Prospective Multicenter Screening With High-Sensitivity Cardiac Troponin T for Wild-Type Transthyretin Cardiac Amyloidosis in Outpatient and Community-Based Settings

Abstract

Background: High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings.

Methods and Results: This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population.

Conclusions: Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a life-threatening disease characterized by the accumulation of wild-type transthyretin (TTR) that forms amyloid fibrils in the myocardium. ATTRwt-CA results from age-related changes in the stability of wild-type TTR and the incidence of ATTRwt-CA increases with advancing age.^1–4

Several studies have shown that the incidence of ATTRwt-CA is higher than had been thought in specific populations, such as an autopsy series, in patients with heart failure with preserved ejection fraction (HFpEF), or in patients with severe aortic stenosis.^5–8 Conversely, the prevalence of ATTRwt-CA in primary care practice remains unclear, especially in patients without heart failure (HF) hospitalization.

High-sensitivity cardiac troponin T (hs-cTnT) has been reported to have diagnostic, prognostic, and therapeutic monitoring value for cardiac amyloidosis (CA).^2,9–12 Nevertheless, it seems that hs-cTnT has not been widely used as a diagnostic tool for CA, despite the fact that it can be easily measured in daily clinical practice. We previously reported that hs-cTnT showed high sensitivity and high negative predictive value for technetium-99 m pyrophosphate (^{99 m}Tc-PYP) scintigraphy positivity among patients with clinically suspected CA.¹² In the present exploratory investigation into the diagnostic performance of hs-TnT for CA, we performed systemic screening using hs-cTnT to detect ATTRwt-CA in regional primary outpatient clinics.

Methods

Study Design and Study Population

This study was a prospective multicenter study. Consecutive individuals aged 70 years or older who visited any of 8 outpatient internal medicine clinics in Kochi Prefecture, Japan, between June 2019 and July 2021 and gave consent to participate in the study were enrolled. Individuals were eligible for enrollment in this study regardless of whether cardiac symptoms were present or absent, regardless of whether the hospital visit was an initial visit or a regular visit, and regardless of whether the patient was taking medications or not. Patients with a prior diagnosis of CA, patients with a history of hospitalization for HF, and patients on hemodialysis were excluded.

This study consisted of 3 steps. First, peripheral blood samples were obtained from all individuals at the clinics to measure hs-cTnT levels using an Elecsys troponin T high-sensitivity immunoassay (Roche Diagnostics, Rotkreuz, Switzerland). According to previous studies,^9–12 hs-cTnT levels ≥0.03 ng/mL were used to select patients to proceed to the second step of the study for diagnostic workup for ATTRwt-CA. In the second step, patients with elevated (≥0.03 ng/mL) hs-cTnT levels were referred to Kochi Medical School Hospital for further evaluation, which included remeasurement of hs-cTnT, measurements of laboratory variables, 12-lead electrocardiography (ECG), echocardiography, and ^{99 m}Tc-PYP scintigraphy. In the third step, tissue biopsies were performed in patients who met 1 of the following criteria: (1) positive uptake on ^{99 m}Tc-PYP scintigraphy; and (2) strong suspicion of CA based on a review of other clinical data for patients with negative uptake on ^{99 m}Tc-PYP scintigraphy according to the Japanese Circulation Society (JCS) 2020 guideline.²

This investigation was performed in accordance with the Declaration of Helsinki. It was approved by the Ethics Committee on Medical Research of Kochi Medical School Hospital (Reference no. ERB-106740), and informed consent was obtained from all individuals in accordance with the Ethics Committee guidelines.

Clinical Evaluation

In the second step, 1 experienced cardiologist (T.K.) examined clinical manifestations, including medical history, and conducted the examinations described below at Kochi Medical School Hospital.

hs-cTnT was measured as described above and B-type natriuretic peptide (BNP) was measured using an enzyme immunoassay (TOSOH, Tokyo, Japan). To exclude immunoglobulin light chain (AL) amyloidosis, serum immunoglobulins and free light-chain κ/λ ratio, and serum and/or urine M protein were measured.

