Covert Transthyretin Amyloidosis Mimicking Advanced Obstructive Hypertrophic Cardiomyopathy Despite Multiple Negative ^99mTc-PYP Radionuclide Scans

Abstract

Background

We present the case of a 74-year-old woman diagnosed with obstructive hypertrophic cardiomyopathy.

Case Summary

Amyloidosis was initially considered because she was genotype positive in the transthyretin gene. However, because of 2 negative 99m technetium pyrophosphate radionuclide scans, this diagnosis was considered unlikely, and endomyocardial biopsy was deferred. She had an adverse response to all attempted medical therapies for her left ventricular outflow tract obstruction and ultimately underwent surgical myectomy. Surgical pathology revealed transthyretin (TTR) amyloidosis.

Discussion

This case highlights the limitations of diagnostic testing and reinforces the consideration of more invasive procedures to determine the true underlying cause of disease. This helps clinicians provide the most advanced level of treatment available.

Take-Home Messages

TTR amyloidosis can mimic hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. 99m Technetium pyrophosphate scans are useful to investigate the presence of TTR amyloid, but if suspicion persists despite negative testing, it is reasonable to perform an endomyocardial biopsy.

Graphical Abstract

History of Presentation

A 73-year-old, Caucasian woman was initially referred to our clinic in July 2017 for hypertrophic cardiomyopathy (HCM) found during evaluation for paroxysmal atrial fibrillation (AF) a year prior to our consultation. She presented with NYHA functional class III symptoms and grade 3/6 systolic murmur. Her electrocardiogram showed sinus bradycardia with a first-degree atrio-ventricular block and normal limb lead voltage (Figure 1). She had a history of intolerance to beta blockers due to exacerbation of baseline bradycardia.

Take-Home Messages

• •TTR amyloidosis can mimic hypertrophic cardiomyopathy with left ventricular outflow tract obstruction.
• •99m Technetium pyrophosphate scans are useful to investigate the presence of TTR amyloid, but if suspicion persists despite negative testing, it is reasonable to perform an endomyocardial biopsy.

Figure 1.

Initial Electrocardiogram

Past Medical History

Her medical history showed hypertension, hyperlipidemia, and paroxysmal AF.

Differential Diagnosis

Differential diagnosis included HCM with left ventricular outflow tract (LVOT) obstruction, hypertensive heart disease, and amyloidosis.

Investigations

Initial echocardiogram showed normal left ventricular function, asymmetric septal hypertrophy (maximal wall thickness 13 mm), systolic anterior motion of the mitral valve (SAM) with mitral-septal contact, long anterior mitral valve leaflet (28 mm), and dynamic LVOT obstruction with peak left ventricular outflow gradients of 9 mm Hg at rest, 29 mm Hg with the Valsalva maneuver, and 81 mm Hg after standing from a lying position (Figure 2). The patient's exercise tolerance was reduced, reaching stage 2 of a Bruce protocol, completing 5 minutes 16 seconds and 6.7 METs, which was 83% of expected exercise duration. A stress echocardiogram revealed a 144-mm Hg outflow gradient post exercise without wall motion abnormality.

Figure 2.

Initial Echocardiogram

(A) Left ventricular wall thickness 13 mm. (B) Presentation of systolic anterior motion. (C) CW Doppler of standing gradient, LVOT 82 mm Hg. LVOT = left ventricular outflow tract.

Genotype analysis revealed a heterozygous pathogenic variant in the transthyretin (TTR) gene (c.238 A>G; p.Thr80Ala). This is the second most common TTR variant in the United States and affects approximately 1% of the North-Western Ireland population.¹ Her ancestry is from Tipperary, Ireland, which is more south-centrally located. Subsequently, a 99m technetium pyrophosphate (^99mTc-PYP) scan with single-photon emission computed tomography was performed to investigate the presence of transthyretin cardiac amyloidosis (ATTR-CA). This was repeated as the initial result was thought to be false negative due to poor tracer uptake in the ribs; however, the second exam was negative as well (Figure 3, Video 1). Amyloid cardiomyopathy was deemed unlikely given the negative ^99mTc-PYP scans and lack of neurologic symptoms, despite the pathogenic variant.

