- Email: [email protected]
Integrated Imaging in Hypertrophic Cardiomyopathy
Accepted Manuscript Integrated Imaging in Hypertrophic Cardiomyopathy Lubna Choudhury, MD, Vera H. Rigolin, MD, Robert O. Bonow, MD, MS PII:
S0002-9149(16)31605-8
DOI:
10.1016/j.amjcard.2016.09.033
Reference:
AJC 22177
To appear in:
The American Journal of Cardiology
Received Date: 31 May 2016 Revised Date:
23 September 2016
Accepted Date: 27 September 2016
Please cite this article as: Choudhury L, Rigolin VH, Bonow RO, Integrated Imaging in Hypertrophic Cardiomyopathy, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Integrated Imaging in Hypertrophic Cardiomyopathy
Lubna Choudhury MD, Vera H. Rigolin, MD,
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Robert O. Bonow MD, MS
Author Affiliations: Bluhm Cardiovascular Institute, Division of Cardiology, Northwestern
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University Feinberg School of Medicine, Chicago IL
Corresponding Author:
Lubna Choudhury, MD Division of Cardiology Northwestern University Feinberg School of Medicine 676 North St Clair, Suite 600 Chicago, IL 60611
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Phone: 312-695-0059 Fax: 312-695-0063 Email: [email protected]
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Running head: Imaging in Hypertrophic Cardiomyopathy
ACCEPTED MANUSCRIPT 2 Abstract Hypertrophic cardiomyopathy (HC) has a very heterogeneous clinical spectrum and lends itself to multimodality imaging for evaluation and management. This review addresses clinical
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applications of cardiac imaging in patients with HC. Integrating various modalities of
echocardiography and cardiac magnetic resonance (CMR) are discussed in the clinical context such as diagnosis, evaluation, management, risk stratification and family screening of HC
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patients. The utility of peri-procedure imaging techniques are highlighted for guiding surgical and transcatheter septal reduction procedures. More limited roles of invasive or computed
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tomography (CT) coronary angiography are discussed for HC patients with chest pain and risk factors for coronary artery disease. Nuclear techniques though available for decades, play a more limited role in contemporary routine management, but may assist in risk assessment. Newer CMR and echo imaging techniques are discussed in their emerging roles for further
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characterization of HC patients and family members with prospects of preclinical diagnosis. The strengths of the different imaging modalities are presented as well as a flow diagram summarizing integrated imaging in this disease. In conclusion, integrated imaging using the
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various imaging modalities predominantly echocardiography and CMR based on the clinical
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picture, plays an essential role in the management of HC patients.
Key words: Hypertrophic Cardiomyopathy, Imaging, Echocardiography, Cardiac Magnetic Resonance
ACCEPTED MANUSCRIPT 4 Introduction Hypertrophic cardiomyopathy (HC) is the most common single gene cardiac disorder, characterized by left ventricular (LV) hypertrophy in the absence of another condition likely to
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produce that degree of hypertrophy.1, 2 HC has a heterogeneous clinical spectrum and lends itself to multimodality imaging for evaluation and management. Echocardiography as well as cardiac magnetic resonance (CMR) imaging are essential for the delineating the morphology of LV
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hypertrophy in HC,3,4 identifying myocardial fibrosis,5 and stratifying risk 6,7 Myocardial perfusion imaging, including single photon emission tomography8 and positron emission
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tomography (PET)9 assist in predicting risk of adverse outcomes. Imaging also reveals subtle abnormalities in the pre-clinical phase in individuals carrying a causative genetic mutation.10, 11 This review addresses clinical applications of cardiac imaging in patients with HC for establishing diagnosis, determining morphology, evaluating and managing symptoms, assessing
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risk for adverse outcomes and family screening. Diagnosis of HC
Patients with HC are often asymptomatic and diagnosed because of a heart murmur, an
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abnormal electrocardiogram, or incidentally by an echocardiogram performed for unrelated purposes. The diagnosis is also often made during evaluation of cardiac symptoms or screening
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because of a family history of HC or sudden death. Once HC is suspected, the diagnosis must be confirmed by imaging.
Echocardiography is the principal test for establishing the HC diagnosis, using the criteria of increased LV wall thickness (≥15 mm) in the absence of another condition likely to produce that degree of hypertrophy.1,2 The hypertrophy can involve any location in the LV wall, and in patients with a family history of HC or a causative genetic mutation, lesser degrees of
ACCEPTED MANUSCRIPT 5 hypertrophy are diagnostic.1 Two dimensional transthoracic echocardiography provides qualitative and quantitative assessment of LV morphology (Figure 1)12 and function, left atrial volume, and mitral valve anatomy and function including systolic anterior motion (SAM).13
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Color flow and spectral Doppler assessment of hemodynamics, including LV outflow tract
(LVOT) obstruction,14 mitral regurgitation (Figure 2A), and pulmonary artery systolic pressure, are essential components of the echocardiographic examination. M-mode echocardiography is
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particularly suited to visualize SAM (Figure 2B). Diastolic function is assessed by both mitral inflow velocities15 and Doppler tissue imaging (Figure 3).16 Abnormal diastolic filling patterns
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are associated with higher left atrial volumes and higher left atrial pressures and these derangements have been shown to be associated with a higher incidence of serious adverse events. 17 For example, such patients may be at risk of developing atrial fibrillation or stroke and may warrant more frequent rhythm evaluation. Newer echocardiographic techniques will become
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more important in the future; in particular strain imaging can detect early abnormalities in myocardial mechanics in genotype positive HC patients who have not yet developed hypertrophy 18
and may provide an opportunity to modify the HC phenotype prior to the development of LV
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hypertrophy with future drug discovery. This technique can also distinguish the physiological LV hypertrophy of athletic remodeling from HC.19 CMR techniques can also elucidate regional
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myocardial dysfunction in HC patients, who have depressed end-systolic circumferential and longitudinal shortening using tissue tagging by spatial modulation of magnetization (SPAMM).20 CMR tissue tagging has been used for the evaluation of LV torsion which can be calculated using displacement encoded stimulated echo (DENSE) imaging.21 Patients who are HC mutation carriers without LV hypertrophy have been shown to have higher LV torsion. 22 In a study of intramural cardiac function and the extent of fibrosis in HC using DENSE, intramural systolic
ACCEPTED MANUSCRIPT 6 strain was significantly depressed within areas of late gadolinium enhancement (LGE) but also in the most hypertrophic regions without LGE, suggesting that myocardial disarray or other nonfibrotic processes affect systolic function in patients with HC.23 Another recent CMR
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technique of diffusion tensor imaging to analyze the cross-myocyte components of diffusion shows evidence of abnormal myocardial laminar orientations in diastole in HC patients
independent of LGE.24 In contrast to LGE which detects macroscopic fibrosis, the emerging
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CMR technique of T1 mapping can estimate extracellular volume fraction related to diffuse interstitial fibrosis in HC and this has been correlated with diastolic dysfunction in HC.25 While
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these newer CMR techniques shed light on more detailed myocardial structural and functional abnormalities in HC, they are not routinely used in clinical practice.
Echocardiography is well suited to identify abnormalities of the mitral valve apparatus (Figure 4A) that are common in HC, 26 including elongation of one or both leaflets,27 anomalous
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papillary muscles or chordae,28 direct papillary muscle insertion into the mitral leaflet (Figure 4B), chordal rupture, and mitral valve prolapse. An eccentric, anteriorly directed jet of mitral regurgitation should suggest an intrinsic mitral valve abnormality.27 Unusual locations of
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hypertrophy not readily apparent on the 2D echocardiography can be demonstrated by CMR,4 as
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it affords high-resolution delineation of the full extent and distribution of hypertrophy, including biventricular hypertrophy (Figure 5A), with no artifacts due to imaging windows or patient body habitus. Abnormal papillary muscle morphology (Figure 5B) and insertion are particularly well visualized by CMR 29 and may contribute to LVOT obstruction.29 CMR is well suited to elucidate myocardial scarring (Figure 5C and 5D) commonly seen in HC as well as recognizing variants of HC such as apical hypertrophy (Figure 5D) or aneurysms6. Other diseases that cause increased LV wall thickness can mimic HC, and imaging plays a
ACCEPTED MANUSCRIPT 7 crucial role in differentiating HC from these conditions (Table 1). Myocardial delayed enhancement patterns by CMR may identify alternative diagnoses, such as Cardiac amyloidosis30 (Figure 6), sarcoidosis 31or Fabry’s disease.32 A common conundrum is differentiating HC from
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the physiologic cardiac adaptations resulting from athletic training. The largest and most
definitive series of highly trained athletes33 reported a maximum wall thickness of 16 mm, with only 1.7% of men and no women manifesting a wall thickness >12 mm. In addition, the male
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athletes with LV wall thickness >12 mm also had LV dilation (LV end-diastolic dimension 5563 mm).33 This degree of LV cavity dilation is unusual in HC and usually occurs only in the end-
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stage phase of the disease, characterized by LV dilation and scarring on CMR (Figure 6C), associated with progressive systolic dysfunction and symptomatic heart failure. The ratio of diastolic wall thickness to LV end-diastolic volume by CMR less than 0.15 mm/m2/mL has a sensitivity of 80% and specificity of 99% for an athlete's heart.34 In the gray areas of overlap
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between athletes and HC patients with mild hypertrophy (wall thickness 12-15 mm), other features beyond cavity dimensions such as left atrial enlargement, unusual heterogeneous patterns of LV hypertrophy, and abnormalities of LV diastolic filling are useful.35 Regional
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systolic LV deformation measured by tissue Doppler-derived longitudinal strain and strain rate imaging is within normal limits in athletes,36 whereas patients with HC have impaired systolic
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function with both heterogeneity of velocities and asynchrony of motion.37 The strengths of the various imaging modalities in evaluation of the key features of the HC phenotype are summarized in Table 2.
