ORIGINAL ARTICLE
Cardiac Magnetic Resonance Imaging Findings Predict Major Adverse Events in Apical Hypertrophic Cardiomyopathy Kate Hanneman, MD,* Andrew M. Crean, MRCP,*w Lynne Williams, MD,w Hadas Moshonov, PhD,* Susan James, MD,* Laura Jime´nez-Juan, MD,* Christiane Gruner, MD,w Patrick Sparrow, MRCP,* Harry Rakowski, MD,w and Elsie T. Nguyen, MD, FRCPC*
Purpose: The purpose of this study was to determine the prognostic significance of cardiac magnetic resonance imaging (MRI) findings in patients with apical hypertrophic cardiomyopathy (HCM). Materials and Methods: Cardiac MRI studies of 93 consecutive patients with apical HCM were retrospectively evaluated. Quantification of late gadolinium enhancement (LGE) was determined and expressed as a percentage of total left ventricular (LV) myocardial mass (%LGE). Morphologic features including presence of apical aneurysm, right ventricular hypertrophy, and LV thrombus were also assessed. Clinical data were collected during follow-up to assess for occurrence of major adverse events, defined as: heart failure, stroke, appropriate automatic implantable cardioverter defibrillator discharge, sustained ventricular tachycardia, aborted sudden cardiac death, and/or all-cause death. Results: The mean age of the patients was 54.9 ± 13.8 years, and 72.0% (n = 67) were male. LGE, right ventricular hypertrophy, apical aneurysm, and LV thrombus were identified in 69.4%, 25.8%, 18.3%, and 4.3%, respectively. Mean %LGE was 10.8% ± 11.1%. Over 2.4 ± 1.7 years of follow-up, 14 subjects (15.1%) experienced a major adverse event (event rate, 6.3%/y): heart failure (6.5%), stroke (6.5%), appropriate automatic implantable cardioverter defibrillator discharge (2.2%), sustained ventricular tachycardia (2.2%), aborted sudden cardiac death (1.1%), and all-cause death (0.0%). Presence of apical aneurysm and extent of LGE were significant predictors of major adverse events [odds ratio (OR) 4.6, P = 0.015; and OR 1.4/ 5% LGE, P = 0.030, respectively]. Patients with both apical aneurysm and >5% LGE were at highest risk for major adverse events (OR 6.7, P = 0.004) and had shortest event-free survival (P = 0.001). Conclusions: Within our population of apical HCM patients, the extent of LGE and the presence of an apical aneurysm identified by cardiac MRI were both significant predictors of major adverse clinical events. Key Words: hypertrophic cardiomyopathy, apical hypertrophic cardiomyopathy, cardiac magnetic resonance imaging, late gadolinium enhancement
(J Thorac Imaging 2014;29:331–339)
From the *Department of Medical Imaging; and wDivision of Cardiology, Peter Munk Cardiac Center, University Health Network, University of Toronto, Toronto, ON, Canada. The authors declare no conflicts of interest. Reprints: Elsie T. Nguyen, MD, FRCPC, Department of Medical Imaging, Toronto General Hospital, Room 1C567, NCSB, 585 University Ave. Toronto, ON, Canada M5G 2N2 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Thorac Imaging
Volume 29, Number 6, November 2014
H
ypertrophic cardiomyopathy (HCM) is characterized pathologically by myocyte disarray, hypertrophy, and interstitial fibrosis.1 The majority of patients with HCM have asymmetrical hypertrophy with a predilection for the basal septum and anterior wall. Apical HCM, representing 7% to 10% of all HCM, is a distinct morphologic subtype primarily affecting the left ventricular (LV) apex.2–4 The clinical course of apical HCM was previously thought to be relatively benign with a low incidence of sudden death.2 However, more recent studies have found apical HCM to be associated with greater than previously recognized cardiovascular mortality and significant morbidity, including ventricular and atrial arrhythmias, sudden death, heart failure (HF), and stroke.4–10 Predicting which patients are at risk for adverse events remains a clinical challenge. Transthoracic echocardiography is considered the noninvasive imaging standard for the diagnosis of HCM.11 However, cardiac magnetic resonance imaging (MRI) offers unique strengths in the evaluation of patients with suspected or confirmed apical HCM, including the ability to optimally visualize the LV apex, accurately quantify LV mass, and assess myocardial fibrosis.12 Myocardial fibrosis, as detected by late gadolinium enhancement (LGE), has been shown to correlate with risk for ventricular arrhythmias and development of HF in HCM.9,13–18 We hypothesized that cardiac MRI findings including LGE and apical aneurysms may identify patients with apical HCM who are at increased risk for adverse events. The aim of this study was to assess the prognostic significance of cardiac MRI imaging findings in patients with apical HCM.
