) complications included the need for a second be a less morbid and safer technique than standard valve in 17.2% and LVOT obstruction in 9.3%, but no mitral valve replacement in this high-risk group of cases of significant paravalvular leak (33).The patients. Cardiopulmonary bypass and the aortic cross ongoing MITRAL (Mitral Implantation of Trans- clamp times appear to be shorter with this technique catheter Valves) trial will determine the feasibility compared to standard annular decalcification and and safety of this approach (47) and will also shed mitral valve replacement. The risks of conduit-related light on what criteria should be used to determine complications such as thrombosis and kinking appear appropriate candidates for this technique. Up until to be uncommon in the early experience but will need now, CT-based evaluation has largely been empiric to be studied carefully. with application of some of the principles of patient selection from transcatheter aortic valve replace- TRANSCATHETER MITRAL VALVE ment, which has obvious limitations. On the basis of IMPLANTATION our experience and existing classifications of MAC, we propose a grading scheme based on pathoana- The concept of transcatheter mitral valve implanta- tomic criteria relevant to guide therapeutic options tion for severe mitral valve disease due to MAC is an with severe symptomatic MS and/or MR in the setting experimental emerging solution for a difficult prob- of MAC (Table 1, Figure 13). lem. The initial experience with transcatheter balloon-expandable SAPIEN valve (first generation DIRECT TRANSATRIAL IMPLANTATION. In the balloon expandable valve) (Edwards Lifesciences, recent era of transcatheter interventions, surgical Irvine, California) implantation for severe MAC has attempts have been made at direct transatrial im- shown some promise in retrospective studies (45,46). plantation of transcatheter valves in a previously Among the 2 currently available transcatheter valves placed mitral ring or degenerated mitral bio- approved for clinical use in the United States, the first prostheses (48). In the presence of severe MAC, this is generation balloon expandable valve is the only de- still in the preliminary phase. Several limitations vice whose design also allows for implantation in the exist including the complex anatomy of the mitral 1332 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

FIGURE 15 Transseptal Balloon Expandable Transcatheter Valve Implantation for Severe MAC

In this patient with circumferential MAC (A, side-by-side 3D en face views from left atrial and left ventricular side), a decision was made to implant a 26-mm SAPIEN XT (second generation balloon expandable valve) prosthesis via transseptal approach with the use of a transapical rail. Note the heavily calcified annulus on fluoroscopy (B), facilitating positioning of the valve. Post-deployment, the stent appears in stable position (C). Intraprocedure TEE reveals excellent opening of the bioprosthesis (D), with minor jets of peri-prosthetic regurgitation (E). TEE ¼ transesophageal echocardiography; other abbreviation as in Figure 1. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1333 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

FIGURE 16 Septal Reduction Therapy Before Transcatheter Mitral Valve Replacement

(Left) Cardiac CTA of a patient with severe MAC and severe basal septal hypertrophy (basal septal thickness 20 mm) who underwent alcohol septal ablation. (Right) Following ablation, the basal septum has thinned (arrows) with a corresponding increase in left ventricular outflow tract size. A simulated 29-mm SAPEIN 3 prosthesis is represented by a red rectangle. Abbreviations as in Figures 1 and 5.

