Systemic Amyloidosis Presenting with Angina Pectoris

Angina in patients with normal-appearing coronary arteries can be due to abnormalities in coronary flow reserve secondary to microvascular disease (1). Although these abnormalities are often associated with risk factors for coronary artery disease, they may also result from intrinsic disease of the vascular wall. Amyloidoses represent a heterogeneous group of disorders that result from extracellular deposition of amyloid fibrils. The most common form in the western world is immunoglobulin light-chain-related (AL) or primary amyloidosis (2). Cardiovascular involvement in AL amyloidosis is the most common cause of morbidity and death. Patients with myocardial amyloid deposition can present with congestive heart failure due to restrictive cardiomyopathy and sudden cardiac death. In addition to myocardial involvement, the vascular system, including the microcirculation, may also be involved (3). We describe a subset of patients who presented with angina pectoris, normal epicardial coronary arteries on coronary angiography, and abnormal coronary flow reserve as the initial manifestation of systemic amyloidosis. Methods Patients Between January 1993 and February 1997, 153 patients underwent coronary flow reserve studies for chest pain and had normal coronary angiograms. Clinical details were obtained at the time of evaluation. The decision to perform cardiac evaluations was made by the attending cardiologist. Coronary Physiology Evaluation Diagnostic coronary angiography was performed, as described elsewhere (4). Coronary flow reserve in response to acetylcholine (endothelial-dependent) and adenosine (non-endothelial-dependent) were studied according to a previously reported protocol (4). After baseline coronary angiography was done, a 0.014-inch Doppler guidewire (EndoSonics, Rancho Cordova, California) was introduced within a 2.2-French coronary infusion catheter through an 8-French guiding catheter into the left anterior descending coronary artery. After baseline flow velocity was stabilized, a bolus of intracoronary adenosine (24 to 36 g) was administered for measurement of coronary flow reserve. Selective intracoronary infusions of increasing concentrations of acetylcholine (10 6, 10 5, and 10 4 mol/L) were then performed for a total duration of 3 minutes. After acetylcholine was infused, 200 g of intracoronary nitroglycerin was administered to reverse vasoconstriction. Symptoms, hemodynamic data, electrocardiographic results, Doppler velocities, and coronary angiographic results were recorded at the end of each infusion. Doppler flow velocity spectra were analyzed online to determine time-averaged peak velocity. Coronary flow reserve was calculated as the ratio of hyperemic to basal average peak velocity of the distal vessel. Volumetric coronary blood flow was determined by using the following equation: coronary blood flow=cross-sectional area average peak velocity 0.5 (4). Endothelial-independent coronary flow reserve was calculated as the maximal coronary blood flow in response to maximal hyperemia in response to adenosine divided by the resting coronary blood flow. Endothelial-dependent coronary flow reserve was calculated by using the following equation: (coronary blood flow after intracoronary acetylcholine infusion resting coronary blood flow)/resting coronary blood flow 100 (%). Histologic Evaluation Tissue was obtained from all patients before death. Myocardial tissue was studied in two patients; fat aspirate and bone marrow biopsy samples were obtained in all five patients. Amyloid was identified by Congo red staining with pathognomonic green bi-refringence when viewed under cross-polarized light (5). Follow-up All patients were followed prospectively after evaluation. Hospital records were reviewed and cardiac events were confirmed by reviewing hospital records. Role of the Funding Source The funders of this study did not have any role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Clinical Features Of the 153 patients studied, systemic amyloidosis was later diagnosed in 5. The clinical characteristics of these 5 patients are presented in the Table. Four patients presented with typical exertional angina, and 1 patient presented with acute non-Q-wave myocardial infarction. The mean age was 60 years (range, 52 to 65 years). None of the 5 patients had any other clinical or biochemical evidence of amyloidosis at the time of initial presentation, and their electrocardiograms were normal. Echocardiography was performed at the initial presentation, and no evidence of cardiac amyloidosis was seen. Exercise stress testing yielded abnormal results in all patients; it reproduced their anginal symptoms and demonstrated significant ST-segment depression early. Exercise stress imaging also revealed reversible perfusion defects in 3 patients who underwent imaging studies. Table. Patient Characteristics at Initial Presentation Angiographic and