LhttLHe

iH5w(

Journal of the American College of Cardiology Vol. 60, No. 10, 2012© 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.05.023

EDITORIAL COMMENT

Hypertrophic CardiomyopathyRefining the Lens of Cardiac MagneticResonance to Evaluate LateGadolinium Enhancement*

David A. Bluemke, MD, PHD, Eunice Yang, BA

Bethesda, Maryland

Hypertrophic cardiomyopathy (HCM) is the most commoninheritable cardiomyopathy, affecting about 1 in 500 indi-viduals. Echocardiography is most commonly used fordiagnosis and the diagnostic criteria are quite straightfor-ward: abnormally increased thickness of the left ventricular(LV) wall in the absence of other causes of hypertrophy.Indeed, there are few other myocardial diseases for whichsuch a “simple” anatomic measurement seems sufficient fordiagnosis. However, sophisticated new imaging methodshave the potential to move well beyond anatomy alone forthe assessment of HCM.

See page 922

Cardiac magnetic resonance (CMR) can be used to assessLV wall thickening, but the cost is 3 to 4 times more thanechocardiography. CMR physicians have long observedHCM patients for which echocardiography did not detectabnormal wall thickening, although the converse (echocar-diography only detected cases) is much less likely. In a largeseries of more than 300 patients, Maron et al. (1) showedthat 12% of patients had abnormal wall thickening by CMRthat was underestimated or undetected by echocardiogra-phy. Do those “missed” cases by echocardiography matter interms of patient outcome, especially in regard to the greatercost of CMR? For example, apical HCM is more likely tobe missed by echocardiography than magnetic resonanceimaging, but those patients have less frequent adverse eventsthan do those with outflow tract obstruction. What addi-tional information can CMR provide?

The substrate for arrhythmia in HCM is thought to bemyocardial scar (2,3). In 2002, Choudhury et al. (4) dem-

*Editorials published in the Journal of the American College of Cardiology reflect theviews of the authors and do not necessarily represent the views of JACC or theAmerican College of Cardiology.

From Radiology and Imaging Sciences, National Institutes of Health ClinicalCenter, Bethesda, Maryland. This research was funded by the National Institutes of

Health (NIH) Intramural Program. Drs. Bluemke and Yang have reported that theyhave no relationships relevant to the contents of this paper to disclose.

onstrated the use of CMR to detect enhancing areas ofmyocardial tissue in HCM. These late gadolinium enhance-ment (LGE) areas on CMR reminded the investigators ofmyocardial scar on postmortem specimens. Yet pathologycorrelation with CMR to determine the etiology of theenhancing areas is rare, requiring antemortem or pre-explant CMR evaluation. Moon et al. (5) observed a single28-year-old male who underwent CMR and cardiac trans-plant 49 days later. O’Hanlon et al. (6) also described apatient with CMR prior to death and autopsy. These rarebut important observations have helped to validate therelationship between LGE tissue on CMR and myocardialfibrosis in hypertrophic cardiomyopathy. At present, LGE/“fibrosis” has been reported in 60% to 70% of all HCMsubjects using CMR imaging (7).

Since those early studies, LGE detected by CMR hasbeen rapidly investigated as a potential biomarker formalignant arrhythmia in HCM. The presence of LGE ismore frequent in HCM patients with tachyarrhythmia(8–10). Importantly, several studies have indicated thatLGE is an independent risk factor for adverse outcome inHCM (6,11). Once again in HCM, could we have another“simple” biomarker in HCM: does simply the presence of

GE (rather than the extent or pattern) place the patient atigh risk? If LGE is present, does that risk information helphe clinical cardiologist manage the HCM patient? Al-hough 60% to 70% of patients with a CMR will haveGE/fibrosis, the incidence of sudden cardiac death inCM is only about 0.5% per year. Perhaps further detailed

valuation of LGE/fibrosis by CMR would be informative.In this issue of the Journal, Todiere et al. (12) present

mportant insights regarding change of LGE over time inCM. The authors measured focal myocardial scarring in

