Role of Tag Team Rounds in Accurate Diagnosis and Management of Cardiac Amyloidosis

Abstract

Clinical Condition

Cardiac Amyloidosis (CA).

Key Questions

When should infiltrative cardiomyopathy be suspected, and what is the differential diagnosis? What is the diagnostic yield of a technetium Tc 99m pyrophosphate (^99mTc-PYP) scan, cardiac magnetic resonance (CMR), and molecular imaging with amyloid positron emission tomography (PET) tracer for CA? Are they able to distinguish between types of CA? What is the diagnostic yield of an endomyocardial biopsy for CA? How is transthyretin amyloid cardiomyopathy (ATTR-CM), treated and what is the prognosis? How do tag team rounds build on the current system of diagnosis and management of CA?

Outcome

Tag team rounds between heart failure, pathology, and hematology teams resulted in timely and accurate diagnosis of hereditary ATTR-CM in a patient with new-onset heart failure.

Take-Home Message

A nonbiopsy diagnosis of CA is more challenging when a monoclonal gammopathy is present. Tag team rounds allow for correct and timely diagnosis of ATTR amyloid when a monoclonal protein is found.

Visual Summary

Visual Summary.

Timeline of the Case

Date	Events
March 2024	75-year-old woman with hypertension, atrial fibrillation, and atrial flutter presented to routine outpatient visit in SVT and in acute decompensated heart failure, prompting inpatient admission. Transesophageal echocardiogram and cardioversion performed for suspected atypical atrial flutter after aggressive intravenous diuresis.
March 2024	TTE: Increased LV wall thickness, biatrial dilatation, and reduced tissue Doppler velocities concerning for an infiltrative cardiomyopathy. Because of the patient’s age and voltage discrepancy on ECG, cardiac amyloidosis (CA) was suspected.
April 2024	Initial work-up for CA: 99mTc-PYP scan + Laboratory tests: serum free light chain ratio, serum immunofixation, urine free light chain ratio, and urine immunofixation. PYP scan showed grade 1 uptake Serum immunofixation demonstrated a monoclonal IgG lambda protein Monoclonal gammopathy renders results of PYP scan insufficient, and a nonbiopsy diagnosis is no longer possible.
April 2024	CMR demonstrated diffuse LGE and inability to null myocardium, all consistent with CA.
April 2024	Hematology team consulted because of gammopathy, and decision was made after discussion with the heart failure cardiologist to perform endomyocardial biopsy to determine type of cardiac amyloid infiltration.
April 2024	EMB samples demonstrated positive Congo red staining. Samples were sent to Mayo Clinic Laboratories for further characterization. Mass spectrometry demonstrated ATTR amyloid and Val142lle mutation suggesting hereditary ATTR amyloid.
May 2024	Serum genetic testing confirmed Val142lle mutation. To characterize monoclonal gammopathy further, a bone marrow biopsy showed 4.1% clonal plasma cells, suggesting monoclonal gammopathy of undetermined significance.
May 2024	Patient treated with tafamidis for ATTR amyloid. Neurologist evaluated patient for polyneuropathy, and she was approved for treatment with vutrisiran as well.
Take-Home Message	•A nonbiopsy diagnosis of cardiac amyloidosis is not possible in the presence of a monoclonal gammopathy. •A multidisciplinary team (or tag team rounds) approach ensures accurate and timely diagnosis and treatment of cardiac amyloid.

EMB = endomyocardial biopsy; TTE = transthoracic echocardiogram; other abbreviations as in Table1.

A 75-year-old woman with a history of atrial fibrillation and typical atrial flutter treated with pulmonary vein isolation (PVI) and cavotricuspid isthmus ablation 2 years prior, and hypertension, presented to the electrophysiology clinic for routine follow-up. She reported progressive lethargy and exertional dyspnea for 1 week. She was hypervolemic on examination, and an electrocardiogram (ECG) demonstrated supraventricular tachycardia (SVT) with a ventricular rate of 147 beats/min (Figure 1). She was admitted for management of SVT and acute decompensated heart failure. She underwent diuresis to euvolemia. Atypical atrial flutter was suspected, given the sustained nature of the arrhythmia and prior history of ablation, and a cardioversion was performed. ECG in normal sinus rhythm showed a low-amplitude QRS, particularly in the limb leads (Figure 2).

Take-Home Messages

• •A nonbiopsy diagnosis of CA is more challenging when a monoclonal gammopathy is present.
• •Tag team rounds are essential for correct and timely diagnosis of ATTR amyloid when a monoclonal protein is found.

Figure 1.

Supraventricular Tachycardia With Ventricular Rate of 147 Beats/Min

Figure 2.

