Cardiac amyloidosis: can advances in diagnostics and treatments improve survival?

Abstract

Amyloidosis is a generalised clinical disorder characterised by extracellular deposition of amyloid fibrils. Symptomatic cardiac amyloidosis is typically associated with light chain (AL) amyloidosis in the western world. Amyloid deposition in the myocardium causes restrictive cardiomyopathy. Cardiac manifestations affect patient’s performance status and limit therapeutic options. We present a case of rapidly progressing cardiac amyloid deposition due to AL amyloidosis presenting with typical features of restrictive cardiomyopathy. We also discuss the advances in non-invasive diagnostic techniques applied in this case and currently available novel treatments. Early diagnosis and better response to novel treatments could potentially improve the overall survival in this group of patients.

BACKGROUND

Presence of cardiac failure and benign low level serum paraproteinaemias are not uncommon in the elderly, but presence of diastolic heart failure and multi-organ involvement should alert clinicians. True incidence of cardiac amyloidosis is unknown partly because systemic light chain (AL) amyloidosis is significantly under-diagnosed. Patients can rapidly deteriorate and the current gold standard for diagnosis is myocardial biopsy. The procedure is invasive and fraught with complications as a proportion of patients could have coagulopathies. Median overall survival for cardiac amyloidosis is less than a year and performance status determines choice and outcome to treatment. We highlight the fact that early diagnosis can be achieved with use of non-invasive diagnostics. We also discuss the new therapeutic choices currently available that provide hope for these patients

CASE PRESENTATION

A 55-year-old Caucasian man was initially admitted with history of breathlessness and pedal oedema of 5 months’ duration. He had pneumonia 3 years earlier and had no significant cardiac risk factors. Chest radiograph (CXR) showed venous congestion; electrocardiography (ECG) showed low QRS voltages with inferolateral T wave inversion. Troponin T was negative. Exercise tolerance testing was inconclusive. Echocardiogram showed mild left ventricular hypertrophy (LVH) with normal biventricular function. Left atrium (LA) diameter 5.1 cm. Right atrium (RA) is mildly dilated (approx 4 cm diameter). Mitral valve (MV) EA ratio was 1.8 and MV deceleration time was 211 ms. Mild tricuspid regurgitation was observed and pulmonary artery systolic pressure 34 mmHg. Pulmonary venous flow on trans-thoracic echocardiogram could not be obtained. Hepatic venous flow was not imaged.

He had normal serum liver and renal biochemistry. He was treated for cardiac failure with furosemide and spironolactone and reviewed in clinic 6 weeks later. In view of progressive symptoms and signs of restrictive cardiomyopathy, such as ascending pitting oedema of the lower limbs, ascites and elevated jugular venous pressure (JVP), serum electrophoresis and autoantibody screen was performed. Coronary angiogram was performed to rule out coronary ischaemia as a likely cause of ECG changes. Cardiac magnetic resonance (CMR) imaging showed mild pericardial effusion, dilated atria and concentric LVH (fig 1, panel I). Late gadolinium enhancement (LGE) was observed suspicious of amyloid deposition. He was readmitted with worsening dyspnoea (NYHA 3), fatigue, reduced appetite and three pillow orthopnoea.

Figure 1.

Cardiac imaging. Panel I is a gadolinium enhanced MRI of the heart showing pleural effusion (A), atrial dilatation (B) and gadolinium enhancement of the ventricles (C). Panel II is a whole body serum amyloid P scan with amyloid infiltration of heart (D), spleen (E) and liver (F).

On physical examination, he had no macroglossia and skin was normal. He was afebrile with a heart rate of 76/min, blood pressure of 104/71 mmHg, elevated JVP and extensive dependent oedema. He was saturating 97% O₂ on air, respiratory rate of 18/min. Heart sounds were normal and respiratory examination revealed bibasal crepitations. Abdomen was distended with palpable liver edge.

INVESTIGATIONS

Laboratory investigations revealed anaemia with haemoglobin 11.8 g/dl, impaired renal function with urea 18.7 mmol/L and creatinine 217 mmol/L, serum albumin low at 31g/l and alkaline phosphatase elevated at 530 U/L. The 24 hour urine protein excretion was 3 g/l. Serum electrophoresis showed monoclonal lambda band on immunofixation only and lambda light chains were present in urine. Autoantibody screen was normal. Congo red staining on rectal biopsy confirmed presence of amyloid in submucosal vessels. Serum free light chain analysis (sFLC) showed altered kappa/lambda ratio of 0.02 with lambda light chains increased at 852.18 ng/ml. Troponin T was mildly elevated at 0.17 ng/ml. Plasma N-terminal brain natriuretic peptide (NT-pro BNP) was elevated at 3783 pg/ml. Serum amyloid P (SAP) component scintigraphy showed moderate total body amyloid load with uptake in liver, spleen and heart (fig 1, panel 2). Bone marrow aspirate confirmed benign monoclonal gammopathy (MGUS) with 7% plasma cells and trephine biopsy stained for Congo red was negative.