MATERIALS AND METHODS Patient Population This retrospective study was approved by our institutional research ethics board. The requirement for written informed consent was waived. Study subjects were identified through the database of a dedicated HCM clinic at a large tertiary referral center. Consecutive patients with a diagnosis of apical HCM by cardiac MRI, with clinical documentation and at least 1 cardiac MRI performed between 2003 and 2012, were included. Diagnosis of apical HCM was defined by LV hypertrophy confined to the apex and an apical wall thickness of Z15 mm (measured in enddiastole) or a maximum apical to maximum basal wall thickness ratio of Z1.3 as established by 2 experienced www.thoracicimaging.com |
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observers by consensus review of imaging findings.15 Exclusion criteria included patients who had additional septal hypertrophy or isolated mid-cavity hypertrophy, evidence of LV cavity obstruction (including isolated midcavity obstruction) on echocardiography and cardiac MRI, and coronary artery disease as assessed by catheter angiography.19 Patients who had experienced an adverse clinical event before cardiac MRI were not excluded.
Cardiac MRI Protocol Cardiac MRI studies were performed using 1.5 T (MAGNETOM Avanto; Siemens Healthcare, Erlangen, Germany) or 3 T (MAGNETOM Verio; Siemens Healthcare) scanners with commercially available cardiac surface coils. LV function was assessed using retrospectively gated cine steady-state free-procession (SSFP) techniques in short-axis orientation acquired to cover the entire LV volume. Typical imaging parameters were as follows: slice thickness 6 to 8 mm (0 to 2 mm gap), in-plane resolution 1.4 1.7 mm, temporal resolution 30 to 40 ms. One slice was acquired per end-expiratory breath-hold. Short-axis LGE images were acquired using a 2dimensional inversion recovery prepared gradient recalled echo sequence 10 to 20 minutes after the intravenous administration of 0.2 mmol/kg bodyweight of gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Berlin, Germany) or gadobutrol (Gadovist; Bayer HealthCare Pharmaceuticals), followed by a flush of 20 mL of saline. The entire LV was covered in short-axis orientation from base to apex (8 to 10 slices), acquiring a single slice per end-expiratory breath-hold with the following typical imaging parameters: slice thickness 6 to 8 mm; in-plane resolution 1.81.4 mm; temporal resolution 160 to 200 ms. Two-, 3-, and 4-chamber planes were also obtained to visualize the apex. Optimal inversion time to null the normal myocardial signal was determined for each patient using a Look-Locker sequence (TI scout). Single-slice horizontal and vertical longaxis LGE images were also obtained.
Cardiac MRI Analysis Postprocessing analysis was performed independently by 2 experienced observers offline using commercially available software (CMR 42; Circle Cardiovascular Imaging Inc., Calgary, Canada). LV endocardial and epicardial borders were manually contoured on short-axis SSFP images to assess for end-diastolic and end-systolic volumes and LV ejection fraction (LVEF); and on short-axis LGE images to assess for LV mass and extent of LGE. Papillary muscles were considered part of the blood volume. The presence of LGE was qualitatively assessed by visual inspection of all available LGE images and was graded as present or absent for each patient. Quantitative analysis was performed using a signal intensity threshold of 5 SD above visually normal remote myocardium, as described previously20–23 (Fig. 1). Addition of the areas of LGE contoured on all short-axis slices multiplied by slice thickness yielded the total volume of delayed enhancement in grams (myocardial density of 1.05 g/m3), which was subsequently expressed as a percentage of total LV myocardial mass (%LGE). Maximum LV end-diastolic wall thickness was measured on basal and apical SSFP short-axis slices. The presence or absence of right ventricular (RV) hypertrophy (thickening of the RV wall measuring Z3 mm at end-diastole on short axis or 4-chamber slices), LV apical
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aneurysm (defined as a discrete thin-walled dyskinetic or akinetic segment of the distal LV chamber with a relatively wide communication with the LV cavity), and ventricular thrombus (assessed using standard LGE and cine SSFP sequences) was recorded.24 To measure interobserver agreement, LGE images of a random subset of 40 patients were selected for reanalysis by a second experienced and blinded observer. In this subset, maximum wall thickness and %LGE were recorded for each segment according to the 17-segment model proposed by the American Heart Association.25
Clinical Data Data were abstracted on demographic characteristics, clinical outcomes, and symptoms from clinical documentation and the electronic patient record. Major adverse events were defined as HF, appropriate automatic implantable cardioverter defibrillator (AICD) discharge, sustained ventricular tachycardia (VT), stroke, aborted sudden cardiac death (SCD), and all-cause death. Rhythm disturbances were identified by 24-hour Holter ECG monitoring performed every 1 to 3 years in patients without an AICD or by device interrogation every 6 months in those patients with an AICD. Sustained VT was defined as Z3 consecutive beats, lasting >30 seconds at a rate of Z120 beats/min. HF events were defined as any of the following: progression to New York Heart Association (NYHA) functional class III or IV in the absence of obstruction; hospital admission for HF other than due to transient atrial fibrillation; decline in LVEF to 5% LGE (P = 0.001). Patient age and LVEF were both significant predictors of major adverse events (OR 1.1, P = 0.025; and OR 0.93, P = 0.032, respectively). There was no statistically significant association between LV thrombus, RV hypertrophy, maximum LV wall thickness, family history of HCM or family history of SCD, and occurrence of a major adverse event (P > 0.05 for all). In a multivariable logistic regression model, none of the variables included (%LGE, presence of apical aneurysm, LVEF, and age) remained significant predictors of major adverse events (P > 0.05).
