The quintessential form of diastolic heart failure in older adults: Wild type transthyretin cardiac amyloidosis

Abstract Wild‐type transthyretin cardiac amyloidosis (ATTRwt) is now recognized as a common cause of heart failure with preserved ejection fraction (HFpEF). In this review, we aim to describe the unique epidemiologic, pathophysiologic, and clinical features associated with ATTwt cardiac amyloidosis. Compared to other etiologies of HFpEF, ATTRwt cardiac amyloidosis affects almost exclusively older adults, demonstrating a characteristic age‐dependent penetrance that impacts both the diagnosis and treatment of the disease. In addition, ATTR cardiac amyloidosis demonstrates a unique pathophysiology in contrast to other etiologies of HFpEF, which results in a characteristic phenotype that can raise suspicion for ATTRwt cardiac amyloid in the appropriate demographic. With these distinguishing features in mind, we aim to describe the specific signs, symptoms, and imaging characteristics associated with ATTRwt cardiac amyloidosis, including the role of nuclear scintigraphy that has essentially eliminated the need for biopsy in most patients with suspected disease. Finally, we review the evidence behind the available therapeutic agents, as well as those under investigation, which will change the way we manage older patients with ATTRwt cardiac amyloidosis in the coming years.

autopsy studies. For example, in a cohort of 85 patients over 80 years of age evaluated for systemic amyloid deposition at autopsy, 25% of myocardial specimens demonstrated cardiac amyloid deposition. 3 Another study of 256 autopsy specimens from patients over 85 years of age identified a similar 25% prevalence of myocardial amyloid deposition. 4 While both studies suggest high histologic prevalence, the clinical significance of these findings, specifically their relation to prevalence and incident HF was not clear. To clarify the relationship between HF and amyloid deposition, another autopsy study among those with a diagnosis of clinical HFpEF (n = 109) found that ATTR amyloid deposition was sufficient to explain the phenotype in 5% of the sample. 5 Notably, among those diagnosed with HFpEF at an age of less than 65 years, no amyloid deposition was observed at autopsy as compared to patients with HFpEF over 80, where ATTRwt was found in 40% of patients. A more recent prospective study among 120 hospitalized older patients with HFpEF and increased ventricular wall thickness (>12 mm) on echocardiography used nuclear scintigraphy to screen for transthyretin cardiac amyloidosis, revealing diffuse myocardial retention of the radiotracer, DPD, consistent with ATTRwt cardiac amyloidosis in 13% of the cohort. 6 In this study, the patients with ATTRwt cardiac amyloidosis were also on average older than those with other etiologies of HFpEF with a mean age of 86 vs 81 years. Importantly, an equal number of men and women were identified as having ATTRwt cardiac amyloidosis using this active ascertainment approach. This is in contrast to previously reported sex and racial differences between ATTRwt and those with hereditary transthyertin cardiac amyloidosis (ATTRh), with ATTRwt more commonly diagnosed in white men. 7,8 The results of a very recent analysis of patients hospitalized for HF again support the higher prevalence of this disease than previously recognized, delineating a prevalence of cardiac amyloidosis to be 55 per 100 000 HF hospitalizations in the United States in 2012 prior to the advent of a non-biopsy approach to diagnosis. 9 The definition of a rare disease in the United States is one that affects less than 200 000 patients and in Europe, is defined as one that affects less than one in every 2000 patients. This translates to a prevalence of less than 50 to 60 per 100 000 patients. 10 Therefore, it is very likely that ATTR cardiac amyloidosis may not represent a rare disease among older patients hospitalized with HFpEF.
It is also worth noting the age dependent penetrance of ATTRwt cardiac amyloidosis. This is important to consider when comparing to patients with ATTRh, which is an autosomal dominant disease due to mutation in TTR gene. 7 Compared to patients with ATTRh cardiac amyloidosis, ATTRwt patients tend be older in age at diagnosis compared to patients with ATTRh, though this is dependent on the mutation in cases of hereditary ATTR. One 2012 study among a cohort of 65 patients with ATTR cardiac amyloidosis reported the average age at diagnosis of ATTRwt to be 77 vs 71 years for ATTRh with a V122I mutation, the most common ATTR mutation implicated in ATTRh in the United States. 