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Case report
Isolated cardiovascular involvement in light chain amyloidosis
  1. Ahamed Shaheer Ahmed1,
  2. Sampath Kumar1,
  3. Gautam Sharma1 and
  4. Sudheer Arava2
  1. 1Cardiology, All India Institute of Medical Sciences, New Delhi, India
  2. 2Pathology, All India Institute of Medical Sciences, New Delhi, India
  1. Correspondence to Professor Gautam Sharma; drgautamsharma12{at}gmail.com

Abstract

A 50-year-old woman presented with complaints of palpitations and breathlessness of 6 months’ duration. She was being treated elsewhere as a case of dilated cardiomyopathy. On evaluation she had racoon eyes, poor progression of R wave on ECG and low-voltage complexes in the limb leads. Echocardiography revealed biventricular hypertrophy, diastolic dysfunction and moderate systolic dysfunction. Cardiac MRI showed features suggestive of amyloidosis. Bone marrow biopsy revealed raised plasma cell count, and endomyocardial biopsy showed amyloid deposits in the myocardium. Free lambda light chain levels were elevated, even though serum and urine electrophoresis did not show any monoclonal band. In this ‘text book case of cardiac amyloidosis’, apart from cardiovascular system no other organ system was affected, which is uncommon in primary light chain amyloidosis. The patient was started on CyBorD (cyclophosphamide, bortezomib and dexamethasone) regimen.

  • heart failure
  • cardiovascular medicine

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Background

Light chain amyloidosis (AL amyloidosis) is a multisystem disorder. The kidneys are the most commonly affected, followed by the heart. Isolated cardiovascular involvement is rare in AL amyloidosis, accounting for <5% of the cases. AL amyloidosis usually presents with symptoms of nephrotic range proteinuria, neuropathy and heart failure. Due to the vast array of symptoms in amyloidosis, cardiac involvement gets unnoticed and is picked up at a later stage. Cardiac involvement in amyloidosis portends a poor prognosis.

We report this case due to the presence of classic features of cardiac amyloidosis and the rarity of isolated cardiac AL amyloidosis.

Case presentation

A 50-year-old woman with no known comorbidities presented with complaints of palpitations for 6 months and breathlessness on exertion with NYHA (New York Heart Association) class II for 3 months. She was being treated elsewhere as a case of dilated cardiomyopathy. On examination jugular venous pressure was elevated, with prominent Y descent and Kussmaul’s sign (video 1). The patient had periorbital ecchymosis (figure 1). The rest of the systemic and cardiovascular examinations were unremarkable. Chest X-ray was normal. ECG revealed low-voltage QRS complexes in the limb leads, poor progression of R wave (pseudoinfarct pattern) in the precordial leads, left anterior hemiblock, left ventricular hypertrophy (according to Cornell voltage criteria) and prolonged PR interval (figure 2).

Video 1
Figure 1

Periorbital ecchymosis.

Figure 2

ECG showing low-voltage QRS complexes in the limb leads and poor progression of R waves (pseudoinfarct pattern) in the precordial leads.