An ECG was recorded according to current recommendations.¹³ Echocardiography was performed in accordance with the American Society of Echocardiography guidelines¹⁴ using a commercially available system (Vivid E95; GE Vingmed, Horton, Norway) by an experienced echocardiologist (Y.O.) who was blinded to clinical data. Left ventricular (LV) ejection fraction (EF) was calculated using the biplane volumetric modified Simpson’s method. LV global longitudinal strain (GLS) was measured from 3 apical views. Relative apical sparing was defined using a cut-off value of >2.1 for the mean apical longitudinal strain (LS) to mean basal LS ratio.¹⁵

^{99 m}Tc-PYP scintigraphy was performed using a dual-head Siemens Symbia T2 or T6 (Siemens Medical, Germany) single-photon emission computed tomography/computed tomography camera. Patients were administered 740 MBq of ^{99 m}Tc-PYP (PDRadiopharma Inc., Tokyo, Japan) intravenously, and planar views were obtained at 3 h.¹⁶ The scan was considered positive when it revealed Grade 2 or 3 ^{99 m}Tc-PYP uptake in the ventricle according to the Perugini grading scale.^16–18

Diagnostic Criteria

The diagnosis of ATTR-CA was made by biopsy-proven TTR in at least 1 involved organ and positive uptake on ^{99 m}Tc-PYP scintigraphy according to the JCS 2020 guideline.² The subtype of wild-type TTR amyloid was established on the basis of TTR mutations on genetic testing and/or apparent signs and a family history indicative of hereditary ATTR. CA was established on the basis of the following criteria: (1) endomyocardial biopsy (EMB)-proven TTR amyloid deposition; and (2) in the absence of an EMB, biopsy-proven TTR amyloid deposits in ≥1 extracardiac organ with positive myocardial uptake on ^{99 m}Tc-PYP scintigraphy and meeting echocardiographic criteria.^2,19,20

Statistical Analysis

All data were assessed for normality using the Shapiro-Wilk test. Categorical variables are presented as numbers and percentages, and continuous variables are presented as the mean±SD for normally distributed variables and as the median with interquartile range (IQR) for non-normally distributed variables. Statistical analyses were performed using IBM SPSS statistics version 21.0 (IBM Corp., Armonk, NY, USA).

Results

Clinical Characteristics of the Study Population: First Step of Evaluation

In all, 1,141 individuals were examined in the first step. Figure 1 shows a flow chart of the study population. The median age of individuals was 77 years (IQR 73–81 years), and 454 (39.8%) of individuals were male. The median hs-cTnT level was 0.010 ng/mL (IQR 0.007–0.015 ng/mL). The distribution of hs-cTnT levels is shown in Figure 2.

Figure 1.

Flowchart of the study process and patient population. ATTRwt-CA, wild-type transthyretin cardiac amyloidosis; ECG, electrocardiography; hs-cTnT, high-sensitivity cardiac troponin T; ^{99 m}Tc-PYP, technetium-99 m pyrophosphate.

Figure 2.

Distribution of high-sensitivity cardiac troponin T (hs-cTnT) in the study population.

Patients With Elevated hs-cTnT Levels: Second Step of Evaluation

Elevated (≥0.03 ng/mL) hs-cTnT levels were found in 55 (4.8%) of the 1,141 individuals at the first step. Patients with elevated hs-cTnT levels were recommended to undergo further examination at Kochi Medical School Hospital. However, 22 (40%) patients declined further examination (Figure 1). Finally, 33 patients (median age 81 years; IQR 76–85 years; 51.5% male) underwent second step evaluation. The clinical characteristics of these 33 patients are presented in the Table. The median values of hs-cTnT and BNP in these 33 patients were 0.036 ng/mL and 52.7 pg/mL, respectively. Distributions of hs-cTnT levels at the first and second steps are shown in Figure 3. Twenty-two (66.7%) patients had elevated (≥0.03 ng/mL) hs-cTnT levels at both examinations.

Table.

