REVIEW URRENT C OPINION
Role of imaging in evaluation of sudden cardiac death risk in hypertrophic cardiomyopathy Jeffrey B. Geske and Steve R. Ommen
Purpose of review Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and is associated with sudden cardiac death (SCD) – an uncommon but devastating clinical outcome. This review is designed to assess the role of imaging in established risk factor assessment and its role in emerging SCD risk stratification. Recent findings Recent publications have highlighted the crucial role of imaging in HCM SCD risk stratification. Left ventricular hypertrophy assessment remains the key imaging determinant of risk. Data continue to emerge on the role of systolic dysfunction, apical aneurysms, left atrial enlargement and left ventricular outflow tract obstruction as markers of risk. Quantitative assessment of delayed myocardial enhancement and T1 mapping on cardiac MRI continue to evolve. Summary Recent multicenter trials have allowed multivariate SCD risk assessment in large HCM cohorts. Given aggregate risk with presence of multiple risk factors, a single parameter should not be used in isolation to determine implantable cardiac defibrillator candidacy. Use of all available imaging data, including cardiac magnetic resonance tissue characterization, allows a comprehensive approach to SCD stratification and implantable cardiac defibrillator decision-making. Keywords hypertrophic cardiomyopathy, imaging, risk stratification, sudden cardiac death
INTRODUCTION Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy in the absence of an identifiable hemodynamic cause and remains the most common heritable cardiomyopathy [1]. While most patients have a normal lifespan, annual mortality rates range between 1 and 5%, depending on patient selection [2]. Although relatively uncommon, sudden cardiac death (SCD) is a tragic outcome that can accompany HCM. In young people, HCM is the most common cause of SCD [3]. The histopathologic substrate of HCM consists of disorganized myocardium, small-vessel disease, and fibrosis [4]. The underlying cause of fibrosis in HCM is not fully understood, but likely represents a combination of ventricular remodeling secondary to underperfused, severely thickened myocardium; myofibril disarray; and increased afterload due to dynamic left ventricular outflow tract (LVOT) obstruction [5]. In this setting, arrhythmogenesis arises from a multitude of possible inciting events, including ischemia, autonomic dysfunction, atrial arrhythmias, and bradycardia [6].
Implantable cardiac defibrillator (ICD) implantation is the sole effective therapy for SCD prevention in patients with HCM; however, implantation is not without potential complications, and studies have shown considerable associated morbidity, particularly in younger patients [7,8]. Much of the difficulty in selection of appropriate ICD candidates stems from the vast disease heterogeneity, which manifests genetically, phenotypically, and clinically. This is compounded by the relative infrequency of HCM in general cardiovascular practices and the low event rate within small populations of HCM patients. In approaching risk stratification for SCD in HCM, cardiac imaging has played a crucial role. There is no denying that image-based phenotyping Divisions of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Correspondence to Steve R. Ommen, MD, 200 First St S.W. Rochester, MN 55905, USA. Tel: +1 507 284 8260; fax: +1 507 266 0103; e-mail: [email protected] Curr Opin Cardiol 2015, 30:493–499 DOI:10.1097/HCO.0000000000000202
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KEY POINTS The role of multimodality cardiac imaging in HCM continues to evolve, with quantitative echocardiography and cardiac MRI tissue characterization playing central roles. Recently, clinical and cardiac imaging factors have been incorporated into a risk prediction model, providing a validated SCD risk stratification tool in HCM. Although numerous risk factors for SCD have been identified in HCM, the ability to predict relatively infrequent but clinically devastating events remains imperfect, and further investigation of novel risk factors is needed.
enhances identification of patients at high SCD risk and those who can be reassured [6].
RISK STRATIFICATION Current HCM guidelines outline an organized approach to SCD risk stratification [9]. HCM patients with a prior history of SCD or sustained ventricular tachycardia have recurrent risks as high as 10% per year, and thus ICD implantation for secondary prophylaxis is clearly indicated (class I recommendation). For primary prevention, strong consideration is given to three risk determinants: family history of SCD in a first-degree relative; recent unexplained syncope; and massive hypertrophy, defined by a maximal left ventricular wall thickness of at least 30 mm. Each of these indications has been studied individually [10–12], and if present, a single risk factor may justify ICD implantation (class IIa recommendation). Beyond these three determinants, the presence of nonsustained ventricular tachycardia on Holter monitoring and abnormal blood pressure response during exercise (defined as either a failure to increase by at least 20 mmHg or a drop of at least 20 mmHg during effort) [13] provide additional risk stratification. This guideline approach has been validated, and SCD risk increases with risk factor aggregation [14]. Despite knowledge of these individual risk factors, clinical decision-making with regard to ICD implantation can be difficult. Irrespective of a relatively low annual risk of events within a general HCM population, 50% of the patients may have at least one risk factor [15]. As such, it is important to recognize that risk factors serve as imprecise clinical surrogates of the underlying arrhythmogenic substrate, with positive predictive values of any lone risk factor less than 20–25% [16]. 494
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Recently, O’Mahony et al. [17 ] performed a multicenter evaluation of more than 3600 HCM patients spanning a median of 5.7 years, with a 5% rate of SCD or appropriate ICD shock. Utilizing this large cohort, they developed the first validated risk prediction model for SCD in patients with HCM. The prespecified model components mirrored the guideline algorithm, comprising age, maximal left ventricular wall thickness, left ventricular function (assessed by fractional shortening), left atrial size (assessed by left atrial diameter), LVOT gradient, family history of SCD, nonsustained ventricular tachycardia, and unexplained syncope. Of these, only left ventricular fractional shortening was nonsignificant in univariate Cox regression modeling. The model can be accessed indirectly through www.HCMRisk.org. Even with the sophistication afforded by multivariate risk model and decades of research, our ability to risk-stratify a given individual remains imperfect. This is highlighted by the fact that SCD remains a reality in patients with no discernible risk factors, with a frequency of just less than 1% per year [18]. As imaging technology evolves, the search to better characterize hypertrophy and define the underlying cellular substrate may yield further insights.