CMR also delineates LVOT anatomy, and CMR or transesophageal echocardiography (TEE) is useful in patients in whom a subaortic membrane is suspected as a possible cause or contributor to the subvalvular gradient, especially in those patients with mild hypertrophy and
ACCEPTED MANUSCRIPT 8 significant gradient (Figure 7). Evaluation of Symptoms Major pathophysiologic mechanisms of symptoms in HC are LV diastolic dysfunction,
an important role in elucidating the etiology of symptoms.
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LVOT obstruction, mitral regurgitation, myocardial ischemia and arrhythmias.1, 2 Imaging plays
Dyspnea results from the complex interplay between diastolic dysfunction, LVOT
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obstruction, and mitral regurgitation, any or all of which can produce significant pulmonary hypertension. Diastolic dysfunction is assessed echocardiographically by mitral inflow velocities
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and Doppler tissue imaging.15,16 The majority of patients with HC have LVOT obstruction either at rest or with exercise.38 SAM with resultant mitral regurgitation (Figure 2) is often exacerbated by exercise, and stress echocardiography (Figure 8) can elucidate dynamic LVOT obstruction in patients with exertional symptoms who may have no significant LVOT gradients at rest,38 thus
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making these patients candidates for medical therapy with beta blockers with or without disopyramide and failing that, septal reduction therapy. Therefore, stress echocardiography with exercise is recommended over Valsalva maneuver or amyl nitrate to evaluate exertional
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symptoms. Indeed, stress echocardiography is recommended in such patients to not only elucidate provocable LVOT obstruction as a mechanism of their exertional symptoms, but also to
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demonstrate increased mitral regurgitation with exercise that can lead to significantly elevated pulmonary artery systolic pressure, that in turn contributes to exertional dyspnea. Even in those patients who do not have significant provocable LVOT obstruction demonstration of significant mitral regurgitation by stress echocardiography causing exertional dyspnea can lead to surgical consideration of possible mitral valve repair. In addition, the estimation of pulmonary artery systolic pressure post exercise can be very useful to document exercise induced pulmonary
ACCEPTED MANUSCRIPT 9 hypertension (likely a result of diastolic dysfunction) as a potential mechanism of exertional dyspnea. Elucidation of these hemodynamic parameters by stress echocardiography are often more important than assessing wall motion abnormalities in these patients, most of whom do not
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have obstructive epicardial coronary artery disease (CAD). Hence these measurements are often obtained before assessing wall motion at peak exercise. On the other hand stress
echocardiography for ischemia evaluation becomes more important in older HCM patients with
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risk factors for CAD. Unexplained syncope is a risk factor for sudden cardiac death in HC.1 However, lightheadedness or syncope in HC can be hemodynamic in origin. Eliciting these
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symptoms with stress echocardiography demonstrating a significant LVOT gradient and decrease in blood pressure during (or immediately after) exercise identifies the mechanism and can thus provide an explanation for syncope so that an ICD is not automatically considered for such patients for primary prevention of sudden cardiac death. Echocardiography and CMR also
6C,D).
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identify the subgroup of patients who progress to symptomatic LV systolic dysfunction (Figure
Chest pain in HC often represents myocardial ischemia due to coronary microvascular
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dysfunction9, 39 superimposed on the increased oxygen demands of LV hypertrophy and LVOT obstruction. Stress echocardiography has low sensitivity for detecting microvascular ischemia, as
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wall motion may be preserved when there is microvascular dysfunction. Myocardial perfusion imaging, however, often reveals reversible perfusion defects in HC patients in the absence of obstructive epicardial CAD.8 Hence, perfusion imaging may be useful in evaluating chest pain due to coronary microvascular ischemia in patients without obstructive epicardial CAD. Conversely, in older patients or those with CAD risk factors, invasive or CT coronary angiography is necessary to detect concomitant obstructive CAD.1, 2, 40 Coronary angiography or
ACCEPTED MANUSCRIPT 10 CT angiography also identifies myocardial bridging which is a common finding in HC patients.41 Management When patients with HC are determined to have symptoms due to LVOT obstruction, the
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recommended initial management is medical therapy. The role of imaging in stable patients with HC on medical therapy is mainly relegated to serial evaluations of LV wall thickness, LVOT obstruction, mitral regurgitation, cavity dimensions and function.1, 2 Assessing LVOT gradients
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with stress echocardiography is useful to evaluate ongoing symptoms on medical therapy. Echocardiography is also useful to identify symptomatic patients who have severe mitral
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regurgitation in whom surgical mitral valve repair may be required regardless of the LVOT gradient.
Patients with refractory symptoms and with LVOT gradients ≥50 mmHg at rest or with provocation are candidates for septal reduction therapy including surgical septal myectomy 1,2, 42
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or alcohol septal ablation.43 Imaging is essential for identifying candidates for intervention and pre-procedural planning to determine the optimal approach, while intra-procedural TEE is important in obtaining optimal results.
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For planning septal myectomy, 2D-Doppler echocardiography is the principal test for determining location and severity of septal hypertrophy, mitral regurgitation and LVOT
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obstruction and thus suitability for surgery and predicting postoperative outcome.1, 2, 44 However, preoperative CMR is valuable in identifying additional features that are important in surgical planning, such as anomalous papillary muscle insertions,29 redundant chordal structures, excessive midventricular or papillary muscle hypertrophy 45 or subaortic membrane, that may require surgical correction in addition to septal myectomy. Intraoperative TEE (Figure 9) is particularly useful to assure adequate surgical resection and determining need for concomitant
ACCEPTED MANUSCRIPT 11 MV repair. Intraoperative TEE also assesses the immediate results and excludes important complications such as ventricular septal defect or aortic insufficiency,46 and residual gradients after septal myectomy can be evaluated with dobutamine administration (Figure 10).
