Chest Pain and a Very Abnormal Stress Echocardiogram

Information about a real patient is presented in stages (boldface type) to expert clinicians (Drs. Chetan Shenoy and Mark Birkenbach), who respond to the information, sharing their reasoning with the reader (regular type). The authors’ commentary follows.

A 44-year-old male presented to his primary care physician with a nearly 2-year history of chest pressure worse with exertion, and dyspnea. He described his symptoms as substernal pressure, 4–5/10 in intensity, lasting 15–20 minutes, associated with diaphoresis, occurring several times a week, relieved by rest, and worsening over the 4 months prior to the visit. He denied resting symptoms. His medical history was only notable for congenital cataracts; he denied hypertension and diabetes mellitus. A review of systems for other symptoms was negative. His surgical history included knee arthroscopy and cataract surgery. His family history was significant for type 2 diabetes mellitus, hypertension, prostate cancer, and congenital cataracts. He denied tobacco, alcohol or illicit drug use. He did not take any medications and had no drug allergies. His vital signs and physical examination were unremarkable.

Dr. Shenoy:

The presentation of exertional substernal chest pain and dyspnea relieved by rest is consistent with stable angina. Using prediction models by Genders et al., this patient has a 31% probability of coronary artery disease (CAD) from a basic model that incorporates age, sex and symptoms, and a probability of 19% from a clinical model that also incorporates cardiovascular risk factors.¹ While many other diagnoses are possible, evaluation for obstructive CAD would be the most appropriate first step in this patient with stable angina and an intermediate pre-test probability.

Patient Presentation (continued):

His physician requested an exercise stress echocardiogram. The pre-exercise resting echocardiogram showed a left ventricular ejection fraction (LVEF) of 55–60% with no regional wall motion abnormalities and normal LV wall thickness. There were no significant valvular abnormalities. The resting electrocardiogram (ECG) showed normal sinus rhythm, first-degree AV block with a PR interval of 210 ms, no ST or T wave abnormalities and normal voltage. He exercised for 9 minutes and 50 seconds, achieving 150 Watts of workload (6.8 METS). His resting heart rate rose from 64 bpm to a maximal heart rate of 152 bpm, representing 85% of the age-predicted maximal heart rate. The stress echocardiogram showed severe wall motion abnormalities with akinesis of the septal, anterior and apical segments (Figure 1). The LV dilated with stress and the stress LVEF was estimated at 20–25%. There was no exercise-induced mitral regurgitation. The stress ECG did not show significant ST-segment changes. At the end of his exercise, he also had severe dyspnea with auscultation revealing pulmonary edema. He denied chest pain.

Figure 1:

Images from the patient’s stress echocardiogram, including the 4-chamber (rest: A and B; stress: E and F), 2-chamber (rest: C and D; stress: G and H), 3-chamber (rest: I and J; stress: M and N) and short axis (rest: K and L; stress: O and P) views, demonstrating dilation of the left ventricle and multiple regional wall motion abnormalities with stress.

Dr. Shenoy:

While exercise electrocardiography is recommended as a Class I recommendation for a patient with an intermediate pre-test probability, interpretable ECG, and at least moderate physical functioning, exercise stress echocardiography was also a reasonable option for this patient (Class IIa; Level of Evidence: B).² Coronary computed tomography angiography (CCTA) would also have been reasonable (Class IIb; Level of Evidence: B),² however, echocardiography has the added advantage of evaluating non-coronary cardiac causes of his symptoms (e.g., valvular heart disease), and confirming their exertional nature. The stress echocardiographic findings in this case are markedly abnormal and suggest high-risk – left main or multi-vessel – obstructive CAD. Given the severe dyspnea and pulmonary edema, hospitalization and coronary angiography should be considered as the next steps.

Patient Presentation (continued):

The patient was hospitalized. Laboratory testing revealed a mildly elevated troponin I of 0.108 µg/L (reference range 0.000–0.045 μg/L) and normal metabolic, blood, and lipid panels.

Dr. Shenoy:

With exercise-induced acute pulmonary edema, a very abnormal stress echocardiogram, and elevated troponin, the presentation fits an acute coronary syndrome (ACS). He warrants guideline-directed therapy for ACS including urgent invasive coronary angiography to define his coronary anatomy, and for potential revascularization.

Patient Presentation (continued):

The patient underwent coronary angiography via the radial approach, which revealed no CAD. Given his exercise-induced symptoms and wall motion abnormalities, he was made to exercise on a stationary recumbent bicycle on the cardiac catheterization table to assess for exercise-induced coronary spasm. Coronary angiography repeated after a few minutes of vigorous exercise failed to reveal any abnormalities. However, the exercise again resulted in severe shortness of breath and pulmonary edema.

