Cardiac amyloidosis (CA) describes a group of heterogeneous diseases that are characterized by the extracellular fibril deposition of amyloid protein in the myocardium. The abnormal protein is usually derived from light-chain amyloidosis, mutant transthyretin amyloidosis and wild-type transthyretin. Patients with ischemic strokes and amyloidosis have been sporadically reported, however, they are not well summarized. In the present study, a case of cerebral ischemic stroke, secondary to CA was described. This patient presented with dyspnea on exertion, without any evidence of atrial fibrillation. A biopsy revealed deposition of amyloid in the myocardium and Congo Red staining was positive. He suffered from acute infarction of left basal ganglia, resulting from occlusion of the left middle cerebral arterial 6 months prior to admission. However, re-examination of cerebral magnetic resonance imaging in the present hospital revealed an old infarction in the region of the left basal ganglia with a normal appearance of the left middle cerebral artery. Transesophageal echocardiography (TEE) and cardiac magnetic resonance (CMR) both discovered intra-cardiac thrombi, confirming the diagnosis of cardiogenic cerebral embolism. The present study indicates that patients with CA may additionally present with cardiogenic cerebral embolism, and TEE and CMR imaging may help to avoid missing the presence of intra-cardiac thrombi.
Immunoglobulin light chain amyloidosis (AL) amyloidosis is a monoclonal plasma cell disorder in which the precursor protein is an immunoglobulin light chain or light chain fragment. It may occur as a primary disease or in association with multiple myeloma or other plasma cell dyscrasias. In primary amyloidosis, there is 2:1 preponderance for λ over κ light chain synthesis (
Thromboembolism also contributes significantly to morbidity and mortality. Intracardiac thrombosis was found in 51% (
A 50-year-old man was admitted to our department presenting with exertional dyspnea for >1 year. Physical examination was as follows: BP 100/60 mmHg, HR 90 bpm, normal cardiac auscultation with scattered purpura periorbitally and on the neck and abdomen.
Laboratory tests including routine blood culture, hepatic and renal functions, and coagulation test were within normal values. At 6 months before admission, 3 months before admission and at the point of admission, test results were as follows: Uric acid, 266, 364 and 428 µmol/l; cardiac troponin I (cTnI), 0.02, 0.03 and 0.05 µg/l; N-terminal pro-brain natriuretic peptide (NT-proBNP), 2,080, 4,351 and 7,821 pg/ml. Serum immunofixation electrophoresis was normal. Urine immunofixation electrophoresis was negative for free light chain κ (FLCκ) and monoclonal protein, but positive for free light chain λ (FLCλ). Serum FLCκ was 6.93 mg/dl, FLCλ140.75 mg/dl, κ/λ 0.049↓; serum total LCκ427 mg/dl↓, total LCλ165 mg/dl↓, κ/λ 2.59. Electromyography showed neurogenic injury of bilateral tibialis anterior muscle. 99mTc-MDP bone scan, bone marrow and abdominal fat aspiration biopsies showed no abnormality. Cerebral magnetic resonance imaging (MRI) showed an old infarction in the left basal ganglia, however, the appearance of magnetic resonance angiography (MRA) was normal (
Based on the above findings, diagnoses of CA (AL-type), restrictive cardiomyopathy and chronic heart failure were made.
Benazepril, spironolactone and metoprolol were prescribed for chronic heart failure; for anticoagulation, with consideration of old cerebral embolism, the risk of recurrent stroke, and the existing thrombus in atrium and left ventricle, low molecular weight heparin was prescribed; bortezomib was chosen as the first line chemotherapy for amyloidosis. Autologous stem cell transplant was under consideration, however, after 6 months, the patient deteriorated and died of decompensate heart failure.
Half a year before admission, the patient visited a local hospital for right extremity aphasia and dyskinesia. Cerebral MRI detected new infarction in the left basal ganglia. MRA showed nearly total occlusion of the distal left middle cerebral artery (MCA) (
A literature search on Pubmed and Medline database was performed from January 1980 to December 2016 using key words ‘cerebral infarct/ischemic stroke/cerebral embolism/cerebral thrombosis’, and ‘cardiac amyloidosis’, and ‘heart plus amyloidosis’, resulting a total of 35 articles. Case reports were included, and reports without adequate details or full text were excluded. A total of 7 articles with reference information on 9 patients (including our patient in the present study) qualified for the literature review and served as the study population for the purpose of analysis (
In the 9 patients, 4 were male, with a median age of 52.9 years (range, 29–83 years), and ~80% of them were diagnosed at >40 years of age. AL-type amyloidosis was relatively common, accounting for 57% of discovered cerebral embolic events, while other types, such as familial amyloidosis and senile systemic amyloidosis were also involved, especially in older patients (
Symptoms of patients with CA and cerebral embolism were nonspecific, including manifestations of heart failure and ischemic stroke. Recurrent strokes (
All 9 patients were negative for intra-cardiac thrombus by TTE. However, 4 of whose (including our case) medical history and electrocardiogram showing no evidence of atrial fibrillation, revealed intra-cardiac thrombus (
In addition to the routine treatment of heart failure, 4 patients (
Amyloidosis is a group of diseases that result from the extracellular deposition of amyloid, a fibrillar material derived from various precursor proteins that self-assemble with highly ordered abnormal cross β-sheet conformation (
Prognosis of CA is generally poor. For patients with AL amyloidosis, the median survival is 6 months after appearance of congestive heart failure (
Intra-cardiac thrombus in patients of CA are common. Roberts and Waller demonstrated that 14 patients (26%) were presented with at least one intra-cardiac thrombus in 54 necropsy patients with CA (
Mechanisms of intra-cardiac thrombus in CA includes the following points: First, blood stasis and associated cardiac intracavitary turbulence may contribute to mural thrombosis (
In fact, due to deficiency of coagulation factors, abnormal fibrin polymerization, hyperfibrinolysis, platelet dysfunction, and vascular damage caused by local amyloid deposition, hemorrhage tendency in patients with amyloidosis is more common than thrombophilia (
If intra-cardiac thrombus is detected, anticoagulation therapy may be indicated to prevent systemic circulation embolism; however, anticoagulation therapy may exacerbate the hemorrhagic tendency that is known in amyloidosis due to fragile blood vessel walls secondary to amyloid deposition and the coexisting coagulopathy. Melo
In conclusion, this report presents a case of CA with cardioembolic cerebral stroke although no clues of atrial fibrillation, while subcutaneous bleeding tendency occurs simultaneously. Cardiac embolus is a rare cause of ischemic stroke in adults but could be progressive rapidly, recurrent and fatal. Summarizing the key aspects of this rare disease based on a review of available literatures, we emphasize the importance of making a thorough search for cardiac problems in all stroke patients with low risk of cerebrovascular diseases, and the crucial role of TEE and CMR in detecting the intra-cardiac thrombus of CA patients.