valve and the risk of LVOT obstruction in the pres- PERCUTANEOUS TRANSSEPTAL DELIVERY. Perhaps ence of an intact anterior mitral valve leaflet (49). the most direct, but challenging, approach to trans- We have adopted a different strategy in some catheter first generation balloon expandable valve patients, which is the hybrid approach with direct implantation in the mitral position is the transseptal implantation of the first generation balloon expand- route. This approach has been increasingly used for able transcatheter valve in the native mitral position treatment of bioprosthetic mitral valve dysfunction through either standard sternotomy or right mini- but also for patients with failed ring annuloplasties thoracotomy facilitated with the use of extracorpo- and severe MAC (46,53). Transseptal access has a real circulation to maintain hemodynamic stability numberofimportantadvantagessuchasavoiding (50).Wehavealsoperformedthistechniquethrough thoracotomy or sternotomy, and using left atrial an on-pump beating heart technique without the procedural techniques familiar to structural inter- need for aortic cross clamp and . ventionalists. A slightly superior and slightly anterior Potential advantages for this hybrid strategy transseptal puncture (relative to the long axis of the include: 1) using a combination of direct visualization left ventricle) will allow placement of a wire guide and fluoroscopy can facilitate accurate placement of that is directed posteroinferiorly, away from the the prosthesis in a relatively short time; 2) open sur- LVOT. Following transseptal puncture, a steerable gical approach allows resection of the anterior mitral sheath can be placed in the left atrium. Through the leaflet to reduce the potential for LVOT obstruction; steerable left atrial sheath, the LV cavity can be and 3) paravalvular leak can be detected at the time of directly cannulated with a wire loaded into a 6-F or 7- implantation and attempts can be made to repair the F coronary guiding catheter. The initial wire can then site of the leak at the time of surgery or subsequently be changed for a stiff wire such as a Safari (Boston using percutaneous paravalvular leak closure tech- Scientific, Marlborough, Massachusetts), Confida niques (51) (Figure 14). (Medtronic), Lunderquist (Cook Medical, Bloo- The early experience with transatrial balloon- mington, Indiana), or Amplatz Extra/Super Stiff expandable valve implantation for severe MAC has (Boston Scientific), and placed in the LV cavity. If it is been performed in few patients using both first desired for coaxial engagement and support, the wire generation balloon expandable valve and Melody can be exteriorized via an LV apical puncture (Medtronic, Minneapolis, Minnesota) valves (52) and (Figure 15) (54). Following pre-dilation of the intera- it is expected that it will be only a matter of time trial septum with a 10- to 14-mm balloon, the first before advances in technology address the limitations generation balloon expandable valve delivery system that have been previously discussed. is advanced through the femoral venous sheath into 1334 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

CENTRAL ILLUSTRATION Challenges of Transcatheter Mitral Valve Implantation in Patients With MAC

Eleid, M.F. et al. J Am Coll Cardiol Img. 2016;9(11):1318–37.

Optimizing prosthesis anchoring while minimizing paravalvular leak and left ventricular outflow tract obstruction are key goals for transcatheter valve therapy in the setting of MAC.

the inferior vena cava, where the balloon and valve echocardiography. Three things must be carefully are articulated taking care the marker “E” is pointed evaluated: 1) LVOT obstruction due to anterior downwards to allow the system to flex towards the displacement of the anterior mitral leaflet, or excess left heart (46). The system is advanced into the left protrusion of the first generation balloon expandable atrium as flexion is applied and subsequently into the valve into the LVOT; 2) paravalvular leaks, which are left ventricle. If there is difficulty advancing across commonplace since the annulus is not uniform; and the septum, a second dilation can be performed from 3) valve stability. A period of observation to ensure the contralateral femoral vein, but this is usually not valve stability is important, as if the valve were to necessary. Care must be taken to align the valve embolize into the left atrium, it is preferable to have it extremely carefully to the mitral annular plane. It is remain on the wire for stability rather than floating very helpful to have a fluoroscopic “marker” of freely in the left atrium. Using these techniques the calcification to target the distal and mid portions of first generation balloon expandable valves can be the first generation balloon expandable valve, delivered successfully in the vast majority of cases, whether second or third generation. The valve is then and it is likely that this will become the preferred deployed under rapid pacing in the usual fashion and procedural technique for transcatheter mitral valve the results carefully assessed with transesophageal implantation in carefully selected patients. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Eleid et al. 1335 NOVEMBER 2016:1318– 37 Imaging and Therapy for Severe MAC