Normal Sinus Rhythm With Heart Rate of 70 Beats/Min and Low-Amplitude QRS in Limb Leads

A transthoracic echocardiogram (TTE) demonstrated a left ventricular ejection fraction of 50% to 55%, increased LV wall thickness (septal and posterior wall thickness of 12 mm), severely reduced right ventricular function, biatrial enlargement, and severe tricuspid regurgitation (Figure 3, Video 1). These findings along with the history of atrial arrhythmias, low-voltage ECG, and heart failure symptoms were concerning for an infiltrative cardiomyopathy.

Figure 3.

Transthoracic Echocardiogram

(A) Normal-sized left ventricular (LV) cavity with increased LV wall thickness. (B) Restrictive filling pattern. (C, D) Significantly reduced septal and lateral eʹ velocities.

Question 1

What findings lead to a suspicion of infiltrative cardiomyopathy? What is the differential diagnosis?

Answer 1

Infiltrative cardiomyopathy involves the myocardial deposition of a substance resulting in increased LV wall thickness. Inasmuch as the mechanism for the increased wall thickness is infiltration and not actual myocyte hypertrophy, the ECG demonstrates a relatively low amplitude QRS. Additional systemic features of CA include polyneuropathy, carpal tunnel syndrome, arthritis requiring joint replacement, biceps tendon rupture, and autonomic dysfunction evidenced by new hypotension and urinary incontinence.

The differential diagnosis includes amyloidosis, glycogen storage diseases such as Fabry disease, iron overload, and cardiac sarcoidosis. Relatively uncommon infiltrative cardiomyopathies are Danon disease, Friedrich ataxia, and Pompe disease. Infiltrative cardiomyopathies can be classified as intracellular vs extracellular myocardial infiltration and by the presence or absence of increased LV wall thickness on imaging, the latter being more clinically relevant (Table 1).

Table 1.

Differential Diagnosis of Infiltrative Cardiomyopathy

Increased LV Wall Thicknessa	Normal LV Wall Thickness
Amyloidosis	Iron overload cardiomyopathy
Fabry disease	Sarcoidosis
Danon disease
Friedrich ataxia

LV = left ventricular.

^aPresence of increased LV wall thickness should also raise possibility of hypertrophic cardiomyopathy and hypertensive heart disease, which are noninfiltrative cardiomyopathies.

With recent advances in multimodality imaging, the type of infiltrative cardiomyopathy can be well characterized through a combination of TTE, PET imaging, cardiac MR (CMR) and radionuclide imaging.¹

Once CA is suspected, the next diagnostic step is to evaluate for the 2 most common types: AL amyloid and ATTR amyloid. This has important therapeutic and prognostic implications. AL amyloid represents a plasma cell dyscrasia treated with chemotherapy, whereas ATTR amyloid represents the deposition of a misfolded transthyretin protein treated with novel therapeutic agents.

On history, our patient described chronic neuropathic pain in her legs and recent falls. Her parents and 2 brothers had died of heart disease around 70 years of age. A patient with these TTE findings and a significant family history should raise suspicion for CA, particularly a hereditary type. The patient therefore underwent a technetium Tc 99m pyrophosphate (^99mTc-PYP) scan and laboratory testing, including serum and urine free light chain ratio and immunofixation to evaluate for the presence of a monoclonal protein. The ^99mTc-PYP images obtained 3 hours after injection demonstrated grade 1 uptake (Figure 4). Serum free light chain ratio showed lambda predominance and serum immunofixation characterized this as a monoclonal IgG lambda protein.

Figure 4.

^99mTc-Pyrophosphate With Grade 1 Uptake

Single-photon emission computed tomography helps differentiate true myocardial uptake from blood pool uptake.

Question 2

What is the diagnostic yield of a ^99mTc-PYP scan? Can it distinguish between types of CA?

Answer 2

^99mTc-PYP scan is a key diagnostic test for ATTR amyloid.² The diagnostic accuracy of a grade 2 or 3 ^99mTc-PYP scan approaches a specificity and positive predictive value of 100% but a sensitivity of 70%, only in the absence of a monoclonal protein. Importantly, >1 in 5 patients with AL CA may have grade 2 or 3 uptake on ^99mTc-PYP scan, therefore, presence of a monoclonal protein requires referral to a hematologist and histological typing. The guidelines mandate the use of SPECT/CT with ^99mTc-PYP scan to differentiate between blood pool and myocardial uptake.¹

A CMR was completed for further evaluation. CMR revealed increased T1 signaling, diffuse late gadolinium enhancement (LGE) and inability to null the myocardium, all highly suggestive of CA (Figure 5).

Figure 5.

