Estimating nuclear scanning capacity requirements for patients with suspected cardiac transthyretin amyloidosis

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-shortening disease, caused by the deposition of misfolded transthyretin amyloid fibrils in the extracellular space of the myocardium, leading to increased wall thickness and diastolic dysfunction that can result in heart failure (HF).1 Among patients with confirmed ATTR-CM, HF with a normal left ventricular ejection fraction (LVEF) is the predominant presentation, and an important clue to the underlying diagnosis is the presence of otherwise unexplained left ventricular hypertrophy.2 Increased left ventricular wall thickness (LVWT) in patients with HF has been proposed as a red flag for cardiac amyloidosis that should prompt further investigations to confirm or exclude the diagnosis.3 The prevalence of ATTR-CM is uncertain, and, consequently, so is the number of patients that might be referred to an HF service with suspected ATTR-CM. The Hull LifeLab database, containing 20 years of data for patients who have been referred to a community HF clinic, offers a unique opportunity to investigate this issue. The aim of this analysis was to understand the prevalence and characteristics of patients who should be considered for referral for nuclear scintigraphy to exclude or confirm a diagnosis of ATTR-CM, based on the presence of HF with a normal or mildly reduced ejection fraction and an increased LVWT. Between August 2000 and January 2020, consecutive referrals to a community HF clinic were enrolled in a longitudinal epidemiological study at a single clinic (The Hull LifeLab). Patients consented for the use of their medical information prior to investigation. The study was approved by the Hull and East Yorkshire Local Research Ethics Committee. All patient identifiable information was anonymized before analysis. For the present analysis, we focused only on patients with HF who had at their initial visit (i) a diagnosis of HF, based on symptoms and signs together with a raised N-terminal pro-brain natriuretic peptide (NT-proBNP) (≥400 ng/L)4; (ii) LVEF ≥45%, corresponding to mild or no evidence of LVSD, as determined by echocardiography; and (iii) measurements of LVWT. Patients were defined as being suitable for further investigations for a possible diagnosis of ATTR-CM if either the left ventricular posterior wall thickness or interventricular septal wall thickness was increased. An international position statement proposes an LVWT greater than or equal to 12 mm,5 whereas another study suggests a cut-off of 14 mm.3 Accordingly, we provide analyses using both criteria. We also present data for those with and without hypertension, defined as systolic blood pressure ≥140 mmHg.6 Of the original 7378 patients assessed in the clinic, 4788 had data available for NT-proBNP, LVEF, and LVWT, of whom 1735 had HF with normal or mildly reduced LVEF (Figure 1). Of these 1735, 884 (51%) had an LVWT ≥12 mm, and 282 (16%) had a LVWT ≥14 mm (Figure 2), which represents approximately 18% and 6%, respectively, of all patients for whom we had data on left ventricular systolic function, LVWT, and a contemporaneous NT-proBNP. Excluding patients with hypertension reduced the proportion who should be considered for nuclear scintigraphy to 7% those with a LVWT ≥12 mm and 2% of those with a LVWT ≥14 mm (Figure 3). Patients with an LVWT ≥12 mm (Table 1) were more likely to have a history of hypertension or diabetes and a higher systolic blood pressure, were less likely to be treated with a beta blocker, and were more likely to be treated with a loop diuretic. Patients with greater wall thickness also had a longer QRS duration, had a higher NT-proBNP, and were more likely to have severe aortic valve disease. Left atrial size was not different between the two groups, but the left ventricular end-diastolic dimension indexed for body surface area (BSA) was slightly lower in the group with greater wall thickness. Similar findings were observed when comparing those with an LVWT ≥14 mm to those with a LVWT <14 mm (Table 1). ≥12 mm (n = 884) <12 mm (n = 884) ≥14 mm (n = 884) <14 mm (n = 884) Epidemiologically, patients with HF and a normal LVEF are more likely to be women.7 However, men are more likely to have increased LVWT, which could be due to myocardial hypertrophy or infiltration with ATTR and is consistent with the observation that ATTR-CM is much more common in men than women.8 These data have important service implications. A diagnosis of ATTR-CM should be considered for patients with HF, a normal or near-normal LVEF, and an unexplained increase in LVWT. Where active intervention rather than palliative care is being considered, further investigation should include bone scintigraphy (to detect ATTR-CM), a monoclonal protein screen (to support a diagnosis of AL amyloidosis), and, where appropriate, a fat biopsy to obtain a tissue diagnosis of AL amyloid.3, 5 We acknowledge limitations of the data, which represent a single region in the UK and may not be representative of other HF services. Incomplete data may reduce the accuracy of our estimates. Routine measurement of NT-proBNP was only adopted in 2008. We also acknowledge that additional red flags for ATTR-CM such as a history of carpal tunnel syndrome were not routinely recorded. This analysis shows that 51% of patients with HF and a normal or mildly reduced LVEF have an LVWT ≥12 mm and that 16% have an LVWT ≥14 mm. Such patients should be considered for further investigations to confirm or exclude ATTR-CM in the absence of alternative causes of LVH such as hypertension and aortic stenosis, although these diagnoses do not preclude concomitant ATTR-CM.9 This analysis may help inform the planning of HF services and for the volume of nuclear scans required to investigate ATTR-CM. The authors would like to thank all the patients that have agreed to enrolment in the LifeLab database and consented their data to be used for epidemiological research. The study was sponsored by Pfizer.