Clinical Characteristics of Patients at the Second Step of Evaluation (n=33)

Age (years)	81 [76~85]
Male sex	17 (51.5)
Symptoms
NYHA functional class I/II/III/IV	23 (69.7)/10 (30.3)/0 (0)/0 (0)
Chest pain	3 (9.1)
Palpitation	7 (21.2)
Comorbidities
Carpal tunnel syndrome	1 (3.0)
Lumbar canal stenosis	3 (9.1)
Pacemaker implantation	2 (6.1)
Medication
ACEi/ARB	20 (60.6)
β-blocker	1 (3.0)
Diuretics	9 (39.1)
Calcium channel blocker	19 (57.6)
Laboratory data
eGFR (mL/min/1.73 m2)	50.0±16.9
BNP (pg/mL)	52.7 [34.5~142.3]
hs-cTnT (ng/mL)
First step	0.039 [0.034~0.048]
Second step	0.036 [0.026~0.047]
Electrocardiography
Atrial fibrillation	4 (12.1)
Atrioventricular block	8 (24.2)
Low voltage in limb leads	5 (15.2)
Poor R wave progression	9 (27.3)
LVH	4 (12.1)
Bundle branch block	5 (15.2)
Echocardiography
LVDd (mm)	43.8 [41.7~49.2]
LVDs (mm)	26.8 [24.0~32.3]
IVS (mm)	10.4±1.8
PWT (mm)	9.3±1.5
LVH	5 (15.2)
LVEF (%)	61.0 [57.0~62.1]
E/A ratio	0.6 [0.57~0.74]
E/e′ average	9.3 [8.1~12.1]
LAVI (mL/m2)	42.5±12.6
GLS (%)	−17.7 [−15.0~−18.2]
Apical sparing pattern	2 (6.0)
99 mTc-PYP scintigraphy
Grade 0/1/2/3	31 (94.0)/1 (3.0)/0 (0)/1 (3.0)

Data are shown as the mean±SD, median [interquartile range], or n (%). ^{99 m}Tc-PYP, technetium-99 m pyrophosphate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; hs-cTnT, high-sensitivity cardiac troponin T; IVS, interventricular septum; LAVI, left atrial volume index; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; NYHA, New York Heart Association; PWT, posterior wall thickness.

Figure 3.

Changes in high-sensitivity cardiac troponin T (hs-cTnT) levels in patients who underwent the second step of evaluation. Elevated hs-cTnT levels in this study were defined as those ≥0.03 ng/mL (red horizontal line).

The median LVEF in the 33 patients was 61%, and 5 (15.2%) patients had LV hypertrophy (LVH) with LV wall thickness ≥12 mm. The median GLS was −17.7% and an apical sparing pattern was seen in 2 patients. On ^{99 m}Tc-PYP scintigraphy, Grade 3 uptake was seen in 1 patient (Patient #1) and Grade 1 uptake was seen in another patient (Patient #2). Grade 0 uptake was seen in the remaining 31 patients on ^{99 m}Tc-PYP scintigraphy, which was concluded to be negative (Table).

Diagnosis of ATTRwt-CA: Third Step of Evaluation

At the completion of the second step of the study, 2 patients were suspected of having CA and a tissue biopsy (as described below) was performed in both. Of the remaining 31 patients, 12 were diagnosed with heart disease other than CA: aortic valve stenosis in 2 patients, ischemic heart disease in 4 patients (including 2 patients with a history of myocardial infarction), hypertensive heart disease in 5 patients, and pacing-induced LV systolic dysfunction in 1 patient.

In the third step of this study, 2 patients were diagnosed with ATTRwt-CA. Both these patients were male and had elevated (≥0.03 ng/mL) hs-cTnT levels at the first and second steps. Among patients with elevated hs-cTnT at both measurements, the prevalence of ATTRwt-CA was 9.1% (2/22). Among all individuals aged ≥70 years who visited outpatient internal medicine clinics, the prevalence of ATTRwt-CA was estimated to be at least 0.18% (2/1,141). With regard to sex, the prevalence of ATTRwt-CA was at least 0.44% (2/454) in males and 0% (0/687) in females.

Patients With a Diagnosis of ATTRwt-CA

Patient #1 (Figure 4) was an 87-year-old man. In a steady state, he complained of exertional dyspnea with New York Heart Association (NYHA) functional class II. hs-cTnT levels at the first and second steps were 0.057 and 0.072 ng/mL, respectively. An ECG showed LVH. Echocardiography showed LVEF of 58.5%, diffuse LVH (LV wall thickness of 13–16 mm), and pericardial effusion. GLS was −11.1% and an apical sparing pattern was observed (apical LS/basal LS=13.3). ^{99 m}Tc-PYP scintigraphy showed Grade 3 uptake. CA was strongly suspected on the basis of these findings. TTR amyloid deposition was revealed by abdominal fat biopsy. This patient was clinically diagnosed with ATTRwt. (The patient did not want to have genetic testing.)