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Invasive coronary angiography can also be useful prior to planned septal myectomy to
evaluate for the need for concomitant coronary bypass grafting, while prior to alcohol septal ablation, it can define the septal perforator anatomy and reveal concomitant epicardial coronary
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stenoses that may need percutaneous coronary intervention for amelioration of symptoms. In patients undergoing alcohol septal ablation, contrast echocardiography (Figure 11) identifies the
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myocardial territory perfused by the target vessel.47 Before alcohol infusion, Doppler echocardiography during intracoronary balloon inflation in the target septal perforator determines if occluding flow in that territory results in a decrease in LVOT gradient. Dual chamber pacing therapy has a limited role in treating symptomatic patients but can be
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useful in elderly patients with LVOT obstruction who have prohibitive risks for surgical myectomy and do not have suitable coronary anatomy for alcohol septal ablation.48 Doppler echocardiography (Figure 12) can guide adjustment of the atrioventricular delay for optimal
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reduction in LVOT gradient.48
Imaging with echocardiography or CMR is useful for assessing LV and papillary muscle
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morphology after septal reduction therapy.49, 50 Echocardiography is particularly useful after invasive interventions 51 to evaluate possible residual LVOT obstruction or mitral regurgitation in patients with recurrent symptoms. Assessing the risk of sudden death is a major focus of the evaluation of every patient with HC, due to the efficacy of the implantable cardioverter defibrillator (ICD) in preventing sudden cardiac death (SCD) in this disease. A patient’s risk of SCD in HC is primarily determined by
ACCEPTED MANUSCRIPT 12 history and not derived from imaging. The long recognized morphologic feature of HC that is significantly associated with sudden death is extreme LV hypertrophy 52 (LV wall thickness >30 mm), though most sudden deaths occur in patients with maximum wall thicknesses of 20-30
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mm.53 Severity of LVOT obstruction has been linked to heart failure-related death in HC.38
Echocardiography is the mainstay in evaluating both of these parameters. More recently, strain imaging may also have a role in risk stratification, as recent data have linked ambulatory
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evidence of nonsustained ventricular tachycardia with significantly reduced peak longitudinal systolic strain.54 While CMR provides more precise assessment of the magnitude of LV
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hypertrophy, (a parameter, although originally established as a risk factor by echocardiographic imaging, is thought to be of the same prognostic significance by CMR), its unique contribution to risk assessment is identification and quantification of myocardial fibrosis by LGE on contrast CMR, using both visual methods and dedicated software.5, 7 Extensive fibrosis is a common
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finding at postmortem examination of patients who have died suddenly.55 and extensive fibrosis detected by LGE on CMR has been linked to ventricular arrhythmias and adverse events in HC. 7, 56,57
Fibrosis is also associated with systolic dysfunction and heart failure.58 Patients with a
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mild phenotype of HC on CMR imaging, with mild hypertrophy and no significant fibrosis, appear to be low risk patients who do not warrant consideration of ICD implantation for primary
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prevention of SCD. CMR is thus emerging as an essential tool for routine risk assessment in HC, although further studies are required. In patients who are unable to undergo CMR, cardiac dual source CT may be an alternative method for detecting and quantifying myocardial fibrosis.59 Myocardial perfusion imaging also provides prognostic information, as young HC patients with ischemia have a higher mortality rate.8 and ischemia has been implicated as a cause of myocardial scarring.58 In older HC patients, ischemia on myocardial perfusion imaging is
ACCEPTED MANUSCRIPT 13 associated with more adverse events60 regardless of concomitant epicardial CAD. Patients with the lowest coronary flow reserve on quantitative PET perfusion imaging have an increased risk of adverse cardiovascular events.9 However, due to limited availability, PET is not routinely used
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for risk stratification in HC.
Left atrial dilatation can be evaluated by both echocardiography and CMR and is a strong predictor of atrial fibrillation in HC. 61 In turn, the development of atrial fibrillation is associated
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with worse outcomes including more severe heart failure and stroke.62
Since HC is a genetic disease, echocardiographic screening of family members of HC
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patients is strongly recommended, 1, 2 with ongoing serial imaging every few years or earlier if symptoms develop or borderline imaging abnormalities are found. CMR has a role in family screening if echocardiographic image quality is suboptimal or if there is borderline LV hypertrophy. CMR is particularly important in a family member with an apparently normal
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echocardiogram but abnormal electrocardiogram, and although current guidelines do not recommend CMR for making the diagnosis in all family members of HC patients, we would recommend a low threshold be used for CMR imaging for screening when there is a family
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history of sudden cardiac death, as the identification of HC phenotype has important implications for primary prevention in such families. Individuals carrying gene mutations for HC may
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manifest abnormalities on imaging such as myocardial crypts by CMR,63 abnormal strain imaging by echocardiography,18 and reduced coronary flow reserve on quantitative PET perfusion imaging 64 before LV hypertrophy becomes apparent. These are considered early phenotypic manifestations of HC and therefore these individuals should be followed periodically for development of increased LV wall thickness. Integrated imaging, predominantly with echocardiography and CMR, is essential in the
ACCEPTED MANUSCRIPT 14 diagnosis, evaluation, management, risk stratification and family screening of HC patients (Figure 13). Stress echocardiography adds valuable diagnostic information regarding the mechanism of HC symptoms, thus enabling appropriate therapeutic choices. For example,
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patients with nonobstructive HC do not need to be considered for septal reduction therapies. Mitral valve abnormalities are common in HC, and symptomatic patients with severe mitral regurgitation may be candidates for mitral valve repair regardless of the LVOT gradient. CMR
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can be particularly useful in uncovering LV hypertrophy in family members of HC patients with a family history of SCD when echocardiography is equivocal or suboptimal, in whom the
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diagnosis of HC has implications for primary prevention of SCD. CMR is particularly useful for distinguishing HC from other conditions that may mimic HC. Late gadolinium enhancement by CMR is uniquely suited to evaluate extent of myocardial fibrosis, which has an increasing role in risk assessment for adverse outcomes. The technique of CMR T1 mapping is being explored as
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an additional tool in assessing diffuse myocardial fibrosis in HC and its correlates. TEE may be needed to rule out a subaortic membrane as a potential cause of the LVOT gradient, particularly in patients with a high LVOT gradient despite mild septal hypertrophy. Intraoperative TEE and
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peri-procedural transthoracic echo with contrast play an essential role in guiding surgical and transcatheter septal reduction procedures respectively. Invasive or CT coronary angiography is
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reserved for HC patients with chest pain and risk factors for CAD. Nuclear techniques play a more limited role but may assist in risk assessment. Tissue Doppler imaging is emerging for evaluating individuals with sarcomere gene mutations who have not yet developed the phenotypic findings of LV hypertrophy. Newer MRI and echo techniques can provide insights in abnormal myocardial mechanics in HC and further studies are needed to determine their place in HC imaging.
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methods for distinguishing athlete’s heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy. Circulation 1995;91:1596-1601.
36. Teske AJ, Prakken NH, De Boeck BW, Velthuis BK, Doevendans PA, Cramer MJ.
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Echocardiographic deformation imaging reveals preserved regional systolic function in endurance athletes with left ventricular hypertrophy. Br J Sports Med 2010;44:872-878.
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37. Cardim N, Oliveira AG, Longo S, Ferreira T, Pereira A, Reis RP, Correia JM. Doppler tissue imaging: regional myocardial function in hypertrophic cardiomyopathy and in athlete’s heart. J Am Soc Echocardiogr 2003;16:223-232.
38. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ.
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Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295-303. 39. Camici P, Chiriatti G, Lorenzoni R, Bellina RC, Gistri R, Italiani G, Parodi O, Salvadori
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PA, Nista N, Papi L, Antonio L'Abbate. Coronary vasodilatation is impaired in both hypertrophied and non-hypertrophied myocardium of patients with hypertrophic
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cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1991;17:879-886. 40. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation 2003;108:2342-2348. 41. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Tajik AJ, Holmes DR. Myocardial
ACCEPTED MANUSCRIPT 21 bridging in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;42:889-894.
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42. Heric B, Lytle BW, Miller DP, Rosenkranz ER, Lever HM, Cosgrove DM. Surgical management of hypertrophic obstructive cardiomyopathy: early and late results. J Thorac Cardiovasc Surg 1995;110:195-208.
cardiomyopathy. Lancet 1995;346:211-214.
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43. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive
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44. McCully RB, Nishimura RA, Bailey KR, Schaff HV, Danielson GK, Tajik AJ. Hypertrophic obstructive cardiomyopathy: preoperative echocardiographic predictors of outcome after septal myectomy. J Am Coll Cardiol 1996;27:1491-1496. 45. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR,
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Udelson JE, Manning WJ, Appelbaum E. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220-228
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46. Ommen SR, Park SH, Click RL, Freeman WK, Schaff HV, Tajik AJ. Impact of intraoperative transesophageal echocardiography in the surgical management of
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hypertrophic cardiomyopathy. Am J Cardiol 2002;90:1022–1024. 47. Nagueh SF, Lakkis NM, He ZX, Middleton KJ, Killip D, Zoghbi WA, Quinones MA, Roberts R, Verani MS, Kleiman NS, Spencer WH 3rd. Role of myocardial contrast echocardiography during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1998;32:225-229. 48. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME Kieval RS.
ACCEPTED MANUSCRIPT 22 Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a randomized,
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double-blind, crossover study (M-PATHY). Circulation 1999;99:2927-2933. 49. Kwon DH, Smedira NG, Thamilarasan M, Lytle BW, Lever H, Desai MY. Characteristics and surgical outcomes of symptomatic patients with hypertrophic cardiomyopathy with
Thorac Cardiovasc Surg 2010;140:317-324.