HYPERTROPHY ASSESSMENT Evaluation of left ventricular hypertrophy has long been considered as a critical aspect of SCD risk stratification in HCM. While current guidelines utilize a maximal left ventricular wall thickness cut-off of 30 mm to define massive hypertrophy (Fig. 1), it is key to recognize that SCD risk does not precipitously increase at a cut-off of 30 mm, but, rather, increases in a linear fashion [11]. Numerous prognostic studies in HCM have looked at left ventricular hypertrophy, with the vast majority utilizing echocardiography [19]. Cardiac MRI continues to emerge as a useful clinical tool in HCM, including for hypertrophy quantitation, and may prove particularly useful if echocardiographic windows are limited. Cardiac MRI-derived left ventricular mass index has been demonstrated to be a univariate but not multivariate predictor of ventricular arrhythmias [20]. While both modalities assess two-dimensional wall thickness, several small studies have compared cardiac MRI and echocardiographic measures, with statistically significant differences between measures on the same patient [21,22]. Although chosen historically and incorporated into current guidelines, the maximal left ventricular wall thickness does not provide information regarding hypertrophy distribution and geometry. Cardiac Volume 30 Number 5 September 2015
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FIGURE 1. Massive hypertrophy. Transthoracic echocardiography obtained from the parasternal long axis demonstrates massive septal hypertrophy (septal thickness 31 mm).
MRI allows various measures of wall dimension, and reporting both maximal left ventricular wall thickness and mean end-diastolic thickness may be of value [20]. Unfortunately, wall thickness in isolation is not enough to guide ICD decision-making. Sorajja et al. [23] found that while patients below 30 years of age with massive hypertrophy had a high incidence of SCD, middle-aged or elderly patients with massive hypertrophy did not. Perhaps more worrisome is the finding that genotype-positive, phenotype-negative HCM patients can still demonstrate conventional risk factors for SCD even in the absence of left ventricular hypertrophy [24].
involves the right ventricular septal insertion points and mid-myocardium. Unlike ischemic scar, which is typically discrete and well demarcated, DME in HCM is often patchy (Fig. 2). The proportion of patients with presence of DME on MRI has varied widely within the literature, spanning from 40% to nearly 80% [28,29], with most studies demonstrating presence in approximately two-thirds of the patients. From a technical perspective, there are numerous influences on DME imaging, including scanner vendor, phase-sensitive versus magnitude reconstruction, single-shot versus segmented acquisition, type and volume of contrast, time of acquisition after contrast injection, and reliability of inversion time. Whereas some studies have assessed SCD risk on the basis of presence or absence of DME, others have sought to quantify DME. There is an ongoing controversy as to the ideal quantitation method of DME in HCM; two predominant techniques have emerged: the full width at half-maximum method and the six standard deviation method. The full width at half-maximum method involves detecting the point of greatest signal intensity, and defining abnormal myocardium as that with a signal least half of this signal intensity. Alternatively, the six standard deviation method has been frequently used, which selects an area of ‘normal’ nulled myocardium and defines abnormal as six standard deviations higher than that value. Use of the latter technique may result in underestimation of patchy, intermediate DME [5]. Given the numerous technical determinants of image acquisition (which may have influenced the wide
DELAYED MYOCARDIAL ENHANCEMENT There is increasing interest in delayed myocardial enhancement (DME; also known as late gadolinium enhancement) on cardiac MRI for SCD risk stratification in HCM. Assessment of DME is a cardiac MRI technique whereby a gadolinium-based contrast agent is administered intravenously, with subsequent imaging (typically 10 min after administration) performed to assess for cardiac retention of gadolinium. The presence of residual gadolinium implies the presence of fibrosis. Gadolinium tends to accrue in areas with a larger volume of distribution volume and greater extracellular space, given slower washout. In HCM, DME correlates with the presence of excess collagen on histopathologic assessment [25]. The relationship of DME and fibrosis has also been well demonstrated in ischemic heart disease [26,27]. While fibrosis distribution in patients with HCM varies on a case-by-case basis, most commonly DME
FIGURE 2. Delayed myocardial enhancement. Diffuse, patchy delayed enhancement on cardiac MRI, present at right ventricular insertion points () with varying intensity throughout the interventricular septum (open arrows) and anteriorly (closed arrows).
