Case 3 -

Senile Amyloid Involving Myocardium in Patient with Coronary Artery Disease and Bypass Surgery Mary Sheppard, Royal Brompton Hospital, London, England

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Clinical History 75 year old male with routine bypass surgery as well as Mitral valve repair for floppy mitral valve. Prolonged bypass time 5 hours. Did not regain cardiac output and died on the operating table. At autopsy vein grafts to LAD,posterior descending coronary artery and obtuse marginal branch. No macroscopic evidence of acute or chronic myocardial infarction. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Case 3 - Figure 2 Case 3 - Figure 3 Case 3 - Figure 4 Case 3 - Figure 5 Case 3 - Figure 6 Case 3 - Figure 7 Case 3 - Figure 8 Introduction Coronary artery bypass surgery is still one of the most common procedures undertaken in cardiac surgery. It is a procedure that is not been done as frequently as before due to the widespread use of angioplasty and stent insertion for coronary artery disease over the last 30 years. Nowadays more and more elderly patients are having cardiac bypass surgery particularly those who are obese and diabetic with diffuse severe coronary artery disease so these have a higher mortality compared to the elective younger patients. Complications of CABG include pump failure post operatively with hypoperfusion and resulting multi organ failure with cerebral, liver, mesenteric and renal failure. Bleeding is often a problem due to use of ant platelet agents and coagulopathy due to prolonged bypass. There may also be acute myocardial infarction which can occur with thrombosis within the native vessels and also in the grafts. Stroke may occur after surgery due to thromboembolism or poor perfusion. There may also be damage to the aorta leading to dissection. Arrhythmias may occur during surgery which may lead to sudden death. Patients may also die suddenly post surgery with pulmonary thromboembolism or lethal arrhythmia. Wound infection and septicaemia may occur especially in diabetic patients. [1] Because the patients are elderly one must look out for other unexpected findings which may result in death. Background The clinical history in this case was that this patient died shortly after bypass surgery for ischaemic heart disease. The surgery had gone well with a short bypass time and no problems during the procedure. He died in the recovery room after suffering a cardiac arrest. He was aged 71 and it was an elective procedure for worsening angina over past year prior to death. He had a previous history of angina and hypertension. Our local medical examiner did not accept it and the autopsy was done as a hospital post mortem. Macroscopic Findings The macroscopic findings showed a heavy heart weighing 600g which on sectioning showed circumferential thickening of the left ventricle to 18mm thickness. There was no macroscopic evidence of infarction, either acute or chronic. Examination of the graft shows a left internal mammery (LIMA) to the left anterior descending coronary artery (LAD). The LIMA was intact with no thrombosis, dissection or complications and the proximal and distal LAD showed no acute thrombosis or dissection. The proximal LAD showed significant atheroma. The saphenous vein graft to the posterior descending coronary artery was also intact with no thrombosis and while there was significant stenosis of the right coronary artery with atheroma there were no complications of dissection, thrombosis or occlusion. The proximal anastomosis site for the vein graft in the aorta and the distal anastomoses were also intact. Microscopic examination Routinely in coronary artery bypass surgery (CABG) blocks are taken from the proximal LIMA graft, the anastomoses site and distal native vessel and anteroseptal wall of the left ventricle. Samples are also taken from the proximal saphenous vein graft, the anastomoses site and the distal posterior coronary artery as well as posterior left ventricle muscle wall. We also do a circumferential doughnut of the right and left ventricle to see if any ischaemic damage has occurred. Routine blocks are also taken from the proximal native vessels where there is significant atheroma. In this case microscopically surprisingly we found diffuse acellular hyaline pink material throughout all the vessels both in the LIMA graft, the vein graft and also in the epicardial coronary arteries as well as the intramural vessels. The material was mainly in the media and appeared to be replacing the media with some proliferation of the intima. There was no complete occlusion or thrombosis of the vessels. In the myocardium itself there was no evidence