Correspondence *Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

Email dr_b_wright@yahoo.co.uk

The case

A 49-year-old woman presented at hospital complaining of chest pain over the previous 10 days, both at rest and with exertion. She had had bilateral carpel tunnel syndrome for 1 year in her right hand and for 3 months in her left hand, and was waiting to undergo decompression treatment; otherwise, she was fit and well and was not receiving any medication. At presentation, the patient's blood pressure was 160/70 mm Hg and no abnormalities were detected on physical examination. Initial findings on electrocardiogram (Figure 1) and echocardiogram were normal, and her levels of hemoglobin, D-dimer and troponin I were all within normal range. The patient was discharged from hospital, but underwent follow-up exercise-tolerance testing as an outpatient 2 months later. After 7 mins of the BRUCE PROTOCOL, electrocardiography revealed inferolateral ST-segment depression to a maximum of 2 mm, associated with chest and jaw pain. Treatment with a -blocker (atenolol at 100 mg daily) and a calcium-channel blocker (amlodipine at 5 mg daily) was prescribed.

Figure 1 Initial electrocardiogram of the patient at presentation with no signs of cardiac dysfunction.

 

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Two months after initial presentation, coronary angiography revealed smooth, unobstructed coronary arteries and good left ventricular function. After the patient reported having had two episodes of palpitations, she was monitored by ambulatory electrocardiography over 7 days, but no abnormalities were detected. Since the patient reported symptomatic relief while taking -blockers and calcium-channel blockers, this treatment continued for 5 months. -blocker therapy was then replaced with a potassium-channel activator (nicorandil at 10 mg twice daily) because of sensations of a swollen tongue and an itchy arm.

Three weeks after her new therapy regimen had begun, the patient was admitted to the emergency department following an episode of body shaking and gurgling, witnessed by her husband. No neurological abnormalities were detected by physical examination, but the patient did have findings of macroglossia, ankle edema, left pleural effusion, hypoxia (partial pressure of oxygen 8.3 kPa) and a C-reactive protein level of 111 mg/l (normal range <10 mg/l). Chest radiography revealed cardiomegaly and moderate left pleural effusion. At this stage, the patient was diagnosed with parapneumonic effusion and seizure, secondary to hypoxia, and she began a course of antibiotic treatment. A routine electrocardiogram revealed anterolateral Q waves and small QRS complexes in the standard leads (Figure 2).

Figure 2 An electrocardiogram of the patient showing evidence of infiltration and pseudo-infarction, with anterolateral Q waves and small QRS complexes in the standard leads.

 

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On her second day in hospital, the patient was found cyanosed with no respiratory effort. Although the initial impression was that she was in a POSTICTAL STATE, electrocardiographic monitoring revealed ventricular fibrillation, which returned to sinus rhythm following electrical defibrillation. Over the next 10 days, the patient received antiarrhythmic drug therapy intravenously, with high-dose amiodarone at 300 mg for 2 h then 900 mg for the following 22 h, with subsequent titration to a maintenance dose of 200 mg daily. She also received a -blocker (carvedilol at 3.125 mg twice daily), potassium (two Sando-K™ tablets three times daily) and intravenous magnesium supplementation (72 mmol magnesium sulfate over 24 h). During this time, the patient had another three episodes of nonsustained ventricular tachycardia and one episode of ventricular fibrillation.

Another echocardiogram showed 20 mm concentric hypertrophy in the patient's left ventricle with impaired function. There was also evidence of a stiff, thickened right heart, and a stiff, restricted tricuspid valve, which was confirmed by cardiac MRI. Further laboratory investigations detected free immunoglobulin light chains in the patient's serum (714 mg/l; normal range 8.1–33 mg/l), in addition to significant non-light-chain proteinuria (1.17 g/24 h; normal range 0–0.15 g/24 h) (Table 1). A CT scan of the patient's head did not show signs of infarction, hemorrhage or cerebral edema, and her level of creatinine was 94.6 M (1.07 mg/dl) (normal range <106.1 M [<1.2 mg/dl]). A tongue biopsy was carried out to investigate the patient's symptoms of macroglossia. Congo red staining revealed characteristic apple-green BIREFRINGENCE, and a diagnosis of amyloidosis was confirmed. A subsequent bone-marrow biopsy also revealed evidence of monoclonal PLASMA CELL DYSCRASIA (40–50% of marrow cellularity). To support her left ventricular function, the patient was prescribed an angiotensin-converting-enzyme inhibitor (ramipril at 7.5 mg daily), a loop diuretic (furosemide at 80 mg daily) and a potassium-sparing diuretic (spironolactone at 50 mg daily). An implantable cardioverter-defibrillator (ICD) was fitted for early termination of ventricular arrhythmias.

Table 1 Summary of clinical investigations leading to a diagnosis of cardiac amyloidosis, compared with normal values.

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The patient was discharged from hospital and examined within 2 weeks at a specialist amyloidosis centre. By the time of consultation, her clinical condition had deteriorated. Her ICD had discharged on at least one occasion, and she was nauseous and breathless at rest. Physical examination revealed evidence of congestive heart failure with tachycardia, hypotension (blood pressure 95/55 mm Hg), elevated jugular venous pressure (+6 cm) and bibasal pleural effusions. Her level of serum creatinine had elevated to 143.2 M (1.62 mg/dl), and her proteinuria had increased to 2.6 g/24 h. Iodine-123-labeled serum-amyloid-P-component scintigraphy revealed a small amyloid protein load in the spleen, kidneys and bone marrow. Laboratory analyses again detected the presence of monoclonal immunoglobulin light chains in the patient's serum and urine, and further examination of the tongue biopsy confirmed systemic primary amyloidosis (AL amyloidosis), with positive Congo red and immunostaining (Table 1).