DISCUSSION This study has demonstrated that the exent of LGE and the presence of apical aneurysms are significant predictors of major adverse events in patients with apical HCM as identified by cardiac MRI. LGE on cardiac MRI can be used to detect myocardial fibrosis and has been shown to identify HCM patients who are at increased risk for adverse events.17,18,26,27 We report the presence of LGE in 69.4% of patients in our study, which is in keeping with the results of a recent review that reported a weighted mean prevalence of LGE of 65% in 1814 HCM patients.28 In our study, the mean extent of LGE was 10.8% of LV myocardium. A prior study reported lower values for the extent of LGE in patients with apical HCM (4.9%). In contrast to our study, a lower proportion of patients with an apical aneurysm were included (12.5% vs. 18.3% in our TABLE 4. ORs for the Prediction of Major Adverse Clinical Events Age Family history SCD Shortness of breath Chest pain Syncope LVEF Maximum LV wall thickness Presence of LGE Extent of LGE (%LGE) Apical aneurysm
OR
95% CI
P
1.05 0.94 1.53 0.56 2.42 0.93 1.04 6.38 1.41 4.63
1.00, 1.10 0.10, 8.43 0.48, 4.87 0.14, 2.17 0.56, 10.54 0.86, 0.99 0.91, 1.19 0.78, 51.96 1.04, 1.93 1.35, 15.95
0.025 0.953 0.472 0.398 0.239 0.032 0.559 0.083 0.030 0.015
Univariable logistic regression analysis in the prediction of major adverse clinical events. For %LGE, ORs are for a 5% increase in %LGE. P-values in bold are statistically significant. Major adverse events were defined as HF, appropriate AICD discharge, sustained VT, aborted SCD, stroke, and/or all-cause death.
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study), and they utilized a higher signal intensity threshold for LGE quantification (6 vs. 5 SD in our study), which may account for this difference.16 Several different signal intensity thresholds as well as visual assessment for LGE have been proposed.26 Recent studies have concluded that use of higher grayscale thresholds (4 to 6 SD) may yield the best agreement with the extent of LGE identified by visual assessment and may be the most reproducible method for quantification of LGE in HCM.21–23,28,29 Use of lower grayscale thresholds may significantly overestimate the extent of LGE in patients with HCM when compared with visual assessment.22,30 We used a 5 SD threshold for LGE quantification, as this threshold has recently been demonstrated to provide the best representation of total fibrosis burden on the basis of quantitative histopathology.23 In our cohort, the extent of LGE was highest in apical segments as expected for apical HCM.14 However, LGE was also noted in remote, nonhypertrophied myocardial segments, most significantly the basal and mid-anteroseptum, mainly secondary to nonspecific hinge point LGE. These results are consistent with previous studies that have evaluated the regional distribution of LGE in apical HCM, which have reported the presence of LGE at the mid-ventricle31 and in other nonhypertrophied myocardial segments.16 We confirm an inverse relationship between LVEF and LGE, which has previously been reported in patients with other morphologic forms of HCM.26,32 Patients with apical HCM with low to normal LVEF may warrant closer clinical and imaging follow-up and consideration of medical therapy to inhibit adverse LV remodeling.33,34 A significant proportion of patients in our study experienced a major adverse event (15.1%), suggesting that the clinical course of apical HCM may not be as benign as initially proposed. Several recent studies have suggested that LGE may be an independent predictor of adverse cardiac outcomes in patients with HCM.27,35 The results of our study demonstrate that the extent of LGE is a significant predictor of major adverse clinical events in apical HCM (OR 1.4). Quantification of LGE on cardiac MRI may be useful for risk stratification in patients with apical HCM, particularly in situations in which other evidence of risk is ambiguous.18,29 We suggest a threshold of 5% LGE, which had high sensitivity (92.3%) and high negative predictive value (97.1%) for major adverse events. Patients with an apical aneurysm may be at increased risk for adverse events including SCD, appropriate AICD discharge, HF, and stroke.36 The presence of an apical aneurysm was the single strongest predictor of major adverse events in our cohort of patients with apical HCM (OR 4.6). Our results confirm a statistically significant association between the presence of apical aneurysm and %LGE (P = 0.013), in keeping with prior studies that have suggested that apical aneurysms are composed predominantly of fibrosis and may act as a substrate for ventricular tachyarrhythmias.36,37 The presence of an apical aneurysm and the extent of LGE did not remain significant predictors of major adverse events in a multivariable model; however, this analysis was limited by the number of events and the fact that apical aneurysms are composed of fibrosis; therefore, these variables are not independent of each other. In our study, patients with both an apical aneurysm and >5% LGE on cardiac MRI had the highest combined risk for major adverse events (OR 6.7), suggesting that identification of both imaging findings may r
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Cardiac MRI in Apical HCM
FIGURE 3. Kaplan-Meier survival curves for major adverse event-free survival after cardiac MRI with respect to the presence of apical aneurysm (A), %LGE (B), and both variables combined (C). Event-free survival was significantly reduced in patients with both the presence of an apical aneurysm and >5% LGE. Major adverse events were defined as HF, appropriate AICD discharge, sustained VT, stroke, aborted SCD, and all-cause death.