11 In the same, now larger cohort of 300 patients, the average age at diagnosis of ATTRwt is 77 years while the average age of diagnosis of ATTRh is younger (Figure 1). For the two most common TTR mutations in the United States, mean age at diagnosis for the V122I mutation was 71 years and for the Thr60Ala mutation was 57. Notably, there are some patients diagnosed with ATTRwt cardiac amyloidosis as early as age 47. 12  None relation) and symptoms of HF. 13,14 Infiltration of the conduction system also leads to various arrhythmias including atrial fibrillation, bundle branch blocks, and other bradyarrhythmias. In addition to the myocardium, amyloid deposition may also occur in peripheral nerves, manifesting clinically as motor, sensory, or autonomic neuropathies. A neuropathic phenotype is more common in some patients with ATTRh depending on the particular mutation, but is relatively rare in subjects with ATTRwt cardiac amyloidosis. 7 The gastrointestinal manifesta- slowly progressive process that likely begins years or even decades before the diagnosis is typically made. 15 The described changes can be quantified with pressure-volume analyses by reduction in end systolic elastance, a measure of chamber contractility, and increased effective arterial elastance (Ea), a measure of vascular load dependent on peripheral resistance and heart rate. 14 As a result, ATTR cardiac amyloidosis leads to a unique HFpEF phenotype that occurs without concomitant hypertension. The diagnosis should therefore be considered in an advanced age adult with HFpEF and low or normal blood pressure or in whom antihypertensive therapy is being de-prescribed. reported the prevalence of low voltage to be 60% when using Sokolow index (sum of R wave in V 1 and the largest of S wave in V 5 or V 6 ), 34% when using limb lead criteria (<0.5 mV), and 13% when using precordial lead criteria (<1 mV). The Sokolow index showed a significant association with adverse outcomes including hospitalization, transplant and death. 25 The combination of low voltage on ECG with increased ventricular thickness on echocardiogram should raise suspicion for the diagnosis. In accordance, Quarta and colleagues studied the ratio of total QRS voltage to LV wall thickness to predict the presence of cardiac amyloidosis (ATTR and AL) among other causes of increased wall thickness, such as hypertrophic cardiomyopathy or hypertensive heart disease. 26 In this multicenter retrospective study based on pooled data from amyloidosis referral centers, 262 patients with cardiac amyloidosis of any etiology were studied, including AL (n = 161), ATTRh (n = 71), and ATTRwt (n = 30) and controls included subjects with hypertrophic cardiomyopathy or hypertensive heart disease (n = 298). The total QRS score, the sum of voltages in the limb and precordial leads, divided by the LV wall thickness indexed to height^2.7 had the best diagnostic performance in males (LR 3.6). In females, this method also had high diagnostic performance (LR 3.1) similar to numerous other indices. In this analysis and in others, a pseudo-infarct pattern is another ECG feature that is more common than low voltage, seen in 70% of patients with ATTR cardiac amyloidosis, and thus more sensitive than low voltage. 25 When the pseudo-infarct is present in an older patient, there is the potential to misattribute the ECG findings to underlying coronary artery disease as opposed to ATTR cardiac amyloidosis. Additionally, a positive troponin, attributable to myocardial apoptosis from amyloid infiltration, may be present and can be inappropriately assumed to be the result of an acute coronary syndrome, sometimes leading to invasive assessments. 27 Conduction abnormalities on ECG are also extremely common in cardiac amyloidosis given the infiltrative nature of the disease, though they are not specific and occur commonly with advancing age. Atrial arrhythmias, including atrial flutter and atrial fibrillation, are highly prevalent in ATTRwt cardiac amyloidosis, having a lifetime risk of 90% among patients with ATTRwt cardiac amyloidosis. 28 Heart block and bundle branch block are also very common ECG finding in ATTRwt cardiac amyloidosis and~30% of subjects require permanent pacing over time. A recent study of older patients with conduction disease or HF requiring pacemaker implantation screened patients for ATTR cardiac amyloidosis using nuclear scintigrahy. 29 In this cohort (n = 143, mean age 79), there was a low prevalence of ATTRwt cardiac amyloidosis at 4% (n = 5), though only one quarter of the sample (n = 25) had HF. Larger studies are needed to clarify the prevalence among older adults with HF undergoing pacemaker implantation.

