Author + information
- ∗University of Virginia, Charlottesville, Virginia
- †Icahn School of Medicine at Mount Sinai, New York, New York
- ↵∗Address for correspondence:
Dr. Jagat Narula, Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, One Gustave L. Levy Place, Mailbox 1030, New York, New York 10029.
Making the diagnosis of cardiac amyloidosis short of myocardial biopsy is an important goal of noninvasive imaging. Before the early 1990s, a “speckled” pattern on echocardiography in a patient with left ventricular hypertrophy signified a potential diagnosis of cardiac amyloidosis. Tissue harmonic imaging began to be instituted at that time, and because this approach makes every patient's myocardium appear speckled, this clue to a potential cause of infiltrative cardiomyopathies, albeit nonspecific, was lost to the imaging community. Additional hints toward the diagnosis can be sought, such as left ventricular hypertrophy with a restrictive filling pattern, biatrial enlargement, thickening of valves and/or the intra-atrial septum, and a pericardial effusion, but these findings too are nonspecific. Thus, imagers have been searching for additional noninvasive markers of this disease that generally requires a tissue biopsy to make the definitive diagnosis.
In 2005, the first report of the identification of amyloidosis with late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) was published (1). It was noted that gadolinium had a predilection for the subendocardium, and in fact, the T1 of the subendocardium was notably shorter than that of hypertensive controls in the first several minutes after gadolinium infusion. Gadolinium affects the magnetic properties of water molecules in the tissue by shortening the T1 of water, and thus this area appears brighter than surrounding tissues on T1-weighted images. The investigators noted that in these patients, the pattern of global subendocardial enhancement appeared to be characteristic of cardiac amyloidosis, although subsequent studies have demonstrated additional patterns as well. These patients were followed for several years, and an increased gradient between the T1 in the subendocardium and the subepicardium was associated with increased mortality (2).
The mechanism of T1 shortening and LGE in amyloidosis is due at least in part to the increased volume of distribution of gadolinium, a surrogate for extracellular volume, between the beta-pleated sheets of fibrillar proteins infiltrating the myocardium. Inflammation may also play a role. Using T1 mapping, post-contrast T1 of the blood is longer and that of the myocardium shorter in patients with amyloidosis compared to controls (3). When the volume of distribution of gadolinium is quantified using serial measures of T1, it is markedly increased compared with normal controls. In fact, before gadolinium is infused, if one measures the so-called native T1 of the myocardium, it is significantly longer in patients with amyloidosis than in controls (3) and longer than in patients with left ventricular hypertrophy due to aortic stenosis (4).
In this issue of iJACC, 3 reports highlight the utility of CMR in making the diagnosis of amyloidosis, as well as differentiating the subtype. White et al. (5) studied patients with suspected cardiac amyloidosis and compared them to hypertensive controls with left ventricular hypertrophy. They used a so-called TI-scout pulse sequence that is typically used to choose the proper inversion time (TI) before performing inversion-recovery LGE imaging. Of the patients with suspected amyloidosis, two-thirds demonstrated LGE, and 80% of these had evidence of diffuse LGE on the visual T1 assessment on the TI scout sequence. The latter finding was predictive of death in patients with suspected amyloidosis, and the accuracy of the finding compared with histopathology was 85%. Thus, a quick visual assessment with a standard pulse sequence typically acquired in a CMR study was reasonably efficient at identifying patients with cardiac amyloidosis, especially those at higher risk for death. Whether this rapid visual technique performs as well as T1 mapping remains to be elucidated in a controlled comparative study.
The other 2 reports identify methods to discriminate amyloid light-chain (AL) from amyloid transthyretin (ATTR) amyloidosis. Fontana et al. (6) studied native T1 mapping in patients with ATTR or AL amyloidosis compared with normal subjects or patients with hypertrophic cardiomyopathy. The highest values for T1 were seen in patients with AL amyloidosis, followed by those with ATTR amyloidosis, although the area under the receiver-operating curve was similar for both compared with patients with hypertrophic cardiomyopathy (0.84). This is important because many patients with amyloidosis have concomitant renal involvement and severe renal dysfunction and thus are not candidates for gadolinium administration. The third study compared LGE findings in patients with biopsy-proven AL amyloidosis and those with ATTR amyloidosis (7). LGE was much more extensive in patients with ATTR amyloidosis, with 90% demonstrating transmural LGE compared to only one-third of patients with AL amyloidosis. These investigators developed an LGE scoring system that differentiated the 2 types with 87% sensitivity and 96% specificity.
Putting these 3 reports together, CMR techniques are evolving rapidly, and in cardiac amyloidosis, the ability to make the diagnosis noninvasively with more certainty is improving with each passing year. Noncontrast T1 mapping and LGE patterns offer the promise of differentiating AL from ATTR amyloidosis, which is important because newer medical therapies are now in clinical trials that are specific to the type of amyloid deposited in the heart. The editorial in this issue that accompanies these 3 reports identifies their strengths and limitations and discusses the needs for future studies to cement the role of CMR in identifying and differentiating cardiac amyloidosis (8). We are delighted to bring these exciting imaging advances to you. It is our aim to identify where imaging is essential to the management of your patients, such as looking between the sheets for the characterization of cardiac amyloidosis.
Dr. Kramer is supported by grants R01 HL075792 and U01HL117006-01A1 from the National Institutes of Health.
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