Key Information
Objectives
This study has been conducted to investigate the non-invasive diagnostic journey of patients with a transthyretin amyloid cardiomyopathy (aTTR-CM) in Turkey, identify the challenges and uncertainties encountered on the path to diagnosis from the perspectives of expert physicians, and develop recommendations that can be applied in such cases.
Methods
This study employed a three-round modified Delphi method and included 10 cardiologists and five nuclear medicine specialists. Two hematologists also shared their expert opinions on the survey results related to hematological tests during a final face-to-face discussion. A consensus was reached when 80% or more of the panel members marked the “agree/strongly agree” or “disagree/strongly disagree” option.
Results
The panelists unanimously agreed that the aTTR-CM diagnosis could be established through scintigraphy (using either 99mTc-PYP, 99mTc-DPD, or 99mTc-HMPD) in a patient with suspected cardiac amyloidosis (CA) without a further investigation if AL amyloidosis is ruled out (by sFLC, SPIE and UPIE). In addition, scintigraphy imaging performed by SPECT or SPECT-CT should reveal a myocardial uptake of Grade ≥2 with a heart-to-contralateral (H/CL) ratio of ≥1.5. The cardiology panelists recommended using cardiovascular magnetic resonance (CMR) and a detailed echocardiographic scoring as a last resort before considering an endomyocardial biopsy in patients with suspected CA whose scintigraphy results were discordant/inconclusive or negative but still carried a high clinical suspicion of aTTR-CM.
Conclusion
The diagnostic approach for aTTR-CM should be customized based on the availability of diagnostic tools/methods in each expert clinic to achieve a timely and definitive diagnosis.
1. Introduction
Cardiac amyloidosis (CA) was previously considered a rare form of restrictive cardiomyopathy leading to mortality, but it is now increasingly recognized as a contributing factor to heart failure (HF) in elderly patients, particularly those with preserved ejection fraction (1external link, opens in a new tab, 2external link, opens in a new tab). Light chain amyloidosis (AL) and transthyretin amyloid cardiomyopathy (aTTR-CM) are the most common forms encountered in CA diagnosis (3external link, opens in a new tab). aTTR-CM is further classified into two subtypes based on the sequence of the TTR protein: wild-type (wtTTR) and hereditary (vTTR), the latter resulting from genetic variants in the TTR gene. Although AL-CA is a rare condition with an estimated incidence of 8–12 cases per million individuals, emerging data suggest that aTTR-CM is not uncommon, particularly due to wtTTR (1external link, opens in a new tab, 4external link, opens in a new tab–6external link, opens in a new tab). Recent reports using contemporary diagnostic strategies estimate that the prevalence of wtTTR is as high as 10%–16% among older patients diagnosed with heart failure or aortic stenosis (7external link, opens in a new tab–9external link, opens in a new tab). However, CA in general remains an under detected cause of heart failure, which is associated with high mortality if not treated appropriately during the early stages of the disease (10external link, opens in a new tab).
In Turkey, the prevalence, incidence, and survival rates of heart failure were on par with those in Western countries. However, a notable difference was observed in the age of onset, with HF manifesting 8–10 years earlier in the Turkish population (11external link, opens in a new tab). Although there is currently a lack of epidemiological data on TTR mutations in Turkey, a recent diagnostic study using multicenter next-generation sequencing (NGS) technology was conducted at 23 centers across Turkey suggested that TTR mutations were rare in Turkey, with only one TTR mutation identified among 392 patients with hypertrophic cardiomyopathy (HCM) (12external link, opens in a new tab). Another multicenter, national, observational study examined 886 patients who applied to the cardiology clinics in 22 centers managed to identify 15 (1.69%) patients with CA who were diagnosed by endomyocardial biopsy (13external link, opens in a new tab). A prospective, observational, single-center study from Turkey also reported 15 patients (17.6%) with a positive specific scintigraphy result, confirming the presence of ATTR-CA among 85 patients with heart failure with preserved ejection fraction (HFpEF) (14external link, opens in a new tab).
Endomyocardial biopsy also has been described as the gold standard for the diagnosis of aTTR-CM by ESC 2021 guideline, with approximately 100% sensitivity and specificity only if specimens are collected from >4 multiple sites and tested for amyloid deposits using Congo red staining (15external link, opens in a new tab, 16external link, opens in a new tab). However, one biopsy result cannot eliminate amyloidosis possibility when there is a high clinical suspicion, and there can be false negative results from superficial and inadequately prepared and dyed samples. In addition, there are several concerns on serious acute or delayed complication risks of endomyocardial biopsies for patients such as perforation with pericardial tamponade, pneumothorax, and puncture of the central arteries (17external link, opens in a new tab). Several studies have attempted to assess the sensitivity and specificity of non-invasive methods for the diagnosis of aTTR-CM. Current literature indicates that establishing the diagnosis of aTTR-CM is possible primarily through the use of technetium-labeled cardiac scintigraphy [99mTc-pyrophosphate (99mTc-PYP), 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), and 99mTc-hydroxymethylene diphosphonate (99mTc- HMDP) scintigraphy]. This method involves planar and SPECT imaging and has a specificity and positive predictive value of up to 100% when the results of serum free light chain assay (sFLC) and serum and urine protein electrophoresis with immunofixation (SPIE and UPIE) excluded AL-CA (18external link, opens in a new tab).
The task force recommendations on the diagnosis and treatment of CA and guidelines for the diagnosis and treatment of acute and chronic heart failure published by the European Society of Cardiology (ESC) outlined and proposed similar diagnostic algorithms for aTTR-CM (16external link, opens in a new tab, 19external link, opens in a new tab). In addition, the multidisciplinary consensus published by the American Society of Nuclear Cardiology (ASNC) with expert representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), the American Society of Echocardiography (ASE), the European Association of Nuclear Medicine (EANM), the Heart Failure Society of America (HFSA), the International Society of Amyloidosis (ISA), the Society for Cardiovascular Magnetic Resonance (SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) broadly defined the appropriate use and interpretation of echocardiography, cardiovascular magnetic resonance (CMR), and technetium-labeled cardiac scintigraphy in patients with an established or suspected CA diagnosis (20external link, opens in a new tab). Current literature and guidance on CA diagnosis also emphasize the importance of clinical context and the crucial need to exclude AL amyloidosis. However, the definitions and recommendations in the related guidelines and consensus studies were developed based on the assumption that all diagnostic methods are available in clinics; all quality, standardization, and accreditation requirements are met; and all specialists have ideal experience with these diagnostic criteria and imaging methods.
Despite that the recommendations from international expert societies provide important guidance to physicians for the diagnosis and treatment of diseases, they may fall short in offering solutions for situations where physicians have difficulty in establishing a diagnosis in actual clinical practice within the scope of capabilities of their clinics. The heterogeneity of patients with CA as well as the incapacity of diagnostic tools make it difficult to diagnose aTTR-CM.
These challenges lead to differences in diagnostic approach across different centers and significant delays to achieve accurate diagnosis in Turkey as well as in many other developed and developing countries (21external link, opens in a new tab). This study has been conducted to investigate the non-invasive diagnostic journey of patients diagnosed with aTTR-CM in Turkey, identify the challenges and uncertainties encountered on the path to diagnosis from the perspectives of expert physicians, and develop practical recommendations that can be applied in such cases.