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range in reported incidence) and differing methods of quantitation, it is clear that further efforts in DME standardization would be of benefit. Within HCM, DME has been associated with ventricular arrhythmias [28,30]. Furthermore, among a population of largely low-risk or asymptomatic HCM patients, the presence of DME was an independent predictor of all-cause and cardiac mortality, although not specifically SCD [31]. Two large recent studies have assessed the role of DME in SCD risk stratification in HCM. Ismail et al. prospectively studied 711 HCM patients with a median follow-up of 3.5 years, with a primary end point of SCD or aborted SCD attained by 3.1% of the patients [32]. Among them, 66% had DME encompassing a median of 5.9% of left ventricular mass (quantified using the full width at half-maximum method). The extent, but not the presence, of DME was predictive of the primary end point on univariate analysis, but was not significant in multivariate analysis. A study by Chan et al. [33 ] prospectively assessed DME in 1293 HCM patients, with a similar follow-up (median 3.3 years) and incidence of SCD or appropriate ICD shock (3%). DME was assessed in a core laboratory, and was found to be present in only 42% of the patients, with a median of 5% of left ventricular mass quantified (using the six standard deviation method). Unlike in the study by Ismail et al., DME extent was associated with an increased risk of SCD events even after adjustment for other relevant disease variables. A large, actively enrolling clinical trial, HCMR (Novel Markers of Prognosis in Hypertrophic Cardiomyopathy) (ClinicalTrials.gov identifier NCT01915615), may provide further insight upon its completion in 2018. &&
ALCOHOL SEPTAL ABLATION-RELATED SCAR The treatment of choice for medically refractory symptoms in obstructive HCM is septal reduction therapy [9]. While septal myectomy remains the gold standard, use of alcohol septal ablation (ASA) has been rapidly adopted given avoidance of sternotomy. Myectomy is not associated with postprocedural scar, whereas ASA, which involves intracoronary injection of alcohol to create a controlled septal myocardial infarction, results in a welldemarcated scar on DME (Fig. 3) [34]. The arrhythmogenic risk and rates of SCD following septal reduction therapies remain a topic of considerable debate. There is literature to suggest that after myectomy, there is a lower than expected risk of SCD [35]. While some have reported no increase in rates of SCD following ASA [36,37], others have demonstrated higher rates [38,39]. Long-term, longitudinal 496
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FIGURE 3. Cardiac MRI post alcohol septal ablation. A welldemarcated transmural scar (outlined in red) is seen in the distribution of the first septal perforator 2 months after alcohol septal ablation. Reproduced with permission from Maron [34].
follow-up is needed to further assess the effect of ASA-derived scar on SCD.
T1 MAPPING An emerging cardiac MRI technology is that of T1 mapping (Fig. 4) [40]. Because myocardial nulling may be difficult in patients with diffused, patchy enhancement, alternative tissue characterization techniques are desirable. T1 mapping involves quantitation of T1 relaxation within the myocardium, as fibrotic areas tend to have longer T1 relaxation times before contrast administration and shorter times after contrast [41]. Unlike DME, T1 mapping does not rely upon nulling techniques and potentially allows fibrosis identification even in the absence of gadolinium-based contrast administration. Several investigators have begun to look at T1 mapping within HCM [40–42]; however, there has been a lack of prognostic outcomes studied.
APICAL ANEURYSM/POUCH An apical aneurysm or pouch is present in up to 2% of all HCM patients, and is associated with a 10% annual event rate when considering SCD, appropriate ICD discharge, nonfatal thromboembolic stroke, progressive heart failure, and death [43]. Although apical HCM has generally been considered to be a more ‘benign’ variant of HCM, a recent study of 193 Volume 30 Number 5 September 2015
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FIGURE 4. T1 mapping. (a) Delayed enhancement image in a patient with hypertrophic cardiomyopathy demonstrates diffuse, patchy enhancement. (b) T1 mapping reveals heterogeneous T1 value reduction at sites corresponding to areas of delayed enhancement. Reproduced with permission from Lu et al. [40].
patients with apical HCM by Klarich et al. [44] revealed worse survival than expected when compared with age-matched population controls. Within that series, apical pouches were noted in 15% of the patients. In the largest cardiac MRI series of apical pouches in HCM (56 cases), apical aneurysms were most prominent in apical HCM, but were seen in all other distributions of hypertrophy as well [45 ]. The fact that only a third of the aneurysms had been previously identified on transthoracic echocardiography underscores the need for multimodality imaging in HCM.
of nonsustained ventricular tachycardia in the model clouds interpretation. Left atrial dimension has been associated with higher SCD risk in HCM asymptomatic/minimally symptomatic patients without conventional risk factors, albeit at a low event rate [50 ]. Left atrial size may serve as a barometer for filling pressures in HCM [51]. Taken together, these results imply that a normal left atrial size may indicate favorable prognosis and diastolic function. Left atrial diameter is considered in the prediction model put forth by O’Mahony et al. [17 ].