Dr. Shenoy:

Interesting! Although epicardial coronary artery spasm has been described in patients with purely exercise-induced angina, it is frequently associated with symptoms at rest. The normal findings on exercise coronary angiography and the exercise-induced pulmonary edema make epicardial coronary artery spasm less likely. In the absence of CAD and significant valve disease (excluded by physical examination and the resting echocardiogram), the next possibility that needs to be investigated is non-ischemic cardiomyopathy (NICM). Currently, the best modality for evaluation of a newly-diagnosed NICM after initial echocardiography is cardiovascular magnetic resonance imaging (CMR).

Patient Presentation (continued):

A regadenoson stress CMR was performed next. Cine CMR confirmed a normal LVEF of 62% with no resting regional wall motion abnormalities. The LV was concentrically thick at 1.4 cm (Figure 2). The right ventricular (RV) size and systolic function were normal. The aortic valve was bicuspid in morphology with mild aortic insufficiency. Stress perfusion CMR revealed extensive sub-endocardial perfusion defects involving 13 of 16 AHA segments, not corresponding to coronary artery territories (Figure 3). Late gadolinium enhancement (LGE) CMR revealed extensive sub-endocardial LGE matching the perfusion defects (Figure 4) with some areas of mid-myocardial LGE. There was no intracardiac thrombus.

Figure 2:

Cine CMR images in basal short axis (A), mid short axis (B), apical short axis (C), 4-chamber (D), 3-chamber view (E), and 2-chamber (F) views, demonstrating an increase in left ventricular wall thickness at 1.4 cm (red arrows).

Figure 3:

Stress perfusion CMR images in basal short axis (A), mid short axis (B), and apical short axis (C) views, demonstrating multiple perfusion defects in a non-coronary distribution (red arrows).

Figure 4:

LGE CMR images in basal short axis (A), mid short axis (B), apical short axis (C), 4-chamber (D), 3-chamber view (E), and 2-chamber (F) views, demonstrating diffuse subendocardial (red arrows) and mid-myocardial LGE.

Dr. Shenoy:

The CMR findings confirm a NICM. Subendocardial LGE typically indicates an ischemic etiology, based on the wave-front phenomenon of ischemic cell death. However, LGE involving most – if not all – LV segments in a distribution that is discordant with coronary artery territories, argues against an ischemic cardiomyopathy. The unique pattern of diffuse subendocardial LGE is typically seen in only 2 NICMs – cardiac amyloidosis, an infiltrative cardiomyopathy, and eosinophilic myocarditis, an inflammatory cardiomyopathy. Other imaging features common to these distinct NICMs include increased wall thickness, the presence of a pericardial effusion and the presence of intracardiac thrombus, of which, the latter 2 were not seen in our case. Intracardiac thrombus in cardiac amyloidosis is typically seen in the atria (right atrium more common than the left atrium), while in eosinophilic myocarditis, it is typically seen in the ventricles (LV more common than the RV). T1 mapping and measurement of the extracellular volume (ECV) may help differentiate the 2 since cardiac amyloidosis is the exemplar of interstitial myocardial disease with a massively elevated ECV, which is not seen with other cardiomyopathies. However, the presence of edema in eosinophilic myocarditis may also lead to an increased ECV. For our patient, the best next step would be evaluation for a plasma cell dyscrasia.

Patient Presentation (continued):

The patient had serum immunofixation and a free light chain assay. An M-spike was absent, but the free light chain assay showed an increase in the lambda free light chains to 12.2 mg/dL (reference range 0.57–2.63 mg/dL) with a normal kappa free light chain level of 0.63 mg/dL (reference range 0.33–1.94 mg/dL), resulting in an abnormal kappa/lambda ratio of 0.05 (reference range 0.26–1.65).

Dr. Shenoy:

The combination of a plasma cell dyscrasia – as proven by the abnormal free light chain ratio – and the CMR findings is highly suggestive of light chain (AL) cardiac amyloidosis. Although unlikely in our younger patient, it is important to note that almost 1 in 4 patients with transthyretin (ATTR) amyloidosis have associated monoclonal gammopathy of unknown significance (MGUS), some of whom may have an abnormal free light chain ratio. Thus, an endomyocardial biopsy (EMB) or an abdominal fat pad biopsy, and a bone marrow biopsy are recommended next to reach a definitive diagnosis. Abdominal fat pad biopsy using needle aspiration has a 70–80% sensitivity for identifying amyloid deposition.

Patient Presentation (continued):

An EMB was performed and 7 samples were obtained from the RV aspect of the interventricular septum, which revealed cardiac amyloidosis with endocardial, interstitial, and perivascular deposits.