of acute infarction or fibrosis and there was no evidence of this pink acellular material in the muscle or interstitium of the heart itself. There was also widespread involvement of the epicardial vessels. In addition, similar deposits were found in the pulmonary arteries, the gastrointestinal tract, arteries, the spleen and liver with few vessels involved in the kidney. Obviously, given the appearance it suggests amyloid. We did Congo red staining which confirmed this and gave apple green birefringent with polarisation. Sections were sent for immunohistochemistry which were negative for kappa and lamba chain and positive for transthyretin. Differential Diagnosis None Final Diagnosis Senile Amyloid Involving Myocardium in Patient with Coronary Artery Disease and Bypass Surgery. Case Discussion/Review of Literature What is the role of senile amyloid in causing death after cardiac bypass surgery? This is a controversial area. Senile systemic amyloid, wild type (non mutant transthyretin) is the precursor protein of senile systemic amyloid (SSA) and occurs predominantly in the heart. It is almost exclusively in men older than 65 years. This form of amyloid does have systemic distribution although clinically for this to be evident, other than carpal tunnel syndrome which is common, or to cause any compromise is very unusual. It has been considered a benign entity. Outside the heart, lung involvement predominates, but it can also be found in the gastrointestinal tract, liver, spleen and endocrine glands. Autopsy studies suggest that up to 22-36% of individuals older than 80 years have amyloid deposits in cardiac tissue but these are generally not severe enough to affect cardiac function [2, 3]. Autopsy studies have revealed amyloid also in the bone marrow and tongue, while kidney involvement is less common. Despite its benign course, it may present with congestive cardiac failure with pronounced myocardial involvement. [4] Isolated atrial amyloid (IAA) is one of the most common of the age related amyloids in the heart and may play a role in atrial fibrillation. The pattern of IAA deposition was studied in 100 elderly patients which increased with age, more pronounced in females with left atrial deposition being more pronounced than right. The distribution was uneven being more pronounced in the anterior wall than in both the posterior and left atrial appendage. IAA deposition was heavier in those patient s with a history of chronic atrial fibrillation than in those with sinus rhythm [5]. In contrast to the pronounced male predominance in SSA, isolated atrial amyloid (IAA) is more common in older women. The precursor protein in IAA is atrial natriuretic peptide which is deposited in the atria. There is no systemic component to this type of amyloid. Although very prevalent in the elderly population and also those with chronic heart failure, it is of little clinical significance, perhaps except for its association with atrial fibrillation. Most common amyloid to affect the heart in the ventricle is AL amyloidosis which is usually fatal within 6 months of diagnosis the most common underlying disease being immunoglobulin light chain gammopathy. The next most frequent is transthyretin-related hereditary amyloidosis which is due to a mutant form of transthyretin (TTR). Hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis, a group of severe diseases with variable neurological and organ involvement. There can be extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. The most common mutation in TRR is Val30Met. The existence of exclusively or predominantly cardiac phenotypes should lead clinicians to consider the possibility of ATTR in all patients who present with an unexplained increase in left ventricular wall thickness at echocardiography . It is noted in this case that most of the deposition of amyloid is in the blood vessels in the media and adventitia with no total occlusion or thrombosis of the vessels. There is none of the interstitial or nodular deposition that one sees typically with AL associated amyloid. While some reviews state that senile amyloid is rarely symptomatic [6] a study of intramyocardial vascular involvement in patients with primary amyloidosis (AL) and senile systemic amyloidosis (SSA) showed all patients has focal transmural and vascular involvement by amyloid. In SSA the amyloid deposits were concentrated largely in the adventitia and external media which is also what we found in this case. The degree of vascular involvement and wall thickening is much great in AL than SSA. [7] More recently senile systemic amyloidosis has been put forward as a cause of cardiac dysfunction in elderly individuals