Figure 3.

Tc-PYP Scan Planar Results During Initial Evaluation

The picture on the left initial exam was thought to be erroneous due to poor uptake in the ribs. The picture on the right was repeat exam and thought to be satisfactory with same negative results. Tc-PYP = technetium pyrophosphate.

Management

Disopyramide 150 mg 3 times daily for treatment of LVOT obstruction was started but promptly discontinued after 7 days because of a new left bundle branch block. These changes resolved 2 days after stopping disopyramide. Because of her age and frailty, she subsequently underwent dual-chamber pacemaker implantation to initiate forced ventricular pacing with short atrio-ventricular delay for the treatment of LVOT obstruction and to enable beta blocker therapy and reinitiation of disopyramide. After 3 months, repeat echocardiogram showed a drop in ejection fraction (EF) from 65% to 50%, so her disopyramide was stopped, and forced pacing was discontinued to allow restoration of normal conduction. Recurrent AF prompted amiodarone therapy and an AF ablation; amiodarone was stopped 3 months later with no further AF.

She continued to be symptomatic for several years; echocardiogram showed an EF of ∼60% and peak LVOT gradients of 71 mm Hg with Valsalva maneuver. Elective cardiac catheterization showed no significant coronary disease, normal cardiac index of 4 L/min/m², and elevated biatrial filling pressures with mild to moderate pulmonary hypertension (mean pulmonary artery pressure 39 mm Hg, pulmonary vascular resistance 1.9 WU, pulmonary capillary wedge pressure 24 mm Hg, right atrial pressure 12 mm Hg). Mavacamten, then recently approved, was initiated at a low dose of 2.5 mg daily due to her history of reduced EF on previous therapies, which was then decreased further to 2.5 mg twice weekly to maintain relief of LVOT obstruction without reducing her EF below 50%; timeline of follow-up visits and outcomes are shown in Table 1. Despite our cautious efforts, her LVEF continued to fall below 50%, prompting permanent discontinuation of mavacamten.

Table 1.

Timeline per REMS Protocol After Initiating Mavacamten

Visits	NYHA Functional Class	Peak LVOT Gradient (at Rest or With Provocation)	EF	Dose Adjustment
Baseline	III	71 mm Hg	60	Started 2.5 mg daily
4 weeks	I	41 mm Hg	50%	Temporarily stopped
8 weeks	III	52 mm Hg	60%	2.5 mg twice weekly
12 weeks	II	27 mm Hg	52%	2.5 mg twice weekly
16 weeks	III	14 mm Hg	40%	Stopped permanently

EF = ejection fraction; LVOT = left ventricular outflow tract; REMS = risk evaluation and mitigation strategy.

Six weeks later, her limiting symptoms recurred. Repeat echocardiogram showed normalization of left ventricular function and severe LVOT obstruction with a Valsalva gradient of 80 mm Hg. Surgical myectomy with residual leaflet excision was then performed with complete resolution of LVOT obstruction and an uneventful postoperative course. Pathologic examination of the myectomy specimen revealed parenchymal nodules of amyloid deposition, altogether involving approximately 10% of the resected myocardium. The periphery of each nodule displayed an interstitial pattern. The presence of amyloid was confirmed by ancillary stains: light purple color on Trichrome stain, salmon pink color on Congo red stain, and apple green birefringence on cross-polarization light microscopy examination of the Congo red–stained slide.

The remainder of the myocardium and the endocardium did not contain amyloid. The uninvolved myocardium showed mild to moderate cardiomyocyte hypertrophy. There was no other histologic evidence of HCM: no disarray and only very focal interstitial fibrosis. Intramyocardial vascular thickening was caused by amyloid deposition only. Multiple intramyocardial vessels were involved with mural thickening from amyloid only, both within the nodular amyloid deposits and within myocardium not otherwise involved (Figure 4).