| Noninvasive imaging
Until recently, the gold standard for diagnosis of any form cardiac amyloidosis was endomyocardial biopsy. Given that this is an invasive procedure, often only performed at specialized centers and requiring expertise not only in the performance of the procedure but in the pathological interpretation, this diagnostic modality is less than ideal for many older patients and did not facilitate early diagnosis. However, the role of noninvasive imaging has markedly expanded the diagnostic possibilities and has shown promise in its ability to diagnose the ATTR cardiac amyloidosis without the need for a biopsy.
The first and most common imaging modality that may raise sus- Nuclear scintigraphy is the noninvasive imaging modality that can establish the diagnosis of ATTR cardiac amyloidosis without the need for biopsy. Scintigraphy uses technetium-labeled bisphosphonates to localize amyloid deposition to the heart. Cardiac retention of these radiotracer is scored according to a grading system devised by Perugini et al with grade 0 indicating absent myocardial uptake, grade 1 indicating mild myocardial uptake less than bone, grade 2 indicating moderate myocardial uptake equal to bone, and grade 3 indicating high myocardial uptake greater than bone. 33 Importantly, this modality may identify amyloid deposition before the development of abnormalities on echocardiography or MRI, leading to earlier diagnosis. 34 The consensus for use of scintigraphy as a non-biopsy approach to diagnosis comes from a large cohort study of 1217 patients with suspected cardiac amyloidosis of which 374 had endomyocardial biopsy and all of whom underwent nuclear scintigraphy. 35 For these cases, radiotracer uptake was found to have over 99% sensitivity and 86% specificity for diagnosing ATTR cardiac amyloidosis. Lower specificity in this study resulted from a false positive scan that can occur in cases of AL amyloidosis. However, in the setting of negative serum and urine immunofixation and normal serum free light chain ratio, the positive predictive value for cardiac ATTR amyloid with grade 2 or 3 uptake on nuclear scan was 100%. A subsequent multicenter analysis of 171 patients, 121 with TTR cardiac amyloidosis, not only confirmed the high sensitivity and specificity of scintigraphy but also showed a higher degree of uptake to be associated with worse survival. 36 There are other scintigraphic features used to differentiate AL vs ATTR cardiac amyloidosis. A 2014 study of 45 subjects with cardiac amyloidosis (73% ATTR cardiac amyloidosis, 27% AL amyloid) assessed cardiac retention of radiotracer by calculation of a heart-to-contralateral ratio (H/CL) in which a region of interest is drawn over the heart and corrected for contralateral counts. 37 A H/CL ratio over 1.5 was 97% sensitive and 100% specific for ATTR cardiac amyloidosis. Of note, this ratio and cutoff for diagnosis depends on the time of assessment as the isotope washes out of the myocardium over time. In accordance with the above findings, a diagnostic algorithm has been previously published to facilitate early and accurate diagnosis in the older patient who is suspected to have cardiac amyloidosis (Figure 3)

| Stabilizers, silencers, and degraders
With the emergence of targeted therapies to treat the specific pathophysiology associated with disease, the designation of ATTR cardiac amyloidosis as a universally fatally disease is now challenged. At this point in time, transthyretin stabilizers, which work by preventing tetramer destabilization, the rate limiting step in transthyretin amyloid production, have been studied most extensively. 40 48 Patisiran is a small inferring RNA that has been studied in phase III multicenter controlled trials in patients with ATTR hereditary polyneuropathy. In those with cardiac involvement (n = 126, 56%), patients randomized to treatment with pasitiran showed preserved cardiac output compared to placebo and other indications of less ventricular strain including higher left ventricular end-diastolic volume and lower LV wall thickness and mass. 49 Inotersen is an antisense oligonucleotide drug that inhibits hepatic production of TTR amyloid that has been studied in a phase III trial in patients with hereditary FAP, the majority of whom demonstrated a cardiac phenotype (n = 108, 63%). Administration of the drug in a sample of 172 patients led to improvements in the primary outcome of functional capacity and quality of life assessment though no difference in ventricular strain over time. 50 Both approaches to TTR silencing are being applied to ATTRwt cardiac amyloidosis, with phase III trials anticipated in late 2019 and early 2020.

| Future directions
ATTRwt cardiac amyloidosis is a disease with an age-dependent pene-