confer incremental risk over either imaging finding alone and may warrant consideration of AICD insertion in SCD riskassessment strategies.38 Echocardiography, when performed without contrast agents, may miss over half of apical aneurysms, highlighting the additional benefit of cardiac MRI evaluation in this population.16,36 There are several limitations pertaining to our study, including a relatively low number of observed adverse events. As a retrospective study, there were minor differences in the cardiac MRI protocol between patients. Interstudy variability in technique is an important consideration, as variations in cardiac MRI parameters, including the type of gadoliniumbased contrast agent, contrast volume, and magnetic field strength, may affect quantification of LGE.39 We included MRI studies performed at both 1.5 and 3 T in our study, and this factor could potentially influence LGE quantification. In addition, use of contrast agents with different relaxivities may r
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also influence quantification of LGE.40 A small percent of patients in our study did not undergo LGE imaging because of a contraindication to contrast administration. Analysis was limited by the number of observed clinical events and the fact that there were no deaths in the follow-up period. In addition, this study was performed at a single tertiary referral center in North America, and therefore our results may not be applicable to other apical HCM populations. In conclusion, the results of this study confirm that the presence of an apical aneurysm and the extent of LGE identified by cardiac MRI are significant predictors of major adverse events in patients with apical HCM. Large prospectively designed longitudinal studies are still required to definitively establish LGE and apical aneurysms as causally related to adverse events and to evaluate the incremental prognostic value of cardiac MRI findings in addition to traditional risk factors. www.thoracicimaging.com |
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REFERENCES 1. Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopathology. 2004;44:412–427. 2. Yamaguchi H, Ishimura T, Nishiyama S, et al. Hypertrophic nonobstructive cardiomyopathy with giant negative T waves (apical hypertrophy): ventriculographic and echocardiographic features in 30 patients. Am J Cardiol. 1979;44:401–412. 3. Arad M, Penas-Lado M, Monserrat L, et al. Gene mutations in apical hypertrophic cardiomyopathy. Circulation. 2005;112: 2805–2811. 4. Eriksson MJ, Sonnenberg B, Woo A, et al. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:638–645. 5. Moro E, D’Angelo G, Nicolosi GL, et al. Long-term evaluation of patients with apical hypertrophic cardiomyopathy. Correlation between quantitative echocardiographic assessment of apical hypertrophy and clinical-electrocardiographic findings. Eur Heart J. 1995;16:210–217. 6. Webb JG, Sasson Z, Rakowski H, et al. Apical hypertrophic cardiomyopathy: clinical follow-up and diagnostic correlates. J Am Coll Cardiol. 1990;15:83–90. 7. Moon J, Shim CY, Ha JW, et al. Clinical and echocardiographic predictors of outcomes in patients with apical hypertrophic cardiomyopathy. Am J Cardiol. 2011;108: 1614–1619. 8. Chen CC, Lei MH, Hsu YC, et al. Apical hypertrophic cardiomyopathy: correlations between echocardiographic parameters, angiographic left ventricular morphology, and clinical outcomes. Clin Cardiol. 2011;34:233–238. 9. Fattori R, Biagini E, Lorenzini M, et al. Significance of magnetic resonance imaging in apical hypertrophic cardiomyopathy. Am J Cardiol. 2010;105:1592–1596. 10. 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;15:1784–1791. 11. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. 2003;42:1687–1713. 12. Moon JC, Fisher NG, McKenna WJ, et al. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004;90:645–649. 13. van der Wall EE, Bax JJ, Schalij MJ. Detection of apical hypertrophic cardiomyopathy; which is the appropriate imaging modality. Int J Cardiovasc Imaging. 2008;24:683–685. 14. Yamada M, Teraoka K, Kawade M, et al. Frequency and distribution of late gadolinium enhancement in magnetic resonance imaging of patients with apical hypertrophic cardiomyopathy and patients with asymmetrical hypertrophic cardiomyopathy: a comparative study. Int J Cardiovasc Imaging. 2009;25:131–138. 15. Suzuki J, Shimamoto R, Nishikawa J, et al. Morphological onset and early diagnosis in apical hypertrophic cardiomyopathy: a long term analysis with nuclear magnetic resonance imaging. J Am Coll Cardiol. 1999;33:146–151. 16. Kim K, Kim H, Hwang I, et al. Myocardial scarring on cardiovascular magnetic resonance in asymptomatic or minimally symptomatic patients with “pure” apical hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2012;14:52. 17. Moon JC, Reed E, Sheppard MN, et al. The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;43:2260–2264. 18. Chan RH, Maron B, Olivotto I, et al. Prognostic utility of contrast-enhanced cardiovascular magnetic resonance in hypertrophic cardiomyopathy: an international multicenter study. J Am Coll Cardiol. 2012;59:E1570.
