Paul D. Thompson, MD: Don’t Be Thick Headed With Thick Hearts

From the desk of Dr. Paul D. Thompson:

Paul D. Thompson, MD

“Diagnostic anchoring” refers to clinicians’ tendency to make a diagnosis and to avoid considering the alternatives. I have had several patients referred to me over my career with the diagnosis of hypertrophic cardiomyopathy (HCM), who turned out to have cardiac amyloidosis. Amyloidosis and other diseases that produce left ventricular hypertrophy (LVH) are called “HCM phenocopies” because they copy the HCM phenotype but do not have the genotype.

Recognizing HCM phenocopies, and not succumbing to diagnostic anchoring, is now critically important because there are new treatments for some HCM phenocopies that can prevent progression and even initiate regression of the non-HCM disease. The following is a compilation of what I knew about this topic plus material presented in a web-based lecture on November 20, 2020, entitled “Highlighting Hypertrophic Cardiomyopathy and Fabry Cardiac Disease”.

The differential diagnosis of a thick heart includes classical HCM, long-standing poorly treated hypertension, cardiac amyloidosis, alpha-galactosidase A (a-GSA) deficiency or Fabry disease, lysosomal associated membrane protein–2 deficiency (LAMP-2) also called Danon or LAMP-2 disease, and hydroxychloroquine (HCQ) treatment.

HCM is the most frequent cause of thick hearts and affects 1/250 individuals.HCM is autosomal dominant and not sex-linked. It typically produces more septal than other wall hypertrophy. Indeed, HCM was historically called asymmetric septal hypertrophy or ASH. Clinicians should consider diagnoses other than HCM if there is no family history of HCM, when the disease onset is late in life, and when there is symmetric LVH or LVH that does not include the septum. But be careful because if anything typifies HCM, it is its variability. HCM can produce apical and symmetrical LVH, appear late in life, and occur in non-inherited patterns. One notorious example of a non-inherited pattern involved a cluster of HCM patients due to sperm-donation from an undiagnosed HCM carrier! ¹

Long-standing, poorly treated hypertension (HBP) can cause LVH, but this is now a rare HCM mimic because HBP is usually diagnosed and treated before the LVH is extreme.

Cardiac amyloidosis is presently recognized more frequently as causing thick hearts because of increased awareness of the disease and the use of non-echo imaging techniques such as magnetic resonance imaging (cMRI) and technetium 99 pyrophosphate scanning. Amyloidosis comes in three varieties.² Deposition of antibody light chains produces AL amyloidosis. These light chains are produced by clonal plasma cells so it is treated as a variant of multiple myeloma. Inherited transthyretin (TTR) amyloidosis is due to mutations in the TTR gene. A gene mutation is present in approximately 3% of African Americans, but mutations occur in other populations including the Irish.

There is also a non-inherited or “wild type” (wt) TTR amyloidosis. TTR amyloidosis is more frequent in men, especially old men, despite not being sex-linked. TTR amyloidosis produces orthopedic issues such as biceps tendon ruptures, carpal tunnel symptoms, spinal stenosis, and palmar tendon nodules, which may appear years before the cardiac amyloidosis becomes obvious. Amyloidosis should also be considered in patients with LVH and peripheral neuropathy since amyloid also invades peripheral nerves. It is important to diagnose TTR amyloidosis because new treatments such as tafamidis can help preserve functional capacity and reduce cardiovascular mortality.³ Interestingly, 20% of patients with wtTTR have asymmetric septal hypertrophy making wtTTR a worthy HCM phenocopy. ²

Patients whose LVH is due to HCM and especially those whose LVH is due to HBP should have impressive voltage criteria for LVH whereas patients with amyloidosis have either normal or decreased LV voltage. But a history of HBP that has been mysteriously cured and no longer requires anti-HBP drugs suggests new peripheral neuropathy another symptom of amyloidosis.

Fabry disease is another treatable cause of thick hearts. Fabry is X-linked and results from a decrease in lysosomal a-GSA activity resulting in the accumulation of glycosphingolipids in lysosomes. About 0.03% of the population carries the Fabry gene. It usually produces concentric LVH with LGE of the posterior wall and, in contrast to HCM, spares the septum.

Fabry also can produce ascending aortic enlargement and aortic insufficiency. Fabry should be considered with late-onset LVH especially if there is aortic enlargement. The disease is more common and severe in men, because of the X-linked inheritance. This inheritance pattern means that men can be diagnosed by measuring serum a-GSA activity because they don’t produce any, but that women must have gene analysis to detect the genetic defect. Fabry also causes AV conduction disease. Even though Fabry usually causes diffuse LVH, it can produce septal hypertrophy ASH and even systolic anterior motion of the mitral valve so Fabry should be excluded in all thick hearts. Both enzyme replacement therapy and migalastat, which helps chaperone a-GSA to lysosomes, reduce LVH in Fabry.⁴

Danon or LAMP-2 disease is another rare, X-linked lysosomal glycogen storage disease. It usually presents in children who also have muscle weakness and intellectual disability.

Finally, HCQ can also produce a lysosomal storage disorder that mimics HCM becauseHCQ inhibits lysosomal function.⁵ HCQ is no longer recommended for COVID-19 treatment but is still used to treat rheumatoid arthritis and other inflammatory diseases, so should be considered as a cause of LVH in patients treated with this drug.

We are all taught to make a differential diagnosis for every patient’s condition, but this is especially important with thick-hearted patients to avoid missing a treatable disease.

1. Maron BJ, Lesser JR, Schiller NB, Harris KM, Brown C, Rehm HL. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. JAMA. 2009;302(15):1681-1684. doi: 10.1001/jama.2009.1507 [doi].

2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891. doi: S0735-1097(19)34729-1 [pii].

3. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi: 10.1056/NEJMoa1805689 [doi].

4. Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry disease with the pharmacologic chaperone migalastat. N Engl J Med. 2016;375(6):545-555. doi: 10.1056/NEJMoa1510198 [doi].

5. Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquine-induced cardiomyopathy: Case report, pathophysiology, diagnosis, and treatment. Can J Cardiol. 2014;30(12):1706-1715. doi: 10.1016/j.cjca.2014.08.016 [doi].