The patient consented to a trial of chemotherapy, but the overall poor prognosis associated with AL amyloidosis was explained to her. Unfortunately, she died suddenly at home the following week, 20 days after ICD implantation. Examination of the ICD recorder showed an agonal rhythm at the time of death, which was not amenable to electrical defibrillation.

Discussion of diagnosis

At initial presentation, the patient's chest pains were indicative of angina pectoris in a patient waiting to undergo carpal tunnel decompression treatment. Normal findings on physical examination, electrocardiogram and echocardiogram, and levels of D-dimer and troponin I within the normal range, excluded other major causes of chest pain at rest, such as myocardial infarction and pulmonary embolus. Exercise-tolerance testing also indicated that the patient had angina pectoris, but a coronary angiogram did not show evidence of obstructive disease in the coronary arteries, and she also had good left ventricular function. Although the cause of her palpitations remained unclear, diagnoses of CARDIAC SYNDROME X or gastroesophageal reflux disease were considered at this stage.

The patient's ventricular dysrhythmias were initially associated with cessation of -blockade therapy. Detection of cardiac dysfunction by echocardiography, however, combined with symptoms of macroglossia, led to clinical investigations for AL amyloidosis.

In retrospect, bilateral carpal tunnel syndrome might have been the first indication of amyloidosis in this patient, and her swollen tongue was probably amyloid-related macroglossia rather than an adverse reaction to -blocker therapy. The patient's initial symptoms of chest pain and treatment with -blockers might have suppressed her ventricular arrhythmias, inadvertently delaying the correct diagnosis.

There are estimated to be about 2,000–2,500 new cases of AL amyloidosis in the US annually, with cardiac involvement in 50% of cases.¹ Consequences of amyloid deposition depend upon the organ systems involved. Typically, global amyloid deposition causes a restrictive cardiomyopathy, with progressive congestive cardiac failure causing dyspnea at rest or with exertion, orthopnea, peripheral edema, and sometimes ascites. Occasionally, angina pectoris is present, which is thought to be caused by obstructive amyloid deposition within the intramural arteries. In rare cases, arrhythmias are the presenting feature, either as a result of destruction of normal conducting circuits, or generation of new local circuits with abnormal propagation.

Treatment and management

Patients with symptomatic cardiac AL amyloidosis have a poor prognosis, with a median survival of 6 months.² Chemotherapy usually offers little survival benefit, as patients do not usually survive long enough to receive adequate cyclical chemotherapy, and rapid high-dose chemotherapy is associated with an increased risk of treatment-related mortality.^{3, 4, 5} Cause of death in such cases is unclear, but cardiac failure or complex ventricular arrhythmias are considered potential causes.^{4, 6, 7} Prevention of arrhythmia is difficult because amyloid proteins have destructive effects on surrounding heart tissue and can interrupt its normal electrical circuitry. There is no proven benefit of pharmacological therapy as a primary preventative strategy. Although pacemakers might alleviate some rhythm disturbances such as bradycardias and nodal block, they would not be beneficial for ventricular arrhythmias, because the abnormal rhythm is a tachycardia. Heart transplantation has a poor outcome in most cases,⁸ and is only appropriate for some patients, such as younger people without myeloma, or in cases where amyloid protein deposits have not affected other organs. Prompt intervention with an ICD or external defibrillation to convert the arrhythmia back to sinus rhythm is the only management option, particularly for patients whose arrhythmias are resistant to therapy with antiarrhythmic drugs. We suggest such intervention might provide an immediate survival advantage, enabling patients to receive adequate chemotherapy to suppress further amyloid protein deposition.

Unfortunately, in the case described here, ICD therapy did not help, and the patient died 20 days after implantation. Without an ICD, however, the patient could not have been discharged from hospital because she had a high frequency of ventricular arrhythmias. Although an ICD did not prolong the patient's survival so she could proceed with chemotherapy, it did enable her to seek specialist advice and undergo further investigations.

Three additional reports describe the use of an ICD in patients with cardiac amyloidosis. Falk et al.⁹ studied 11 patients with arrhythmogenic cardiac amyloidosis. Ten of these patients underwent successful ICD implantation, but only two had survived at the last follow-up. The median survival time for these patients was only 3.5 months; sudden death occurred in six individuals and electromechanical dissociation was the documented terminal rhythm in two patients. Hess and White¹⁰ described implantation of an ICD in a 50-year-old man presenting with refractory ventricular fibrillation, who was later diagnosed with coronary artery disease and cardiac amyloidosis. Coronary artery disease might have led to an early diagnosis of amyloidosis, but with an ICD he was still alive 15 months after presentation, having responded to treatment for plasma cell dyscrasia. Mercando et al.¹¹ also reported the use of an ICD in a patient with cardiac amyloidosis, but did not specify how long the patient survived.

Conclusion

This case highlights the importance of recognizing early symptoms of AL amyloidosis, which can appear benign and are not always recognized, but can lead to a rapidly progressive, infiltrative, multiorgan disease. Presenting features of cardiac involvement might include angina-like chest pain and ventricular arrhythmia, but findings on coronary angiogram can appear normal. An ICD is useful for the management of ventricular arrhythmia in such cases, but early diagnosis and chemotherapy are vital to improve patient outcomes.

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