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19. Gruner C, Care M, Siminovitch K, et al. Sarcomere protein gene mutations in patients with apical hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2011;4:288–295. 20. Nazarian S, Bluemke DA, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation. 2005;112:2821–2825. 21. Spiewak M, Malek LA, Misko J, et al. Comparison of different quantification methods of late gadolinium enhancement in patients with hypertrophic cardiomyopathy. Eur J Radiol. 2010;74:e149–e153. 22. Harrigan CJ, Peters DC, Gibson CM, et al. Hypertrophic cardiomyopathy: quantification of late gadolinium enhancement with contrast-enhanced cardiovascular MR imaging. Radiology. 2011;258:128–133. 23. Moravsky G, Ofek E, Rakowski H, et al. Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR. JACC Cardiovasc Imaging. 2013;6:587–596. 24. McMahon CJ, Moniotte S, Powell AJ, et al. Usefulness of magnetic resonance imaging evaluation of congenital left ventricular aneurysms. Am J Cardiol. 2007;100: 310–315. 25. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Int J Cardiovasc Imaging. 2002;18:539–542. 26. Maron MS, Appelbaum E, Harrigan CJ, et al. Clinical profile and significance of delayed enhancement in hypertrophic cardiomyopathy. Circ Heart Fail. 2008;1:184–191. 27. Bruder O, Wagner A, Jensen CJ, et al. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;56: 875–887. 28. Noureldin RA, Liu S, Nacif MS, et al. The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2012;14:17. 29. Maron MS. Contrast-enhanced CMR in HCM: What lies behind the bright light of LGE and why it now matters. JACC Cardiovasc Imaging. 2013;6:597–599. 30. Flett AS, Hasleton J, Cook C, et al. Evaluation of techniques for the quantification of myocardial scar of differing etiology using cardiac magnetic resonance. JACC Cardiovasc Imaging. 2011;4:150–156. 31. Amano Y, Takayama M, Fukushima Y, et al. Delayedenhancement MRI of apical hypertrophic cardiomyopathy: assessment of the intramural distribution and comparison with clinical symptoms, ventricular arrhythmias, and cine MRI. Acta Radiol. 2011;52:613–618. 32. Choudhury L, Mahrholdt H, Wagner A, et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;40: 2156–2164. 33. Maron MS. Clinical utility of cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2012;14:13. 34. 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. 35. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–1374. 36. 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. r
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37. Lim KK, Maron BJ, Knight BP. Successful catheter ablation of hemodynamically unstable monomorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and apical aneurysm. J Cardiovasc Electrophysiol. 2009;20: 445–447. 38. Gersh BJ, Maron BJ, Bonow RO, et al. ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm
r
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Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58:e212–e260. 39. Bluemke DA, Yang E. Hypertrophic cardiomyopathy: refining the lens of cardiac magnetic resonance to evaluate late gadolinium enhancement. J Am Coll Cardiol. 2012;60: 930–931. 40. Rudolph A, von Knobelsdorff-Brenkenhoff F, Wassmuth R, et al. Assessment of nonischemic fibrosis in hypertrophic cardiomyopathy: Comparison of gadopentetate dimeglumine and gadobenate dimeglumine for enhanced cardiovascular magnetic resonance imaging. J Magn Reson Imaging. 2014; 39:1153–1160.
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Cardiac Magnetic Resonance Imaging Findings Predict Major Adverse Events in Apical Hypertrophic Cardiomyopathy Kate Hanneman, MD,* Andrew M. Crean, MRCP,*w Lynne Williams, MD,w Hadas Moshonov, PhD,* Susan James, MD,* Laura Jime´nez-Juan, MD,* Christiane Gruner, MD,w Patrick Sparrow, MRCP,* Harry Rakowski, MD,w and Elsie T. Nguyen, MD, FRCPC*
Purpose: The purpose of this study was to determine the prognostic significance of cardiac magnetic resonance imaging (MRI) findings in patients with apical hypertrophic cardiomyopathy (HCM). Materials and Methods: Cardiac MRI studies of 93 consecutive patients with apical HCM were retrospectively evaluated. Quantification of late gadolinium enhancement (LGE) was determined and expressed as a percentage of total left ventricular (LV) myocardial mass (%LGE). Morphologic features including presence of apical aneurysm, right ventricular hypertrophy, and LV thrombus were also assessed. Clinical data were collected during follow-up to assess for occurrence of major adverse events, defined as: heart failure, stroke, appropriate automatic implantable cardioverter defibrillator discharge, sustained ventricular tachycardia, aborted sudden cardiac death, and/or all-cause death. Results: The mean age of the patients was 54.9 ± 13.8 years, and 72.0% (n = 67) were male. LGE, right ventricular hypertrophy, apical aneurysm, and LV thrombus were identified in 69.4%, 25.8%, 18.3%, and 4.3%, respectively. Mean %LGE was 10.8% ± 11.1%. Over 2.4 ± 1.7 years of follow-up, 14 subjects (15.1%) experienced a major adverse event (event rate, 6.3%/y): heart failure (6.5%), stroke (6.5%), appropriate automatic implantable cardioverter defibrillator discharge (2.2%), sustained ventricular tachycardia (2.2%), aborted sudden cardiac death (1.1%), and all-cause death (0.0%). Presence of apical aneurysm and extent of LGE were significant predictors of major adverse events [odds ratio (OR) 4.6, P = 0.015; and OR 1.4/ 5% LGE, P = 0.030, respectively]. Patients with both apical aneurysm and >5% LGE were at highest risk for major adverse events (OR 6.7, P = 0.004) and had shortest event-free survival (P = 0.001). Conclusions: Within our population of apical HCM patients, the extent of LGE and the presence of an apical aneurysm identified by cardiac MRI were both significant predictors of major adverse clinical events. Key Words: hypertrophic cardiomyopathy, apical hypertrophic cardiomyopathy, cardiac magnetic resonance imaging, late gadolinium enhancement