TREATMENT

The patient symptomatically responded to cyclophosphamide and dexamethasone, which he tolerated well. He significantly improved with reduction in pedal oedema and dyspnoea. He continued to have postural hypotension and dizziness. MV inflow doppler post-treatment appeared less restrictive. While an inpatient due to postural hypotension, he succumbed to a cardiac arrest (pulseless electrical activity) 7 months after initial diagnosis.

DISCUSSION

Restrictive cardiomyopathy is either secondary to an underlying systemic disorder or due to an idiopathic cause. Detailed clinical history inclusive of family history and a thorough systemic examination supplemented by non-invasive tests can establish a reversible cause:¹ they include scleroderma, haemochromatosis, amyloidosis, Gaucher’s disease, Loeffler’s syndrome, carcinoid and Churg Strauss syndrome.

In the western world, AL amyloidosis is the commonest cause of cardiac amyloidosis. Amyloid infiltration stiffens the myocardium and up to 50% of patients develop diastolic failure. Cardiac conduction abnormalities are frequent with atrial fibrillation or flutter being more common. AL amyloidosis is a systemic condition with clinical and/or laboratory evidence of organ involvement, including tongue, gastrointestinal tract, skin, heart, liver, kidney, bone marrow and peripheral and autonomic nervous systems. Cardiac features are worsened by presence of either a coexistent nephrotic syndrome or autonomic neuropathy. Systemic amyloid A amyloidosis rarely involves the heart and senile systemic amyloidosis follows a benign course. Other hereditary forms of systemic amyloidosis have been described. Incidence of cardiac amyloidosis is difficult to establish as patients are asymptomatic in early stages and AL amyloidosis is under-diagnosed in the elderly.

When cardiac AL amyloid deposition is suspected, haematological investigations, cardiac imaging and cardiac biomarkers are required to confirm and prognosticate. Most patients have MGUS with normal blood count although a small proportion of patients have features consistent with myeloma. Because MGUS is commoner in older patients, histological evidence for amyloid by Congo Red staining should be sought in bone marrow and rectal biopsies. Up to 21% of patients have absent serum and urinary paraprotein.² sFLC assay is sensitive in 94% of patients with AL amyloidosis and can be used to diagnose and monitor patients on treatment. In a small study, 51 patients with cardiac AL amyloidosis who demonstrated treatment-related amyloid regression also showed reduction in sFLC and improvement in cardiac biomarkers.³

Electrocardiogram findings are common with low QRS voltages and pseudo infarct pattern being more frequent. Echocardiographic features are non-specific but LVH, biatrial enlargement and septal thickening with pericardial effusion are present in advanced disease. CMR shows a characteristic pattern of abnormal myocardial and blood-pool gadolinium kinetics with global subendocardial LGE in cardiac amyloidosis. SAP scintigraphy is based on the principle that serum amyloid P component binds to all types of amyloid fibrils. But there are limitations in imaging the moving heart and sensitivity is 90%.⁴ Myocardial biopsy remains the gold standard for confirmatory diagnosis.

NT- pro BNP produced by ventricular myocytes is generally elevated in cardiac failure but excessively in cardiac amyloidosis and falls with response to treatment.² In a recent study, patients with elevated cardiac biomarkers NT-BNP and troponin T had median survival of 3.5 months.⁵

Supportive care and optimising cardiac function remain key, but specific treatments to suppress the plasma cell clone are essential. Response to treatment is a significant predictor of survival.⁶ Melphalan and steroids is still the standard frontline treatment for AL amyloidosis.⁷ Novel treatments such as thalidomide,⁸ bortezomib⁹ and lenalidomide have shown promising clinical activity in myeloma. Better response rates observed with novel treatments in AL amyloid patients could improve survival in these patients.

Presence of cardiac failure and benign low level serum paraproteinaemias are not uncommon in the elderly, but presence of diastolic heart failure and multi-organ involvement should alert clinicians. Sudden death is common and patients should be screened for dysrhythmias. Median overall survival for cardiac amyloidosis is less than a year¹⁰ and performance status determines choice and outcome to treatment. Early diagnosis with use of non-invasive diagnostics and availability of novel agents provide hope.

LEARNING POINTS

• Amyloid infiltration of the heart causes restrictive cardiomyopathy.

• Commonest cause of cardiac amyloidosis in the UK is AL amyloidosis.

• Serum free light chain analysis is mandatory in view of the higher sensitivity of detecting circulating monoclonal light chain in up to 95% of patients.

• MRI scan of the heart and serum amyloid P scintigraphy should be considered as they provide more confirmatory findings.

• Early diagnosis of cardiac amyloidosis is essential as performance status determines overall survival.