Statistics from Altmetric.com
In recent years, transthyretin cardiac amyloidosis (ATTR-CA) has transformed from a historically under-recognised disease to a crucial concern in cardiology driven by increased awareness, advent of non-invasive confirmatory algorithms using nuclear scintigraphy and development of effective pharmacological treatments. Approximately 25% of people over 85 years of age have ATTR deposition in the myocardium at autopsy, while severe aortic stenosis (AS) affects >3% of individuals over 75 years. On the background of an ageing population, with both wildtype ATTR-CA and AS highly prevalent in older adults, the coexistence of ATTR-CA with AS (AS-ATTR) is particularly pertinent to cardiologists.
Prior studies have demonstrated that 8%–16% of patients with severe AS have coexistent ATTR (AS-ATTR)1–5 (table 1). Case ascertainment for ATTR-CA in a cohort with AS can be challenging as the two disease entities share common features, including older age, increased left ventricular (LV) wall thickness, diastolic dysfunction and elevated natriuretic peptides. Conceptually, a natural assumption may be that the two pathological processes are summative, specifically that the increased afterload from AS in combination with restrictive filling from infiltration with ATTR would result in more advanced disease and worse outcomes than either entity in isolation.
In the current study, Patel and colleagues6 seek to better characterise the AS-ATTR cohort in comparison with AS alone, ATTR-CA alone, and older age controls without AS or ATTR-CA. A total of 583 patients were recruited from four prospective cohorts: (1) 81 controls from a sample of older adult patients of European origin; (2) 36 patients with AS-ATTR from two prospective observational studies in the UK and Vienna, Austria, in which patients 75 years or older with severe AS referred for a transcatheter aortic valve implantation (TAVI) underwent pre-TAVI nuclear cardiac scintigraphy for ATTR-CA screening, with positive testing defined as Perugini grade 2 or 3 uptake; (3) 359 patients with AS alone from the above cohort with severe AS and a negative ATTR-CA work-up; and (4) and 107 consecutively referred, newly diagnosed patients with ATTR-CA from the UK National Amyloidosis Centre.
Compared with AS alone, AS-ATTR had higher left ventricular mass index (LVMi) (but not significantly different), greater elevation in cardiac biomarkers, worse diastolic function with higher left-sided filling pressures, but similar global longitudinal strain (GLS), and lower LV contractility (as measured by myocardial contraction fraction (MCF)) and longitudinal right ventricular (RV) contractility (as measured by tricuspid annular plane systolic excursion). In general, the cardiac parameters for subjects with AS-ATTR were worse compared with those with AS alone. Compared with ATTR-CA alone, AS-ATTR had lower LVMi, similar RV longitudinal contractility and cardiac biomarkers, but higher LV contractility; the only characteristics that appeared worse were diastolic function and left-sided filling pressures. The latter finding of worse diastolic parameters in AS-ATTR compared with ATTR-CA alone is likely driven by the increased afterload from AS in combination with myocardial amyloid burden. Surprisingly, traditional prognostic markers in ATTR-CA (N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin-T) were no worse in AS-ATTR compared with ATTR-CA alone, which is contrary to what would be expected given the additional haemodynamic insult on the LV from a fixed LV outflow obstruction. As noted by the authors, comparison of characteristics across the four groups suggests that AS-ATTR may be an intermediate phenotype between AS alone and ATTR-CA alone, rather than summative. An alternative hypothesis, however, is that active screening of those with severe AS may elicit earlier detection of ATTR-CA and this intermediate phenotype may simply be reflective of a lower myocardial amyloid burden.
Screening patients with AS for AS-ATTR
Although it is not practical or clinically feasible to screen every patient with AS for coexistent ATTR-CA using nuclear scintigraphy, the data herein provide insight into this unique population. Findings from the current study underscore the importance of maintaining a high clinical suspicion for coexistent ATTR-CA in older patients with AS; with systematic screening, patients with AS-ATTR may be identified at an earlier stage of disease, although with advanced diastolic dysfunction over and above what one would expect with ATTR-CA alone. Previous studies have recommended focused screening of patients with high-yield clues or ‘red flags’ for enrichment to maximise yield of diagnosing AS-ATTR while limiting cost and inconvenience (table 1). Ultimately, the question is which characteristics are most sensitive and specific for coexisting AS and ATTR-CA.
