Atypical cardiac amyloidosis phenotypes identified at transplant: a case series

Abstract

Background

Transthyretin amyloidosis (TTR) is increasingly implicated as an aetiology of advanced cardiomyopathy. Typically, both genetic variant (TTRv) and wild-type (TTRwt) amyloidosis present with a restrictive phenotype. We present a series of three patients who were found to have cardiac amyloidosis on explant following heart transplant (HT) who had atypical, non-restrictive phenotypes.

Case Summary

All three patients were men, three were Black, and only one had an alternative pre-HT explanation for their advanced, dilated cardiomyopathy. Pre-HT transthoracic echocardiograms were notable for left ventricular (LV) dilation (>95th percentile for height and gender), low EF, and normal LV wall thickness. Explants showed varying amounts of amyloid deposition, ranging from diffuse biventricular patterns to perivascular involvement. Mass spectrometry confirmed the presence of TTRv (two cases) and TTRwt (one case).

Discussion

Patients with dilated cardiomyopathy may harbour cardiac amyloidosis. Uncertainty remains regarding the contribution of amyloidosis to the development of a dilated phenotype. The pathogenic Val142Ile variant seen in two of these patients, a variant common in Black patients, suggests a need for further investigation into the potential relationship between TTRv amyloidosis and dilated cardiomyopathy.

Learning Points.

• Cardiac amyloidosis can be seen in patients with dilated cardiomyopathy

• Genetic testing and pre-transplant pyrophosphate scan may be helpful to identify cases of amyloid cardiomyopathy with an atypical, dilated phenotype

Introduction

Cardiac amyloidosis is an increasingly recognized cause of advanced cardiomyopathy requiring evaluation for heart transplant (HT).¹ Transthyretin proteins, produced in the liver, can deposit in remote organs including most commonly the heart and peripheral nervous system. Transthyretin amyloidosis (TTR) is broadly differentiated into variant (TTRv) and wild type (TTRwt) based on the presence or absence of amino acid variants.² In the USA, the most prevalent pathologic TTR variant is the substitution of isoleucine for valine at position 142 (Val142Ile). An estimated one in 33 Black Americans (3%) are carriers for this variant, with an attendant increased risk of heart failure and mortality.³ Cardiac amyloidosis most commonly results in a restrictive cardiomyopathy.⁴ The incidence of atypical phenotypes, including dilated cardiomyopathy, associated with TTR amyloidosis is poorly characterized.

We retrospectively reviewed explant pathology from HT at Cedars-Sinai Medical Center between 1 November 2019 and 31 October 2020 (n = 121) and identified three explants with amyloid deposition and a non-restrictive phenotype by pre-transplant echocardiogram. Of the three patients identified, two carried a pre-HT diagnosis of amyloidosis following positive 99m-Technetium-pyrophosphate scans, while the explant finding was unexpected in one case. Explants were evaluated by gross examination, light microscopy, and immunohistochemical staining (kappa light chains, lambda light chains, beta-2-microglobulin, amyloid A, and transthyretin). Additionally, pre-HT transthoracic echocardiograms (TTE) and laboratory studies were reviewed. Pre-HT physical exams were notable only for evidence of mild volume overload in all cases. Finally, TTR was further subtyped by mass spectrometry and genetic sequencing.

Timeline

Patient 1
Pre-heart transplant evaluation	Diagnosed with dilated cardiomyopathy secondary to ischaemic heart disease
Heart transplant
Explant analysis	Found to have diffuse LV and RV amyloid deposition with genetic testing significant for the pathogenic TTR c.424G > A (p.Val142Ile) mutation
Patient 2
Pre-heart transplant evaluation	Diagnosed with non-ischaemic dilated cardiomyopathy with amyloidosis following positive pyrophosphate scan
Heart transplant
Explant analysis	Found to have diffuse LV and RV amyloid deposition with mass spectrometry confirming TTRwt
Patient 3
Pre-heart transplant evaluation	Diagnosed with non-ischaemic dilated cardiomyopathy with amyloidosis following positive pyrophosphate scan
Heart transplant
Explant analysis	Found to have mild, focal LV amyloid depositions with genetic testing significant for the pathogenic Ttr C.424g > A (P.Val142ile) mutation