(J Thorac Imaging 2014;29:331–339)
From the *Department of Medical Imaging; and wDivision of Cardiology, Peter Munk Cardiac Center, University Health Network, University of Toronto, Toronto, ON, Canada. The authors declare no conflicts of interest. Reprints: Elsie T. Nguyen, MD, FRCPC, Department of Medical Imaging, Toronto General Hospital, Room 1C567, NCSB, 585 University Ave. Toronto, ON, Canada M5G 2N2 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Thorac Imaging
Volume 29, Number 6, November 2014
H
ypertrophic cardiomyopathy (HCM) is characterized pathologically by myocyte disarray, hypertrophy, and interstitial fibrosis.1 The majority of patients with HCM have asymmetrical hypertrophy with a predilection for the basal septum and anterior wall. Apical HCM, representing 7% to 10% of all HCM, is a distinct morphologic subtype primarily affecting the left ventricular (LV) apex.2–4 The clinical course of apical HCM was previously thought to be relatively benign with a low incidence of sudden death.2 However, more recent studies have found apical HCM to be associated with greater than previously recognized cardiovascular mortality and significant morbidity, including ventricular and atrial arrhythmias, sudden death, heart failure (HF), and stroke.4–10 Predicting which patients are at risk for adverse events remains a clinical challenge. Transthoracic echocardiography is considered the noninvasive imaging standard for the diagnosis of HCM.11 However, cardiac magnetic resonance imaging (MRI) offers unique strengths in the evaluation of patients with suspected or confirmed apical HCM, including the ability to optimally visualize the LV apex, accurately quantify LV mass, and assess myocardial fibrosis.12 Myocardial fibrosis, as detected by late gadolinium enhancement (LGE), has been shown to correlate with risk for ventricular arrhythmias and development of HF in HCM.9,13–18 We hypothesized that cardiac MRI findings including LGE and apical aneurysms may identify patients with apical HCM who are at increased risk for adverse events. The aim of this study was to assess the prognostic significance of cardiac MRI imaging findings in patients with apical HCM.
MATERIALS AND METHODS Patient Population This retrospective study was approved by our institutional research ethics board. The requirement for written informed consent was waived. Study subjects were identified through the database of a dedicated HCM clinic at a large tertiary referral center. Consecutive patients with a diagnosis of apical HCM by cardiac MRI, with clinical documentation and at least 1 cardiac MRI performed between 2003 and 2012, were included. Diagnosis of apical HCM was defined by LV hypertrophy confined to the apex and an apical wall thickness of Z15 mm (measured in enddiastole) or a maximum apical to maximum basal wall thickness ratio of Z1.3 as established by 2 experienced www.thoracicimaging.com |
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observers by consensus review of imaging findings.15 Exclusion criteria included patients who had additional septal hypertrophy or isolated mid-cavity hypertrophy, evidence of LV cavity obstruction (including isolated midcavity obstruction) on echocardiography and cardiac MRI, and coronary artery disease as assessed by catheter angiography.19 Patients who had experienced an adverse clinical event before cardiac MRI were not excluded.
Cardiac MRI Protocol Cardiac MRI studies were performed using 1.5 T (MAGNETOM Avanto; Siemens Healthcare, Erlangen, Germany) or 3 T (MAGNETOM Verio; Siemens Healthcare) scanners with commercially available cardiac surface coils. LV function was assessed using retrospectively gated cine steady-state free-procession (SSFP) techniques in short-axis orientation acquired to cover the entire LV volume. Typical imaging parameters were as follows: slice thickness 6 to 8 mm (0 to 2 mm gap), in-plane resolution 1.4 1.7 mm, temporal resolution 30 to 40 ms. One slice was acquired per end-expiratory breath-hold. Short-axis LGE images were acquired using a 2dimensional inversion recovery prepared gradient recalled echo sequence 10 to 20 minutes after the intravenous administration of 0.2 mmol/kg bodyweight of gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Berlin, Germany) or gadobutrol (Gadovist; Bayer HealthCare Pharmaceuticals), followed by a flush of 20 mL of saline. The entire LV was covered in short-axis orientation from base to apex (8 to 10 slices), acquiring a single slice per end-expiratory breath-hold with the following typical imaging parameters: slice thickness 6 to 8 mm; in-plane resolution 1.81.4 mm; temporal resolution 160 to 200 ms. Two-, 3-, and 4-chamber planes were also obtained to visualize the apex. Optimal inversion time to null the normal myocardial signal was determined for each patient using a Look-Locker sequence (TI scout). Single-slice horizontal and vertical longaxis LGE images were also obtained.