Figure 4.

Slides From Surgical Pathology of Resected Myocardium From the Septal Wall During Myectomy

(A) H&E stain, 100×: A lower power image shows the patchy nature of the amyloid deposition (red arrow), adjacent to uninvolved, hypertrophic myocardium (green arrow). (B) H&E stain, 400×: The hypertrophic cardiomyocytes display mildly enlarged, “boxy” nuclei (green arrows) and increased cytoplasm. However, there is no myocyte disarray or intramyocardial vascular hyperplasia/fibrosis. (C) Trichrome stain, 100×: There is only focal interstitial fibrosis (blue arrows), not to the level usually seen in HCM. (D) Congo red stain, 100×, with cross-polarization light microscopy: Amyloid deposition rather than myointimal hyperplasia/fibrosis causes focal intramyocardial arterial thickening in this case (pink arrow). Most of the myocardium in this case was negative for amyloid on Congo red staining (green arrow). H&E = hematoxylin and eosin; HCM = hypertrophic cardiomyopathy.

Liquid chromatography tandem mass spectrometry analysis of Congo red–positive amyloid deposits detected a peptide profile consistent with ATTR-type amyloid deposition and additionally identified a low level of an amino-acid-sequence abnormality in the transthyretin protein (Legacy: Thr60Ala; HGVS: p.Thr80Ala) consistent with her known genotype (Figure 5). She then underwent a third Tc-PYP scan with single-photon emission computed tomography 6 years after her first scan, which was negative for amyloid again (Figure 6, Video 2).

Figure 5.

Proteomic Profile of the Cardiac Biopsy Specimen

The two columns labeled “sample 1” and “sample 2” represent two separate analyses from Congo red-positive deposits isolated by laser microdissection in the case. Rows corresponding to universal amyloid proteins are highlighted with a double blue/orange star. The numbers in the green boxes correlate with the total number of MS/MS spectra detected of the protein in each row (only spectra with >95% probability of a match to an identified protein are considered for diagnostic interpretation). The proteins highlighted with a blue star represent the amyloid-specific markers detected. There are many spectra corresponding to transthyretin in this case, as well as very low but still detectable spectra of a mutant transthyretin protein with T60A mutation. Image credit: Jason Theis. MS/MS = tandem mass spectrometry.

Figure 6.

Tc-PYP Scan Results After Septal Myectomy Negative for Amyloidosis (Planar and SPECT)

SPECT = single photon emission computed tomography; Tc-PYP = technetium pyrophosphate.

Outcome and Follow-Up

Based on the mass spectroscopy results from the surgical specimen that showed the same amino acid sequence as that shown from her genotype, she is confirmed with diagnosis of hereditary TTR amyloidosis. The patient was additionally seen by the NYU Dysautonomia Center, and no overt signs of autonomic or peripheral neuropathy were found; however, the vibration threshold was increased in her lower legs, which may be an early sign of small nerve fiber involvement. Treatment with tafamidis was initiated. Postoperative echocardiogram showed no SAM, no residual gradient, and LVEF of 50%. She has finally improved and has NYHA functional class I to II symptoms.

Discussion

Exhaustive exploration of the differential diagnoses for patients with cardiomyopathy has become the norm since the development of disease-specific therapies for HCM, ATTR-CA, and Fabry disease. Maurizi et al² reported that out of 343 patients presenting with suspicion of HCM, ∼9% had unrecognized CA, which increased to ∼26% for patients older than 80 years, suggesting that all patients presenting with an HCM phenotype should have routine clinical and genetic investigations to evaluate for CA. Rowin et al³ found 5 of 150 HCM patients older than 60 years had a positive PYP scan for TTR amyloid. All patients with positive scans were nonobstructed. Longinow et al⁴ reported 2.7% (n = 36) of 1,299 patients with CA had LVOT obstruction, and 58% (n = 21) of them were ATTR-CA. Alashi et al⁵ found that 1% (n = 18/2,472) of patients undergoing myectomy for obstructive hypertrophic cardiomyopathy had amyloidosis.

