Clinical Radiology xxx (2013) e1ee10
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Review
The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy E.T.D. Hoey a, *, J.K. Teoh b, I. Das a, A. Ganeshan a, H. Simpson b, R.W. Watkin b a b
Department of Radiology, Heart of England NHS Foundation Trust, Birmingham, West Midlands, UK Department of Cardiology, Heart of England NHS Foundation Trust, Birmingham, West Midlands, UK
art icl e i nformat ion Article history: Received 14 June 2013 Received in revised form 6 September 2013 Accepted 13 November 2013
Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiovascular disorder. Although many HCM patients remain asymptomatic, sudden death (SD) can occur as the initial manifestation of the disease. It has been hypothesized that myocardial architectural disorganization and scarring represent an unstable electrophysiological substrate that creates susceptibility to malignant ventricular arrhythmias. Cardiovascular magnetic resonance imaging (CMR) is widely used for the diagnosis of HCM, especially in patients with an incomplete or inconclusive echocardiography study. CMR can provide precise non-invasive assessment of biventricular function, wall thickness, and assessment of myocardial fibrosis, using inversion recovery gadolinium-enhanced sequences. CMR is also one of the most promising avenues of research in HCM, and in recent years, has provided many new insights and identified a number of potential adverse prognostic indicators for SD. Future work is still needed to integrate CMR findings into traditional risk assessment algorithms. This paper reviews the evolving role of CMR for risk stratification in HCM including assessment of myocardial hypertrophy, fibrosis and ischaemia. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Hypertrophic cardiomyopathy (HCM) is the most common inheritable myocardial disorder, with an estimated prevalence of 1:500.1 It is inherited as an autosomal dominant trait in 50e60% of cases with over 600 mutations identified in sarcomeric genes.2 These mutations cause an increase in myocyte stress, eventually leading to left ventricular (LV) hypertrophy (LVH; most commonly with asymmetric involvement of the interventricular septum)
* Guarantor and correspondent: E.T.D. Hoey, Department of Radiology, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham, West Midlands B9 5SS, UK. Tel.: þ44 790 370 4446; fax: þ44 113 243 2799. E-mail address: [email protected] (E.T.D. Hoey).
and fibrosis. HCM has a wide variability in penetrance and although most cases are phenotypically expressed in adolescence or early adulthood, delayed emergence of LVH can occur in midlife or later.3 Symptoms of HCM are wide ranging and include exertional dyspnoea, chest pain, pre-syncope, and syncope, resulting from differing combinations of dynamic LV outflow tract (LVOT) obstruction, diastolic and systolic LV dysfunction, and supraventricular/ ventricular arrhythmias.4 Although many patients remain asymptomatic with a benign natural history, sudden death (SD) can occur as the initial manifestation of the disease in otherwise asymptomatic or mildly symptomatic young (10 beats) bursts of non-sustained VT identified over serial monitoring periods carry the greatest weight as an indication for Table 1 Conventional risk factors for sudden death in hypertrophic cardiomyopathy. 1. 2. 3. 4. 5.
Family history of 1 hypertrophic cardiomyopathy-related Sudden Death One of more episodes of unexplained recent syncope Massive left ventricular hypertrophy (thickness 30 mm) Non-sustained ventricular tachycardia on ambulatory 24 h electrocardiography Hypotensive or attenuated blood pressure response to exercise.
primary prevention ICD placement.1,4,8,11 Decision-making dilemmas inevitably occur and clinical judgment and experience are necessary. A number of disease features have been described as potential arbitrators when the level of risk based on conventional markers is ambiguous and may be useful in resolving uncertain ICD decisions on a case-bycase basis (Table 2).8 Despite many recent advances, risk stratification in HCM is an incomplete science, and there is a clear need to identify novel markers of susceptibility to SD.4
Non-invasive imaging Traditionally, the diagnosis of HCM relies upon a combination of clinical assessment and two-dimensional transthoracic echocardiography (TTE) to identify an unexplained increase in LV wall thickness in the presence of a non-dilated LV cavity.12 CMR has a number of advantages over TTE including an unrestricted field of view and much improved definition of the endocardial margins, which enables more precise assessment of any hypertrophied regions that may be incompletely visualised at TTE. In particular, apical HCM and apical aneurysms secondary to mid-ventricular HCM are both commonly missed on TTE, because of foreshortening effects.13 In addition, CMR is the only cardiac imaging technique that can provide noninvasive assessment of myocardial fibrosis, which is recognized as an adverse prognostic indicator.14 In many centres, CMR imaging is now routinely performed in all new patients with suspected HCM, which is endorsed by recent consensus guidelines.12 Cardiac computed tomography (CT) angiography can also be used to assess morphology and function (in addition to coronary artery evaluation), but requires a retrospective ECG-gated acquisition protocol, which carries a high radiation burden. Currently, cardiac CT has inferior temporal resolution, and lacks the soft tissue characterization capabilities of CMR and is usually reserved for cases with a contraindication to CMR, such as a non-MRI compatible pacemaker.