Coronary Blood Flow Findings All five patients had normal coronary angiograms and normal left ventricular end-diastolic pressure. The endothelium-independent coronary flow reserve, as assessed by intracoronary injection of adenosine, was abnormal in all patients (mean value, 1.9 0.3) (Table). In response to selective infusion of acetylcholine, an endothelial-dependent vasodilator, the percentage change in coronary blood flow was attenuated in all patients (mean, 14.8% 24.4%). Histologic Findings The diagnosis of amyloidosis was confirmed histologically by using Congo red staining in subcutaneous fat aspirates and bone marrow samples from all patients. Two patients had right ventricular biopsy, which revealed interstitial amyloid deposition that was primarily pericellular without forming nodules. Amyloid deposition was identified in the endocardium and within the media of the walls of intramyocardial coronary vessels without luminal obstruction (Figure). Figure. Vascular deposition of amyloid without luminal obstruction. Top. Middle. Bottom. Clinical Course A diagnosis of microvascular angina was initially made on the basis of the interpretation of coronary flow reserve studies and abnormal results of noninvasive stress testing. Patients received nitrates, calcium-channel blockers, and angiotensin-converting enzyme inhibitors, but no improvement was seen and their symptoms sometimes worsened. The diagnosis of AL amyloidosis was made 21 16.0 months later, when the patients presented with clinical manifestations of systemic amyloidosis (including renal insufficiency in three patients) and congestive heart failure. Evidence of monoclonal light chain in serum or urine was present at that time, and all patients had reduction in standard lead voltages with pseudoinfarct pattern as well as the characteristic echocardiographic findings of cardiac amyloidosis. The clinical course was complicated by the development of congestive heart failure in all patients and cardiac death in four patients. Discussion Our study demonstrates for the first time that patients with systemic amyloidosis can present with angina pectoris before the typical systemic manifestations of amyloidosis develop. This presentation was associated with impairment of both endothelial-dependent and endothelial-independent coronary flow reserve at the level of the microcirculation, probably secondary to amyloid infiltration of the vascular smooth-muscle cells. Amyloid deposition in the intramyocardial coronary arteries has been described in autopsy studies (3, 6, 7), endomyocardial biopsy studies (8), and case reports (9-13). The extent of vascular involvement is dependent on the type of amyloidosis. Vascular involvement may be present in 88% to 90% of patients with AL amyloidosis compared with 4% to 26% of patients with senile amyloidosis (8, 14). Although it has been commonly described in association with interstitial amyloid deposition, isolated vascular involvement causing ischemic symptoms has been described (9, 13). The vascular amyloid deposition initially occurs in the media; with increasing severity, amyloid infiltrates the adventitia and intima, resulting in complete or near-complete luminal obliteration of the intramyocardial arteries. The epicardial arteries are usually spared significant amyloid deposition. Our results are in accordance with the hypothesis that the tendency of AL amyloidosis to deposit in the intramyocardial vessels may result in symptoms consistent with myocardial ischemia in the absence of myocardial involvement during the early stages of the process (15). Despite the frequent vascular involvement in amyloidosis, ischemic symptoms secondary to amyloid coronary disease have been rarely described (3, 6, 9-13). In a study of 108 patients with cardiac amyloidosis (3), 5 patients had evidence of myocardial injury at autopsy, and such injury was clinically evident in only 2. The myocardial injury occurred in the absence of significant atherosclerotic epicardial coronary artery disease. Accurate diagnosis in this group of patients has diagnostic, therapeutic, and prognostic implications. A clue to the diagnosis may be the age of the patient; we noted in our series that the mean age was, in general, approximately 10 years older than that reported in patients with microvascular angina (1, 16, 17). Other factors, such as male sex and the absence of significant coronary artery risk factors, contrast with the features of most patients evaluated for chest pain and normal coronary angiogram at our institution, who are significantly younger (mean age, 55 years), are predominantly female, and have one or more cardiovascular risk factors (17). The combination of endothelial-dependent and endothelial-independent impairment of coronary flow reserve may also provide clues to the diagnosis of amyloidosis because it may represent an intrinsic disease of the vascular wall. This combined abnormality was present in only 20% of the othe