Cardiac Magnetic Resonance Images

(A) Biatrial enlargement with trivial pericardial effusion. (B, C) Diffuse late gadolineum enhancement in atria and ventricles.

Question 3

What is the diagnostic yield of CMR for CA? Does CMR help differentiate between the various types?

Answer 3

CMR has great diagnostic accuracy for CA but is unable to differentiate between the various subtypes. Specifically, difficulty nulling the myocardium has a specificity of 100% and sensitivity of only 40.6%.³ Similarly, LGE is quite prevalent in CA but is unable differentiate the subtypes. It does, however, predict mortality. According to 1 meta-analysis, LGE has a sensitivity of 85% and specificity of 92% for CA.⁴ Increased native T1 signaling has a 92% sensitivity and 91% specificity. As amyloid infiltration is extracellular, extracellular volume is elevated and has the potential to be used for monitoring treatment response. However, increased ECV is present in all extracellular infiltrative cardiomyopathies and is nonspecific.⁴

Question 4

Can molecular imaging with amyloid PET tracers be used as an alternative diagnostic modality?

Answer 4

The use of amyloid PET tracers for CA diagnosis requires further investigation and standardization. Amyloid-binding PET radiotracers include C-Pittsburgh compound B (¹¹C-PiB), ¹⁸F-flutemetamol, ¹⁸F-florbetapir, ¹⁸F-florbetaben, and ¹²⁴I-evuzamitide (p5+14). Each tracer has varying affinity for amyloid fibrils, and the sensitivity and specificity for ATTR and AL subtypes of cardiac amyloid is under investigation. PET radiotracers can detect amyloid deposits in the body, allowing for quantification of overall disease burden. Further studies are needed before this modality can be adopted into clinical practice.⁵

It is important to reiterate that owing to the gammopathy, the ^99mTc-PYP scan could not be used to reliably diagnose or exclude ATTR amyloid. The patient was referred to the hematology team for further evaluation of the monoclonal gammopathy. After discussion between the hematologist and the heart failure cardiologist, it was decided that biopsy confirmation was necessary. Endomyocardial biopsy (EMB) was done to determine the predominant process involving the heart. The diagnostic yield of various imaging modalities for CA is summarized in Table 2.

Table 2.

Diagnostic Yield of Imaging Modalities for Cardiac Amyloid

Imaging Modality		Diagnostic Accuracy for Cardiac Amyloid
Tc PYP		∼100% specificity, 70% sensitivitya for ATTR amyloid
CMR	Inability to null myocardium	100% specificity, 40.6% sensitivity
	Diffuse LGE	92% specificity, 85% sensitivity
	Increased native T1 signaling	91% specificity, 92% sensitivity
PET CT		Limited data from small, single-center studies

ATTR = transthyretin amyloid; CMR = cardiac magnetic resonance; LGE = late gadolinium enhancement; PET CT = positron emission tomography computed tomography; Tc-PYP = technetium Tc 99m pyrophosphate.

^aIn the absence of a monoclonal protein.

The EMB showed positive staining for Congo red stain (Figure 6). The sample was sent for further characterization via liquid chromatography tandem mass spectrometry (LC MS) to the Mayo Clinic Laboratories in Rochester, Minnesota.

Figure 6.

Pathology Slides

(A) Hematoxylin and eosin stain (original magnification: ×100) shows amorphous, acellular material depositing within the cardiomyocytes. (B) Congo red stain (original magnification: ×100) without polarization highlights the deposits with a pink color. (C) Crystal violet stain (original magnification: ×100) demonstrates deposits with a fuchsia color. (D) Periodic acid–Schiff stain (original magnification: ×100) shows a pale material filling up the cardiomyocytes.

Question 5

What is the diagnostic yield of an EMB in CA diagnosis?

Answer 5

Before the advent of multimodality imaging, biopsy was the mainstay of diagnosis. In the current era, EMB becomes essential when a monoclonal protein is detected because it renders the noninvasive work-up inadequate. EMB can be performed safely in the cardiac catheterization laboratory by trained cardiologists through the internal jugular venous approach. As CA is a diffuse infiltrative process, the diagnostic yield of an EMB is high, particularly when 3 to 5 samples are obtained. Evaluation of the sample by LC MS is the gold standard, with a reported sensitivity of 88% and specificity of 96%.⁶

Interestingly, the LC MS results showed a peptide profile consistent with ATTR amyloid. An amino acid sequence abnormality was detected in the transthyretin protein consistent with Val142lle mutation, suggesting hereditary ATTR type CA. No monoclonal protein was detected.

The hematology team then conducted a bone marrow biopsy to evaluate the gammopathy. Bone marrow biopsy revealed 4.1% clonal plasma cells and was deemed to be a monoclonal gammopathy of undetermined significance.