In this patient, the potential for CA was evaluated extensively considering her pathogenic variant in the TTR gene. Despite the genetic testing results, she was deemed clinically unaffected at initial presentation because of 2 negative ^99mTc-PYP scans and was subsequently treated for HCM with LVOT obstruction. Strikingly, she did not tolerate negative inotropic therapy, including the cardiac myosin inhibitor mavacamten, which caused left ventricular dysfunction even at a very low dose. We hypothesize that her underlying amyloid pathology likely contributed to this adverse response.

Gilmore reported a 74% sensitivity of grade 2 or 3 positive ^99mTc-PYP scans, and Poterucha reported a sensitivity of 94%.^6,7 These sensitivity percentages highlight that cases of amyloid may be missed. Therefore, in clinical scenarios even with LVOT obstruction, when there are pathogenic TTR variants or adverse responses to negative inotropic medications, a biopsy should be considered even with a grade 0 to 1 scan because of the possibility of covert amyloidosis. We propose an algorithm suggesting a pathway of when to consider endomyocardial biopsy; such biopsy is performed with low periprocedural risk at high-volume centers with specific expertise⁸ (Figure 7).

Figure 7.

Hypertrophic Heart Disease

Graphical paradigm for the differential diagnosis of HCM, amyloidosis, and Fabry disease, including proposed indication for endomyocardial biopsy. EM = electron microscopy; TTR = transthyretin protein; GLA = Galactosidase Alpha; HCM = hypertrophic cardiomyopathy; Lyso-Gb3 = Globotriaosylsphingosine; LC = light chains; IEF = immunofixation electrophoresis; PYP = pyrophosphate scintigraphy.

Could our patient have both HCM and amyloidosis? The prevalence of HCM is 1 in 500 people.⁹ The exact incidence of ATTR-CA is unknown, with prevalence studies varying from country to country. Therefore, the prevalence of both conditions together would be near impossible to gather at the time of this report. However, we conclude that even if the 2 diagnoses coexist, her major pathology was amyloidosis because there was no fiber disarray and only focal interstitial fibrosis that is inconsistent with the typical HCM phenotype. Mild myocyte hypertrophy to the extent seen in her case can be found in amyloidosis. SAM and mitral-septal contact have been reported in amyloidosis and are not exclusive to obstructive HCM.¹⁰ In such patients, we propose that pharmacologic treatment of amyloidosis should be considered with concurrent/subsequent treatment of LVOT obstruction by surgery.

Conclusions

Patients who present with HCM must be evaluated for mimickers as they may be the true underlying cause of their phenotypic expression. In this case, the patient had no signs of amyloid other than her genetic testing results and was subsequently treated for obstructive HCM. However, she could not be managed medically even with advanced therapy, most likely because she had amyloidosis. Despite the pathogenic variant, her multiple negative ^99MTc-PYP scans and symptomatic LVOT obstruction obscured the correct diagnosis. Physicians should be aware of the 6%-26% false-negative rate associated with Tc-PYP scans and the possible manifestation of CA as LVOT obstruction. Biopsy should be considered when there is remaining suspicion of ATTR in these patients.

Funding Support and Author Disclosures

Dr Massera has received consulting fees from Chiesi Pharmaceuticals, Cytokinetics, Sanofi, and Tenaya Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Initial ^99mTc-PYP Scan With SPECT

SPECT = single photon emission computed tomography; Tc-PYP = technetium pyrophosphate.

Video 2

^99mTc-PYP Scan With SPECT After Surgical Pathology Revealed Amyloid Deposits

SPECT = single photon emission computed tomography; Tc-PYP = technetium pyrophosphate.