Corresponding Author
Key Words: amyloidosis, biomarkers, cardiac troponin, cardiomyopathy, diagnostic performance, transthyretin amyloid cardiomyopathy
Cardiac amyloidosis is an infiltrative cardiomyopathy (CM), which is characterized by the accumulation of amyloid fibrils in the extracellular matrix in the myocardium, leading to progressive organ dysfunction. The majority of amyloid CM cases are due to misfolding of 1 of 2 proteins: 1) monoclonal immunoglobulin light chain (AL) produced in bone marrow plasma cell disorders; and 2) transthyretin (TTR), a thyroxine and retinol transport protein predominantly produced by the liver.1
Transthyretin amyloid cardiomyopathy (ATTR-CM) due to an idiopathic etiology is associated with aging and referred to as wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). ATTR-CM caused by pathogenic variants of TTR is referred to as variant transthyretin amyloid cardiomyopathy (ATTRv-CM). The most common mutation in the United States is the valine-to-isoleucine substitution at position 122 (pV142I), which is carried by 3.5% of African Americans, resulting in 1.5 million allele carriers in the country.2 Data suggest that the prevalence of ATTR-CM is much higher than previously established, especially in older patients with heart failure. Given a median survival of 3.5 years in untreated ATTRwt-CM and 2.5 years in untreated ATTRv-CM (pV142I subtype), early recognition of this disease is crucial to initiate disease-modifying therapies, which can significantly impact survival and quality of life.3 Currently, the diagnostic algorithm for ATTR-CM includes monoclonal protein testing to rule out AL amyloidosis and technetium-99m pyrophosphate scintigraphy (Tc-99m-PYP) to noninvasively diagnose the disease accurately, bypassing the need for endomyocardial biopsy in most cases.
Several mechanisms can lead to myocardial injury in patients with ATTR-CM: amyloid precursor toxicity, amyloid interstitial infiltration, amyloid vascular involvement, and nonamyloid related causes such as diastolic/systolic dysfunction, atherosclerotic coronary artery disease, coronary microvascular dysfunction, hypotension, and tachyarrhythmias.4 Cardiac biomarkers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) have predominantly played a prognostic role in cardiac amyloidosis. Kristen et al5 noted that even minimally raised plasma cardiac troponins are associated with worse prognosis of patients with AL amyloidosis, and surpassed well-established predictors of survival in patients with AL. However, few studies have investigated the diagnostic utility of these cardiac biomarkers, which can serve to further expedite the diagnostic pathway of ATTR-CM, especially in non–tertiary care centers, which might not have access to advanced imaging techniques.6
Vergaro et al7 evaluated the diagnostic value of NT-proBNP and hs-cTnT in a cohort of patients from Italy, France, and United Kingdom and found that cutoffs of NT-proBNP <180 ng/L and hs-cTnT <14 ng/L reliably excluded the diagnosis of cardiac amyloidosis; 66% of patients had cardiac amyloidosis in the derivation cohort. This study included patients being evaluated for both AL/ATTR amyloidosis, 2 groups with different biomarker characteristics. However, the diagnostic impact of NT-proBNP and hs-cTnT has not been investigated in a U.S. cohort of patients.
In this issue of JACC: CardioOncology, Michieli et al8 examine the predictive value of hs-cTnT and NT-proBNP in patients undergoing Tc-99m-PYP for suspected ATTR-CM in a large U.S. cohort of 1,442 patients. For the study, patients who underwent Tc-99m-PYP between 2013 and September 2022 at the Mayo Clinic (Rochester, Minnesota, USA) and had at least 1 hs-cTnT available within 6 months of pyrophosphate scintigraphy imaging were included; 1,378 of 1,442 patients also had NT-proBNP levels assessed. Michieli et al present several interesting findings in the first large retrospective study in a U.S. cohort to assess the diagnostic role of serum cardiac biomarkers in ATTR-CM.
