This study is the first to describe the prevalence of oeCAD among patients with ATTR-CM and its associations to major clinical outcomes. The main findings are as follows: 1) approximately one quarter of ATTR-CM patients in our cohort had concurrent oeCAD, the majority of whom were diagnosed prior to ATTR-CM diagnosis, 2) upon clinical presentation with ATTR-CM, most patients underwent some form of oeCAD-related investigation, the majority of these being negative, 3) among ATTR-CM patients with oeCAD, the majority did not exhibit manifestations of this at the time of ATTR-CM diagnosis and during follow-up, and 4) a diagnosis of oeCAD was not associated with adverse outcomes in ATTR-CM patients. Overall, these findings suggest that, while oeCAD is prevalent among patients with ATTR-CM, it typically precedes ATTR-CM diagnosis and does significantly impact prognosis for most patients.
Cardiac amyloidosis is recognized to be associated with intramural microvascular disease in the absence of oeCAD, and much of this evidence comes from histopathologic studies of AL amyloidosis patients.3 This small vessel disease can result in symptoms of angina, and may contribute to unstable coronary syndromes or progressive HF.7 Multiple reports have described cardiac amyloidosis presenting with signs and/or symptoms of ischemic heart disease,12,13 It has been reported that between 10–20% of cardiac amyloidosis patients initially present with symptoms of chest pain, and that up to two-thirds of patients have significant intramural coronary amyloid deposits, many associated with focal microscopic changes of ischemic injury.14,15 Older pathologic studies describe the prevalence of intramural coronary artery amyloid deposits as much lower in ATTR-CM compared with AL cardiac amyloidosis,16–18 while more recent studies have confirmed coronary amyloid deposits in ATTR-CM patients.6 Perivascular and interstitial myocardial deposits may cause compression of coronary microvasculature that can also contribute to symptoms of ischemic heart disease.19 Significant coronary microvascular dysfunction was demonstrated by Dorbala, et al in a mixed cardiac amyloidosis subtype (ATTR and AL) cohort of patients without epicardial coronary artery disease undergoing N-13 ammonia positron emission tomography, and patients had reduced peak vasodilator stress myocardial blood flow and flow reserve.19
While amyloid infiltration of the epicardial coronary artery wall is also common in histopathologic studies, it generally does not result in obstructive disease.14 Our study is consistent with earlier reports that a clinical diagnosis of oeCAD is rare once patients receive a diagnosis of ATTR-CM,4,6 and that most patients with oeCAD are diagnosed prior to receiving a ATTR-CM diagnosis. Because of similarities in clinical presentation between oeCAD and cardiac amyloidosis, many ATTR-CM patients undergo investigation for oeCAD at the time of presentation. Beyond similar signs and symptoms, many cardiac amyloidosis patients have ECG abnormalities that may mimic oeCAD, and many have chronically elevated troponin values. In our study, the majority of investigations for oeCAD at the time of ATTR-CM diagnosis were negative. It has been postulated that cardiac amyloidosis may accelerate pre-existing atherosclerotic epicardial coronary artery diease via the deposition of amyloid deposits around coronary vessels,7,8 however the findings from our study do not support this in patients with ATTR-CM. Mortality and hospitalization rate were similar between patients and without oeCAD, and very few patients required further investigations for oeCAD after ATTR-CM diagnosis. Although beyond the scope of this study to confirm, these findings might suggest that medications commonly used to treat oeCAD that are poorly tolerated in patients with ATTR-CM, especially beta-blockers, may be safely reduced or even discontinued in patients with a prior oeCAD diagnosis, although this requires further research, and a cautious approach to titration of these medications in this setting is still recommended.
There are a number of important limitations to our analysis. This was a single-center, retrospective, observational cohort study, and therefore the presence of bias cannot be excluded. Patients did not undergo evaluation for microvascular dysfunction, and therefore the prevalence of this and its impact on our results is uncertain. Similarly, autopsy data was not available for deceased patients, and so correlation of clinical with histopathologic findings cannot be performed, although several previous studies have examined this. Lastly, our report lacks detailed descriptions of medical management changes for ATTR-CM patients, including anti-anginal agents often used to treat oeCAD. A recent report describing rates of beta-blocker prescription among a mixed subtype cohort of cardiac amyloidosis patients found that their use was not infrequent, with approximately 1/3 of patients continuing to take them after diagnosis, the majority for treatment of arrhythmia.20