Investigations

Echocardiography showed biatrial enlargement, concentric biventricular hypertrophy, diastolic dysfunction, moderate left ventricular systolic dysfunction with an ejection fraction of 35% and atrial electromechanical dissociation (videos 2–4) (figures 3–5). Global longitudinal strain was preserved at the apex and impaired at the base (figure 6). Based on the clinical features, ECG and echocardiographic findings, a provisional diagnosis of cardiac amyloidosis was made. A 24-hour ECG monitoring revealed Mobitz type 1 second-degree atrioventricular block. Cardiac MRI was done and revealed subendocardial atrial and ventricular late gadolinium enhancement. Moreover, there were biventricular hypertrophy, thickening of interatrial septum, reversal of the nulling pattern of the myocardium on inversion recovery images, increased T1 mapping values and loss of atrial contraction (figures 7–9). Serum as well as urine electrophoresis and immunofixation did not reveal monoclonal proliferation band. Free light chain assay showed elevated free lambda light chain levels and altered free kappa to lambda light chain ratio. IgA, IgM and IgG levels were normal. Bone marrow aspiration revealed 12% plasma cells. There was no evidence of amyloid deposition on abdominal fat pad biopsy. Endomyocardial biopsy showed amyloid deposits on Congo red stain and was negative for serum amyloid A on immunohistochemistry (figure 10). The patient underwent coronary angiography, which was normal. There was no proteinuria on 24-hour urine analysis. Nerve conduction study was normal. There was no organomegaly, free fluid or lymphadenopathy on ultrasonography of the abdomen. Blood biochemistry revealed normal creatinine, liver enzymes and alkaline phosphatase. Skeletal survey did not show any lytic lesion. Hence, a diagnosis of isolated cardiovascular AL amyloidosis was made. N terminal (NT) pro brain natriuretic peptide (pro BNP), cardiac troponin I and dFLC (differential between involved and uninvolved Free Light Chain) levels were 2346 ng/L, 0.8 ng/mL and 233 mg/L, respectively. These correspond to stage IIIa in cardiac staging system and stage III in the revised Mayo clinic staging system, with a median survival of around 14–18 months.

Video 2
Video 3
Video 4
Figure 3

Echocardiography in apical four-chamber view showing dilated left and right atrium with biventricular hypertrophy. LV, left ventricle; RV, right ventricle.

Figure 4

Pulse wave Doppler echocardiography across the mitral valve showing the presence of E wave and the absence of A wave (atrial electromechanical dissociation).

Figure 5

M mode echocardiography across the left ventricle at the level of the mitral valve tip showing left ventricular hypertrophy (*), presence of E wave (arrow) and absence of A wave (atrial electromechanical dissociation).

Figure 6

Speckle tracking echocardiography showing apical sparing. ANT SEPT, anteroseptal; ANT LAT, anterolateral; INF-SEPT, inferoseptal; INF LAT, inferolateral.

Figure 7

Cardiac MRI showing thickened interatrial septum (arrow).

Figure 8

Cardiac MRI showing diffuse atrial and ventricular subendocardial late gadolinium enhancement (arrows).

Figure 9

Cardiac MRI showing inversion of the normal nulling pattern on T1 scout images.

Figure 10

Endomyocardial biopsy on microscopy reveals the presence of (A and B) extracellular eosinophilic hyalinised extracellular material in the interstitium (arrow) and on the wall of the intramyocardial blood vessels. (C) Congo red stain highlights the congophilia (arrow) of the deposited material which on polarised microscopy (D) revealed apple-green birefringence (arrow). (E) Immunohistochemistry (IHC) for serum amyloid A (SAA) protein is negative.

Treatment

The patient was started on diuretics and mineralocorticoid receptor antagonist for heart failure and CyBorD (cyclophosphamide, bortezomib and dexamethasone) regimen for amyloidosis. Anticoagulation with vitamin K antagonist was initiated in view of atrial systolic dysfunction.

Outcome and follow-up

On follow-up of 6 months, the patient’s heart failure symptoms have markedly improved. She is currently in NYHA functional class I.

Discussion

Amyloidosis is a rare conglomerate of disorders characterised by extracellular deposition of proteinaceous amyloid fibrils.1 The incidence of amyloidosis ranges from one to five cases per million population in various studies.2 3 The most common form of amyloidosis is the AL amyloidosis (67%), followed by AA amyloidosis (12%).4 Cardiac involvement, which is seen in almost 50% cases of AL amyloidosis, is a prominent feature in ATTR amyloidosis (although rare in the Val30Met variant), hereditary AApoA1 amyloidosis and extremely rare in AA amyloidosis.4 5 AL amyloidosis involves a vast array of organ systems, such as the kidney, heart, nervous system, gastrointestinal system, coagulation cascade and soft tissue. As seen in our case, isolated involvement of cardiovascular system in AL amyloidosis is rare and occurs in only around 3.9% of cases.6