Results from this study suggest that patients with AS-ATTR tend to have higher values for cardiac biomarkers (NT-proBNP and troponin-T), worse diastolic parameters and lower MCF than AS alone.6 However, these were identified as individual predictors and not entered into multivariable models for predicting AS-ATTR, as that was not an intent of the study. Castaño and colleagues2 found independent predictors for AS-ATTR of thicker interventricular septum, higher LVMi, lower stroke volume, higher E/A ratio, lower deceleration time and impaired systolic function, with lower LVEF, MCF, GLS and mitral annular tissue Doppler S’; however, in multivariable models, average S’ best predicted AS-ATTR with a value ≤6 cm/s conferring 100% sensitivity. Nitsche et al 3 found that commonly obtained clinical parameters including low voltage to mass ratio (Sokolow-Lyon index on ECG/LVMi on echocardiogram) and low stroke volume index identified patients with AS-ATTR. Notably, GLS, extracellular volume on cardiac myocardial resonance imaging and MCF had a lower discriminatory ability. A separate study developed a scoring system that incorporated carpal tunnel syndrome, right bundle branch block, age ≥85 years, high sensitivity troponin-I >20 ng/L, interventricular septal thickness ≥18 mm, E/A ratio >1.4 and Sokolow-Lyon index <1.9 mV on ECG; in this study, a score ≥2 points yielded a specificity of 52.1% and a sensitivity of 93.6% for the presence of ATTR-CA in an AS cohort.5 Additionally, AS-ATTR frequently presents with a low-flow, low-gradient AS pattern,7 as was noted in over 50% of those in the study by Nitsche et al.3
Implications of coexisting AS-ATTR
Multiple contemporary studies demonstrated similar survival in those with AS-ATTR compared with AS alone.3–5 7 8 Since there may be treatment inertia due to the complexities of coexistent AS and ATTR-CA, proactive care is indicated because valve intervention in the form of TAVI is critical to ensure improved survival.4 5 7 8 Despite equivalent survival, patients with AS-ATTR experience increased rates of heart failure hospitalisation compared with AS alone.8 In an elderly cohort, quality of life and avoidance of worsening heart failure are key considerations. Hence, even after treatment of AS, appropriate identification of patients with ATTR-CA is vital to facilitating initiation of medical therapy and ATTR-CA-targeted treatment.
Carving through the complexities to a central theme is the need to recognise characteristics suggestive of ATTR-CA in patients with AS and the necessity for a high clinical suspicion to pursue further diagnostic testing, especially in patients with persistent symptoms post-AS intervention. In particular, we recommend screening patients with high-risk features for AS-ATTR as shown in figure 1 and table 1. These include low-flow, low-gradient AS, low voltage to mass ratio, echocardiographic parameters of mitral annular tissue Doppler S’ ≤6 cm/s, decreased MCF, deceleration time <200 ms, high E/A ratio, and those with a history of carpal tunnel syndrome, lumbar spinal stenosis or biceps tendon rupture. By enriching patients with AS for screening based on these characteristics, earlier identification of patients with AS-ATTR may be achieved.
Efforts to characterise AS-ATTR have shed light on fundamental considerations for this unique population.1–5 7 8 However, many unanswered questions remain. First, while there are several proposed screening algorithms for ATTR-CA in patients with AS, the ideal combination of parameters that should trigger additional testing with nuclear scintigraphy remains incompletely defined. Second, although we have well-validated staging systems for ATTR-CA, whether these can be extrapolated to the AS-ATTR population is unclear; in particular, cardiac biomarkers may not be applicable. AS, itself, can result in elevated cardiac biomarkers and renal dysfunction, which are the basis of the most commonly used staging systems and as such may inaccurately classify patients at a higher stage of disease despite a lower myocardial amyloid burden. A potential strategy to determine the extent of amyloid infiltration in this cohort may be obtaining cardiac MRI to estimate native T1 and extracellular volume; however, this is not widely available. Third, a biological question is whether AS may accelerate amyloidosis and whether shear forces increase production of transthyretin (TTR) oligomers leading to more rapid deposition. Also, it is not known if pressure overload in the myocardium from AS may lead to an increase in ATTR amyloidogenicity, causing rapid accumulation of ATTR in the myocardium and possibly the aortic valve. Finally, given differences between the AS-ATTR and ATTR-CA phenotypes, whether there is similar long-term efficacy of ATTR-CA-directed therapies (including TTR stabilisers or RNA knockdown agents) in AS-ATTR requires study.
Patient consent for publication
Contributors Both authors have read and approved the manuscript. Both authors contributed significantly to the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Commissioned; internally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.