Appearance of MRA and MRI-DWI sequence. (A) Normal appearance of the left MCA; (B) Encephalomalacia loci in the left basal ganglia; (C) Nearly total occlusion of the distal M1 and proximal M2 segment of the left MCA; (D) Cerebral infarcts in the left basal ganglia and corona radiata (red arrow). MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; MCA, middle cerebral artery.
ECG showing one degree atrioventricular block (PR interval >0.20s), low voltage in limb leads, left axis deviation, poor R-wave progression in the precordial leads (red arrow).
CMR showing subendocardial mural thrombi in the basal segment of left ventricular lateral wall and right ventricular septal wall (red arrow). CMR, cardiac magnetic resonance.
Appearance of echocardiography. (A) TTE showing symmetrical thickening of both ventricular wall with characteristic ‘granular sparkling’ appearance and a small amount of pericardial effusion (red arrow); (B) TEE showing left auricle appendage thrombus (size ~11*37 mm; red arrow). TEE, transesophageal echocardiography.
Myocardium biopsy. (A) Hypertrophy in partial cells, nuclear enlargement, fibrous tissue hyperplasiaand degeneration within cardiac muscle fibers, and amyloid deposit in some areas (H&E, ×200 magnification); (B) Special stain showing positive in Congo red stain, supporting the diagnosis of amyloidosis (Congo red stain, ×300 magnification) (red arrow).
Summary of literature reports on CA with ischemic stroke.
Author, year | No. of reported patients | Refs. |
---|---|---|
Cho |
2 | ( |
Rice |
1 | ( |
Bøtker |
1 | ( |
Owa |
1 | ( |
Yamano |
1 | ( |
Gillmore |
1 | ( |
Saux |
1 | ( |
Present case, 2016 | 1 |
Clinical data of patients with cardiac amyloidosis and ischemic stroke.
A, Age, sex and clinical observations | |||||||||
---|---|---|---|---|---|---|---|---|---|
Author, year | Patient no. | Age (years) | Sex (F/M) | Atrial fibrillation | Intracardiac thrombus | Ischemic stroke | Organ infarction | Refs. | |
Cho |
1 | 29 | F | No | No | Right basal ganglia and corona radiata | No | ( |
|
Cho |
2 | 73 | F | No | Left atrial appendage thrombi | Right PCA and left MCA territories | No | ( |
|
Rice |
3 | 34 | M | No | No | Right frontal and left MCA territory (recurrent) | NA | ( |
|
Bøtker |
4 | 46 | F | No | Mural thrombi in the left atrium | Left and right temporoparietal area (recurrent) | Kidney, spleen | ( |
|
Owa |
5 | 47 | F | No | Mitral valve and left atrium | Both cerebral hemispheres (recurrent) | Spleen | ( |
|
Yamano |
6 | 67 | M | No | No | Right temporal lobe | NA | ( |
|
Gillmore |
7 | 83 | M | Yes | NA | Right cerebral infarct | NA | ( |
|
Saux |
8 | 55 | NA | No | No | Left MCA territory | NA | ( |
|
Present case, 2016 | 9 | 50 | M | No | Left atrium, and both ventricles | Left basal ganglia and ventricular lateral wall | No | Present | |
Cho |
1 | No | Heparin and warfarin | Alive | NA | Yes | No | No | ( |
Cho |
2 | Hypertension | LMWH and warfarin | Alive | AL amyloidosis with multiple myeloma | Yes | Yes | No | ( |
Rice |
3 | No | Heparin and Coumadin | Alive | NA | Yes | No | No | ( |
Bøtker |
4 | No | No | Deceased | AL | Yes | No | No | ( |
Owa |
5 | No | No | Deceased | Familial amyloid polyneuropathy | Yes | No | No | ( |
Yamano |
6 | Hypertension | No | Alive | Senile systemic amyloidosis | Yes | No | No | ( |
Gillmore |
7 | NA | Warfarin | Alive | Mutant transthyretin amyloidosis | Yes | No | No | (129 |
Saux |
8 | NA | No | Deceased | AL amyloidosis with multiple myeloma | Yes | Yes | No | ( |
Present | 9 | No | LMWH and dabigatran | Deceased | AL | Yes | Yes | Yes | Present |
PCA, posterior cerebral artery; MCA, middle cerebral artery; LMWH, low-molecular-weight heparin; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; CMR, cardiac magnetic resonance, AL, amyloid light chain.