Are we missing a lot of cardiac amyloidosis?

Are we missing a lot of cardiac amyloidosis?

Amyloidosis is caused by deposition of products of protein misfolding in extracellular tissue, most commonly the light chains (lambda and kappa), transthyretin, and serum amyloid A [1]. They can be detected by immunofixation tests of serum and urine in most cases. A tissue biopsy like from the bone marrow or endomyocardial biopsy to prove cardiac involvement is the final proof. Tc99m-pyrophosphate scintigraphy (bone scan used for the heart) is now taken as almost equivalent to biopsy in TTR amyloidosis due to inherent problems for endomyocardial biopsy. Most people are reluctant for an endomyocardial biopsy and processing of the specimen is not widely available.

Transthyretin (TTR) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine and retinol to the liver. Transthyretin amyloidosis can present to the neurologist with carpal tunnel syndrome or familial amyloidotic polyneuropathy while AL amyloidosis often presents to the nephrologist! Liver involvement can also be there in amyloidosis. Lumbar spinal stenosis is another association. Compression is caused by amyloid deposition causing thickening of the ligamentum flavum and narrowing of the spinal canal [2].

The hallmark of cardiac amyloidosis is thickening of ventricular walls seen on echocardiography without corresponding higher voltages on electrocardiography. Diastolic dysfunction with a restrictive pattern is seen on Doppler studies.

Amyloid light chain (AL) amyloidosis is a plasma cell dyscrasia, which is distinct from multiple myeloma. AL amyloidosis has a more severe course than transthyretin amyloidosis with median untreated survival of about six months from the onset of cardiac failure. The cardiotoxicity of circulating light chains in addition to the myocardial infiltration is thought to have a role in this more severe manifestation of AL amyloidosis. Capillary fragility due to amyloid infiltration can cause purpuric lesions with minimal trauma [1].

TTR amyloidosis can be wild-type or familial due to missense mutations in the TTR gene [3]. In the wild-type TTR deposition leads to senile amyloidosis, predominantly manifesting as cardiomyopathy. In case of TTR gene mutations, certain mutations are more likely to affect the heart while others cause more neurologic involvement.

An autopsy study of heart failure with preserved ejection fraction (HFpEF) from Mayo Clinic sought to determine the frequency of left ventricular amyloid deposition [4]. They had 109 cases with antemortem diagnosis of HFpEF without clinically apparent amyloid. 131 control subjects were also screened. Screening was done with sulfated Alcian blue. Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type was done subsequently. Quantitative whole-field digital microscopy was used to assess fibrosis. Wild-type TTR amyloid was associated with age at death and male sex. Age and sex adjusted prevalence of wild-type TTR amyloid was higher in HFpEF patients than in control subjects. Moderate or severe interstitial wild-type TTR amyloid deposition consistent with primary etiology of HFpEF was present in 5% cases. This finding suggests that we may be missing a lot of TTR amyloidosis in the large group of HFpEF in the community, especially in the elderly.

Another important group in which TTR amyloidosis is likely is those with aortic stenosis. Up to 15% of cases of aortic stenosis may have underlying amyloidosis. This is more in the subset with low-flow, low-gradient aortic stenosis in which up to 30% may have cardiac amyloidosis. Cardiac amyloidosis is associated with increased risk of heart failure, mortality and even futility with aortic valve replacement. Transcatheter aortic valve replacement may be preferred to surgery in these patients [5].

Tafamidis can be used to treat TTR amyloidosis. Tafamidis binds the thyroxine binding sites of TTR with high affinity and selectivity. This slows the dissociation of TTR tetramers into monomers, inhibiting aggregation. Tafamidis has been shown to slow the progression of peripheral neurologic impairment in TTR polyneuropathy [6]. Tafamidis was approved by US FDA in 2019 for treatment of TTR cardiomyopathy [7].

References

1. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011 Aug 30;124(9):1079-85. doi: 10.1161/CIRCULATIONAHA.110.010447. PMID: 21875922.
2. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014 Aug;119(3):223-8. doi: 10.3109/03009734.2014.895786. Epub 2014 Mar 12. PMID: 24620715; PMCID: PMC4116761.
3. Ton VK, Mukherjee M, Judge DP. Transthyretin cardiac amyloidosis: pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction. Clin Med Insights Cardiol. 2015 Jan 5;8(Suppl 1):39-44. doi: 10.4137/CMC.S15719. PMID: 25628512; PMCID: PMC4284988.
4. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014 Apr;2(2):113-22. doi: 10.1016/j.jchf.2013.11.004. PMID: 24720917; PMCID: PMC3984539.
5. Ternacle J, Krapf L, Mohty D, Magne J, Nguyen A, Galat A, Gallet R, Teiger E, Côté N, Clavel MA, Tournoux F, Pibarot P, Damy T. Aortic Stenosis and Cardiac Amyloidosis: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 Nov 26;74(21):2638-2651. doi: 10.1016/j.jacc.2019.09.056. PMID: 31753206.
6. Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P, Suhr OB, Campistol JM, Conceição IM, Schmidt HH, Trigo P, Kelly JW, Labaudinière R, Chan J, Packman J, Wilson A, Grogan DR. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012 Aug 21;79(8):785-92. doi: 10.1212/WNL.0b013e3182661eb1. Epub 2012 Jul 25. PMID: 22843282; PMCID: PMC4098875.
7. FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis. Available online from FDA website at URL: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated. Accessed on 13 Feb 2022.