Cardiac MRI Analysis Postprocessing analysis was performed independently by 2 experienced observers offline using commercially available software (CMR 42; Circle Cardiovascular Imaging Inc., Calgary, Canada). LV endocardial and epicardial borders were manually contoured on short-axis SSFP images to assess for end-diastolic and end-systolic volumes and LV ejection fraction (LVEF); and on short-axis LGE images to assess for LV mass and extent of LGE. Papillary muscles were considered part of the blood volume. The presence of LGE was qualitatively assessed by visual inspection of all available LGE images and was graded as present or absent for each patient. Quantitative analysis was performed using a signal intensity threshold of 5 SD above visually normal remote myocardium, as described previously20–23 (Fig. 1). Addition of the areas of LGE contoured on all short-axis slices multiplied by slice thickness yielded the total volume of delayed enhancement in grams (myocardial density of 1.05 g/m3), which was subsequently expressed as a percentage of total LV myocardial mass (%LGE). Maximum LV end-diastolic wall thickness was measured on basal and apical SSFP short-axis slices. The presence or absence of right ventricular (RV) hypertrophy (thickening of the RV wall measuring Z3 mm at end-diastole on short axis or 4-chamber slices), LV apical
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aneurysm (defined as a discrete thin-walled dyskinetic or akinetic segment of the distal LV chamber with a relatively wide communication with the LV cavity), and ventricular thrombus (assessed using standard LGE and cine SSFP sequences) was recorded.24 To measure interobserver agreement, LGE images of a random subset of 40 patients were selected for reanalysis by a second experienced and blinded observer. In this subset, maximum wall thickness and %LGE were recorded for each segment according to the 17-segment model proposed by the American Heart Association.25
Clinical Data Data were abstracted on demographic characteristics, clinical outcomes, and symptoms from clinical documentation and the electronic patient record. Major adverse events were defined as HF, appropriate automatic implantable cardioverter defibrillator (AICD) discharge, sustained ventricular tachycardia (VT), stroke, aborted sudden cardiac death (SCD), and all-cause death. Rhythm disturbances were identified by 24-hour Holter ECG monitoring performed every 1 to 3 years in patients without an AICD or by device interrogation every 6 months in those patients with an AICD. Sustained VT was defined as Z3 consecutive beats, lasting >30 seconds at a rate of Z120 beats/min. HF events were defined as any of the following: progression to New York Heart Association (NYHA) functional class III or IV in the absence of obstruction; hospital admission for HF other than due to transient atrial fibrillation; decline in LVEF to 5% LGE (P = 0.001). Patient age and LVEF were both significant predictors of major adverse events (OR 1.1, P = 0.025; and OR 0.93, P = 0.032, respectively). There was no statistically significant association between LV thrombus, RV hypertrophy, maximum LV wall thickness, family history of HCM or family history of SCD, and occurrence of a major adverse event (P > 0.05 for all). In a multivariable logistic regression model, none of the variables included (%LGE, presence of apical aneurysm, LVEF, and age) remained significant predictors of major adverse events (P > 0.05).
DISCUSSION This study has demonstrated that the exent of LGE and the presence of apical aneurysms are significant predictors of major adverse events in patients with apical HCM as identified by cardiac MRI. LGE on cardiac MRI can be used to detect myocardial fibrosis and has been shown to identify HCM patients who are at increased risk for adverse events.17,18,26,27 We report the presence of LGE in 69.4% of patients in our study, which is in keeping with the results of a recent review that reported a weighted mean prevalence of LGE of 65% in 1814 HCM patients.28 In our study, the mean extent of LGE was 10.8% of LV myocardium. A prior study reported lower values for the extent of LGE in patients with apical HCM (4.9%). In contrast to our study, a lower proportion of patients with an apical aneurysm were included (12.5% vs. 18.3% in our TABLE 4. ORs for the Prediction of Major Adverse Clinical Events Age Family history SCD Shortness of breath Chest pain Syncope LVEF Maximum LV wall thickness Presence of LGE Extent of LGE (%LGE) Apical aneurysm
OR
95% CI
P
1.05 0.94 1.53 0.56 2.42 0.93 1.04 6.38 1.41 4.63
1.00, 1.10 0.10, 8.43 0.48, 4.87 0.14, 2.17 0.56, 10.54 0.86, 0.99 0.91, 1.19 0.78, 51.96 1.04, 1.93 1.35, 15.95
0.025 0.953 0.472 0.398 0.239 0.032 0.559 0.083 0.030 0.015
Univariable logistic regression analysis in the prediction of major adverse clinical events. For %LGE, ORs are for a 5% increase in %LGE. P-values in bold are statistically significant. Major adverse events were defined as HF, appropriate AICD discharge, sustained VT, aborted SCD, stroke, and/or all-cause death.