Patient 1

Patient 1 is a 67-year-old Black man with a pre-HT diagnosis of ischaemic cardiomyopathy who had an extensive history of coronary artery disease requiring both remote coronary artery bypass graft surgery and placement of multiple drug-eluting stents. This individual had no personal history of hypertension or diabetes but had comorbid chronic kidney disease and required a dual-heart–kidney transplant. Pre-HT TTE was notable for ventricular dilation [left ventricular (LV) internal diameter end diastole (LVIDd) 6.2 cm, interventricular septum (IVS) 1.0 cm], reduced ejection fraction (EF) (18%), and moderate right ventricular (RV) dilation and dysfunction (Figure 1AandB). Explant review showed diffuse LV and RV amyloid deposition and mass spectrometry confirmed Val142Ile TTR amyloid (Figure 2). Genetic testing revealed a pathogenic TTR c.424G > A mutation, as well as two rare variants of uncertain significance (KCNA5 c.1661G > A, MYH7 c.345 + 1G > A). The patient’s post-HT course was notable for the development of orthostasis and neuropathy which was felt to be related to amyloidosis. Unfortunately, the patient had a complex post-HT course and expired 18 months post-transplant.

Figure 1.

Transthoracic echocardiogram images. Representative parasternal long- and four-chamber transthoracic echocardiogram (TTE) images for patient 1 (A–B), patient 2 (C–D), and patient 3 (E–F).

Figure 2.

Immunohistochemical staining for transthyretin protein. Immunohistochemical staining (brown) of transthyretin protein showing diffuse deposition from patient 1.

Patient 2

Patient 2 is a 65-year-old Black man with hypertension whose pre-HT evaluation included a coronary angiogram without evidence of coronary artery disease, a bone marrow biopsy revealing IgG Kappa monoclonal gammopathy of unknown significance (MGUS), and a negative fat pad biopsy. A 99m-Tc-PYP scintigraphy without CT/SPECT scan was also conducted during the HT evaluation process given uncertainty about the family history of cardiac disease which was positive. The patient had no personal history of neuropathy, carpal tunnel, or orthostasis. Pre-HT TTE showed severe LV dilation (LVIDD 8.0 cm, IVS 1.0 cm), reduced EF (15%), and mild RV dilation (Figure 1CandD). These findings led to a pre-HT diagnosis of dilated cardiomyopathy with cardiac amyloidosis. Explant pathology showed diffuse LV and RV amyloid deposition (Figure 3) and mass spectrometry confirmed TTRwt amyloid. Genetic testing was likewise negative for any variants in the TTR gene. The patient’s post-HT has been uncomplicated without graft dysfunction.

Figure 3.

Haematoxylin and eosin stain of heart explant. Ventricular slide showing diffuse involvement and deposition of amyloid fibrils from patient 2.

Patient 3

Patient 3 is a 71-year-old Black man with non-ischaemic dilated cardiomyopathy attributed to amyloidosis due to a pre-HT positive pyrophosphate scan and hypertension. A 99m-Tc-PYP scintigraphy without CT/SPECT scan was conducted during the HT evaluation process at an outside centre as a part of an advanced cardiomyopathy evaluation. Pre-HT TTE was again notable for LV dilation (LVIDD 6.1 cm, IVS 1.2 cm) and dysfunction (EF 25%; Figure 1E-F). In this case, the RV function was normal. Amyloid distribution was limited and focused in the LV. Mass spectrometry showed Val142Ile and genetic testing revealed the pathogenic TTR c.424G > A variant. The patient’s post-HT course was notable for the development of both autonomic neuropathy and carpal tunnel syndrome requiring a carpal tunnel release and the initiation of a TTR gene silencing agent. Aside from these symptoms, the patient continues to do well without evidence of graft dysfunction.