SYSTOLIC DYSFUNCTION
LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION
&
Decreases in fractional shortening in HCM have been correlated with increased risk of SCD, highlighting the dynamic nature of SCD risk prediction [46 ]. HCM may progress to an end-stage, ‘burned out’ dilated cardiomyopathy in a minority of patients. In one series, this rate was as high as 8.8% [47], but it has been our experience that we encounter this far less frequently. ICD therapy may be considered in nonobstructive HCM patients with advanced heart failure (New York Heart Association functional class III or IV) on maximal medical therapy with a reduced ejection fraction (less than or equal to 50%) [48]. In one series, during a mean follow-up period of 5 3 years after progression to end stage, SCD occurred in 47% of the patients [46 ]. Extensive DME may carry additional adverse prognostic risk in patients with end-stage dilated HCM [49]. &
&
LEFT ATRIAL SIZE Spirito et al. [10] demonstrated that left atrial dimension was an independent predictor of death in a multivariate model, although the lack of inclusion
&
&&
Dynamic LVOT obstruction often accompanies HCM, an end-result of narrowing of the LVOT, acceleration of blood flow along the hypertrophied septum, and systolic flow pushing the mitral apparatus into the LVOT. Although systolic anterior motion of the mitral valve can be well visualized with cardiac MRI and phase-contrast imaging does provide flow assessment, Doppler echocardiography remains the standard approach to hemodynamic assessment of HCM (supplemented by hemodynamic catheterization should there be a discrepancy between clinical assessment and echocardiographic findings). Approximately one-third of HCM patients demonstrate resting obstruction, one-third exhibit labile/provocable obstruction, and one-third have nonobstructive physiology. The presence of obstructive physiology has long been considered as a potential risk factor for SCD. At least five studies have reported a significant association between SCD and LVOT obstruction [19,52,53]. However, numerous other studies have not found an association [19,54]. One potential explanation for this phenomenon is the dynamic nature of LVOT, which can
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change significantly, even over the course of a single diagnostic hemodynamic assessment [55,56]. While the current risk calculator put forth by O’Mahony et al. [17 ] does consider presence of obstructive physiology, current guidelines de-emphasize this finding. &&
CONCLUSION Numerous risk factors for SCD in HCM have been identified; however, it has become increasingly clear that the analysis of multiple risk factors in concert is more beneficial than interpretation in isolation. Recent models have provided an improved toolset for initial assessment of SCD in patients with HCM. As studies continue to accrue longitudinal followup, our ability to detect relatively infrequent events will improve. However, many questions remain unanswered. Are there unknown risk factors contributing to (albeit infrequent) SCD events in patients without conventional risk factors? Are we missing additional structural clues (papillary muscle configuration, electroanatomic mapping)? What role will quantitative tissue characterization play in SCD risk stratification? It is important as we move forward that we do not view SCD risk stratification as a ‘one time’ event. In addition to clinical status, it has been demonstrated that dynamic changes in both systolic and diastolic function remodeling over time have an impact on SCD risk [9,46 ]. These findings emphasize the importance of vigilant follow-up in patients with HCM. Imaging will continue to play a crucial role in evolving SCD risk stratification in HCM. &
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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43. Maron MS, Finley JJ, Bos JM, et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation 2008; 118:1541–1549. 44. Klarich KW, Attenhofer Jost CH, Binder J, et al. Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy. Am J Cardiol 2013; 111:1784–1791. 45. Kebed KY, Al Adham RI, Bishu K, et al. Evaluation of apical pouches in & hypertrophic cardiomyopathy using cardiac MRI. Int J Cardiovasc Imaging 2014; 30:591–597. This is the largest series of apical pouches in HCM identified by cardiac MRI (56 patients). Apical pouches may be underappreciated, as the majority (68%) were not identified on echocardiographic evaluation. 46. Vriesendorp PA, Schinkel AF, de Groot NM, et al. Impact of adverse left & ventricular remodeling on sudden cardiac death in patients with hypertrophic cardiomyopathy. Clin Cardiol 2014; 37:493–498. This study of 41 HCM patients with SCD, each matched to three HCM controls, found that risk of SCD is not static, and that higher risk correlated with symptomatic progression, decreased fractional shortening and worsened diastolic function. 47. Kawarai H, Kajimoto K, Minami Y, et al. Risk of sudden death in end-stage hypertrophic cardiomyopathy. J Card Fail 2011; 17:459–464. 48. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006; 114:216–225. 49. Machii M, Satoh H, Shiraki K, et al. Distribution of late gadolinium enhancement in end-stage hypertrophic cardiomyopathy and dilated cardiomyopathy: differential diagnosis and prediction of cardiac outcome. Magn Reson Imaging 2014; 32:118–124. 50. Spirito P, Autore C, Formisano F, et al. Risk of sudden death and outcome in & patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol 2014; 113:1550–1555. An intriguing investigation of 653 HCM patients with no conventional risk factors for SCD and minimal symptoms, demonstrating a SCD event rate of 0.6%/year. This finding emphasizes the need for further identification of SCD risk factors in HCM. 51. Geske JB, Sorajja P, Nishimura RA, Ommen SR. The relationship of left atrial volume and left atrial pressure in patients with hypertrophic cardiomyopathy: an echocardiographic and cardiac catheterization study. J Am Soc Echocardiogr 2009; 22:961–966. 52. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348:295–303. 53. Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:1933–1941. 54. Efthimiadis GK, Parcharidou DG, Giannakoulas G, et al. Left ventricular outflow tract obstruction as a risk factor for sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 2009; 104:695–699. 55. Geske JB, Sorajja P, Ommen SR, Nishimura RA. Variability of left ventricular outflow tract gradient during cardiac catheterization in patients with hypertrophic cardiomyopathy. JACC Cardiovasc Interv 2011; 4:704–709. 56. Geske JB, Sorajja P, Ommen SR, Nishimura RA. Left ventricular outflow tract gradient variability in hypertrophic cardiomyopathy. Clin Cardiol 2009; 32:397–402.