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abnormal papillary muscle morphology undergoing papillary muscle reorientation. J
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50. Valeti US, Nishimura RA, Holmes DR, Araoz PA, Glockner JF, Breen JF, Ommen SR, Gersh BJ, Tajik AJ, Rihal CS, Schaff HV, Maron BJ. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2007;49:350-357. 51. Nagueh SF, Ommen SR, Lakkis NM, Killip D. Zoghbi WA. Schaff HV, Danielson GK,
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Quinones MA, Tajik AJ, Spencer WH. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J
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Am Coll Cardiol 2001;38:1701-1706.
52. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left
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ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778-1785. 53. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD. McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001;357:420-424. 54. Di Salvo G; Pacileo G; Limongelli G; Baldini L; Rea A; Verrengia M; D'Andrea A; Russo
ACCEPTED MANUSCRIPT 23 MG; Calabro R. Non sustained ventricular tachycardia in hypertrophic cardiomyopathy and new ultrasonic derived parameters. J Am Soc Echocardiogr 2010; 23:581-90. 55. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy
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and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol 2000;31:988-998.
56. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR,
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Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of
arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on
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cardiovascular magnetic resonance. J Am Coll Cardiol 2008;51:1369-1374. 57. O'Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb J, Kulkarni M, Dawson D, Sulaibeekh L, Chandrasekaran B, Bucciarelli-Ducci C, Pasquale F, Cowie MR, McKenna WJ, Sheppard MN, Elliott PM, Pennell DJ, Prasad SK. Prognostic significance
874.
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of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:867-
58. Maron MS, Appelbaum E, Harrigan CJ, Buros J, Gibson CM, Hanna C, Lesser JR, Udelson
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JE, Manning WJ, Maron BJ. Clinical profile and significance of delayed enhancement in hypertrophic cardiomyopathy. Circ Heart Fail 2008;1:184-191.
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59. Berliner JI, Kino A, Carr J, Bonow RO, Choudhury L. Cardiac Computed Tomographic Imaging To Evaluate Myocardial Scarring/Fibrosis In Patients With Hypertrophic Cardiomyopathy: A Comparison With Cardiac Magnetic Resonance Imaging. Int J Cardiovasc Imaging 2013;29:191-197. 60. Sorajja P, Chareonthaitawee P, Ommen S, Miller T, Hodge D, Gibbons R. Prognostic utility of single-photon emission computed tomography in adult patients with hypertrophic
ACCEPTED MANUSCRIPT 24 cardiomyopathy. Am Heart J 2006;151:426-435. 61. Nistri S, Olivotto I, Betocchi S, Losi MA, Valsecchi G, Pinamonti B, Conte MR, Casazza
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F, Galderisi M, Maron BJ, Cecchi F. Prognostic significance of left atrial size in patients with hypertrophic cardiomyopathy (from the Italian Registry for Hypertrophic Cardiomyopathy). Am J Cardiol 2006;98:960–965.
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62. Olivotto I, Cecchi F, Casey SA, Dolara A. Traverse JH. Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation
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2001;104:2517-2524.
63. Germans T, Wilde AA, Dijkmans PA, Chai W, Kamp O, Pinto YM, van Rossum AC. Structural abnormalities of the inferoseptal left ventricular wall detected by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am
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Coll Cardiol 2006;48:2518-2523
64. Choudhury L, al-Mahdawi S, French J, Oakley CM, Camici PG. An additional marker for
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familial hypertrophic cardiomyopathy? Cor Art Dis 1993;4:565-567.
ACCEPTED MANUSCRIPT 25 Figure Legends Figure 1. A. Parasternal long axis echocardiogram showing massive (40 mm) septal
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hypertrophy. B. Apical view demonstrating apical HC (arrow). LA = left atrium Figure 2. A. Apical 4 chamber view demonstrating systolic anterior motion of the mitral valve (white arrow) with color Doppler showing mitral regurgitation and turbulence in the left
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ventricular outflow tract B. M-mode echocardiogram demonstrating systolic anterior motion of the mitral valve (arrow). LVOT=left ventricular outflow tract, MR= mitral regurgitation
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MV=mitral valve, SAM=systolic anterior motion
Figure 3. A. Abnormal diastolic function by spectral Doppler of mitral inflow B. Septal annulus tissue Doppler imaging. Doppler findings show elevated left ventricular filling pressures (E/e’= 36).
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Figure 4. A. Myxomatous mitral valve in a HC patient. B. Abnormal papillary muscle inserting directly into the mitral leaflet (arrow). AMVL = anterior mitral valve leaflet.
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Figure 5. Cardiac magnetic resonance (CMR) imaging A. 4 chamber view showing interventricular septal hypertrophy as well as hypertrophy of the right ventricular apical wall
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(arrow) B. abnormal papillary muscles with multiple heads (arrow) C. short axis view showing myocardial scarring (arrow), as grey-white patches in the normal myocardium that appears black. D. CMR showing myocardial scarring (arrow) in apical HC. IVS = interventricular septum Figure 6. Cardiac magnetic resonance imaging A. showing diffuse subendocardial delayed enhancement (arrows) in a patient with AL cardiac amyloidosis in two chamber view and B. Short axis view. C. showing LV dilatation and extensive myocardial delayed enhancement
ACCEPTED MANUSCRIPT 26 (arrows) in a patient with end-stage HC with systolic dysfunction in 4 chamber view and D. Short axis view.
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Figure 7. A. Subaortic membrane (arrow) visualized by transesophageal echo (TEE) in a patient with minimal hypertrophy and severe left ventricular outflow tract (LVOT) obstruction,
MV=mitral valve, LA=left atrium. B. Turbulence in the LVOT by color Doppler imaging. C.
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Subaortic membrane visualized by 3-dimensional TEE (arrow).
Figure 8. Stress echo derived spectral Doppler left ventricular outflow tract (LVOT) velocities
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A. at rest (peak LVOT velocity 4.1 m/sec, peak gradient 68 mm Hg) and B. with treadmill exercise (peak LVOT velocity 5.5 m/sec, peak gradient 121 mm Hg) (arrow) in a patient with obstructive HC. The remaining spectral Doppler signals in panel B may represent contamination from mitral regurgitation.
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Figure 9. Intraoperative transesophageal echo showing A. Systolic anterior motion of the mitral valve. B. Mitral regurgitation. C. Left ventricular outflow tract gradient by CW spectral Doppler. D. Distance of maximal septal wall thickness from aortic valve annulus (arrow). AMVL=anterior
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mitral valve leaflet, CW=continuous wave, LA=left atrium, LV=left ventricle, LVOT=left
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ventricular outflow tract, RA=right atrium, RV=right ventricle. Figure 10. Intraoperative transesophageal echo after cardiopulmonary bypass demonstrating. A. insignificant left ventricular outflow tract (LVOT) gradient post septal myectomy. B. insignificant LVOT gradient with dobutamine. C. Three dimensional TEE image of the mitral valve from the left atrial perspective. Note the double orifice as a result of an Alfieri stitch between the two middle scallops. D. Trace mitral regurgitation. LA=left atrium, LV=left ventricle, MR=mitral regurgitation
ACCEPTED MANUSCRIPT 27 Figure 11. A. Parasternal long axis view demonstrating contrast in the basal septum (arrow) prior to alcohol septal ablation. Left ventricular outflow tract peak velocity and peak gradient B. before and C. after alcohol septal ablation. LVOT= left ventricular outflow tract Vel=velocity,
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PG=peak gradient
Figure 12. Echocardiographic guided adjustment of dual chamber pacemaker atrioventricular
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delay to reduce left ventricular ouflow tract obstruction; A. Gradient before and B after A-V delay optimization A-V=atrioventricular, LVOT=left ventricular outflow tract
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Figure 13. Flow diagram for imaging in HC; LV=left ventricular, MV=mitral valve, LVOT= left ventricular outflow tract, RVSP=right ventricular systolic pressure, SAM=systolic anterior motion, CAD=coronary artery disease, BP=blood pressure, CTA=computerized tomographic
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Table 1. Imaging characteristics by Echocardiography and CMR that help in distinguishing HC from other conditions that may cause LV hypertrophy
parameters
Athlete’s heart
↑↑
↑
↑
LV cavity size
↓
-
↑
Diastolic dysfunction
+
+
-
Abnormal papillary muscle
+
-
+
Abnormal chordal attachment
+
-
SAM of MV
+
-
Elongated Mitral leaflets
+
-
Eccentric Mitral regurgitation
+
-
+
Anteroseptal and inferoseptal foci
+ -
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Subendocardial LGE
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Presence of LGE
-
+ -
-
-
-
-
-
-
-
-
-
-
+
-
-
-
-
-
+
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LGE by CMR
↑↑
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LV wall thickness
Infiltrative disease (Amyloid, Sarcoid, Fabry’s disease)
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Hypertensive heart disease
HC
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Echocardiographic
Mid-myocardial LGE (focal)
+
-
-
+/-
Mid myocardial LGE (linear)
-
+
-
-
LGE = Late gadolinium enhancement, LV= left ventricular, CMR= cardiac magnetic resonance, SAM= systolic anterior motion, MV= mitral valve + = likely to be present, - = likely to be absent, ↑= increased, ↓= decreased.