Discussion

We present a series of patients with TTR cardiac amyloidosis and dilated phenotypes by echocardiography, representing an unusual presentation for cardiac amyloidosis. Classically, echocardiography in cardiac amyloidosis reveals a symmetric hypertrophy of the septal and posterior LV walls, normal-to-small LV cavity size, and preserved EF.^4,5 Right ventricular hypertrophy and systolic dysfunction have also been described. Despite diffuse ventricular involvement in two of the presented cases, there was no echocardiographic evidence of hypertrophy as may be expected. In all cases, pre-HT TTE was notable for a dilated phenotype (Table 1) with elevated LVIDD and reduced EF.

Table 1.

Case transthoracic echo, gross pathology, and mass spectrometry results

Patient	Pre-transplant diagnosis	IVS (mm)	LVIDd (mm)	LVPW (mm)	EF (%)	RV dysfunction	Tricuspid regurgitation	Mitral regurgitation	Pathology amyloid distribution	Mass spectrometry TTR result
1	Ischaemic CMY	10	62	12	18	Moderate	None	Mild	Diffuse: LV and RV	Val142Ile
2	Amyloidosis	10	80	10	15	Moderate	Moderate	Moderate	Diffuse: LV and RV	wt
3	TTR-CMY	12	61	11	25	Mild	Mild	Moderate	Mild, focal: LV	Val142Ile

^aIVS, intraventricular septum; LVIDd, left ventricular internal diameter, diastole; LVPW, left ventricular posterior wall; EF, ejection fraction; RV, right ventricle; LV, left ventricle; TTR, transthyretin; CMY, cardiomyopathy; wt, wild type.

The question of why these patients developed a dilated phenotype remains unknown. Only patient 1 had an alternative pre-HT diagnosis to explain the dilated phenotype, i.e. a history of ischaemic cardiomyopathy and genetic testing revealing a VUS in the MYH7 gene. In the remaining cases, even those with a pre-HT amyloidosis diagnosis, there was an outstanding question if the amyloid was the primary insult resulting in end-stage cardiomyopathy or merely a bystander. Further, the pre-HT diagnoses were reliant on PYP scans which were performed without CT/SPECT. There is the potential for a false positive result in the setting of dilated cardiomyopathy related to pooling of blood which may make these PYP studies difficult to interpret.⁶ Notably, two patients were found to harbour the Val142Ile pathogenic TTR variant. While one patient has advanced ischaemic cardiomyopathy, the other individual did not have significant valvular disease to explain the dilated phenotype and had relatively few comorbidities. The lack of alternative diagnosis suggests that TTR may have contributed in this case.

There has been considerable interest in exploring potential genetic causes underlying the development of dilated cardiomyopathies (DCM). We found that two of our three cases harboured the Val142Ile variant. Our findings suggest that Black patients with dilated cardiomyopathy may benefit from screening for TTR variants. Additionally, the post-HT course for these two patients suggests a potentially pathogenic role for TTR. Both developed complications commonly seen in amyloidosis, including autonomic neuropathy, ultimately requiring the initiation of amyloid-specific therapies. Given the frequency of the Val142Ile variant in Blacks in the USA, continued surveillance and post-HT management for patients undergoing HT for amyloidosis are of the utmost importance.⁷

We hypothesize that heritability of the ventricular size and polymorphism in pathways responsible for response to cardiac injury and stress may interact to contribute to the development of cardiac amyloid with a dilated phenotype. In patients without cardiac disease, twin studies have revealed that LV measurements are associated with high levels of heritability⁸ suggesting that some individuals may be predisposed to a dilated phenotype. In addition, variants in cardiac stress response gene Bcl2-associated athanogene 3 (BAG3) have been associated with dilated cardiomyopathy in African American individuals.⁹ Taken together, we posit that certain individuals may have a genetic predisposition to develop cardiac amyloidosis with a dilated phenotype.

Conclusion

The progression of TTR-related cardiomyopathy is also incompletely known. It may be that in some individuals with TTR cardiomyopathy who experience cardiac stressors (e.g. patient 1 with advanced ischaemic disease), the resultant LV remodelling may result in the dilated phenotype. Further investigation into the prevalence and genetics of this phenotype is needed to elucidate the mechanisms underlying a dilated TTR presentation.

Lead author biography

Dr Rushakoff completed internal medicine residency at Cedars-Sinai where he is currently the chief resident. He plans to train as a cardiologist and is interested in heart failure and heart transplant.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports.