New insight into “HFpEF” – cardiac amyloid no longer a zebra diagnosis?

By Dr. Alice S Chang (biography, no disclosures), Dr. Michael J Diamant (biography, no disclosures), Dr. Margot K Davis (biography and disclosures), and Dr. Krishnan Ramanathan (biography and disclosures)

What care gaps or frequently asked questions I have noticed

In general practice, it is relatively common to see newly diagnosed patients with progressive heart failure (HF) symptoms, such as a 65-year-old previously healthy man with an echocardiogram showing left ventricular hypertrophy (LVH) but otherwise normal systolic function. He is diagnosed with HF with preserved ejection fraction (HFpEF) and started on diuretics. Over time, he develops non-valvular atrial fibrillation and is placed on oral anticoagulation for stroke prevention. Initiating rate control, such as beta-blockers and calcium channel blockers, is poorly tolerated due to hypotension and worsening symptoms. Despite compliance with dietary restrictions and diuretic medications, he has frequent HF exacerbations.

• Why did this patient develop HFpEF?
• Could this patient have cardiac amyloidosis?
• Which investigations are indicated, and how should this patient be best managed?

Cardiac amyloidosis (CA) is an infiltrative disease that is being increasingly identified in those with HFpEF.

Amyloidosis is a group of heterogeneous disorders characterized by the deposition of misfolded protein that aggregates into fibrils, affecting multiple organs including the heart, neural tissues, kidneys, and the gastrointestinal tract (1).  The two most common types associated with cardiac deposition are light chain amyloidosis (AL), typically associated with plasma cell dyscrasias, and transthyretin amyloidosis (ATTR), which may be either acquired (wild-type) or hereditary (due to mutations in the ATTR gene) (2).

Regardless of the type (or subtype), patients with cardiac involvement typically present with HFpEF and signs of diastolic heart failure, such as dyspnea, peripheral edema, and atrial fibrillation (3). The conduction system can also be affected, leading to heart block needing permanent pacemaker implantation or bundle branch blocks  (3).

Despite the similar effect in the heart, AL and ATTR are two patho-physiologically different disease processes leading to CA. In AL disease, the amyloid proteins are light chains produced by clonal plasma cells in the bone marrow (4). These light chains may deposit anywhere in the body except the central nervous system, resulting in rapidly progressive multisystemic disease in the majority of cases (5). Timely diagnosis is important, as the prognosis for untreated AL disease is poor, with median survival less than a year following diagnosis (7). Advances in chemotherapy options and auto-stem-cell transplant have demonstrated large reduction (in some cases complete normalization) of circulating light chains (6).

In contrast to AL disease, ATTR-CA is more insidious in onset and is limited to cardiac and neural tissues (2). In wild-type ATTR-CA (wtATTR), patients present with cardiomyopathy, carpal tunnel syndrome, and often lumbar spinal stenosis. In hereditary ATTR-CA (hATTR), patients present with a combination of cardiomyopathy and polyneuropathy, with the proportion of each dependent on the specific mutation present. Recent studies have revealed that ATTR-CA is a vastly underdiagnosed cause of HFpEF, particularly wtATTR. In patients aged 85 or older undergoing autopsy, wtATTR have identified in up to 25% of (7). Another autopsy study found ATTR-CA in 40% of patients with HFpEF diagnosed after age 65 (8). Among patients undergoing transcatheter aortic valve replacement, 15%  was diagnosed with wtATTR-CA on cardiac biopsy (9).

Despite the surprisingly high prevalence, the diagnosis of ATTR-CA can be challenging and easily missed in clinical practice. Lack of broad awareness among clinicians and the prevalence of concomitant conditions also associated with HFpEF such as hypertension, aortic stenosis, and coronary artery disease can all be major obstacles for appropriate diagnosis and treatment.

With recent advances in diagnostic modalities and treatment options, timely recognition of ATTR-CA has become more crucial. While ATTR-CA is often well tolerated for many years until severe LV wall thickening, diastolic dysfunction, and conduction disease develop, the median survival can be limited to 4 to 6 years from the onset of congestive symptoms (2).

The remainder of this article will focus on the practical tips for recognizing ATTR-CA in the general practice and how to screen for ATTR-CA in these patients.

Data that answer these questions or gaps

1. What are the “red flags” that raise suspicion for ATTR-CA?

ATTR-CA should be considered in all patients presenting with HFpEF, particularly in those older than 60 years presenting with LVH and diastolic dysfunction without long-standing hypertension, coronary artery disease, or aortic stenosis. Males are much more commonly affected with wtATTR, with a male : female ratio of 25- 50:1 (9). Increased prevalence can be seen in those of African descent for certain types of hereditary ATTR-CA (9). Other clinical clues may include prior carpal tunnel syndrome, which is often bilateral and found in 35% of patients (10).

2. How should we screen for ATTR-CA in those presenting with HFpEF?

Many cardiac imaging modalities have evolved to evaluate for CA, including transthoracic echocardiogram with speckle-strain imaging, nuclear imaging, cardiac MRI, and PET scans (8). These advances have made screening and diagnosis of CA possible without the need for routine invasive endomyocardial biopsies. For ATTR-CA, nuclear imaging using technetium-99m-based bone-seeking isotopes, such as Tc-99m pyrophosphate (PYP), has emerged as the screening test of choice, with superb accuracy for TTR-CA (sensitivity >99% and specificity 86%) even in the early stages of disease (11).  Moreover, this test is easily accessible at many centres in British Columbia. When a positive PYP scan is combined with normal serum and urine protein electrophoresis and serum free light chain (SFLC) assay, the specificity and positive predictive value for ATTR-CA each approach 100% (14).  As false positive tests are nearly always due to AL-CA, a screen for AL with serum and urine protein studies should always be done prior to or concomitantly with a PYP scan.