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HC subtype (LV morphology) or LA enlargement
LVOTG
Diastolic dysfunction
Echo Doppler
+
+
+
Stress Echo
+
+
+
CMR
+
+
TEE ± Dobutamine
+
+
+
+
+
+
+
+
+
Ischemia CAD or Myocardial Bridging
Abnormal Myocardial Mechanics
+
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+
+
+ +
+ +
+
+ + +
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Newer CMR modalities: DENSE, DTI
+
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SPECT
Echo Strain imaging
+
Fibrosis
+
Cardiac CT
PET
PH
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MR
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LVH
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Table 2. Strengths of each imaging modality for assessing key features of the HC phenotype
LVH = left ventricular hypertrophy, LA= left atrial, LVOTG=Left ventricular outflow tract gradient, CAD=coronary artery disease, CMR= cardiac magnetic resonance, CT=computed tomography, SPECT=single photon emission computed tomography, PET=positron emission tomography DENSE= displacement encoded stimulated echo, DTI= diffusion tensor imaging, PH=pulmonary hypertension
+ +
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ACCEPTED MANUSCRIPT Suspected HC CMR LV wall thickness Rule out HC mimics Myocardial fibrosis (pattern, extent, quantity) Papillary muscle abnormalities
Echo Doppler
Family Screening
Stress Echo with pre and post exercise Doppler
Nonobstructive
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Significant LVOT obstruction explaining symptoms
Medical Treatment
Alcohol Septal Ablation
Refractory symptoms Septal myectomy ± mitral valve repair±papillary muscle /chordal reconstruction
Chest pain, dyspnea, risk factors for CAD
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AV synchronized pacing
Risk stratification for adverse events
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BP response to exercise Exercise induced symptoms Peak LVOT gradient RVSP Mitral regurgitation severity LV wall motion Submitral apparatus
Equivocal or suboptimal images
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Exertional symptoms
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HC Diagnosed
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LV wall thickness SAM of MV LVOT gradient baseline and Valsalva Diastolic function Mitral regurgitation
Coronary angiography or Coronary CTA
Coronary anatomy Myocardial bridging
Significant papillary muscle abnormality requiring surgical correction TEE (Intraoperative) Mitral regurgitation SAM LVOT gradient Subaortic membrane
S0002-9149(16)31605-8
DOI:
10.1016/j.amjcard.2016.09.033
Reference:
AJC 22177
To appear in:
The American Journal of Cardiology
Received Date: 31 May 2016 Revised Date:
23 September 2016
Accepted Date: 27 September 2016
Please cite this article as: Choudhury L, Rigolin VH, Bonow RO, Integrated Imaging in Hypertrophic Cardiomyopathy, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Integrated Imaging in Hypertrophic Cardiomyopathy
Lubna Choudhury MD, Vera H. Rigolin, MD,
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Robert O. Bonow MD, MS
Author Affiliations: Bluhm Cardiovascular Institute, Division of Cardiology, Northwestern
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University Feinberg School of Medicine, Chicago IL
Corresponding Author:
Lubna Choudhury, MD Division of Cardiology Northwestern University Feinberg School of Medicine 676 North St Clair, Suite 600 Chicago, IL 60611
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Phone: 312-695-0059 Fax: 312-695-0063 Email: [email protected]
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Running head: Imaging in Hypertrophic Cardiomyopathy
ACCEPTED MANUSCRIPT 2 Abstract Hypertrophic cardiomyopathy (HC) has a very heterogeneous clinical spectrum and lends itself to multimodality imaging for evaluation and management. This review addresses clinical
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applications of cardiac imaging in patients with HC. Integrating various modalities of
echocardiography and cardiac magnetic resonance (CMR) are discussed in the clinical context such as diagnosis, evaluation, management, risk stratification and family screening of HC
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patients. The utility of peri-procedure imaging techniques are highlighted for guiding surgical and transcatheter septal reduction procedures. More limited roles of invasive or computed
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tomography (CT) coronary angiography are discussed for HC patients with chest pain and risk factors for coronary artery disease. Nuclear techniques though available for decades, play a more limited role in contemporary routine management, but may assist in risk assessment. Newer CMR and echo imaging techniques are discussed in their emerging roles for further
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characterization of HC patients and family members with prospects of preclinical diagnosis. The strengths of the different imaging modalities are presented as well as a flow diagram summarizing integrated imaging in this disease. In conclusion, integrated imaging using the
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various imaging modalities predominantly echocardiography and CMR based on the clinical
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picture, plays an essential role in the management of HC patients.
Key words: Hypertrophic Cardiomyopathy, Imaging, Echocardiography, Cardiac Magnetic Resonance
ACCEPTED MANUSCRIPT 4 Introduction Hypertrophic cardiomyopathy (HC) is the most common single gene cardiac disorder, characterized by left ventricular (LV) hypertrophy in the absence of another condition likely to
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produce that degree of hypertrophy.1, 2 HC has a heterogeneous clinical spectrum and lends itself to multimodality imaging for evaluation and management. Echocardiography as well as cardiac magnetic resonance (CMR) imaging are essential for the delineating the morphology of LV
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hypertrophy in HC,3,4 identifying myocardial fibrosis,5 and stratifying risk 6,7 Myocardial perfusion imaging, including single photon emission tomography8 and positron emission
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tomography (PET)9 assist in predicting risk of adverse outcomes. Imaging also reveals subtle abnormalities in the pre-clinical phase in individuals carrying a causative genetic mutation.10, 11 This review addresses clinical applications of cardiac imaging in patients with HC for establishing diagnosis, determining morphology, evaluating and managing symptoms, assessing
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risk for adverse outcomes and family screening. Diagnosis of HC
Patients with HC are often asymptomatic and diagnosed because of a heart murmur, an
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abnormal electrocardiogram, or incidentally by an echocardiogram performed for unrelated purposes. The diagnosis is also often made during evaluation of cardiac symptoms or screening
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because of a family history of HC or sudden death. Once HC is suspected, the diagnosis must be confirmed by imaging.
Echocardiography is the principal test for establishing the HC diagnosis, using the criteria of increased LV wall thickness (≥15 mm) in the absence of another condition likely to produce that degree of hypertrophy.1,2 The hypertrophy can involve any location in the LV wall, and in patients with a family history of HC or a causative genetic mutation, lesser degrees of
ACCEPTED MANUSCRIPT 5 hypertrophy are diagnostic.1 Two dimensional transthoracic echocardiography provides qualitative and quantitative assessment of LV morphology (Figure 1)12 and function, left atrial volume, and mitral valve anatomy and function including systolic anterior motion (SAM).13
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Color flow and spectral Doppler assessment of hemodynamics, including LV outflow tract
(LVOT) obstruction,14 mitral regurgitation (Figure 2A), and pulmonary artery systolic pressure, are essential components of the echocardiographic examination. M-mode echocardiography is
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particularly suited to visualize SAM (Figure 2B). Diastolic function is assessed by both mitral inflow velocities15 and Doppler tissue imaging (Figure 3).16 Abnormal diastolic filling patterns
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are associated with higher left atrial volumes and higher left atrial pressures and these derangements have been shown to be associated with a higher incidence of serious adverse events. 17 For example, such patients may be at risk of developing atrial fibrillation or stroke and may warrant more frequent rhythm evaluation. Newer echocardiographic techniques will become
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more important in the future; in particular strain imaging can detect early abnormalities in myocardial mechanics in genotype positive HC patients who have not yet developed hypertrophy 18
and may provide an opportunity to modify the HC phenotype prior to the development of LV
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hypertrophy with future drug discovery. This technique can also distinguish the physiological LV hypertrophy of athletic remodeling from HC.19 CMR techniques can also elucidate regional
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myocardial dysfunction in HC patients, who have depressed end-systolic circumferential and longitudinal shortening using tissue tagging by spatial modulation of magnetization (SPAMM).20 CMR tissue tagging has been used for the evaluation of LV torsion which can be calculated using displacement encoded stimulated echo (DENSE) imaging.21 Patients who are HC mutation carriers without LV hypertrophy have been shown to have higher LV torsion. 22 In a study of intramural cardiac function and the extent of fibrosis in HC using DENSE, intramural systolic
ACCEPTED MANUSCRIPT 6 strain was significantly depressed within areas of late gadolinium enhancement (LGE) but also in the most hypertrophic regions without LGE, suggesting that myocardial disarray or other nonfibrotic processes affect systolic function in patients with HC.23 Another recent CMR
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technique of diffusion tensor imaging to analyze the cross-myocyte components of diffusion shows evidence of abnormal myocardial laminar orientations in diastole in HC patients
independent of LGE.24 In contrast to LGE which detects macroscopic fibrosis, the emerging
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CMR technique of T1 mapping can estimate extracellular volume fraction related to diffuse interstitial fibrosis in HC and this has been correlated with diastolic dysfunction in HC.25 While
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these newer CMR techniques shed light on more detailed myocardial structural and functional abnormalities in HC, they are not routinely used in clinical practice.
