Coronary artery bypass grafting for triple vessel disease in cardiac amyloidosis

Abstract

Cardiac amyloidosis is a rare condition with an estimated incidence of 18–55 per 100 000 person-years. It is associated with either immunoglobulin light chain (AL) or transthyretin amyloid (ATTR), both of which result in a restrictive cardiomyopathy complicated initially by diastolic dysfunction and subsequently followed by biventricular systolic heart failure. Untreated cardiac amyloidosis carries an extremely poor prognosis with an estimated median survival time of less than 1 year in AL and 4 years in ATTR amyloidosis. This is the sixth described report of coronary artery bypass grafting in patients with underlying cardiac amyloidosis.

Background

Amyloidosis results from an accumulation of abnormally folded extracellular protein in tissues; this process may be systemic or localised.¹ Cardiac amyloidosis is an under-recognised cause of restrictive/infiltrative cardiomyopathy, diastolic heart failure, arrhythmia and sudden cardiac death due to pulseless electrical activity arrest.^1–3 It is associated with either immunoglobulin light chain (AL) or transthyretin amyloid (ATTR) deposition. AL amyloidosis is the most common type of amyloidosis in the USA with an approximate incidence of 6–10 cases per million person-years and is associated with plasma cell dyscrasias.⁴ Management of heart failure in cardiac amyloidosis is usually limited to diuretics as the use of guideline-directed medical therapy remains controversial^{2 5} and poorly tolerated due to their blood pressure-lowering and bradycardic effects.⁶ The mainstay of treatment in cardiac AL amyloidosis is directed not at removing deposited amyloid fibrils but limiting further amyloid deposition by eradicating the plasma cell clone by chemotherapy with or without autologous stem cell transplantation.² Studies on the indications and outcomes of coronary interventions in patients with cardiac amyloidosis with coronary artery disease are limited, and all prior studies demonstrated high rates of postprocedural death of patients in the context of low cardiac output.⁷

Case presentation

A man in his early 50s presented to the emergency department with palpitations and progressive dyspnoea on exertion of 2 months duration. He denied orthopnoea, paroxysmal nocturnal dyspnoea or early satiety but did report non-concerning leg swelling. He denied new rashes, easy bruisability or musculoskeletal issues.

The patient’s medical history was notable for persistent atrial fibrillation, hypertension, obstructive sleep apnoea and hemizygote status for haemochromatosis. One week prior to presentation he underwent transoesophageal cardioversion. His family history was unremarkable except for myocardial infarction in a paternal uncle at the age of 30. His home medications included apixaban, diltiazem and amiodarone.

On presentation, the patient was noted to have sinus bradycardia (50 beats per minute) and associated hypotension (90/60 mm Hg) with an otherwise preserved respiratory rate and oxygen saturation. Examination was notable for bilateral pitting oedema extending to the knees and jugular venous distension to the level of the hyoid with hepatojugular reflux. Laboratory diagnostics showed an elevated creatinine (1.5 mg/dL; baseline 1.04 mg/dL), an elevated B-type natriuretic peptide (193 pg/mL; reference range 0–99 pg/mL) and a markedly elevated high-sensitivity troponin (31 058 ng/L; reference range 0–53 ng/L). His symptoms were initially attributed to volume overload in the setting of his underlying atrial fibrillation and obstructive sleep apnoea for which he was started on amiodarone, diltiazem and continuous positive airway pressure, respectively, with minimal improvement in dyspnoea.