In this study, 29.6% of patients were diagnosed with ATTR-CM, and 93% were men, with a median age of 77 years. Patients with ATTR-CM had higher median hs-cTnT and NT-proBNP levels when compared with patients without ATTR-CM. Very low hs-cTnT levels of <6 ng/L had a 100% sensitivity and negative predictive value (NPV) of ruling out ATTR-CM, which only represented 3.5% of the cohort. Similarly, low levels of NT-proBNP of <60 ng/L revealed 100% sensitivity and NPV, but such low levels were only found in 3.8% of the cohort; higher thresholds for both biomarkers resulted in higher false negative results. The percentage of patients with chronic kidney disease (CKD) who were appropriately ruled out was even lower. The combination of both biomarkers, hs-cTnT of <14 ng/L and NT-proBNP of <60 ng/L, had 100% sensitivity and NPV for ruling-out ATTR-CM (present in 3.3% of the cohort). In contrast, high levels of both hs-cTnT and NT-proBNP had low positive predictive value in ruling in ATTR-CM.
It is important to consider that the presence of any false negative results can be detrimental in the diagnostic algorithm of ATTR-CM, given the current availability of disease-modifying, agents which have a significant impact on patient survival, disease progression, and quality of life. Despite the presence of inherent referral bias in a retrospective study, it is impressive that low levels of hs-cTnT of <14 ng/L and NT-proBNP of <60 ng/L had 100% sensitivity and NPV for ruling out ATTR-CM; however, these low levels were present in <4% of the cohort, and only 29.6% of the patients received a final diagnosis of ATTR-CM in the study, pointing to a lower disease prevalence in this select cohort, which can interfere with the generalizability of study results. Furthermore, the majority of the patients were older men with ATTRwt-CM, so the diagnostic significance of biomarkers in patients with ATTRv-CM was not assessed, and it would be relevant to compare the performance of biomarkers in both ATTRwt-CM and ATTRv-CM. It also raises the question whether the cardiac biomarkers might behave differently from a diagnostic standpoint in various TTR pathogenic mutations, depending on the disease stage.
Additionally, studies have shown that cardiac biomarkers are elevated in patients with cardiac amyloidosis due to a multitude of mechanisms, which likely played a role in the poor positive predictive value of hs-cTnT and NT-proBNP for ruling in ATTR-CM. In terms of this study’s baseline patient characteristics and demographics, NYHA functional class for heart failure and body mass index were not specified, which could have an important impact on hs-cTnT and NT-proBNP levels and confound the study findings. Although ATTR-CM is now being increasingly recognized in the medical community, these patients are generally referred to specialists later during the disease course, possibly at more advanced stages of heart failure, and it would be interesting to note the predictive value of cardiac biomarkers at different stages of heart failure.
Another confounding variable in the diagnostic interpretation of cardiac biomarkers is the presence of CKD; 21.5% of patients with ATTR-CM also had CKD in the study, and the percentage of patients appropriately ruled out was very low in this subset. The prevalence of CKD ranges anywhere from 10% to 50% of patients with symptomatic ATTRv-CM in different cohorts, and the late onset of amyloid symptoms (>60 years of age) is strongly linked to CKD.9 Because CKD itself can elevate biomarker levels, further dedicated studies are warranted to elucidate the impact of CKD on diagnostic performance of biomarkers and to potentially propose appropriate diagnostic cutoff values.
The current analysis is instrumental in presenting the first large U.S. cohort study describing the predictive values of hs-cTnT and NT-proBNP in patients undergoing Tc-99m-PYP for suspected ATTR-CM. While the study suggests that cardiac biomarkers in patients undergoing Tc-99m-PYP as part of a noninvasive diagnostic pathway for ATTR-CM have limited utility in ruling in disease, it paves the way for future studies to investigate the diagnostic value of hs-cTnT and NT-proBNP in correctly ruling out patients for ATTR-CM and avoiding further unnecessary noninvasive testing.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
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References
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