Figure 4.

Patient #1 was an 87-year-old male. (A) Electrocardiography showed left ventricular hypertrophy (LVH) by voltage criteria. (B,C) Echocardiography showed a left ventricular ejection fraction of 58.5%, diffuse LVH, and pericardial effusion. Global longitudinal strain (GS) was 11.1% and an apical sparing pattern was observed. (D,E) Technetium-99 m pyrophosphate scintigraphy showed Grade 3 uptake. (F) Amyloid deposition was confirmed by Congo red staining of abdominal fat.

Patient #2 (Figure 5) was a 77-year-old male. In a steady state, he complained of mild exertional dyspnea with NYHA functional class II. hs-cTnT levels at the first and second steps were 0.033 and 0.041 ng/mL, respectively. An ECG showed atrial fibrillation and complete left bundle branch block. Echocardiography showed LVEF of 59%, diffuse borderline LVH (LV wall thickness of 11 mm) and reduced GLS (−11.4%) with an apical sparing pattern (apical LS/basal LS=2.4). ^{99 m}Tc-PYP scintigraphy showed Grade 1 uptake. Although scintigraphy was negative for CA, clinical findings, including a persistently elevated hs-cTnT level, and ECG and echocardiographic findings suggested CA, and we decided to perform EMB upon obtaining patient consent. EMB revealed TTR amyloid deposition in the right ventricle. The absence of a TTR gene mutation was confirmed by genetic testing, and a diagnosis of ATTRwt-CA was finally made.

Figure 5.

Patient #2 was a 77-year-old male. (A) Electrocardiography showed atrial fibrillation and complete left bundle branch block. (B,C) Echocardiography showed a left ventricular ejection fraction of 59% and diffuse borderline left ventricular hypertrophy. Global longitudinal strain (GS) was −11.4% and an apical sparing pattern was observed. (D,E) Technetium-99 m pyrophosphate scintigraphy showed Grade 1 uptake. (F) Amyloid deposition was confirmed by Congo red staining of the myocardium.

Discussion

To the best of our knowledge, this is the first report on a prospective screening investigation using hs-cTnT for ATTRwt-CA in elderly outpatients. There are 2 major findings of this study. First, we identified 2 undiagnosed ATTRwt-CA patients by conducting simple hs-cTnT measurement. The prevalence of ATTRwt-CA was 9.1% in the elderly population with persistently elevated hs-cTnT levels in primary care practice. Measurement of hs-cTnT appears to be a reasonable diagnostic tool for detecting ATTRwt-CA in a community-based setting. The second major finding of this study is that the estimated prevalence of ATTRwt-CA was at least 0.18% in this elderly outpatient population. This study is meaningful in that it demonstrated the approximate prevalence of ATTRwt-CA with a simple screening tool in primary care practice prior to hospitalization for HF and before referral to a specialized cardiovascular hospital.

Utility of hs-cTnT as a Diagnostic Tool for ATTRwt-CA in Community-Based Settings

High-sensitivity cardiac troponins, including hs-cTnT, have been shown to be useful for diagnosing CA.^2,9,10 We previously reported that hs-cTnT showed high sensitivity (97.1%) and high negative predictive value (93.9%) for ^{99 m}Tc-PYP scintigraphy positivity among patients with clinically suspected CA.¹² Recently, Vergaro et al. also reported a good diagnostic performance of hs-cTnT for CA from 3 tertiary referral centers.²¹

Increasing the awareness of ATTRwt-CA not only among cardiologists but also among general clinicians in primary care practice will be important for identifying patients with undiagnosed ATTRwt-CA. Unlike ECG or echocardiography, hs-cTnT can be easily measured in clinical practice without any limitations due to technical challenges. We evaluated whether this simple hs-cTnT-based approach would be a useful diagnostic strategy for ATTRwt-CA in an unselected outpatient population in general medicine. As a result, of the 1,141 elderly individuals, at least 22 showed elevated hs-cTnT levels in 2 measurements. Among the patients with persistently elevated hs-cTnT levels, the prevalence of ATTRwt-CA was 9.1% (2/22). In the 2 patients who were diagnosed with ATTRwt-CA in this study, 1 had a typical presentation but with no previous suspicion of CA and the other was in the early stage of ATTRwt-CA. Both patients had elevated hs-cTnT levels at remeasurement. In terms of the diagnostic usability of hs-cTnT for ATTRwt-CA, measurement of hs-cTnT appears to be a reasonable screening tool for detecting ATTRwt-CA in primary care practice.