Echocardiography is well suited to identify abnormalities of the mitral valve apparatus (Figure 4A) that are common in HC, 26 including elongation of one or both leaflets,27 anomalous
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papillary muscles or chordae,28 direct papillary muscle insertion into the mitral leaflet (Figure 4B), chordal rupture, and mitral valve prolapse. An eccentric, anteriorly directed jet of mitral regurgitation should suggest an intrinsic mitral valve abnormality.27 Unusual locations of
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hypertrophy not readily apparent on the 2D echocardiography can be demonstrated by CMR,4 as
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it affords high-resolution delineation of the full extent and distribution of hypertrophy, including biventricular hypertrophy (Figure 5A), with no artifacts due to imaging windows or patient body habitus. Abnormal papillary muscle morphology (Figure 5B) and insertion are particularly well visualized by CMR 29 and may contribute to LVOT obstruction.29 CMR is well suited to elucidate myocardial scarring (Figure 5C and 5D) commonly seen in HC as well as recognizing variants of HC such as apical hypertrophy (Figure 5D) or aneurysms6. Other diseases that cause increased LV wall thickness can mimic HC, and imaging plays a
ACCEPTED MANUSCRIPT 7 crucial role in differentiating HC from these conditions (Table 1). Myocardial delayed enhancement patterns by CMR may identify alternative diagnoses, such as Cardiac amyloidosis30 (Figure 6), sarcoidosis 31or Fabry’s disease.32 A common conundrum is differentiating HC from
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the physiologic cardiac adaptations resulting from athletic training. The largest and most
definitive series of highly trained athletes33 reported a maximum wall thickness of 16 mm, with only 1.7% of men and no women manifesting a wall thickness >12 mm. In addition, the male
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athletes with LV wall thickness >12 mm also had LV dilation (LV end-diastolic dimension 5563 mm).33 This degree of LV cavity dilation is unusual in HC and usually occurs only in the end-
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stage phase of the disease, characterized by LV dilation and scarring on CMR (Figure 6C), associated with progressive systolic dysfunction and symptomatic heart failure. The ratio of diastolic wall thickness to LV end-diastolic volume by CMR less than 0.15 mm/m2/mL has a sensitivity of 80% and specificity of 99% for an athlete's heart.34 In the gray areas of overlap
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between athletes and HC patients with mild hypertrophy (wall thickness 12-15 mm), other features beyond cavity dimensions such as left atrial enlargement, unusual heterogeneous patterns of LV hypertrophy, and abnormalities of LV diastolic filling are useful.35 Regional
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systolic LV deformation measured by tissue Doppler-derived longitudinal strain and strain rate imaging is within normal limits in athletes,36 whereas patients with HC have impaired systolic
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function with both heterogeneity of velocities and asynchrony of motion.37 The strengths of the various imaging modalities in evaluation of the key features of the HC phenotype are summarized in Table 2.
CMR also delineates LVOT anatomy, and CMR or transesophageal echocardiography (TEE) is useful in patients in whom a subaortic membrane is suspected as a possible cause or contributor to the subvalvular gradient, especially in those patients with mild hypertrophy and
ACCEPTED MANUSCRIPT 8 significant gradient (Figure 7). Evaluation of Symptoms Major pathophysiologic mechanisms of symptoms in HC are LV diastolic dysfunction,
an important role in elucidating the etiology of symptoms.
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LVOT obstruction, mitral regurgitation, myocardial ischemia and arrhythmias.1, 2 Imaging plays
Dyspnea results from the complex interplay between diastolic dysfunction, LVOT
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obstruction, and mitral regurgitation, any or all of which can produce significant pulmonary hypertension. Diastolic dysfunction is assessed echocardiographically by mitral inflow velocities
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and Doppler tissue imaging.15,16 The majority of patients with HC have LVOT obstruction either at rest or with exercise.38 SAM with resultant mitral regurgitation (Figure 2) is often exacerbated by exercise, and stress echocardiography (Figure 8) can elucidate dynamic LVOT obstruction in patients with exertional symptoms who may have no significant LVOT gradients at rest,38 thus
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making these patients candidates for medical therapy with beta blockers with or without disopyramide and failing that, septal reduction therapy. Therefore, stress echocardiography with exercise is recommended over Valsalva maneuver or amyl nitrate to evaluate exertional
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symptoms. Indeed, stress echocardiography is recommended in such patients to not only elucidate provocable LVOT obstruction as a mechanism of their exertional symptoms, but also to
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demonstrate increased mitral regurgitation with exercise that can lead to significantly elevated pulmonary artery systolic pressure, that in turn contributes to exertional dyspnea. Even in those patients who do not have significant provocable LVOT obstruction demonstration of significant mitral regurgitation by stress echocardiography causing exertional dyspnea can lead to surgical consideration of possible mitral valve repair. In addition, the estimation of pulmonary artery systolic pressure post exercise can be very useful to document exercise induced pulmonary
ACCEPTED MANUSCRIPT 9 hypertension (likely a result of diastolic dysfunction) as a potential mechanism of exertional dyspnea. Elucidation of these hemodynamic parameters by stress echocardiography are often more important than assessing wall motion abnormalities in these patients, most of whom do not
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have obstructive epicardial coronary artery disease (CAD). Hence these measurements are often obtained before assessing wall motion at peak exercise. On the other hand stress
echocardiography for ischemia evaluation becomes more important in older HCM patients with
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risk factors for CAD. Unexplained syncope is a risk factor for sudden cardiac death in HC.1 However, lightheadedness or syncope in HC can be hemodynamic in origin. Eliciting these
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symptoms with stress echocardiography demonstrating a significant LVOT gradient and decrease in blood pressure during (or immediately after) exercise identifies the mechanism and can thus provide an explanation for syncope so that an ICD is not automatically considered for such patients for primary prevention of sudden cardiac death. Echocardiography and CMR also
6C,D).
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identify the subgroup of patients who progress to symptomatic LV systolic dysfunction (Figure
Chest pain in HC often represents myocardial ischemia due to coronary microvascular
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dysfunction9, 39 superimposed on the increased oxygen demands of LV hypertrophy and LVOT obstruction. Stress echocardiography has low sensitivity for detecting microvascular ischemia, as
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wall motion may be preserved when there is microvascular dysfunction. Myocardial perfusion imaging, however, often reveals reversible perfusion defects in HC patients in the absence of obstructive epicardial CAD.8 Hence, perfusion imaging may be useful in evaluating chest pain due to coronary microvascular ischemia in patients without obstructive epicardial CAD. Conversely, in older patients or those with CAD risk factors, invasive or CT coronary angiography is necessary to detect concomitant obstructive CAD.1, 2, 40 Coronary angiography or
ACCEPTED MANUSCRIPT 10 CT angiography also identifies myocardial bridging which is a common finding in HC patients.41 Management When patients with HC are determined to have symptoms due to LVOT obstruction, the
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recommended initial management is medical therapy. The role of imaging in stable patients with HC on medical therapy is mainly relegated to serial evaluations of LV wall thickness, LVOT obstruction, mitral regurgitation, cavity dimensions and function.1, 2 Assessing LVOT gradients
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with stress echocardiography is useful to evaluate ongoing symptoms on medical therapy. Echocardiography is also useful to identify symptomatic patients who have severe mitral
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regurgitation in whom surgical mitral valve repair may be required regardless of the LVOT gradient.