3. What are the treatment options for ATTR-CA?

ATTR-CA has been previously regarded as a “hopeless” disease, with treatment limited to symptom management. Traditional HF medications including beta-blockers, angiotensin-converting enzyme inhibitors, and digitalis have been shown to be ineffective, and can have significant adverse effects (11).

Currently, options for disease-modifying therapy are under active investigation. A randomized controlled trial called ATTR-ACT published in the New England Journal of Medicine last year showed promising results for tafamidis in the treatment of ATTR-CA (8). Tafamidis binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis (9). In ATTR-ACT, 441 patients were randomized to tafamidis or placebo and followed for 2.5 years. Tafamadis was associated with a 30% reduction in the risk of death and a 32% reduction in the risk of cardiovascular hospitalization; the number needed to treat to prevent one death was only 7.5. While its approval for use in Canada is pending, tafamidis does offer a promising therapy for a previously untreatable disease. Phase III trials are underway or planned for several other novel agents targeting both wtATTR and hATTR.

What we recommend (practice tip)

1. In all patients presenting with HFpEF, we recommend looking for features that raise suspicion for CA:
   1. Historical features
      1. Male, African descent, age >60
      2. Presence of carpal tunnel syndrome, peripheral neuropathy, autonomic dysfunction
      3. Lack of usual risk factors for HFpEF (eg. Hypertension, diabetes, obesity), chronic kidney disease)
   2. ECG findings
      1. Low voltage despite LVH on imaging
      2. Atrial fibrillation or flutter
      3. Conduction abnormalities such as 1^st degree A-V block and left bundle branch block
   3. Echocardiogram findings
      1. LV and RV wall thickening
      2. HF with mid-range or preserved LVEF (>40%); moderate or severe diastolic dysfunction
      3. Bi-atrial enlargement, pericardial effusions, abnormal speckle-strain pattern

2. We recommend the following tests for screening patients for CA:
   1. Cardiac biomarkers: troponin, BNP
   2. Hematologic work-up: CBC, serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum free light chains (SFLC), renal function and urinalysis
   3. Transthoracic echocardiogram with strain imaging
   4. Technetium-99m pyrophosphate scan

3. We recommend a referral to a heart failure specialist or amyloidosis clinic in cases where diagnosis remains uncertain, or if there is a high suspicion for CA on initial investigations.

References and/or additional reading

1. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28(1):10-21. DOI: 10.1016/j.tcm.2017.07.004. (View)
2. Xin Y, Hu W, Chen X, Hu J, Sun Y, Zhao Y. Prognostic impact of light-chain and transthyretin-related categories in cardiac amyloidosis: A systematic review and meta-analysis. Hellenic J Cardiol. 2019. [Epub ahead of print]. DOI: 10.1016/j.hjc.2019.01.015. (View)
3. Sekijima Y. Hereditary Transthyretin Amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993. Accessed April 3, 2019. (View)
4. Sayed RH, Wechalekar AD, Gilbertson JA, et al. Natural history and outcome of light chain deposition disease. Blood. 2015;126(26):2805-2810. DOI: 10.1182/blood-2015-07-658872. (View)
5. Rafae A, Malik MN, Abu Zar M, Durer S, Durer C. An overview of light chain multiple myeloma: clinical characteristics and rarities, management strategies, and disease monitoring. Cureus. 2018;10(8):e3148. (View)
6. Witteles, R. Cardiac Amyloidosis. American College of Cardiology. Published July 7, 2016. Accessed August 1, 2019. (View)
7. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2‐macroglobulin and tau: a population‐based autopsy study. Ann Med. 2008;40(3):232-239. DOI: 10.1080/07853890701842988. (View with CPSBC or UBC)
8. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. DOI: 10.1016/j.jchf.2013.11.004. (View)
9. Castano A, Haq M, Narotsky DL, et al. Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis. JAMA Cardiol. 2016;1(8):880-889. DOI: 10.1001/jamacardio.2016.2839. (Request with CPSBC or view with UBC)
10. Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM. 1998;91(2):141-157. DOI: 10.1093/qjmed/91.2.141. (Request with CPSBC or view with UBC)
11. Ruberg FL, Maurer MS, Judge DP, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222-228.e1. DOI: 10.1016/j.ahj.2012.04.015. (View with CPSBC or UBC)
12. Milandri A, Longhi S, Gagliardi C, et al. Prevalence, risk factors and correlation with cardiac involvement of carpal tunnel syndrome in amyloidosis. Orphanet J Rare Dis. 20152;10(Suppl 1):P32. DOI: 10.1186/1750-1172-10-S1-P32. (View)
13. Rigopoulos AG, Ali M, Abate E, et al. Advances in the diagnosis and treatment of transthyretin amyloidosis with cardiac involvement. Heart Fail Rev. 2019;24(4):521-533. DOI: 10.1007/s10741-019-09776-3. (Request with CPSBC or view with UBC)
14. Kyriakou P, Mouselimis D, Tsarouchas A, et al. Diagnosis of cardiac amyloidosis: a systematic review on the role of imaging and biomarkers. BMC Cardiovasc Disord. 2018;18(1):221. DOI: 10.1186/s12872-018-0952-8. (View)
15. Grogan M, Dispenzieri A, Gertz MA. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 2017;103(14):1065-1072. DOI: 10.1136/heartjnl-2016-310704. (View)

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