Cardiovascular MRI technique Cardiovascular MRI is performed at our institution using a 1.5 T MRI machine (Ingenia, Philips Healthcare, Best, The Netherlands) using a core imaging protocol15 with the addition of flow-sensitive sequences and stress perfusion imaging if required (Table 3). Black-blood-prepared double inversion recovery fast spin-echo images with T1 weighting are acquired as Table 2 Potential arbitrators cardiomyopathy. 1. 2. 3. 4. 5.
for
clinical
decision
making
in
hypertrophic
Resting left ventricular outflow tract obstruction Extensive MRI-detected late gadolinium enhancement Left ventricular apical aneurysm Coronary artery disease Participant in competitive sport
MRI, magnetic resonance imaging.
Please cite this article in press as: Hoey ETD, et al., The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.11.012
E.T.D. Hoey et al. / Clinical Radiology xxx (2013) e1ee10
e3
Table 3 Summary of institutional magnetic resonance imaging (MRI) protocol for hypertrophic cardiomyopathy.15 Sequence
Planes and coverage
Goal of sequence
Parameters
T1-weighted double inversion recovery fast spin-echo
Transverse from thoracic inlet to diaphragm
Anatomical overview
Steady state free precession
Left ventricular short axis (baseeapex stack) Two-chamber Three-chamber Four-chamber
Delayed enhancement (T1-weighted 2D gradient echo @ 10e15 min)
Left ventricular short axis Two-chamber Four-chamber
Assessment of left ventricular hypertrophy Assessment of left ventricular mass and function Assessment of left ventricular outflow tract compromise, systolic anterior mitral valve motion and mitral regurgitation Assessment for myocardial fibrosis and/or areas of auto-infarction
TR: 1000 ms TE: 35e40 ms 6 mm section thickness Matrix: 256 256 TR: 3e5 ms TE: 1.5e2 ms Flip angle: 55 8 mm section thickness (with 2 mm intersection gap for short axis stack) Matrix: 128 256
Optional T1-weighted multisection gradient-echo first-pass gadolinium perfusion study Stress: IV adenosine infusion of 140 mg/kg/min for 3 min at 4 ml/s. Repeated at rest Optional Phase contrast imaging (PC-MRI)
TR: 5e6 ms TE: 2e3 ms Flip angle: 50 10 mm section thickness Matrix: 256 256
Left ventricular short axis at a basal, mid and apical slice
To detect inducible ischaemia
TR: 2.5 ms TE: 1e1.5 ms Flip angle: 50 10 mm section thickness Matrix: 128 256
Left ventricular outflow tract (through plane and/or in-plane) Mitral valve orifice (through plane)
To quantify any outflow tract peak systolic velocity To assess diastolic filling velocities
TR: 30 ms TE: 1.2 ms Flip angle: 30 5 mm section thickness Voxel size: 2 1.2 6 mm Velocity encoding value: 150e250 cm/s
TR, repetition time; TE, echo time; 2D, two-dimensional; IV, intravenous; PC-MRI, phase contrast magnetic resonance imaging.