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Role of imaging in evaluation of sudden cardiac death risk in hypertrophic cardiomyopathy Jeffrey B. Geske and Steve R. Ommen
Purpose of review Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and is associated with sudden cardiac death (SCD) – an uncommon but devastating clinical outcome. This review is designed to assess the role of imaging in established risk factor assessment and its role in emerging SCD risk stratification. Recent findings Recent publications have highlighted the crucial role of imaging in HCM SCD risk stratification. Left ventricular hypertrophy assessment remains the key imaging determinant of risk. Data continue to emerge on the role of systolic dysfunction, apical aneurysms, left atrial enlargement and left ventricular outflow tract obstruction as markers of risk. Quantitative assessment of delayed myocardial enhancement and T1 mapping on cardiac MRI continue to evolve. Summary Recent multicenter trials have allowed multivariate SCD risk assessment in large HCM cohorts. Given aggregate risk with presence of multiple risk factors, a single parameter should not be used in isolation to determine implantable cardiac defibrillator candidacy. Use of all available imaging data, including cardiac magnetic resonance tissue characterization, allows a comprehensive approach to SCD stratification and implantable cardiac defibrillator decision-making. Keywords hypertrophic cardiomyopathy, imaging, risk stratification, sudden cardiac death
INTRODUCTION Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy in the absence of an identifiable hemodynamic cause and remains the most common heritable cardiomyopathy [1]. While most patients have a normal lifespan, annual mortality rates range between 1 and 5%, depending on patient selection [2]. Although relatively uncommon, sudden cardiac death (SCD) is a tragic outcome that can accompany HCM. In young people, HCM is the most common cause of SCD [3]. The histopathologic substrate of HCM consists of disorganized myocardium, small-vessel disease, and fibrosis [4]. The underlying cause of fibrosis in HCM is not fully understood, but likely represents a combination of ventricular remodeling secondary to underperfused, severely thickened myocardium; myofibril disarray; and increased afterload due to dynamic left ventricular outflow tract (LVOT) obstruction [5]. In this setting, arrhythmogenesis arises from a multitude of possible inciting events, including ischemia, autonomic dysfunction, atrial arrhythmias, and bradycardia [6].
Implantable cardiac defibrillator (ICD) implantation is the sole effective therapy for SCD prevention in patients with HCM; however, implantation is not without potential complications, and studies have shown considerable associated morbidity, particularly in younger patients [7,8]. Much of the difficulty in selection of appropriate ICD candidates stems from the vast disease heterogeneity, which manifests genetically, phenotypically, and clinically. This is compounded by the relative infrequency of HCM in general cardiovascular practices and the low event rate within small populations of HCM patients. In approaching risk stratification for SCD in HCM, cardiac imaging has played a crucial role. There is no denying that image-based phenotyping Divisions of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Correspondence to Steve R. Ommen, MD, 200 First St S.W. Rochester, MN 55905, USA. Tel: +1 507 284 8260; fax: +1 507 266 0103; e-mail: [email protected] Curr Opin Cardiol 2015, 30:493–499 DOI:10.1097/HCO.0000000000000202
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KEY POINTS The role of multimodality cardiac imaging in HCM continues to evolve, with quantitative echocardiography and cardiac MRI tissue characterization playing central roles. Recently, clinical and cardiac imaging factors have been incorporated into a risk prediction model, providing a validated SCD risk stratification tool in HCM. Although numerous risk factors for SCD have been identified in HCM, the ability to predict relatively infrequent but clinically devastating events remains imperfect, and further investigation of novel risk factors is needed.
enhances identification of patients at high SCD risk and those who can be reassured [6].
RISK STRATIFICATION Current HCM guidelines outline an organized approach to SCD risk stratification [9]. HCM patients with a prior history of SCD or sustained ventricular tachycardia have recurrent risks as high as 10% per year, and thus ICD implantation for secondary prophylaxis is clearly indicated (class I recommendation). For primary prevention, strong consideration is given to three risk determinants: family history of SCD in a first-degree relative; recent unexplained syncope; and massive hypertrophy, defined by a maximal left ventricular wall thickness of at least 30 mm. Each of these indications has been studied individually [10–12], and if present, a single risk factor may justify ICD implantation (class IIa recommendation). Beyond these three determinants, the presence of nonsustained ventricular tachycardia on Holter monitoring and abnormal blood pressure response during exercise (defined as either a failure to increase by at least 20 mmHg or a drop of at least 20 mmHg during effort) [13] provide additional risk stratification. This guideline approach has been validated, and SCD risk increases with risk factor aggregation [14]. Despite knowledge of these individual risk factors, clinical decision-making with regard to ICD implantation can be difficult. Irrespective of a relatively low annual risk of events within a general HCM population, 50% of the patients may have at least one risk factor [15]. As such, it is important to recognize that risk factors serve as imprecise clinical surrogates of the underlying arrhythmogenic substrate, with positive predictive values of any lone risk factor less than 20–25% [16]. 494
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Recently, O’Mahony et al. [17 ] performed a multicenter evaluation of more than 3600 HCM patients spanning a median of 5.7 years, with a 5% rate of SCD or appropriate ICD shock. Utilizing this large cohort, they developed the first validated risk prediction model for SCD in patients with HCM. The prespecified model components mirrored the guideline algorithm, comprising age, maximal left ventricular wall thickness, left ventricular function (assessed by fractional shortening), left atrial size (assessed by left atrial diameter), LVOT gradient, family history of SCD, nonsustained ventricular tachycardia, and unexplained syncope. Of these, only left ventricular fractional shortening was nonsignificant in univariate Cox regression modeling. The model can be accessed indirectly through www.HCMRisk.org. Even with the sophistication afforded by multivariate risk model and decades of research, our ability to risk-stratify a given individual remains imperfect. This is highlighted by the fact that SCD remains a reality in patients with no discernible risk factors, with a frequency of just less than 1% per year [18]. As imaging technology evolves, the search to better characterize hypertrophy and define the underlying cellular substrate may yield further insights.