Once a diagnosis of ATTR amyloid is confirmed, genetic testing is pursued to help differentiate hereditary (ATTRv) from wild-type ATTR (ATTRwt) amyloid. Genetic testing in our patient confirmed the hereditary ATTR variant.

Question 6

How is ATTR amyloid treated?

Answer 6

The goals in management of ATTR amyloid are maintenance of euvolemia, normal sinus rhythm, and halting progression of the disease by using novel therapeutic agents such as tafamidis, vutrisiran, and patisiran.

Traditional guideline-directed medical therapy (GDMT) is not well tolerated in CA.⁶ Amyloid deposition over time causes a restrictive physiology whereby the stroke volume becomes relatively fixed. This leads to a greater dependence on heart rate for maintenance of cardiac output and intolerance of bradycardia. β-blockers should be avoided and only used cautiously if indicated for other reasons such as angina or arrhythmias.

Recent advancements in development of therapeutic targets for ATTR amyloid has ushered in a new era in the treatment of this condition. The U.S. Food and Drug Administration has approved the use of tafamidis, an ATTR stabilizer, based on the promising results of the ATTR-ACT study.⁷ This study demonstrated a reduction in all-cause mortality and cardiovascular-related hospitalizations. Vutrisiran and patisiran, ATTR gene silencers, are currently approved for treatment of hereditary ATTR-associated neuropathy. These agents require evaluation and approval through a neurologist. With the promising results of the recent HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) trial, vutrisiran should soon be approved for prescription by cardiologists. This trial demonstrated an overall reduction in all-cause mortality and recurrent cardiovascular events at 36 months with vutrisiran when compared with placebo.⁸ Acoramidis, a gene silencer, also recently received U.S. FDA approval.

However, access to these agents is plagued by several issues in the outpatient setting, such as exorbitant monthly out-of-pocket payments and lack of insurance coverage for all agents. The annual out-of-pocket cost for tafamidis was $6,000 in 2021.⁹ This brings forth a concern for cost-related medication nonadherence, particularly for patients with a low or fixed income.

Our patient received maintenance treatment with a loop diuretic and amiodarone for maintenance of sinus rhythm. Given the results of the biopsy, she was approved for tafamidis. Evaluation by neurology demonstrated evidence of a length-dependent small and large fiber neuropathy with areflexia and distal extremity weakness. Treatment with vutrisiran was initiated after insurance approval.

Question 7

What is the prognosis of patients with ATTR cardiac amyloid?

Answer 7

ATTR-CM is vastly underdiagnosed and is more prevalent than previously thought. Advances in multimodality imaging have allowed for earlier diagnosis of this condition. However, the prognosis of ATTR CA patients remains poor. The median survival from the time of diagnosis has been reported to be 25.6 months for hereditary ATTR vs 43 months for wild-type ATTR.¹⁰ Survival is positively affected by newer therapeutic agents such as tafamidis.

Question 8

How do tag team rounds build on the current system of diagnosis and management of CA?

Answer 8

Amyloidosis is a multisystem disorder that can have varying manifestations early on. At our institution, tag team rounds build on the multidisciplinary approach in the following ways:

• 1.Increasing awareness among health care providers through educational conferences on systemic manifestations and diagnosis of CA. Our hope is that a lower threshold of suspicion for CA will lead to a timely referral when CA is suspected.
• 2.In our experience, a common point of confusion is regarding tests to order, because there are different names for the orders depending on the laboratory being used. Incorporating customized order sets into the electronic medical record (EMR) empowers primary care doctors, inpatient care teams, and general cardiologists to order the initial set of serum studies, urine studies, and imaging tests when there is clinical suspicion of CA.
• 3.A core team of experts is available to discuss nuances that become evident during the patient evaluation. Difficult cases are discussed on an individual basis with the heart failure cardiologist, hematologist/oncologist, pathologist, neurologist, and other necessary specialists. Once a patient is identified as having amyloid, an outpatient clinic appointment is provided (another order via the health system EMR). We have found that using the EMR to streamline the diagnostic work-up, including imaging and laboratory studies, has led to a more complete work-up and less delay in diagnosis.

The advancements in cardiovascular multimodality imaging have allowed for a nonbiopsy diagnosis of patients with ATTR CA. However, there is a role for tissue diagnosis in the subset of patients where a monoclonal protein is detected. Tag team rounds between the cardiovascular imaging specialist, heart failure cardiologist, pathologist, hematologist, and neurologist led to the accurate diagnosis and treatment of this patient.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transthoracic Echocardiogram

Apical 4-chamber view demonstrating biatrial enlargement, increased biventricular wall thickness, and biventricular dysfunction.