contiguous transverse sections, covering the thorax from the diaphragm to the thoracic inlet, to provide an anatomical overview. Cine bright-blood-prepared steady-state free precession (SSFP) sequences are then acquired in a contiguous fashion along the LV short-axis from base to apex. These enable identification of hypertrophied regions as well as quantification of LV function using semi-automated post processing software. SSFP cine images are also acquired in two-, three-, and four-chamber views for further structural assessment. Tagged cine sequences (which use spatial modulation of magnetization to produce geometric grids across the myocardium) in the short axis plane form a core part of the HCM protocol in some centres. Visual assessment of tagging sequences can be helpful to detect subtle HCM-related regional variations in myocardial deformation and quantitative “regional strain rate” data can also be generated, but is time consuming and currently of limited clinical utility. The patient is then administered an intravenous injection of 0.2 mmol/kg gadolinium-based contrast agent at 1e2 ml/s. Imaging is started 10 min after injection time, with a variable inversion time (TI) scout sequence that permits selection of a TI to null normal myocardial signal (typically 200e300 ms).16 Late gadolinium enhancement (LGE) images are acquired in the short axis plane from base
to apex at 1 cm increments using a T1-weighted inversion recovery gradient-echo sequence.16 Further single shot images in mid-two-chamber and mid-four-chamber planes are also obtained, to help improve visualization of any apical disease. An alternative technique is a phase-sensitive inversion recovery sequence, which does not require exact identification of the optimal TI as it utilizes the full range of magnetization values, whereby myocardial fibrosis always appears higher in signal than normal myocardium.17 If there are any signs of LVOT obstruction, velocityencoded phase-contrast (PC-MRI) sequences can be used to estimate the peak systolic velocity using an in-plane or through-plane LVOT acquisition plane.15 Similarly, an assessment of diastolic LV function can be made using a PCMRI sequence acquired through the plane of transmitral inflow with analysis of flow velocity graphs for early and atrial phase filling patterns. Finally, if ischaemic testing is required, it is performed with a first-pass gadolinium-enhanced multisection gradient-echo sequence at stress (following an intravenous adenosine infusion) and repeated at rest.
LV wall thickness Non-invasive diagnosis of HCM is based on an LV wall thickness 15 mm at end diastole (frequently involving the
Please cite this article in press as: Hoey ETD, et al., The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.11.012
e4
E.T.D. Hoey et al. / Clinical Radiology xxx (2013) e1ee10
interventricular septum) and/or a septal to lateral wall thickness ratio >1.3 in a non-dilated LV in the absence of any loading conditions (e.g., systemic hypertension or aortic stenosis). Other causes of LVH requiring distinction from HCM include Fabry’s disease, sarcoidosis, amyloidosis, and athlete’s heart. In many cases, the distinction from HCMrelated LVH will be straightforward based on a combination of clinical features, LVH distribution, LV function, and the presence and pattern of CMR-detected myocardial fibrosis. Morphological adaptation of an athletic heart is often the most challenging to confidently distinguish from HCM. Typically, with athletic remodelling there is mild LVH (usually
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Review
The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy E.T.D. Hoey a, *, J.K. Teoh b, I. Das a, A. Ganeshan a, H. Simpson b, R.W. Watkin b a b
Department of Radiology, Heart of England NHS Foundation Trust, Birmingham, West Midlands, UK Department of Cardiology, Heart of England NHS Foundation Trust, Birmingham, West Midlands, UK
art icl e i nformat ion Article history: Received 14 June 2013 Received in revised form 6 September 2013 Accepted 13 November 2013
Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiovascular disorder. Although many HCM patients remain asymptomatic, sudden death (SD) can occur as the initial manifestation of the disease. It has been hypothesized that myocardial architectural disorganization and scarring represent an unstable electrophysiological substrate that creates susceptibility to malignant ventricular arrhythmias. Cardiovascular magnetic resonance imaging (CMR) is widely used for the diagnosis of HCM, especially in patients with an incomplete or inconclusive echocardiography study. CMR can provide precise non-invasive assessment of biventricular function, wall thickness, and assessment of myocardial fibrosis, using inversion recovery gadolinium-enhanced sequences. CMR is also one of the most promising avenues of research in HCM, and in recent years, has provided many new insights and identified a number of potential adverse prognostic indicators for SD. Future work is still needed to integrate CMR findings into traditional risk assessment algorithms. This paper reviews the evolving role of CMR for risk stratification in HCM including assessment of myocardial hypertrophy, fibrosis and ischaemia. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Hypertrophic cardiomyopathy (HCM) is the most common inheritable myocardial disorder, with an estimated prevalence of 1:500.1 It is inherited as an autosomal dominant trait in 50e60% of cases with over 600 mutations identified in sarcomeric genes.2 These mutations cause an increase in myocyte stress, eventually leading to left ventricular (LV) hypertrophy (LVH; most commonly with asymmetric involvement of the interventricular septum)
* Guarantor and correspondent: E.T.D. Hoey, Department of Radiology, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham, West Midlands B9 5SS, UK. Tel.: þ44 790 370 4446; fax: þ44 113 243 2799. E-mail address: [email protected] (E.T.D. Hoey).