5 HCM patients using LGE CMR. Study subjects under-ent two CMR scans at an average interval of about 2 years

710 � 410 days). The authors considered �1 g of changein LGE mass to be statistically significant. Greater LGE/fibrosis progression (expressed as grams per month) wasassociated with a greater amount of LGE at baseline, apicalpattern of HCM, and worsening New York Heart Associ-ation (NYHA) functional class. No correlations were notedbetween LGE progression and LV mass index, LV volume,or ejection fraction. This study demonstrates that LGE is alate but common disease phenotype that follows the devel-opment of hypertrophy. Interestingly, Todiere et al. (12)also observed two patients with regression of LGE/fibrosis.

What do we know about LGE progression? In ischemiccardiomyopathy, infarct remodeling during the first 3months results in slight decrease in mass of the LGE tissue.This is accompanied by tissue change of the LGE region,from myocyte necrosis to replacement fibrosis. In contrast,we know very little about change in LGE in nonischemiccardiomyopathy. The study by Todiere et al. (12) thusrepresents 1 of the first studies with long-term follow-up of

the LGE findings. In another study, there was no significant

iesdMtsmp

931JACC Vol. 60, No. 10, 2012 Bluemke and YangSeptember 4, 2012:930–1 Gadolinium Enhancement in Hypertrophic Cardiomyopathy

LGE change by CMR after a mean of 1.5 years in subjectswith myocarditis (13). Few other studies have addressedchange in LGE over time.

The study by Todiere et al. (12) also raises importantquestions regarding quantitative imaging by CMR. Thereproducibility of quantitative CMR for most standardmeasures is between 5% and 10% (14). Todiere et al. (12)defined a threshold of LGE signal, above which LGE wassaid to be present. Caution is warranted here, in that athreshold method is likely of value only under the exactCMR circumstances used by the authors. Common CMRvariations, such as gadolinium dose, magnetic field strength,CMR scanner manufacturer, and pulse sequence parametersto name but a few, have significant effects on both thenumerator (signal) and denominator (noise) of the thresh-old. Our experience in an HCM multicenter trial suggeststhat the optimal visual threshold for LGE correlatespoorly with fixed, computer-defined thresholds whensuch thresholds are applied to multiple CMR centers andmanufacturers.

The incidence and rate progression of LGE observed byTodiere et al. (12) was also almost certainly influenced bythe characteristics of the study population. There wasimprovement in NYHA functional class status in 3 of 55patients but worsened NYHA functional class in 13 patientsfollowing medical therapy. Little information is providedregarding concurrent medical issues as well as medicationsinitiated between the 2 scan times. Because the study byTodiere et al. (12) was observational rather than interven-tional, the medications were likely heterogeneous. Angio-tensin II receptor blockers and angiotensin-converting en-zyme inhibitors as well as other therapies have beenassociated with regression of hypertrophy and myocardialfibrosis in animal models as well as humans (15–18). Thus,the relationship of medical therapy to LGE progression willneed further evaluation in subsequent studies.

In conclusion, the evidence that CMR can provideclinically useful and distinct information apart from echo-cardiography for HCM patients continues to increase.Starting with the “simple” parameter of LV wall thickness,the presence and now the progression of LGE/fibrosis may bemportant parameters that can be tracked by CMR. Furtherfforts on CMR reproducibility need to be performed, andtandardization may eventually allow CMR physicians toetermine useful thresholds for LGE presence or absence.ultiple studies already point to LGE CMR as an impor-

ant biomarker to indicate adverse events in HCM. Furthertudies are needed to determine if LGE is a modifiablearker, and if those modifications translate into better

atient outcome.

Reprint requests and correspondence: Dr. David A. Bluemke,Radiology and Imaging Sciences, Clinical Center, National Insti-tutes of Health, 10 Center Drive, Building 10, Room 1C355,Bethesda, Maryland 20892-1182. E-mail: bluemked@nih.gov.