Regarding the cut-off value of hs-cTnT, we selected patients with hs-cTnT ≥0.030 ng/mL for a second evaluation based on previous reports.^9,11,12 In addition, in our previous cohort, a few patients with ATTRwt-CA, especially patients in an early disease stage, had hs-cTnT levels <0.030 ng/mL at the time of diagnosis of ATTRwt-CA.^12,22 Therefore, if we had set a cut-off value of hs-cTnT lower than ≥0.030 ng/mL, we may have found more patients with ATTRwt-CA, increasing the higher prevalence of ATTRwt-CA in this study. However, hs-cTnT levels generally increase with renal dysfunction. A lower threshold would likely result in unnecessary additional evaluations in many patients. In the future, consideration should be given to an appropriate cut-off value of hs-cTnT.

Prevalence of ATTRwt-CA

There are several reports about the prevalence of ATTRwt-CA in elderly patients. It was reported that ATTRwt-CA was detected in 13–40% of elderly HFpEF patients^6,7 and in 12% of patients with severe aortic stenosis.⁸ The prevalence of ATTRwt-CA in the general population and in patients without HF remains unclear.

In the present study, we tried to reveal the prevalence of ATTRwt-CA in elderly outpatients without a history of hospitalization for HF in an outpatient setting using hs-cTnT measurement. Because 40% of individuals with elevated hs-cTnT levels could not be evaluated in the second step of this study, the actual prevalence of ATTRwt-CA may have been underestimated. In our entire study population, the prevalence of ATTRwt-CA in primary care practice was estimated to be at least 0.18% (2/1,141), and 0.37% (2/454) among male patients.

Some recent studies have reported on the prevalence of ATTR-CA in individuals with no symptoms or no previous suspicion of CA. In patients undergoing whole-body bone scintigraphy for any reason, the prevalence of positive bone scintigraphy suggesting ATTR-CA was estimated to be in the range 0.36–2.78%.^23,24 Almost simultaneously with our study, Aimo et al. reported that the prevalence of ATTRwt-CA in elderly subjects aged ≥65 years was 0.46% based on comprehensive screening in a cohort of the general population in Italy.²⁵ Aimo et al. concluded that ATTRwt-CA is uncommon in the general elderly population, but more frequent than expected for a rare disease.

Considering previous reports and our current data collectively, it is presumed that there are still underdiagnosed patients with CA in the general elderly population in the current aging society. In clinical practice, we do not recommend routinely measuring hs-cTnT in elderly people to diagnose ATTRwt-CA. However, when general physicians, not just cardiologists, observe findings that may be related to amyloidosis, such as carpal tunnel syndrome, HF symptoms, and ECG abnormalities, this biomarker would be useful in determining whether or not to proceed with further investigations.

Study Limitations

This study has some limitations. First, 22 of the 55 patients with elevated hs-cTnT levels were not examined in the second step. The prevalence of ATTRwt-CA in those patients is unknown. Second, there may be some patients with ATTRwt-CA among the patients who were negative on screening. Therefore, the prevalence of ATTRwt-CA may have been underestimated. Third, the number of patients in the cohort was relatively small and the data were obtained from a local rural area. A study with a larger cohort is needed. Finally, genetic testing was not performed for 1 patient with diagnosed ATTRwt-CA. In that patient, clinical presentation at an advanced age without signs indicative of hereditary ATTR amyloidosis supported the diagnosis.

Conclusions

In our exploratory prospective screening using hs-cTnT to detect ATTRwt-CA, the prevalence of ATTRwt-CA was 9.1% among outpatients with persistent elevation of hs-cTnT levels in community-based settings. Measurement of hs-cTnT will make it possible to screen for undiagnosed ATTRwt-CA in primary care practice.

Sources of Funding

None.

Disclosures

T.K. and H.K. have received consulting fees or honoraria and remuneration for lectures from Pfizer Japan Inc. H.K. is also a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

The Ethics Committee on Medical Research of Kochi Medical School approved this prospective study (Reference no. ERB-106740).

Data Availability

The deidentified participant data will not be shared.

References

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