Cardiac AL amyloidosis usually presents in the fifth to seventh decade of life, with a slight male preponderance.1 The non-cardiac symptoms almost always precede the cardiac manifestations, which can range from subtle non-related features such as carpal tunnel syndrome to overt renal failure. Early recognition of cardiac amyloidosis is of paramount importance, as the median survival after onset of heart failure symptoms is 6 months.2 The pathogenesis of heart failure in cardiac AL amyloidosis is influenced by two factors: structural damage of the myocardium due to amyloid fibril deposition and proteotoxicity due to circulating amyloid light chain precursors.1 In a study of 232 patients of AL cardiac amyloidosis, periorbital ecchymosis was seen in 12.5%, renal involvement in 75% and hepatosplenomegaly in 50% of cases.6 Periorbital ecchymosis in the presence of heart failure is pathognomonic of AL amyloidosis. The cardiac manifestations include restrictive cardiomyopathy, left atrial systolic dysfunction due to atrial amyloid deposition, valvular regurgitation, pericardial effusion and conduction disturbances.

ECG changes include low-voltage complexes in the limb leads, pseudoinfarct pattern and a prolonged PR interval. Low-voltage limb lead complexes are seldom seen in ATTR amyloidosis.7 The most common feature in echocardiography is thickened interventricular septum, followed by increased myocardial echogenicity, pericardial effusion, biatrial dilation, thickened interatrial septum and valve thickening.6 Left atrial systolic dysfunction can be identified by loss of transmitral A wave on Doppler echocardiography. Longitudinal strain by speckle tracking echocardiography is preserved at the apex, whereas it is severely reduced at the base, also known as the ‘Bulls’ eye’ pattern. Difficulty of nulling myocardium following gadolinium administration and subendocardial late gadolinium enhancement in the ventricle and atrium are the characteristic features of cardiac amyloidosis on cardiac MRI.8 Serum electrophoresis, immunofixation,free light chain assay and immunogobulin levels; urine electrophoresis and immunofixation should be done to determine the nature of amyloidosis and monitor response to therapy. Endomyocardial biopsy provides the definitive diagnosis of cardiac amyloidosis. Management of cardiac amyloidosis requires a two-pronged approach: treatment of heart failure and specific therapy for amyloidosis. Management of heart failure is similar to any other aetiology, but with two exceptions: patients are more susceptible to hypotension with ACE inhibitors/angiotensin receptor blockers and enhanced digoxin toxicity due to altered binding properties. Chemotherapy involves the administration of a proteasome inhibitor bortezomib, along with dexamethasone and low-dose cyclophosphamide. High-dose chemotherapy with autologous stem cell transplant is reserved for patients not responding to first-line regimens.9 Response to treatment is assessed by the difference of the affected and unaffected light chains (dFLC), which if less than 50 mg/dL signifies a favourable response.

Cardiac amyloidosis should be suspected in patients presenting with heart failure associated with carpal tunnel syndrome, peripheral or autonomic neuropathy, periorbital ecchymosis or nephrotic syndrome, along with left ventricular hypertrophy and low-voltage QRS complexes on ECG. The presence of restrictive filling pattern in mitral inflow Doppler, bull’s eye pattern in speckle tracking echocardiography, characteristic cardiac MRI features, altered free light chain ratio, increased plasma cells in bone marrow biopsy and histopathological demonstration of amyloid deposits help in clinching the diagnosis.

Learning points

  • Periorbital ecchymosis in a patient presenting with heart failure is highly suggestive of amyloidosis.

  • In cases with high index of clinical suspicion of amyloidosis, free light chain assay should be done even if serum electrophoresis and immunofixation are negative.

  • Endomyocardial biopsy is the gold standard for diagnosis of cardiac amyloidosis and may be required occasionally following a negative fat pad biopsy.

  • Speckle tracking echocardiography is an invaluable tool in identifying amyloid cardiomyopathy at an earlier stage.

Acknowledgments

We acknowledge Dr Mohamed Kassim Akheela for her work in formatting the images and videos.

References

Footnotes

  • Contributors ASA prepared the manuscript. SK was involved in patient care and data collection. GS was involved in patient care, provided critical inputs and finalised the manuscript. SA did the histopathological examination.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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