Investigations

His ECG showed sinus rhythm with low voltage QRS and a short PR interval of 80 ms (figure 1). A transthoracic echocardiogram showed an ejection fraction of 70% with no regional wall motion abnormalities, a normal left and right ventricular wall thickness, a normal sized right ventricle and an eccentric jet of aortic regurgitation. Given his hemizygote haemochromatosis status and prior reports demonstrating rare yet full penetrance of this allele in causing clinically relevant haemochromatosis,⁸ the shortness of breath was thought to be in the context of restrictive lung disease and further diagnostic work-up was directed towards evaluation of this disease as an underlying aetiology for his presentation. CT chest without contrast showed bilateral prominence of interstitial markings suggestive of interstitial fibrosis, multiple prominent mediastinal nodes with infiltration in mediastinal fat and significant atherosclerosis of the coronary arteries. MRI Ferriscan and cardiac iron analysis showed a normal size and function of the left ventricle with mild mitral and tricuspid regurgitation. MRI Ferriscan liver iron analysis showed possible low signal within the liver, suggestive of iron overload. Given his markedly elevated troponin, a pharmacological nuclear myocardial stress test was performed; however, it was negative for ischaemia or regional wall motion abnormalities.

Figure 1.

ECG showing sinus rhythm with low voltage QRS with short PR interval of 80 ms.

Differential diagnosis

In the setting of a negative haemochromatosis evaluation, several clinical features (hypotension, elevated cardiac filling pressures, a preserved ejection fraction, low voltage on ECG and refractory atrial fibrillation) were felt to be consistent with a diagnosis of cardiac amyloidosis. There was no evidence of gamma gap on the metabolic panel, and serum and urine protein electrophoresis was unremarkable. Kappa and lambda light chains were mildly elevated (kappa 24.49 mg/L, reference range 3.3–19.4 mg/L; lambda 133 mg/L, reference range 5.7–26.3 mg/L) with an abnormal kappa/lambda ratio (0.18, reference range 0.2–1.6). Cardiac MRI showed a normal size and function of the left and right ventricles with subendocardial delayed enhancement and associated abnormal myocardial nulling time suggestive of cardiac amyloidosis. Ultrasound-guided abdominal fat pad biopsy was unremarkable. Genetic testing for hereditary ATTR amyloidosis was negative. CT-guided bone marrow biopsy showed 5% plasma cells with a negative Congo red stain. Immunological work-up and marrow biopsy were suggestive of a monoclonal gammopathy of undetermined significance.

The patient’s symptomatology and troponemia were felt to be unrelated to his haematologic abnormalities, and further diagnostic work-up including left and right heart catheterisation was pursued. Left heart catheterisation showed triple vessel disease with 70–80% stenosis of the distal left main and left circumflex artery and 40–50% stenosis of the right circumflex artery. Right heart catheterisation showed a mild increase of cardiac filling pressures (right atrial 15 mm Hg, right ventricular pressure 53/16 mm Hg, pulmonary artery pressure 49/23 mm Hg and mean pulmonary artery pressure 30 mm Hg), low Fick’s cardiac output of 3 L/min and a cardiac index of 1.6 L/min/m². Endomyocardial biopsy was not performed, with the intention of pursuing it during coronary artery bypass surgery as obtaining a biopsy during the surgical procedure would yield a more optimal tissue sample. He was referred to cardiothoracic surgery for evaluation for coronary artery bypass grafting.

Treatment

The patient underwent bypass grafting (left internal mammary artery obtuse marginal (LIMA-OM), right internal mammary artery to left anterior descending artery (RIMA-LAD)), biatrial Maze with clipping of the left atrial appendage, aortic valve replacement and a myocardial biopsy of the septum along with placement of the left femoral intra-aortic balloon pump. Intraoperatively, he was bradycardic requiring pacing along with notable bleeding from the distal obtuse marginal requiring multiple transfusions.

Outcome and follow-up

His hospital course was complicated by upper gastrointestinal (GI) bleeding requiring increased pressor requirements. Aspirin was held, and octreotide and pantoprazole were started; CT angiography (CTA) was negative for active bleeding. Upper GI endoscopy showed diffuse areas of bloody oozing and clots throughout the lesser curvature of the stomach. Areas of bleeding were clipped with further plans to use the clip as a radiographic marker for embolisation if rebleeding happened to recur. The cardiac CTA conducted 3 days after the procedure to evaluate graft patency did not reveal any evidence of constrictive pericarditis. However, on postoperative day 6 the patient developed refractory shock and hypoxic respiratory failure secondary to cardiac arrest and was transitioned to comfort care.