HYPERTROPHY ASSESSMENT Evaluation of left ventricular hypertrophy has long been considered as a critical aspect of SCD risk stratification in HCM. While current guidelines utilize a maximal left ventricular wall thickness cut-off of 30 mm to define massive hypertrophy (Fig. 1), it is key to recognize that SCD risk does not precipitously increase at a cut-off of 30 mm, but, rather, increases in a linear fashion [11]. Numerous prognostic studies in HCM have looked at left ventricular hypertrophy, with the vast majority utilizing echocardiography [19]. Cardiac MRI continues to emerge as a useful clinical tool in HCM, including for hypertrophy quantitation, and may prove particularly useful if echocardiographic windows are limited. Cardiac MRI-derived left ventricular mass index has been demonstrated to be a univariate but not multivariate predictor of ventricular arrhythmias [20]. While both modalities assess two-dimensional wall thickness, several small studies have compared cardiac MRI and echocardiographic measures, with statistically significant differences between measures on the same patient [21,22]. Although chosen historically and incorporated into current guidelines, the maximal left ventricular wall thickness does not provide information regarding hypertrophy distribution and geometry. Cardiac Volume 30 Number 5 September 2015
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FIGURE 1. Massive hypertrophy. Transthoracic echocardiography obtained from the parasternal long axis demonstrates massive septal hypertrophy (septal thickness 31 mm).
MRI allows various measures of wall dimension, and reporting both maximal left ventricular wall thickness and mean end-diastolic thickness may be of value [20]. Unfortunately, wall thickness in isolation is not enough to guide ICD decision-making. Sorajja et al. [23] found that while patients below 30 years of age with massive hypertrophy had a high incidence of SCD, middle-aged or elderly patients with massive hypertrophy did not. Perhaps more worrisome is the finding that genotype-positive, phenotype-negative HCM patients can still demonstrate conventional risk factors for SCD even in the absence of left ventricular hypertrophy [24].
involves the right ventricular septal insertion points and mid-myocardium. Unlike ischemic scar, which is typically discrete and well demarcated, DME in HCM is often patchy (Fig. 2). The proportion of patients with presence of DME on MRI has varied widely within the literature, spanning from 40% to nearly 80% [28,29], with most studies demonstrating presence in approximately two-thirds of the patients. From a technical perspective, there are numerous influences on DME imaging, including scanner vendor, phase-sensitive versus magnitude reconstruction, single-shot versus segmented acquisition, type and volume of contrast, time of acquisition after contrast injection, and reliability of inversion time. Whereas some studies have assessed SCD risk on the basis of presence or absence of DME, others have sought to quantify DME. There is an ongoing controversy as to the ideal quantitation method of DME in HCM; two predominant techniques have emerged: the full width at half-maximum method and the six standard deviation method. The full width at half-maximum method involves detecting the point of greatest signal intensity, and defining abnormal myocardium as that with a signal least half of this signal intensity. Alternatively, the six standard deviation method has been frequently used, which selects an area of ‘normal’ nulled myocardium and defines abnormal as six standard deviations higher than that value. Use of the latter technique may result in underestimation of patchy, intermediate DME [5]. Given the numerous technical determinants of image acquisition (which may have influenced the wide
DELAYED MYOCARDIAL ENHANCEMENT There is increasing interest in delayed myocardial enhancement (DME; also known as late gadolinium enhancement) on cardiac MRI for SCD risk stratification in HCM. Assessment of DME is a cardiac MRI technique whereby a gadolinium-based contrast agent is administered intravenously, with subsequent imaging (typically 10 min after administration) performed to assess for cardiac retention of gadolinium. The presence of residual gadolinium implies the presence of fibrosis. Gadolinium tends to accrue in areas with a larger volume of distribution volume and greater extracellular space, given slower washout. In HCM, DME correlates with the presence of excess collagen on histopathologic assessment [25]. The relationship of DME and fibrosis has also been well demonstrated in ischemic heart disease [26,27]. While fibrosis distribution in patients with HCM varies on a case-by-case basis, most commonly DME
FIGURE 2. Delayed myocardial enhancement. Diffuse, patchy delayed enhancement on cardiac MRI, present at right ventricular insertion points () with varying intensity throughout the interventricular septum (open arrows) and anteriorly (closed arrows).