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study), and they utilized a higher signal intensity threshold for LGE quantification (6 vs. 5 SD in our study), which may account for this difference.16 Several different signal intensity thresholds as well as visual assessment for LGE have been proposed.26 Recent studies have concluded that use of higher grayscale thresholds (4 to 6 SD) may yield the best agreement with the extent of LGE identified by visual assessment and may be the most reproducible method for quantification of LGE in HCM.21–23,28,29 Use of lower grayscale thresholds may significantly overestimate the extent of LGE in patients with HCM when compared with visual assessment.22,30 We used a 5 SD threshold for LGE quantification, as this threshold has recently been demonstrated to provide the best representation of total fibrosis burden on the basis of quantitative histopathology.23 In our cohort, the extent of LGE was highest in apical segments as expected for apical HCM.14 However, LGE was also noted in remote, nonhypertrophied myocardial segments, most significantly the basal and mid-anteroseptum, mainly secondary to nonspecific hinge point LGE. These results are consistent with previous studies that have evaluated the regional distribution of LGE in apical HCM, which have reported the presence of LGE at the mid-ventricle31 and in other nonhypertrophied myocardial segments.16 We confirm an inverse relationship between LVEF and LGE, which has previously been reported in patients with other morphologic forms of HCM.26,32 Patients with apical HCM with low to normal LVEF may warrant closer clinical and imaging follow-up and consideration of medical therapy to inhibit adverse LV remodeling.33,34 A significant proportion of patients in our study experienced a major adverse event (15.1%), suggesting that the clinical course of apical HCM may not be as benign as initially proposed. Several recent studies have suggested that LGE may be an independent predictor of adverse cardiac outcomes in patients with HCM.27,35 The results of our study demonstrate that the extent of LGE is a significant predictor of major adverse clinical events in apical HCM (OR 1.4). Quantification of LGE on cardiac MRI may be useful for risk stratification in patients with apical HCM, particularly in situations in which other evidence of risk is ambiguous.18,29 We suggest a threshold of 5% LGE, which had high sensitivity (92.3%) and high negative predictive value (97.1%) for major adverse events. Patients with an apical aneurysm may be at increased risk for adverse events including SCD, appropriate AICD discharge, HF, and stroke.36 The presence of an apical aneurysm was the single strongest predictor of major adverse events in our cohort of patients with apical HCM (OR 4.6). Our results confirm a statistically significant association between the presence of apical aneurysm and %LGE (P = 0.013), in keeping with prior studies that have suggested that apical aneurysms are composed predominantly of fibrosis and may act as a substrate for ventricular tachyarrhythmias.36,37 The presence of an apical aneurysm and the extent of LGE did not remain significant predictors of major adverse events in a multivariable model; however, this analysis was limited by the number of events and the fact that apical aneurysms are composed of fibrosis; therefore, these variables are not independent of each other. In our study, patients with both an apical aneurysm and >5% LGE on cardiac MRI had the highest combined risk for major adverse events (OR 6.7), suggesting that identification of both imaging findings may r
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FIGURE 3. Kaplan-Meier survival curves for major adverse event-free survival after cardiac MRI with respect to the presence of apical aneurysm (A), %LGE (B), and both variables combined (C). Event-free survival was significantly reduced in patients with both the presence of an apical aneurysm and >5% LGE. Major adverse events were defined as HF, appropriate AICD discharge, sustained VT, stroke, aborted SCD, and all-cause death.
confer incremental risk over either imaging finding alone and may warrant consideration of AICD insertion in SCD riskassessment strategies.38 Echocardiography, when performed without contrast agents, may miss over half of apical aneurysms, highlighting the additional benefit of cardiac MRI evaluation in this population.16,36 There are several limitations pertaining to our study, including a relatively low number of observed adverse events. As a retrospective study, there were minor differences in the cardiac MRI protocol between patients. Interstudy variability in technique is an important consideration, as variations in cardiac MRI parameters, including the type of gadoliniumbased contrast agent, contrast volume, and magnetic field strength, may affect quantification of LGE.39 We included MRI studies performed at both 1.5 and 3 T in our study, and this factor could potentially influence LGE quantification. In addition, use of contrast agents with different relaxivities may r
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also influence quantification of LGE.40 A small percent of patients in our study did not undergo LGE imaging because of a contraindication to contrast administration. Analysis was limited by the number of observed clinical events and the fact that there were no deaths in the follow-up period. In addition, this study was performed at a single tertiary referral center in North America, and therefore our results may not be applicable to other apical HCM populations. In conclusion, the results of this study confirm that the presence of an apical aneurysm and the extent of LGE identified by cardiac MRI are significant predictors of major adverse events in patients with apical HCM. Large prospectively designed longitudinal studies are still required to definitively establish LGE and apical aneurysms as causally related to adverse events and to evaluate the incremental prognostic value of cardiac MRI findings in addition to traditional risk factors. www.thoracicimaging.com |
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