TRANSAPICAL DELIVERY. Transapical delivery of on unique fixation systems that do not rely on radial first generation balloon expandable valves for treat- force that transcatheter aortic valve replacement ment of native aortic stenosis and for treatment of devices use, and also are designed to minimize the risk failed mitral bioprostheses (55) has led to widespread of LV outflow tract obstruction. Although these valves familiarity with the transapical approach for first gen- were designed for treatment of severe mitral valve eration balloon expandable valve delivery. Other valve regurgitation, their designmaypermitthemtohavean systems have also been implanted successfully in the important role in the treatment of severe MAC. mitral position via transapical approach including the Investigational studies of these devices currently Lotus valve (Boston Scientific) in the setting of exclude MAC; however, it is likely that some or all of prior annuloplasty ring (56). The direct route from the these will be tested in the future as a treatment for LV apex to the mitral valve makes this approach MAC-associated mitral valve dysfunction. It is likely, appealing owing to less technical complexity com- however, that specifically designed devices will need pared to the transseptal or transatrial delivery options. to be developed for treatment of MAC. Special con- Transapical delivery requires both surgical expertise siderations include challenges in anchoring devices in for exposure of the LV apex and interventional cardi- MAC, difficulty in grasping leaflets and the inability to ology expertise for creation of a wire rail with place screws into the annulus. anchoring in a distal pulmonary vein. Pre-procedural ROLE OF SEPTAL REDUCTION THERAPY cardiac computed tomography angiography (CTA) helps to identify any abnormalities of the LV apex such Given the common coexistence of LV hypertrophy as myocardial fibrosis, overlying scar tissue, and the with severe MAC, consideration has recently been optimal rib space for approach. CTA delineates the given to the use of septal reduction therapy to increase coronary artery anatomy so that the major epicardial thesizeoftheLVOTtominimizeriskofLVOT vessels can be avoided during apical access. The most obstruction following transcatheter mitral valve im- coaxial access point to the mitral valve in patients with plantation. Especially in the setting of transseptal or severe MR is typically located anterior and lateral to transapical access where resection of the anterior the true LV apex and can be predicted by cardiac CTA leaflet is not currently an option, septal reduction (57). Optimal location of ventricular puncture is therapy typically with alcohol septal ablation can be further confirmed during intraprocedural TEE by dig- performed 4 to 6 weeks before mitral valve implanta- ital indentation of the myocardium. A stiff J-tipped tion to reduce basal septal hypertrophy (Figure 16). wire is advanced carefully across the mitral valve and Using cardiac CT with simulation of valve deployment, positioned into a pulmonary vein which serves as a rail patients anticipated to have a severe reduction in for valve delivery. LVOT area after valve implantation or those with fi DEDICATED TRANSCATHETER resting LVOT obstruction who also have signi cant fi MITRAL VALVE DEVICES basal septal hypertrophy may bene tfromthis approach to make them better candidates for trans- catheter mitral valve implantation (Figure 16). Impor- To date, 5 different transcatheter mitral valve systems tantly, even patients without resting or provocable have been successfully implanted in humans with LVOT obstruction have the potential to benefitfrom severe native mitral valve regurgitation, although septal reduction therapy if a transcatheter valve for no dedicated devices exist for treatment of MAC severe MAC is planned, thus CT simulation techniques (CardiAQ valve system [Edwards Lifesciences], Tiara play an essential role in this group of patients. valve [Neovasc, Richmond, Canada], FORTIS valve [Edwards Lifesciences], Tendyne valve [Tendyne, CONCLUSIONS Roseville, Minnesota] and Twelve valve [Twelve, Redwood City, California]) (58). Many other dedi- Cardiac imaging approaches as well as percutaneous cated transcatheter mitral valve replacement devices and surgical treatment options are rapidly evolving to are under development. Similar characteristics improvecareforthechallenginggroupofpatientswith among these devices include trileaflet, bovine or severe MAC resulting in MS or MR. Given the high porcine leaflets, nitinol self-expanding frames, fabric morbidity and mortality associated with currently or pericardial sealing skirts, and transapical delivery available treatment for severe MAC, there is a large (CardiAQ is also available for transseptal delivery). need for ongoing research and technologies to better Additional valves in development include the Med- serve this patient population. A good understanding of tronic Mitral (Medtronic) and Highlife (Highlife, Paris, the unique pathoanatomic features of MAC will be France) (59,60). The anchoring of these devices relies necessary for development of future transcatheter 1336 Eleid et al. JACC: CARDIOVASCULAR IMAGING, VOL. 9, NO. 11, 2016 Imaging and Therapy for Severe MAC NOVEMBER 2016:1318– 37

endeavorstargetedatthisgroup.Insummary: improve care of this high risk group of patients; 1) severe MAC resulting in symptomatic mitral stenosis 5) major obstacles to transcatheter mitral valve and/or regurgitation is associated with LV hypertro- implantation for treatment of severe MAC include phy, advancing age, and history of mediastinal irradi- prosthesis anchoring and stability, left ventricular ation; 2) assessment of mitral valve disease severity in outflow tract obstruction, and paravalvular leak severe MAC can be challenging and often requires (Central Illustration); and 6) dedicated transcatheter integration of multimodality imaging with trans- mitral valve replacement devices for treatment of thoracic and transesophageal echocardiography and severe MAC are needed. cardiac CT angiography; 3) surgical mitral valve replacement in the setting of severe MAC is associated REPRINT REQUESTS AND CORRESPONDENCE: Dr. with high operative morbidity and mortality; 4) novel Mackram F. Eleid, Department of Cardiovascular therapeutic strategies for treatment of severe MAC Diseases, Mayo Clinic, 200 First Street SW, Rochester, are currently under development and are needed to Minnesota 55905. E-mail: [email protected].

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