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range in reported incidence) and differing methods of quantitation, it is clear that further efforts in DME standardization would be of benefit. Within HCM, DME has been associated with ventricular arrhythmias [28,30]. Furthermore, among a population of largely low-risk or asymptomatic HCM patients, the presence of DME was an independent predictor of all-cause and cardiac mortality, although not specifically SCD [31]. Two large recent studies have assessed the role of DME in SCD risk stratification in HCM. Ismail et al. prospectively studied 711 HCM patients with a median follow-up of 3.5 years, with a primary end point of SCD or aborted SCD attained by 3.1% of the patients [32]. Among them, 66% had DME encompassing a median of 5.9% of left ventricular mass (quantified using the full width at half-maximum method). The extent, but not the presence, of DME was predictive of the primary end point on univariate analysis, but was not significant in multivariate analysis. A study by Chan et al. [33 ] prospectively assessed DME in 1293 HCM patients, with a similar follow-up (median 3.3 years) and incidence of SCD or appropriate ICD shock (3%). DME was assessed in a core laboratory, and was found to be present in only 42% of the patients, with a median of 5% of left ventricular mass quantified (using the six standard deviation method). Unlike in the study by Ismail et al., DME extent was associated with an increased risk of SCD events even after adjustment for other relevant disease variables. A large, actively enrolling clinical trial, HCMR (Novel Markers of Prognosis in Hypertrophic Cardiomyopathy) (ClinicalTrials.gov identifier NCT01915615), may provide further insight upon its completion in 2018. &&
ALCOHOL SEPTAL ABLATION-RELATED SCAR The treatment of choice for medically refractory symptoms in obstructive HCM is septal reduction therapy [9]. While septal myectomy remains the gold standard, use of alcohol septal ablation (ASA) has been rapidly adopted given avoidance of sternotomy. Myectomy is not associated with postprocedural scar, whereas ASA, which involves intracoronary injection of alcohol to create a controlled septal myocardial infarction, results in a welldemarcated scar on DME (Fig. 3) [34]. The arrhythmogenic risk and rates of SCD following septal reduction therapies remain a topic of considerable debate. There is literature to suggest that after myectomy, there is a lower than expected risk of SCD [35]. While some have reported no increase in rates of SCD following ASA [36,37], others have demonstrated higher rates [38,39]. Long-term, longitudinal 496
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FIGURE 3. Cardiac MRI post alcohol septal ablation. A welldemarcated transmural scar (outlined in red) is seen in the distribution of the first septal perforator 2 months after alcohol septal ablation. Reproduced with permission from Maron [34].
follow-up is needed to further assess the effect of ASA-derived scar on SCD.
T1 MAPPING An emerging cardiac MRI technology is that of T1 mapping (Fig. 4) [40]. Because myocardial nulling may be difficult in patients with diffused, patchy enhancement, alternative tissue characterization techniques are desirable. T1 mapping involves quantitation of T1 relaxation within the myocardium, as fibrotic areas tend to have longer T1 relaxation times before contrast administration and shorter times after contrast [41]. Unlike DME, T1 mapping does not rely upon nulling techniques and potentially allows fibrosis identification even in the absence of gadolinium-based contrast administration. Several investigators have begun to look at T1 mapping within HCM [40–42]; however, there has been a lack of prognostic outcomes studied.
APICAL ANEURYSM/POUCH An apical aneurysm or pouch is present in up to 2% of all HCM patients, and is associated with a 10% annual event rate when considering SCD, appropriate ICD discharge, nonfatal thromboembolic stroke, progressive heart failure, and death [43]. Although apical HCM has generally been considered to be a more ‘benign’ variant of HCM, a recent study of 193 Volume 30 Number 5 September 2015
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(b)
FIGURE 4. T1 mapping. (a) Delayed enhancement image in a patient with hypertrophic cardiomyopathy demonstrates diffuse, patchy enhancement. (b) T1 mapping reveals heterogeneous T1 value reduction at sites corresponding to areas of delayed enhancement. Reproduced with permission from Lu et al. [40].
patients with apical HCM by Klarich et al. [44] revealed worse survival than expected when compared with age-matched population controls. Within that series, apical pouches were noted in 15% of the patients. In the largest cardiac MRI series of apical pouches in HCM (56 cases), apical aneurysms were most prominent in apical HCM, but were seen in all other distributions of hypertrophy as well [45 ]. The fact that only a third of the aneurysms had been previously identified on transthoracic echocardiography underscores the need for multimodality imaging in HCM.
of nonsustained ventricular tachycardia in the model clouds interpretation. Left atrial dimension has been associated with higher SCD risk in HCM asymptomatic/minimally symptomatic patients without conventional risk factors, albeit at a low event rate [50 ]. Left atrial size may serve as a barometer for filling pressures in HCM [51]. Taken together, these results imply that a normal left atrial size may indicate favorable prognosis and diastolic function. Left atrial diameter is considered in the prediction model put forth by O’Mahony et al. [17 ].