. Birkenbach:

Light microscopic examination of semi-thin scout sections stained with methylene blue-azure II showed myocardium with mild focal interstitial fibrosis. The cardiomyocytes were uniform in size and arranged in well-organized parallel arrays. There was no significant interstitial inflammation. Electron micrography revealed multiple interstitial aggregates of haphazardly arranged fibrils estimated to measure between 8 and 11 nm in diameter. There was focal interstitial deposition of cellular debris, likely corresponding to degenerating interstitial cells. The ultrastructural findings were diagnostic for cardiac amyloidosis. Amyloid deposition was seen around small vessels. Mass spectrometry would help understand the structure of the protein deposits and identify the amyloid sub-type.

Patient Presentation (continued):

Mass spectrometry confirmed the AL subtype of amyloid and a bone marrow biopsy revealed 8% monotypic plasma cells. A bone scan demonstrated no extracardiac disease. The patient was offered cyclophosphamide, bortezomib, and dexamethasone (CyBorD) chemotherapy followed by autologous stem cell transplantation. Due to his faith as a Jehovah’s Witness, he was reluctant to pursue stem cell transplantation. He underwent 5 cycles of CyBorD after which he has been stable for over a year without needing any amyloidosis-directed therapies. His cardiac amyloidosis is managed by a team that includes cardiologists and hematologists.

Dr. Shenoy:

Accurate and timely diagnosis of cardiac amyloidosis is critical for appropriate treatment. In this case, the patient’s initial presentation was suggestive of CAD, but the right choices of diagnostic imaging studies led to the correct diagnosis without delay.

Discussion

In this case of AL cardiac amyloidosis, the patient’s presentation with anginal chest pain and the severe stress-induced ischemia were likely manifestations of coronary microvascular dysfunction from perivascular amyloid deposition, possibly with obstruction³. Thus, significant ischemia in patients without epicardial CAD suggests coronary microvascular disease, for which AL cardiac amyloidosis should be considered in the differential diagnosis.

CMR allows a comprehensive and multifaceted approach to evaluation of cardiomyopathy through assessment of morphology, function, perfusion, viability and tissue characterization during a single examination⁴. The locations and patterns of LGE, which represents non-viable myocardial tissue, are often distinct, and help identify the precise etiology of the underlying cardiomyopathy⁴.

CMR markers of cardiac amyloidosis span the spectrum of severity from no LGE but increased extracellular volume (quantified by T1 mapping), to subendocardial LGE and transmural LGE, representing the continuum of cardiac infiltration. In a study of 47 patients with suspected cardiac amyloidosis that underwent CMR and EMB, the diffuse transmural pattern of LGE had a sensitivity of 88%, specificity of 90%, positive predictive value of 88%, and negative predictive value of 90%⁵.

Traditionally, the subtype of cardiac amyloidosis has only been able to be identified by EMB. Given the significantly different treatment regimens and prognosis between the AL and ATTR subtypes, there has been increasing interest in identifying non-invasive techniques to distinguish between the 2. While patients with the ATTRwt (wild type; sporadic from misfolding of wild-type protein with advanced age) subtype generally have higher chamber volumes, lower LVEF and thicker walls as compared to AL and ATTRm (mutant; hereditary from 1 of the >100 mutations of the transthyretin gene) subtypes, echocardiography alone cannot reliably distinguish between the 3. On CMR, LGE is more extensive and more likely to be transmural in ATTRwt compared with the AL subtype. However, the extent of LGE (transmural versus subendocardial) may simply be a marker of the chronicity of the disease. It is possible that the ATTRwt subtype is diagnosed later in the disease process due to fewer and/or later onset of symptoms, while the AL subtype is diagnosed earlier due to multi-organ involvement and more severe symptoms. Patients with the AL subtype may also be sicker with lesser LGE due to direct cardiomyocyte toxicity of the light chains.

Nuclear scintigraphy with bone-avid radiotracers such as ^99mTc-pyrophosphate (^99mTc-PYP), ^99mTc-hydroxymethylenediphosphonate (^99mTc-HMDP), and ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD) can help differentiate between AL and ATTR subtypes. In a recent large multicenter retrospective study of these radiotracers, grade 2 (moderate or uptake equal to bone) or 3 (high or uptake greater than bone) myocardial uptake in the absence of a monoclonal protein in serum or urine, had a specificity and positive predictive value for ATTR cardiac amyloidosis of 100%.

This case of a relatively uncommon disease presenting with commonly occurring symptoms highlights the importance of choosing the right diagnostic test based on the clinical data available at the time, to efficiently and accurately reach the diagnosis.