REFERENCES

1. Maron MS, Maron BJ, Harrigan C, et al. Hypertrophic cardiomyop-athy phenotype revisited after 50 years with cardiovascular magneticresonance. J Am Coll Cardiol 2009;54:220–8.

2. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A.Hypertrophic cardiomyopathy and sudden death in the young: patho-logic evidence of myocardial ischemia. Hum Pathol 2000;31:988–98.

3. Varnava AM, Elliott PM, Mahon N, Davies MJ, McKenna WJ.Relation between myocyte disarray and outcome in hypertrophiccardiomyopathy. Am J Cardiol 2001;88:275–9.

4. Choudhury L, Mahrholdt H, Wagner A, et al. Myocardial scarring inasymptomatic or mildly symptomatic patients with hypertrophic car-diomyopathy. J Am Coll Cardiol 2002;40:2156–64.

5. Moon JC, Reed E, Sheppard MN, et al. The histologic basis of lategadolinium enhancement cardiovascular magnetic resonance in hyper-trophic cardiomyopathy. J Am Coll Cardiol 2004;43:2260–4.

6. O’Hanlon R, Grasso A, Roughton M, et al. Prognostic significance ofmyocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Car-diol 2010;56:867–74.

7. Noureldin RA, Liu S, Nacif MS, et al. The diagnosis of hypertrophiccardiomyopathy by cardiovascular magnetic resonance. J CardiovascMagn Reson 2012;14:17.

8. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequencyof arrhythmias in hypertrophic cardiomyopathy in relation to delayedenhancement on cardiovascular magnetic resonance. J Am Coll Car-diol 2008;51:1369–74.

9. Kwon DH, Setser RM, Popovic ZB, et al. Association of myocardialfibrosis, electrocardiography and ventricular tachyarrhythmia in hyper-trophic cardiomyopathy: a delayed contrast enhanced MRI study. IntJ Cardiovasc Imaging 2008;24:617–25.

10. Maron MS, Appelbaum E, Harrigan CJ, et al. Clinical profile andsignificance of delayed enhancement in hypertrophic cardiomyopathy.Circ Heart Fail 2008;1:184–91.

11. Bruder O, Wagner A, Jensen CJ, et al. Myocardial scar visualized bycardiovascular magnetic resonance imaging predicts major adverseevents in patients with hypertrophic cardiomyopathy. J Am CollCardiol 2010;56:875–87.

12. Todiere G, Aquaro GD, Piaggi P, et al. Progression of myocardialfibrosis assessed with cardiac magnetic resonance in hypertrophiccardiomyopathy. J Am Coll Cardiol 2012;60:922–9.

13. Zagrosek A, Abdel-Aty H, Boye P, et al. Cardiac magnetic resonancemonitors reversible and irreversible myocardial injury in myocarditis.J Am Coll Cardiol Img 2009;2:131–8.

14. Natori S, Lai S, Finn JP, et al. Cardiovascular function in multi-ethnicstudy of atherosclerosis: normal values by age, sex, and ethnicity. AJRAm J Roentgenol 2006;186 Suppl 2:S357–65.

15. Baskin KK, Taegtmeyer H. Taking pressure off the heart: the ins andouts of atrophic remodelling. Cardiovasc Res 2011;90:243–50.

16. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive heartdisease in spontaneously hypertensive rats. Lisinopril-mediated regres-sion of myocardial fibrosis. Hypertension 1996;28:269–75.

17. Rossi MA, Peres LC. Effect of captopril on the prevention andregression of myocardial cell hypertrophy and interstitial fibrosis inpressure overload cardiac hypertrophy. Am Heart J 1992;124:700–9.

18. Weber KT, Brilla CG, Janicki JS. Cardioreparation with lisinopril inthe management of hypertension and heart failure. Cardiology1991;79 Suppl 1:62–73.

Key Words: cardiac magnetic resonance y hypertrophic cardiomyopathyy late gadolinium enhancement y myocardial fibrosis.