Patients with refractory symptoms and with LVOT gradients ≥50 mmHg at rest or with provocation are candidates for septal reduction therapy including surgical septal myectomy 1,2, 42
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or alcohol septal ablation.43 Imaging is essential for identifying candidates for intervention and pre-procedural planning to determine the optimal approach, while intra-procedural TEE is important in obtaining optimal results.
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For planning septal myectomy, 2D-Doppler echocardiography is the principal test for determining location and severity of septal hypertrophy, mitral regurgitation and LVOT
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obstruction and thus suitability for surgery and predicting postoperative outcome.1, 2, 44 However, preoperative CMR is valuable in identifying additional features that are important in surgical planning, such as anomalous papillary muscle insertions,29 redundant chordal structures, excessive midventricular or papillary muscle hypertrophy 45 or subaortic membrane, that may require surgical correction in addition to septal myectomy. Intraoperative TEE (Figure 9) is particularly useful to assure adequate surgical resection and determining need for concomitant
ACCEPTED MANUSCRIPT 11 MV repair. Intraoperative TEE also assesses the immediate results and excludes important complications such as ventricular septal defect or aortic insufficiency,46 and residual gradients after septal myectomy can be evaluated with dobutamine administration (Figure 10).
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Invasive coronary angiography can also be useful prior to planned septal myectomy to
evaluate for the need for concomitant coronary bypass grafting, while prior to alcohol septal ablation, it can define the septal perforator anatomy and reveal concomitant epicardial coronary
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stenoses that may need percutaneous coronary intervention for amelioration of symptoms. In patients undergoing alcohol septal ablation, contrast echocardiography (Figure 11) identifies the
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myocardial territory perfused by the target vessel.47 Before alcohol infusion, Doppler echocardiography during intracoronary balloon inflation in the target septal perforator determines if occluding flow in that territory results in a decrease in LVOT gradient. Dual chamber pacing therapy has a limited role in treating symptomatic patients but can be
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useful in elderly patients with LVOT obstruction who have prohibitive risks for surgical myectomy and do not have suitable coronary anatomy for alcohol septal ablation.48 Doppler echocardiography (Figure 12) can guide adjustment of the atrioventricular delay for optimal
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reduction in LVOT gradient.48
Imaging with echocardiography or CMR is useful for assessing LV and papillary muscle
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morphology after septal reduction therapy.49, 50 Echocardiography is particularly useful after invasive interventions 51 to evaluate possible residual LVOT obstruction or mitral regurgitation in patients with recurrent symptoms. Assessing the risk of sudden death is a major focus of the evaluation of every patient with HC, due to the efficacy of the implantable cardioverter defibrillator (ICD) in preventing sudden cardiac death (SCD) in this disease. A patient’s risk of SCD in HC is primarily determined by
ACCEPTED MANUSCRIPT 12 history and not derived from imaging. The long recognized morphologic feature of HC that is significantly associated with sudden death is extreme LV hypertrophy 52 (LV wall thickness >30 mm), though most sudden deaths occur in patients with maximum wall thicknesses of 20-30
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mm.53 Severity of LVOT obstruction has been linked to heart failure-related death in HC.38
Echocardiography is the mainstay in evaluating both of these parameters. More recently, strain imaging may also have a role in risk stratification, as recent data have linked ambulatory
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evidence of nonsustained ventricular tachycardia with significantly reduced peak longitudinal systolic strain.54 While CMR provides more precise assessment of the magnitude of LV
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hypertrophy, (a parameter, although originally established as a risk factor by echocardiographic imaging, is thought to be of the same prognostic significance by CMR), its unique contribution to risk assessment is identification and quantification of myocardial fibrosis by LGE on contrast CMR, using both visual methods and dedicated software.5, 7 Extensive fibrosis is a common
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finding at postmortem examination of patients who have died suddenly.55 and extensive fibrosis detected by LGE on CMR has been linked to ventricular arrhythmias and adverse events in HC. 7, 56,57
Fibrosis is also associated with systolic dysfunction and heart failure.58 Patients with a
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mild phenotype of HC on CMR imaging, with mild hypertrophy and no significant fibrosis, appear to be low risk patients who do not warrant consideration of ICD implantation for primary
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prevention of SCD. CMR is thus emerging as an essential tool for routine risk assessment in HC, although further studies are required. In patients who are unable to undergo CMR, cardiac dual source CT may be an alternative method for detecting and quantifying myocardial fibrosis.59 Myocardial perfusion imaging also provides prognostic information, as young HC patients with ischemia have a higher mortality rate.8 and ischemia has been implicated as a cause of myocardial scarring.58 In older HC patients, ischemia on myocardial perfusion imaging is
ACCEPTED MANUSCRIPT 13 associated with more adverse events60 regardless of concomitant epicardial CAD. Patients with the lowest coronary flow reserve on quantitative PET perfusion imaging have an increased risk of adverse cardiovascular events.9 However, due to limited availability, PET is not routinely used
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for risk stratification in HC.
Left atrial dilatation can be evaluated by both echocardiography and CMR and is a strong predictor of atrial fibrillation in HC. 61 In turn, the development of atrial fibrillation is associated
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with worse outcomes including more severe heart failure and stroke.62
Since HC is a genetic disease, echocardiographic screening of family members of HC
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patients is strongly recommended, 1, 2 with ongoing serial imaging every few years or earlier if symptoms develop or borderline imaging abnormalities are found. CMR has a role in family screening if echocardiographic image quality is suboptimal or if there is borderline LV hypertrophy. CMR is particularly important in a family member with an apparently normal
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echocardiogram but abnormal electrocardiogram, and although current guidelines do not recommend CMR for making the diagnosis in all family members of HC patients, we would recommend a low threshold be used for CMR imaging for screening when there is a family
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history of sudden cardiac death, as the identification of HC phenotype has important implications for primary prevention in such families. Individuals carrying gene mutations for HC may
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manifest abnormalities on imaging such as myocardial crypts by CMR,63 abnormal strain imaging by echocardiography,18 and reduced coronary flow reserve on quantitative PET perfusion imaging 64 before LV hypertrophy becomes apparent. These are considered early phenotypic manifestations of HC and therefore these individuals should be followed periodically for development of increased LV wall thickness. Integrated imaging, predominantly with echocardiography and CMR, is essential in the
ACCEPTED MANUSCRIPT 14 diagnosis, evaluation, management, risk stratification and family screening of HC patients (Figure 13). Stress echocardiography adds valuable diagnostic information regarding the mechanism of HC symptoms, thus enabling appropriate therapeutic choices. For example,
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patients with nonobstructive HC do not need to be considered for septal reduction therapies. Mitral valve abnormalities are common in HC, and symptomatic patients with severe mitral regurgitation may be candidates for mitral valve repair regardless of the LVOT gradient. CMR
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can be particularly useful in uncovering LV hypertrophy in family members of HC patients with a family history of SCD when echocardiography is equivocal or suboptimal, in whom the
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diagnosis of HC has implications for primary prevention of SCD. CMR is particularly useful for distinguishing HC from other conditions that may mimic HC. Late gadolinium enhancement by CMR is uniquely suited to evaluate extent of myocardial fibrosis, which has an increasing role in risk assessment for adverse outcomes. The technique of CMR T1 mapping is being explored as
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an additional tool in assessing diffuse myocardial fibrosis in HC and its correlates. TEE may be needed to rule out a subaortic membrane as a potential cause of the LVOT gradient, particularly in patients with a high LVOT gradient despite mild septal hypertrophy. Intraoperative TEE and
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peri-procedural transthoracic echo with contrast play an essential role in guiding surgical and transcatheter septal reduction procedures respectively. Invasive or CT coronary angiography is
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reserved for HC patients with chest pain and risk factors for CAD. Nuclear techniques play a more limited role but may assist in risk assessment. Tissue Doppler imaging is emerging for evaluating individuals with sarcomere gene mutations who have not yet developed the phenotypic findings of LV hypertrophy. Newer MRI and echo techniques can provide insights in abnormal myocardial mechanics in HC and further studies are needed to determine their place in HC imaging.
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Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-2779.
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ACCEPTED MANUSCRIPT 18 20. Kramer CK, Reichek, N, Ferrari VA, Theobald T, Dawson J, Axel L. Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation 1994;90:186-194 21. Young AA, Cowan BR. Evaluation of left ventricular torsion by cardiovascular magnetic
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31. Smedema JP, Snoep G, van Kroonenburgh MP, van Geuns RJ, Dassen WR, Gorgels AP, Crijns HJ. Evaluation of the accuracy of gadolinium-enhanced cardiovascular magnetic resonance in the diagnosis of cardiac sarcoidosis. J Am Coll Cardiol 2005;45:1683-1690.