and fibrosis. HCM has a wide variability in penetrance and although most cases are phenotypically expressed in adolescence or early adulthood, delayed emergence of LVH can occur in midlife or later.3 Symptoms of HCM are wide ranging and include exertional dyspnoea, chest pain, pre-syncope, and syncope, resulting from differing combinations of dynamic LV outflow tract (LVOT) obstruction, diastolic and systolic LV dysfunction, and supraventricular/ ventricular arrhythmias.4 Although many patients remain asymptomatic with a benign natural history, sudden death (SD) can occur as the initial manifestation of the disease in otherwise asymptomatic or mildly symptomatic young (10 beats) bursts of non-sustained VT identified over serial monitoring periods carry the greatest weight as an indication for Table 1 Conventional risk factors for sudden death in hypertrophic cardiomyopathy. 1. 2. 3. 4. 5.
Family history of 1 hypertrophic cardiomyopathy-related Sudden Death One of more episodes of unexplained recent syncope Massive left ventricular hypertrophy (thickness 30 mm) Non-sustained ventricular tachycardia on ambulatory 24 h electrocardiography Hypotensive or attenuated blood pressure response to exercise.
primary prevention ICD placement.1,4,8,11 Decision-making dilemmas inevitably occur and clinical judgment and experience are necessary. A number of disease features have been described as potential arbitrators when the level of risk based on conventional markers is ambiguous and may be useful in resolving uncertain ICD decisions on a case-bycase basis (Table 2).8 Despite many recent advances, risk stratification in HCM is an incomplete science, and there is a clear need to identify novel markers of susceptibility to SD.4
Non-invasive imaging Traditionally, the diagnosis of HCM relies upon a combination of clinical assessment and two-dimensional transthoracic echocardiography (TTE) to identify an unexplained increase in LV wall thickness in the presence of a non-dilated LV cavity.12 CMR has a number of advantages over TTE including an unrestricted field of view and much improved definition of the endocardial margins, which enables more precise assessment of any hypertrophied regions that may be incompletely visualised at TTE. In particular, apical HCM and apical aneurysms secondary to mid-ventricular HCM are both commonly missed on TTE, because of foreshortening effects.13 In addition, CMR is the only cardiac imaging technique that can provide noninvasive assessment of myocardial fibrosis, which is recognized as an adverse prognostic indicator.14 In many centres, CMR imaging is now routinely performed in all new patients with suspected HCM, which is endorsed by recent consensus guidelines.12 Cardiac computed tomography (CT) angiography can also be used to assess morphology and function (in addition to coronary artery evaluation), but requires a retrospective ECG-gated acquisition protocol, which carries a high radiation burden. Currently, cardiac CT has inferior temporal resolution, and lacks the soft tissue characterization capabilities of CMR and is usually reserved for cases with a contraindication to CMR, such as a non-MRI compatible pacemaker.
Cardiovascular MRI technique Cardiovascular MRI is performed at our institution using a 1.5 T MRI machine (Ingenia, Philips Healthcare, Best, The Netherlands) using a core imaging protocol15 with the addition of flow-sensitive sequences and stress perfusion imaging if required (Table 3). Black-blood-prepared double inversion recovery fast spin-echo images with T1 weighting are acquired as Table 2 Potential arbitrators cardiomyopathy. 1. 2. 3. 4. 5.
for
clinical
decision
making
in
hypertrophic
Resting left ventricular outflow tract obstruction Extensive MRI-detected late gadolinium enhancement Left ventricular apical aneurysm Coronary artery disease Participant in competitive sport
MRI, magnetic resonance imaging.