SYSTOLIC DYSFUNCTION
LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION
&
Decreases in fractional shortening in HCM have been correlated with increased risk of SCD, highlighting the dynamic nature of SCD risk prediction [46 ]. HCM may progress to an end-stage, ‘burned out’ dilated cardiomyopathy in a minority of patients. In one series, this rate was as high as 8.8% [47], but it has been our experience that we encounter this far less frequently. ICD therapy may be considered in nonobstructive HCM patients with advanced heart failure (New York Heart Association functional class III or IV) on maximal medical therapy with a reduced ejection fraction (less than or equal to 50%) [48]. In one series, during a mean follow-up period of 5 3 years after progression to end stage, SCD occurred in 47% of the patients [46 ]. Extensive DME may carry additional adverse prognostic risk in patients with end-stage dilated HCM [49]. &
&
LEFT ATRIAL SIZE Spirito et al. [10] demonstrated that left atrial dimension was an independent predictor of death in a multivariate model, although the lack of inclusion
&
&&
Dynamic LVOT obstruction often accompanies HCM, an end-result of narrowing of the LVOT, acceleration of blood flow along the hypertrophied septum, and systolic flow pushing the mitral apparatus into the LVOT. Although systolic anterior motion of the mitral valve can be well visualized with cardiac MRI and phase-contrast imaging does provide flow assessment, Doppler echocardiography remains the standard approach to hemodynamic assessment of HCM (supplemented by hemodynamic catheterization should there be a discrepancy between clinical assessment and echocardiographic findings). Approximately one-third of HCM patients demonstrate resting obstruction, one-third exhibit labile/provocable obstruction, and one-third have nonobstructive physiology. The presence of obstructive physiology has long been considered as a potential risk factor for SCD. At least five studies have reported a significant association between SCD and LVOT obstruction [19,52,53]. However, numerous other studies have not found an association [19,54]. One potential explanation for this phenomenon is the dynamic nature of LVOT, which can
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change significantly, even over the course of a single diagnostic hemodynamic assessment [55,56]. While the current risk calculator put forth by O’Mahony et al. [17 ] does consider presence of obstructive physiology, current guidelines de-emphasize this finding. &&
CONCLUSION Numerous risk factors for SCD in HCM have been identified; however, it has become increasingly clear that the analysis of multiple risk factors in concert is more beneficial than interpretation in isolation. Recent models have provided an improved toolset for initial assessment of SCD in patients with HCM. As studies continue to accrue longitudinal followup, our ability to detect relatively infrequent events will improve. However, many questions remain unanswered. Are there unknown risk factors contributing to (albeit infrequent) SCD events in patients without conventional risk factors? Are we missing additional structural clues (papillary muscle configuration, electroanatomic mapping)? What role will quantitative tissue characterization play in SCD risk stratification? It is important as we move forward that we do not view SCD risk stratification as a ‘one time’ event. In addition to clinical status, it has been demonstrated that dynamic changes in both systolic and diastolic function remodeling over time have an impact on SCD risk [9,46 ]. These findings emphasize the importance of vigilant follow-up in patients with HCM. Imaging will continue to play a crucial role in evolving SCD risk stratification in HCM. &
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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43. Maron MS, Finley JJ, Bos JM, et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation 2008; 118:1541–1549. 44. Klarich KW, Attenhofer Jost CH, Binder J, et al. Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy. Am J Cardiol 2013; 111:1784–1791. 45. Kebed KY, Al Adham RI, Bishu K, et al. Evaluation of apical pouches in & hypertrophic cardiomyopathy using cardiac MRI. Int J Cardiovasc Imaging 2014; 30:591–597. This is the largest series of apical pouches in HCM identified by cardiac MRI (56 patients). Apical pouches may be underappreciated, as the majority (68%) were not identified on echocardiographic evaluation. 46. Vriesendorp PA, Schinkel AF, de Groot NM, et al. Impact of adverse left & ventricular remodeling on sudden cardiac death in patients with hypertrophic cardiomyopathy. Clin Cardiol 2014; 37:493–498. This study of 41 HCM patients with SCD, each matched to three HCM controls, found that risk of SCD is not static, and that higher risk correlated with symptomatic progression, decreased fractional shortening and worsened diastolic function. 47. Kawarai H, Kajimoto K, Minami Y, et al. Risk of sudden death in end-stage hypertrophic cardiomyopathy. J Card Fail 2011; 17:459–464. 48. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006; 114:216–225. 49. Machii M, Satoh H, Shiraki K, et al. Distribution of late gadolinium enhancement in end-stage hypertrophic cardiomyopathy and dilated cardiomyopathy: differential diagnosis and prediction of cardiac outcome. Magn Reson Imaging 2014; 32:118–124. 50. Spirito P, Autore C, Formisano F, et al. Risk of sudden death and outcome in & patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol 2014; 113:1550–1555. An intriguing investigation of 653 HCM patients with no conventional risk factors for SCD and minimal symptoms, demonstrating a SCD event rate of 0.6%/year. This finding emphasizes the need for further identification of SCD risk factors in HCM. 51. Geske JB, Sorajja P, Nishimura RA, Ommen SR. The relationship of left atrial volume and left atrial pressure in patients with hypertrophic cardiomyopathy: an echocardiographic and cardiac catheterization study. J Am Soc Echocardiogr 2009; 22:961–966. 52. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348:295–303. 53. Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006; 27:1933–1941. 54. Efthimiadis GK, Parcharidou DG, Giannakoulas G, et al. Left ventricular outflow tract obstruction as a risk factor for sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 2009; 104:695–699. 55. Geske JB, Sorajja P, Ommen SR, Nishimura RA. Variability of left ventricular outflow tract gradient during cardiac catheterization in patients with hypertrophic cardiomyopathy. JACC Cardiovasc Interv 2011; 4:704–709. 56. Geske JB, Sorajja P, Ommen SR, Nishimura RA. Left ventricular outflow tract gradient variability in hypertrophic cardiomyopathy. Clin Cardiol 2009; 32:397–402.
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