Later, his myocardial biopsy showed myocyte hypertrophy and focal interstitial fibrosis with pale pink, glassy, hyaline material on H&E staining (figure 2A) and Congo red stain focally positive for amyloid deposition (figure 2B). Subsequent subtyping as AL amyloid (lambda type) was performed using liquid chromatography with tandem mass spectrometry.

Figure 2.

Histopathology. (A) H&E staining of myocardial biopsy in high power showing infiltration of pale pink, glassy, hyaline material predominantly deposited in the vascular and perivascular location (arrowheads). (B) Congo red staining of myocardial biopsy in low power (10x) showing amorphous pink/red extracellular deposits in the myocardium (arrowheads). (C) Congo red staining under polarised light in low power (10x) showing that the amorphous pink/red extracellular deposits produce an apple green birefringence under polarised microscopy (arrowheads).

Discussion

Amyloidosis is a heterogeneous group of diseases characterised by deposition of an abnormal insoluble fibrillar form of misfolded plasma protein in the extracellular spaces of various tissues and organs; it may be localised or systemic.⁹ In localised amyloidosis, amyloid deposits are restricted to a particular organ or tissue whereas, in systemic amyloidosis, the deposits are present in the viscera, blood vessel walls and connective tissues.¹⁰ Cardiac amyloidosis is an underdiagnosed systemic amyloidosis that is considered as a foremost cause of significant morbidity and mortality.¹¹

The common complications of cardiac amyloidosis include restrictive/infiltrative cardiomyopathy, conduction disorders, embolic events and syncope, yet there is a marked variability in clinical presentations.¹² Classic features of right-sided heart failure including an increased jugular venous pressure, a third heart sound and peripheral oedema may not be evident until cardiac disease has advanced.¹² When compared with ATTR amyloidosis, patients with AL amyloidosis have a more acute presentation, rapid progression and worse survival rates.¹³ Cardiac dysfunction in AL amyloidosis occurs both due to extracellular infiltration of the myocardium and direct toxic effects of circulating light chains.² The median survival time for untreated cardiac amyloidosis is less than 1 year for AL amyloidosis and 4 years for ATTR amyloidosis.^{2 11} Sudden cardiac death in AL cardiac amyloidosis accounts for approximately one-third of the mortality in the first 90 days of diagnosis and is often due to electromechanical dissociation, pulseless electrical activity and complex non-sustained ventricular arrythmia which appear to be somewhat refractory to defibrillator implantation.^{3 13}

The diagnosis of cardiac amyloidosis remains challenging and requires a high index of clinical suspicion. Detection of monoclonal immunoglobulins or free light chains can often be missed in routine laboratory diagnostics.¹² Abdominal fat pad biopsy can identify amyloid deposits only in 60–80% of patients with systemic AL amyloidosis,^{14 15} yet its diagnostic sensitivity in suspected cardiac amyloidosis remains unclear and cannot be used to exclude amyloidosis,¹⁶ similar to the case presented above. Cardiac MRI along with cardiac biopsy provides the most definitive diagnostic evidence of early amyloid cardiomyopathy if the diagnosis is not confirmed by biopsy of other tissue.^{12 17} In cardiac biopsy, both AL and ATTR amyloidosis exhibit similar extracellular amyloid deposition in the myocardium but differ in their patterns of deposition in extracardiac structures, arteries and endocardium, with AL amyloidosis showing diffuse pericellular deposition and ATTR amyloidosis displaying nodular deposition.¹⁸

The high prevalence of coronary microvascular dysfunction in cardiac amyloidosis, even in the absence of epicardial coronary artery disease, gives rise to microscopic changes of myocardial ischaemia resulting in anginal symptoms.^{15 19 20} One study reviewed the pathological specimens from 96 patients with AL cardiac amyloidosis and found obstructive intramural coronary amyloidosis was present in 66% of cases and microscopic changes of myocardial ischaemia was present in 86% of patients.¹⁵

