By Jamie L. W. Kennedy, MD, FACC

Medical Director, Heart Transplant, Inova Heart and Vascular Institute, Falls Church, VA

SYNOPSIS: A screening study of heart failure patients ≥ age 60 years, left ventricular ejection fraction ≥ 40%, and left ventricle wall thickness ≥ 12 mm revealed 6.3% prevalence of transthyretin cardiac amyloidosis, a highly treatable disease.

SOURCE: AbouEzzeddine OF, Davies DR, Scott CG, et al. Prevalence of transthyretin amyloid cardiomyopathy in heart failure with preserved ejection fraction. JAMA Cardiol 2021; Aug 25. doi: 10.1001/jamacardio.2021.3070. [Online ahead of print].

Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure; yet, evidence-based therapies lag far behind heart failure with reduced ejection fraction. Fortunately, the tide is turning. The FDA has approved sacubitril/valsartan for HFpEF based on the PARAGON-HF study. The authors of the EMPEROR-Preserved study found empagliflozin reduced the number of heart failure hospitalizations and lowered cardiovascular death rates.1,2 HFpEF is a heterogeneous disease, including patients with underlying coronary, valvular, inflammatory, pericardial, and infiltrative diseases. These potentially treatable conditions can be overlooked if patient evaluations are not comprehensive.

Cardiac amyloidosis results from the deposition of misfolded proteins in the myocardium. The most common form is transthyretin (ATTR). Hereditary ATTR amyloidosis results from mutations in the gene encoding transthyretin and tends to present at younger ages, as early as age 30 years. The Val122Ile mutation is found in 3.4% of African Americans; there are several other less common mutations, too. Wild-type transthyretin also can deposit in the heart, leading to ATTR amyloidosis in older patients (age > 70 years). Pyrophosphate (PYP) scans are highly sensitive (85% to 97%) and specific (95% to 100%) for ATTR cardiac amyloid.

Less commonly, plasma cell dyscrasias producing immunoglobulin light chains lead to amyloid light-chain (AL) amyloidosis. Treatment is directed at the underlying plasma cell dyscrasia, including autologous hematopoietic cell transplantation in appropriate candidates. Of note, AL amyloidosis can result in both positive and negative PYP scans, so appropriate evaluation of suspected amyloidosis includes blood and urine testing for light chains. AA amyloidosis results from the deposition of amyloid A, an acute phase reactant, in patients with chronic inflammatory conditions. Treatment of AA amyloidosis focuses on the underlying disease.

AbouEzzeddine et al sought to understand the prevalence of ATTR amyloidosis in HFpEF patients in the Rochester, MN, area. They identified patients diagnosed with heart failure and recent echocardiograms demonstrating left ventricular ejection fraction (LVEF) ≥ 40% and LV wall thickness ≥ 12 mm. Patients with a history of LVEF < 40% were excluded, as were patients with significant mitral valve disease. This resulted in a community cohort of 1,235 patients, 16 of whom already carried a diagnosis of ATTR amyloidosis for a prevalence of 1.3%. All were men. An additional eight patients had been diagnosed with AL amyloid and two with AA amyloid.

Patients in the community cohort who did not carry a diagnosis of amyloidosis were approached to participate in the screening study. A total of 286 enrolled and completed testing, including PYP scan and lab testing for light chains. There were 18 patients with positive PYP scans (15 men and three women). Three of these patients exhibited light chain lab abnormalities, which were investigated further. Ultimately, all 18 patients were diagnosed with ATTR amyloidosis for a prevalence of 6.3%. Genetic testing was performed in 16 of 18 patients. No ATTR mutations were identified. Of note, the population studied was 96% white. The authors speculated more diverse populations will include more patients with hereditary ATTR.

Men were much more commonly affected than women (10% vs. 2.2%). The prevalence increased markedly with age, from 0% of sexagenarians to 21% of nonagenarians. Patients diagnosed with ATTR amyloidosis were more likely to have carpal tunnel syndrome (72% vs. 34%) and less likely to be hypertensive or obese. ATTR amyloid patients recorded higher NT-proBNP and troponin levels and fewer medical problems based on the Charlson Comorbidity Index. The authors concluded patients with HFpEF older than age 60 years with LV wall thickness ≥ 12 mm on echocardiography should be screened for ATTR amyloidosis.

COMMENTARY

Tafamidis is a small molecule that binds and stabilizes ATTR tetramers, thereby preventing deposition. The ATTR-ACT trial was a randomized, placebo-controlled study of tafamidis in patients with ATTR amyloid, both hereditary and wild type.3 Tafamidis lowered the mortality rate from 42.9% to 29.5% and the number of cardiovascular hospitalizations from 0.7 to 0.48 per year over a follow-up period of 30 months. Side effects were not significantly different from placebo.

Heart failure is a progressive disease of exercise intolerance, repeated hospitalizations, and, ultimately, death. Tafamidis offers an effective treatment with minimal side effects for the subset of HFpEF patients with ATTR amyloidosis. Screening for amyloidosis with a combination of PYP scan and lab testing for light chains poses minimal risk to patients, and the potential benefit of treatment is substantial. Cardiac MRI also is a reasonable modality to evaluate for amyloidosis and is excellent for identifying other infiltrative, inflammatory, and pericardial diseases. I tend to reserve endomyocardial biopsy for suspected AL amyloidosis and situations with conflicting information.

Following a diagnosis of ATTR amyloidosis, genetic testing should be offered primarily for the benefit of relatives. Tafamidis is prescribed 61 mg daily. No dose adjustments are required for hepatic or renal dysfunction.

REFERENCES

  1. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609-1620.
  2. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; Aug 27. doi: 10.1056/NEJMoa2107038. [Online ahead of print].
  3. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007-1016.