Please cite this article in press as: Hoey ETD, et al., The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.11.012
E.T.D. Hoey et al. / Clinical Radiology xxx (2013) e1ee10
e3
Table 3 Summary of institutional magnetic resonance imaging (MRI) protocol for hypertrophic cardiomyopathy.15 Sequence
Planes and coverage
Goal of sequence
Parameters
T1-weighted double inversion recovery fast spin-echo
Transverse from thoracic inlet to diaphragm
Anatomical overview
Steady state free precession
Left ventricular short axis (baseeapex stack) Two-chamber Three-chamber Four-chamber
Delayed enhancement (T1-weighted 2D gradient echo @ 10e15 min)
Left ventricular short axis Two-chamber Four-chamber
Assessment of left ventricular hypertrophy Assessment of left ventricular mass and function Assessment of left ventricular outflow tract compromise, systolic anterior mitral valve motion and mitral regurgitation Assessment for myocardial fibrosis and/or areas of auto-infarction
TR: 1000 ms TE: 35e40 ms 6 mm section thickness Matrix: 256 256 TR: 3e5 ms TE: 1.5e2 ms Flip angle: 55 8 mm section thickness (with 2 mm intersection gap for short axis stack) Matrix: 128 256
Optional T1-weighted multisection gradient-echo first-pass gadolinium perfusion study Stress: IV adenosine infusion of 140 mg/kg/min for 3 min at 4 ml/s. Repeated at rest Optional Phase contrast imaging (PC-MRI)
TR: 5e6 ms TE: 2e3 ms Flip angle: 50 10 mm section thickness Matrix: 256 256
Left ventricular short axis at a basal, mid and apical slice
To detect inducible ischaemia
TR: 2.5 ms TE: 1e1.5 ms Flip angle: 50 10 mm section thickness Matrix: 128 256
Left ventricular outflow tract (through plane and/or in-plane) Mitral valve orifice (through plane)
To quantify any outflow tract peak systolic velocity To assess diastolic filling velocities
TR: 30 ms TE: 1.2 ms Flip angle: 30 5 mm section thickness Voxel size: 2 1.2 6 mm Velocity encoding value: 150e250 cm/s
TR, repetition time; TE, echo time; 2D, two-dimensional; IV, intravenous; PC-MRI, phase contrast magnetic resonance imaging.
contiguous transverse sections, covering the thorax from the diaphragm to the thoracic inlet, to provide an anatomical overview. Cine bright-blood-prepared steady-state free precession (SSFP) sequences are then acquired in a contiguous fashion along the LV short-axis from base to apex. These enable identification of hypertrophied regions as well as quantification of LV function using semi-automated post processing software. SSFP cine images are also acquired in two-, three-, and four-chamber views for further structural assessment. Tagged cine sequences (which use spatial modulation of magnetization to produce geometric grids across the myocardium) in the short axis plane form a core part of the HCM protocol in some centres. Visual assessment of tagging sequences can be helpful to detect subtle HCM-related regional variations in myocardial deformation and quantitative “regional strain rate” data can also be generated, but is time consuming and currently of limited clinical utility. The patient is then administered an intravenous injection of 0.2 mmol/kg gadolinium-based contrast agent at 1e2 ml/s. Imaging is started 10 min after injection time, with a variable inversion time (TI) scout sequence that permits selection of a TI to null normal myocardial signal (typically 200e300 ms).16 Late gadolinium enhancement (LGE) images are acquired in the short axis plane from base
to apex at 1 cm increments using a T1-weighted inversion recovery gradient-echo sequence.16 Further single shot images in mid-two-chamber and mid-four-chamber planes are also obtained, to help improve visualization of any apical disease. An alternative technique is a phase-sensitive inversion recovery sequence, which does not require exact identification of the optimal TI as it utilizes the full range of magnetization values, whereby myocardial fibrosis always appears higher in signal than normal myocardium.17 If there are any signs of LVOT obstruction, velocityencoded phase-contrast (PC-MRI) sequences can be used to estimate the peak systolic velocity using an in-plane or through-plane LVOT acquisition plane.15 Similarly, an assessment of diastolic LV function can be made using a PCMRI sequence acquired through the plane of transmitral inflow with analysis of flow velocity graphs for early and atrial phase filling patterns. Finally, if ischaemic testing is required, it is performed with a first-pass gadolinium-enhanced multisection gradient-echo sequence at stress (following an intravenous adenosine infusion) and repeated at rest.
LV wall thickness Non-invasive diagnosis of HCM is based on an LV wall thickness 15 mm at end diastole (frequently involving the
Please cite this article in press as: Hoey ETD, et al., The emerging role of cardiovascular MRI for risk stratification in hypertrophic cardiomyopathy, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.11.012
e4
E.T.D. Hoey et al. / Clinical Radiology xxx (2013) e1ee10
interventricular septum) and/or a septal to lateral wall thickness ratio >1.3 in a non-dilated LV in the absence of any loading conditions (e.g., systemic hypertension or aortic stenosis). Other causes of LVH requiring distinction from HCM include Fabry’s disease, sarcoidosis, amyloidosis, and athlete’s heart. In many cases, the distinction from HCMrelated LVH will be straightforward based on a combination of clinical features, LVH distribution, LV function, and the presence and pattern of CMR-detected myocardial fibrosis. Morphological adaptation of an athletic heart is often the most challenging to confidently distinguish from HCM. Typically, with athletic remodelling there is mild LVH (usually