and probably contributes more to cardiac failure after cardiac bypass surgery than suspected in the past [8]. The clinicopathological features of senile systemic amyloidosis remains to be completely understood. A post mortem study of 181 specimens in Japan showed senile amyloid being deposited mainly in the subendocardium of the ventricular wall [9]. In a Swedish study of both familial and senile amyloid, all cases had deposits within the lungs [9]. Two patterns have been described termed pattern A found in all SSA and in some familial cases, had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and composed of tightly packed, short, unorientated fibrils. This material contained 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen only in familial cases, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. [10] There is codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis. [11] One must also remember that you can get isolated valvular amyloidosis in association with calcification of the aortic valve which also contains apo lipoprotein A. In the rare examples of gelsolin mutations it is the conduction system of the heart which is uniquely affected. It is not possible to distinguish between all types of amyloid by echocardiography. Cardiac magnetic resonance (CMR) show global gadolinium late enhancement (GLE) in a subendocardial distribution. It is highly sensitive and specific for the identification of cardiac involvement [12], but it does not indicate prognosis simply by its presence. Diagnosis is done mainly by immunohistochemical confirmation of transthyretin positivity in the amyloid. DNA analysis will show no mutations in senile amyloidosis. While familial amyloid remains a slight possibility in our case, since DNA analysis was not undertaken, the history and age of the patient points to this amyloid being the senile type. Conclusions This case emphasises that cardiac senile amyloid can play a role in death after cardiac surgery when there is widespread vascular involvement. The widespread vascular involvement points to the coronary circulation being unable to withstand the demands made and ischaemia associated with surgery and bypass. There was no obvious problems with the coronary arteries or grafts during surgery and no ischaemic damage in the myocardium at autopsy indicating the surgery had gone well. The cardiac arrest points to lack of responsiveness of the coronary arteries to give an adequate blood supply within the epicardial and intramural coronary vessels when the myocardium needed it in a hypertrophied ventricle. Death is presumed due to a fatal arrhythmia. Treatment The management of cardiac amyloidosis is based on the underlying cause. Treatment of senile systemic amyloidosis is largely supportive. The therapeutic approaches for AL amyloidosis include chemotherapy, autologous stem cell transplantation, and, rarely, cardiac transplantation. The familial variant is potentially curable with a liver +/- cardiac transplantation. In SSA, IAA and AA amyloidosis no specific disease modifying therapies exist. Reference List Sheppard MN. Practical Cardiovascular Pathology. 2nd edition ed. London: Hodder Arnold, 2011. Cornwell III GG, Murdoch WL, Kyle RA. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 1983; 75:618-623. Basu N, Erwig LP. Pathophysiological importance of antineutrophil antibodies in vasculitis. Curr Opin Hematol 2011; 18(1):25-29. Ikeda S, Sekijima Y, Tojo K, Koyama J. Diagnostic value of abdominal wall fat pad biopsy in senile systemic amyloidosis. Amyloid-Journal of Protein Folding Disorders 2011; 18(4):211-215. Steiner I, Hajkova P. Patterns of isolated atrial amyloid: A study of 100 hearts on autopsy. Cardiovasc Pathol 2006; 15(5):287-290. Magy-Bertrand N. Transthyretin amyloidoses. Revue de Medecine Interne 2007; 28(5):306-313. Sharma PP, Payvar S, Litovsky SH. Histomorphometric analysis of intramyocardial vessels in primary and senile amyloidosis: epicardium versus endocardium. Cardiovasc Pathol 2008; 17(2):65-71. Ikeda S. Cardiac amyloidosis: Heterogenous pathogenic backgrounds. Internal Medicine 2004; 43(12):1107-1114. Westermark P, Bergstrom J, Solomon A, Murphy C, Sletten K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid-Journal of Protein Folding Disorders 2003; 10:48-54. Bergstrom J, Gustavsson A, Hellman U et al. Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology. J Pathol 2005; 206(2):224-232. Bergstrom J, Murphy C, Eulitz M et al. Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis. Biochem Biophys Res Commun 2001; 285(4):903-908. Maceira AM, Joshi J, Prasad SK et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005; 111(2):186-193.