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ACCEPTED MANUSCRIPT 22 Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a randomized,
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ACCEPTED MANUSCRIPT 25 Figure Legends Figure 1. A. Parasternal long axis echocardiogram showing massive (40 mm) septal
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hypertrophy. B. Apical view demonstrating apical HC (arrow). LA = left atrium Figure 2. A. Apical 4 chamber view demonstrating systolic anterior motion of the mitral valve (white arrow) with color Doppler showing mitral regurgitation and turbulence in the left
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ventricular outflow tract B. M-mode echocardiogram demonstrating systolic anterior motion of the mitral valve (arrow). LVOT=left ventricular outflow tract, MR= mitral regurgitation
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MV=mitral valve, SAM=systolic anterior motion
Figure 3. A. Abnormal diastolic function by spectral Doppler of mitral inflow B. Septal annulus tissue Doppler imaging. Doppler findings show elevated left ventricular filling pressures (E/e’= 36).
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Figure 4. A. Myxomatous mitral valve in a HC patient. B. Abnormal papillary muscle inserting directly into the mitral leaflet (arrow). AMVL = anterior mitral valve leaflet.
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Figure 5. Cardiac magnetic resonance (CMR) imaging A. 4 chamber view showing interventricular septal hypertrophy as well as hypertrophy of the right ventricular apical wall
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(arrow) B. abnormal papillary muscles with multiple heads (arrow) C. short axis view showing myocardial scarring (arrow), as grey-white patches in the normal myocardium that appears black. D. CMR showing myocardial scarring (arrow) in apical HC. IVS = interventricular septum Figure 6. Cardiac magnetic resonance imaging A. showing diffuse subendocardial delayed enhancement (arrows) in a patient with AL cardiac amyloidosis in two chamber view and B. Short axis view. C. showing LV dilatation and extensive myocardial delayed enhancement
ACCEPTED MANUSCRIPT 26 (arrows) in a patient with end-stage HC with systolic dysfunction in 4 chamber view and D. Short axis view.
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Figure 7. A. Subaortic membrane (arrow) visualized by transesophageal echo (TEE) in a patient with minimal hypertrophy and severe left ventricular outflow tract (LVOT) obstruction,
MV=mitral valve, LA=left atrium. B. Turbulence in the LVOT by color Doppler imaging. C.
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Subaortic membrane visualized by 3-dimensional TEE (arrow).
Figure 8. Stress echo derived spectral Doppler left ventricular outflow tract (LVOT) velocities
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A. at rest (peak LVOT velocity 4.1 m/sec, peak gradient 68 mm Hg) and B. with treadmill exercise (peak LVOT velocity 5.5 m/sec, peak gradient 121 mm Hg) (arrow) in a patient with obstructive HC. The remaining spectral Doppler signals in panel B may represent contamination from mitral regurgitation.
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Figure 9. Intraoperative transesophageal echo showing A. Systolic anterior motion of the mitral valve. B. Mitral regurgitation. C. Left ventricular outflow tract gradient by CW spectral Doppler. D. Distance of maximal septal wall thickness from aortic valve annulus (arrow). AMVL=anterior
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mitral valve leaflet, CW=continuous wave, LA=left atrium, LV=left ventricle, LVOT=left
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ventricular outflow tract, RA=right atrium, RV=right ventricle. Figure 10. Intraoperative transesophageal echo after cardiopulmonary bypass demonstrating. A. insignificant left ventricular outflow tract (LVOT) gradient post septal myectomy. B. insignificant LVOT gradient with dobutamine. C. Three dimensional TEE image of the mitral valve from the left atrial perspective. Note the double orifice as a result of an Alfieri stitch between the two middle scallops. D. Trace mitral regurgitation. LA=left atrium, LV=left ventricle, MR=mitral regurgitation
ACCEPTED MANUSCRIPT 27 Figure 11. A. Parasternal long axis view demonstrating contrast in the basal septum (arrow) prior to alcohol septal ablation. Left ventricular outflow tract peak velocity and peak gradient B. before and C. after alcohol septal ablation. LVOT= left ventricular outflow tract Vel=velocity,
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PG=peak gradient
Figure 12. Echocardiographic guided adjustment of dual chamber pacemaker atrioventricular
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delay to reduce left ventricular ouflow tract obstruction; A. Gradient before and B after A-V delay optimization A-V=atrioventricular, LVOT=left ventricular outflow tract
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Figure 13. Flow diagram for imaging in HC; LV=left ventricular, MV=mitral valve, LVOT= left ventricular outflow tract, RVSP=right ventricular systolic pressure, SAM=systolic anterior motion, CAD=coronary artery disease, BP=blood pressure, CTA=computerized tomographic
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angiogram
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Table 1. Imaging characteristics by Echocardiography and CMR that help in distinguishing HC from other conditions that may cause LV hypertrophy
parameters
Athlete’s heart
↑↑
↑
↑
LV cavity size
↓
-
↑
Diastolic dysfunction
+
+
-
Abnormal papillary muscle
+
-
+
Abnormal chordal attachment
+
-
SAM of MV
+
-
Elongated Mitral leaflets
+
-
Eccentric Mitral regurgitation
+
-
+
Anteroseptal and inferoseptal foci
+ -
AC C
Subendocardial LGE
EP
Presence of LGE
-
+ -
-
-
-
-
-
-
-
-
-
-
+
-
-
-
-
-
+
TE D
LGE by CMR
↑↑
M AN U
LV wall thickness
Infiltrative disease (Amyloid, Sarcoid, Fabry’s disease)
RI PT
Hypertensive heart disease
HC
SC
Echocardiographic
Mid-myocardial LGE (focal)
+
-
-
+/-
Mid myocardial LGE (linear)
-
+
-
-
LGE = Late gadolinium enhancement, LV= left ventricular, CMR= cardiac magnetic resonance, SAM= systolic anterior motion, MV= mitral valve + = likely to be present, - = likely to be absent, ↑= increased, ↓= decreased.
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HC subtype (LV morphology) or LA enlargement
LVOTG
Diastolic dysfunction
Echo Doppler
+
+
+
Stress Echo
+
+
+
CMR
+
+
TEE ± Dobutamine
+
+
+
+
+
+
+
+
+
Ischemia CAD or Myocardial Bridging
Abnormal Myocardial Mechanics
+
SC
+
+
+ +
+ +
+
+ + +
EP
Newer CMR modalities: DENSE, DTI
+
TE D
SPECT
Echo Strain imaging
+
Fibrosis
+
Cardiac CT
PET
PH
M AN U
Cardiac cath
MR
RI PT
LVH
AC C
Table 2. Strengths of each imaging modality for assessing key features of the HC phenotype
LVH = left ventricular hypertrophy, LA= left atrial, LVOTG=Left ventricular outflow tract gradient, CAD=coronary artery disease, CMR= cardiac magnetic resonance, CT=computed tomography, SPECT=single photon emission computed tomography, PET=positron emission tomography DENSE= displacement encoded stimulated echo, DTI= diffusion tensor imaging, PH=pulmonary hypertension
+ +
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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ACCEPTED MANUSCRIPT Suspected HC CMR LV wall thickness Rule out HC mimics Myocardial fibrosis (pattern, extent, quantity) Papillary muscle abnormalities
Echo Doppler
Family Screening
Stress Echo with pre and post exercise Doppler
Nonobstructive
TE D
Significant LVOT obstruction explaining symptoms
Medical Treatment
Alcohol Septal Ablation
Refractory symptoms Septal myectomy ± mitral valve repair±papillary muscle /chordal reconstruction
Chest pain, dyspnea, risk factors for CAD
AC C
AV synchronized pacing
Risk stratification for adverse events
EP
BP response to exercise Exercise induced symptoms Peak LVOT gradient RVSP Mitral regurgitation severity LV wall motion Submitral apparatus
Equivocal or suboptimal images
M AN U
Exertional symptoms
SC
HC Diagnosed
RI PT
LV wall thickness SAM of MV LVOT gradient baseline and Valsalva Diastolic function Mitral regurgitation
Coronary angiography or Coronary CTA
Coronary anatomy Myocardial bridging
Significant papillary muscle abnormality requiring surgical correction TEE (Intraoperative) Mitral regurgitation SAM LVOT gradient Subaortic membrane