The management of amyloid cardiomyopathy includes cautious use of diuretics and aldosterone antagonists.^{7 8} Guideline-directed medical therapy, which remains the standard of care in heart failure with reduced and preserved ejection fraction, may be of little benefit or even hazardous in cardiac amyloidosis.²¹ Neurohormonal antagonists such as ACE inhibitors have a limited role, especially in hypotensive patients.^{22 23} Beta-blockers are poorly tolerated due to significant reductions in cardiac output as cardiac amyloid predisposes to severe diastolic dysfunction.^{8 17 22} Digitalis and calcium channel blockers are relatively contraindicated as they may be selectively concentrated in amyloidotic tissue causing increased toxicity.9 21 24–26 The benefits of implantation of pacemakers or cardioverter defibrillators remains uncertain in the prevention of sudden cardiac death secondary to electromechanical dissociation.²¹

Chemotherapy with or without autologous stem cell transplantation, while not able to clear already existing amyloid, suppresses clonal plasma cells, limiting further amyloid production and deposition.^{7 9 27} Cardiac transplantation is controversial and reserved for highly selected patients with limited extracardiac involvement.² One study evaluated a small series of patients and demonstrated greater long-term mortality due to ongoing disease progression in cardiac and non-cardiac organs, highlighting the fact that the presence of AL amyloid is a relative contraindication to transplantation.^28–30

The literature regarding indications for coronary interventions and mortality outcomes in patients with cardiac amyloidosis and concomitant coronary artery disease is very limited.^{7 26} To the best of our knowledge, there are only five published case reports (comprising six patients) of coronary artery bypass grafting in patients with cardiac amyloidosis.^{7 31–34} Of these six patients, five died shortly after surgery secondary to extremely low cardiac output state and multiorgan failure^{7 31–33} and one survived the initial postoperative period but died a few months later in the setting of electromechanical dissociation.³⁴ In our case, postoperative constrictive pericarditis could have worsened the dilatation defect caused by amyloid cardiomyopathy, leading to rapid patient decompensation. However, cardiac CT angiography performed 3 days after the procedure showed no signs of constrictive pericarditis. Studies have shown that constrictive pericarditis typically develops around 2 weeks after cardiac surgery,^35–37 but our patient experienced rapid decompensation within 5–6 days, making constrictive pericarditis unlikely.

Current preoperative risk models such as Euroscore II are invalid in patients with cardiac amyloidosis, as diastolic dysfunction is not considered and usual indicators for preoperative risk such as functional status and left ventricular ejection fraction may offer false reassurance. Despite preoperative symptoms of myocardial ischaemia with substantial coronary artery disease as shown by angiography, the divergent pathophysiological mechanism of intraluminal microangiopathy in cardiac amyloidosis creates difficulty in predicting revascularisation outcomes.^{7 27 33} Our patient’s cardiac MRI was suggestive of amyloidosis and left heart catheterisation showed triple vessel disease that prompted endomyocardial biopsy and cardiac bypass grafting, respectively. Unfortunately, like the majority of cases of cardiac amyloidosisand coronary artery bypass grafting, our patient died in the earlypostoperative period with poor cardiac output and cardiac arrest.

Learning points.

• Cardiac amyloidosis mainly involves intramyocardial arteries rather than epicardial arteries, causing localised areas of ischaemic injury resulting in refractory heart failure and anginal symptoms.

• The management of coronary artery disease with coexisting cardiac amyloidosis remains challenging.

• In general, it appears that coronary artery bypass grafting is not a reasonable option even when the coronary anatomy would suggest surgery as the management of choice.

• Given the high surgical risk and uncertain outcome of bypass grafting in cardiac amyloidosis with coronary artery involvement, further research on its appropriate management is crucial.

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Consent obtained from next of kin.