EDITORIAL COMMENT
Left Ventricular Hypertrophy and Excess Cardiovascular MortalityIs Late Gadolinium Enhancement the Imaging Link?*
Michael L. Chuang, MD* and
Warren J. Manning, MD, FACC*, ,*
* Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
* Reprint requests and correspondence: Dr. Warren J. Manning, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215 (Email: wmanning{at}bidmc.harvard.edu).
Key Words: cardiovascular magnetic resonance • gadolinium • hypertension • left ventricular hypertrophy • magnetic resonance imaging
Left ventricular hypertrophy (LVH) is well established as a predictor of excess cardiovascular morbidity and mortality. Initial studies demonstrated an association between electrocardiographic LVH and likelihood of adverse events, but at acceptable levels of specificity, the sensitivity of the electrocardiogram for LVH is low. Subsequently, M-mode echocardiographically determined LVH was shown to predict cardiovascular morbidity and mortality independent of clinical risk factors including age, sex, smoking, and diabetes (1). The additional risk associated with LVH has been attributed to factors such as subendocardial ischemia related to perfusion gradient or increased arrhythmogenicity due in part to changes in myocardial substrate, but noninvasive in vivo methods for characterizing myocardial composition are neither widely available nor commonly used in the clinical setting.
Although not currently approved by the Food and Drug Administration (FDA) for imaging of the heart, gadolinium chelates are widely used in cardiovascular magnetic resonance (CMR) as T1-shortening contrast agents. Work in the mid-1980s, with a canine coronary-ligation model, demonstrated that irreversibly injured myocardium exhibits significantly shortened T1 as compared with normal myocardium when imaged 5 min after intravenous injection of high-dose (0.5 mmol/kg) gadolinium (2,3). These and similar early studies were limited by the relatively low image contrast (typically <50%) between normal and irreversibly injured myocardium achieved with spin-echo CMR imaging. Subsequent work with inversion-recovery segmented gradient echo CMR methods were able to achieve signal intensity differences of up to 500% between normal and infarcted myocardium (4,5), where normal myocardium is dark and infarcted myocardium is enhanced (bright). The fundamental technique is straightforward: intravenous injection of gadolinium contrast followed by inversion recovery imaging after a 10- to 15-min delay. This is known in the CMR world as late gadolinium enhancement (LGE), delayed enhancement, delayed hyperenhancement, or delayed contrast enhancement.
With inversion-recovery segmented gradient echo methods, comparison with necropsy in animals demonstrated that LGE is able to identify and accurately localize even very small infarcts (4). Both animal and human studies showed that LGE is able to identify both acute and chronic permanent myocardial injury and differentiates between irreversibly injured and stunned or hibernating myocardium. Further, LGE imaging has excellent agreement with positron emission tomography for determination of extent of myocardial scar (6) and is superior to single photon emission-computed tomography for identifying small infarcts, due to the enhanced spatial resolution of CMR methods (7). Landmark studies by Kim et al. (8) and others (9,10) showed that extent and transmurality of LGE was predictive of recovery of function after mechanical revascularization. Whereas initial data suggested that LGE was specific for irreversible ischemic injury (4), subsequent studies showed that LGE was associated with a multiplicity of conditions, including hypertrophic cardiomyopathy (HCM) (11,12), myocarditis (13), nonischemic dilated cardiomyopathy (14), cardiac sarcoidosis (15), cardiac amyloidosis (16), Anderson-Fabry disease (17), and pulmonary arterial hypertension (AH) (18). Specific conditions are associated with characteristic patterns of LGE. For example, LGE in HCM commonly occurs in the interventricular septum at the right ventricular insertion points, whereas LGE in myocardial infarction has a subendocardial or transmural distribution.
Our present understanding of the mechanism of LGE is that it represents a relative paucity of viable myocytes. In the healthy state, the majority (approximately 75%) of myocardial tissue volume is occupied by normal myocytes (19), which do not allow gadolinium chelates to cross their intact sarcolemmal membranes. Acute necrosis allows gadolinium to diffuse across damaged membranes, whereas scar is characterized by increased extracellular matrix that can host gadolinium; in either case, the tissue concentration of gadolinium is increased relative to viable myocardium, leading to shorter T1 and bright signal on CMR imaging.
Hypertrophic cardiomyopathy is strongly associated with LGE (11,12), but LVH associated with aortic stenosis (AS) might also result in positive LGE scans (20,21). In this issue of the Journal, Rudolph et al. (22) extend our knowledge of the range of conditions associated with LGE. They compared LGE findings in patients with HCM and AS with patients with LVH secondary to AH, a condition not previously associated with LGE. To their credit, subjects  40 years of age had coronary artery disease rigorously excluded by coronary angiography, whereas younger subjects were all free of clinical risk factors. Consistent with prior studies, LGE was very common (72%) among HCM subjects and most commonly located at the right ventricular free-wall insertion points. The presence and extent of LGE were significantly associated with increasing left ventricular (LV) mass index. Among those with AS, 62% displayed LGE in a patchy, noncoronary distribution that was associated with increasing LV mass index. Most provocative are the findings that 50% of AH subjects with LVH exhibited LGE with a trend toward greater LV mass index among AH subjects with LGE. Like AS, the LGE pattern was patchy, predominantly nonsubendocardial, and averaged 5% of LV mass.
The study of Rudolph et al. (22) adds prolonged AH with LVH to the range of conditions associated with cardiac LGE and is broadly in accord with a contemporaneous publication by Andersen et al. (23). Just as preliminary work suggests LGE in HCM might be a predictor of sudden death (14) or ventricular arrhythmias (24), perhaps LGE in the AH with LVH population will prove to be the imaging link to increased cardiovascular risk in this population. Kwong et al. (25) have shown that, among a variety of patients without known prior myocardial infarction, the presence of any LGE was a significant predictor of cardiovascular morbidity and mortality even after accounting for ejection fraction, resting wall-motion abnormalities, and angiographic coronary artery disease.
However, before we can advocate CMR for the large population of patients with AH and LVH, considerable work needs to be done. A majority of subjects with LVH by echocardiography did not have CMR LVH and were excluded from the Rudolph et al. (22) study, but their thresholds for LVH are greater than other published values (26) and might represent an extreme. What is the optimal spatial resolution for LGE imaging in patients with AH and LVH? What signal intensity difference constitutes LGE? And most importantly, in this population, does LGE provide independent incremental prognostic value to justify the expense of CMR and potential risk of gadolinium exposure? It seems that the next steps include confirmation of the prevalence of LGE among patients with AH and establishing whether LGE has independent prognostic value with respect to cardiovascular morbidity and mortality.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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