The Future for Patients with Transthyretin Cardiac Amyloidosis is Looking Brighter!

“Life can only be understood backward, but it must be lived forwards.”

In this issue of Circulation¹, there is a retrospective report from the National Amyloidosis Center (NAC) in the United Kingdom (UK) on patients evaluated over the last two decades with transthyretin cardiac amyloidosis (ATTR-CA). These data are unique—as they are not only the largest cohort of ATTR-CA patients carefully phenotyped to date but are a nationally representative sample as almost all patients in the UK with amyloidosis are evaluated at the NAC. Additionally, this is a natural history study because the only approved disease-modifying therapy, tafamidis, was not sanctioned by the National Institute for Health and Care Excellence (NICE) and is unavailable widely in the UK, principally because of the high cost.² The authors demonstrate significant improvements in survival over the 20-year period, with shifts in the severity of those diagnosed with ATTR-CA to a more favorable phenotype and early disease stage at diagnosis.

What has led to beneficial changes in the phenotype of those affected with ATTR-CA?

There is an increasing awareness that ATTR-CA has an age-dependent penetrance and is encountered throughout clinical practice, including in those with: heart failure, often but not always in the setting of a preserved ejection fraction (HFpEF),³ significant aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), multiple orthopedic manifestations, or concomitant peripheral or autonomic neuropathy. The emergence of clinical clues and the development of diagnostic algorithms supported by cardiovascular societies^{4, 5} (for the first time there was a specific section dedicated to cardiac amyloidosis in the ACC/AHA/HFSA Guidelines on the Management of Heart Failure⁶) has contributed to the dramatic increase in the number of patients being diagnosed. Advancements in imaging, particularly nuclear scintigraphy that permits a definitive diagnosis of ATTR-CA without biopsy, have simplified the diagnostic approach. A non-biopsy approach has allowed the diagnosis to be made by the initial provider, assuming the right clinical scenario including: a phenotype by echocardiography or cardiac magnetic resonance imaging (cMRI) that is suggestive of ATTR-CA, which often involves increased wall thickness with a non-dilated left ventricle (e.g., high relative wall thickness), no evidence of monoclonal proteins by immunofixation of the serum or urine along with a normal kappa and lambda free light chain assay, and myocardial retention of the technetium isotope confirmed by SPECT imaging. This approach avoids the need to refer patients to centers capable of performing endomyocardial biopsies, as well as delays related to utilization of pathological techniques to confirm transthyretin is the precursor protein causing amyloidosis. Additionally, while cMRI does not have the same specificity as technetium-based imaging for identification of ATTR-CA, features such as inability to null the myocardium and expansion of the extracellular volume often raise suspicion for ATTR-CA in a patient with a previously undefined cardiomyopathy.

In addition to a greater awareness and advances in imaging, the availability of effective disease-modifying therapies contributes to the rising number of patients being diagnosed. Currently available therapies including transthyretin stabilizers and silencers that prevent progressive amyloid deposits in affected organs, thereby stabilizing the phenotype or slowing its progression.^{7, 8} Such therapies are more effective before the onset of significant cardiac dysfunction, which places the current report in appropriate clinical context and is a rationale for the emerging enthusiasm among patients and the clinicians providing care.

Compared to 20 years ago, there has been a >27-fold increase in the last 5 years in the number of patients diagnosed with ATTR-CA. Wild-type ATTR-CA, which was not seen prior to 2007 at the NAC, will become the most common form encountered by clinicians in the future because of the aging worldwide population. Diseases such as ATTR-CA, which afflict mainly individuals who are septuagenarians or older, has seen increases that parallel epidemiologic shifts from the tsunami of adults living to advanced ages. Finally, greater use of genetic testing may underlie changes seen in those who have variant ATTR-CA. Indeed, it is gratifying to see that the greatest improvement in survival was observed among individuals with the Val122Ile variant, who are almost exclusively of West African ancestry and have historically been marginalized and had less access to genetic testing.

What are the implications and clinical importance of these changes?

Our long-term goal is to diagnose ATTR-CA at an early stage of disease and institute therapy to preserve functional capacity, health status and quality of life and to extend long-term survival. Achieving such goals will require addressing several clinical management issues through ongoing research. First, while current data does not support a role for standard heart failure therapy in ATTR-CA patients⁹, with an earlier diagnosis and a less severe phenotype, certain therapies commonly employed for the treatment of HFpEF may prove to be beneficial, including mineralocorticoid receptor antagonists (MRA), angiotensin receptor/neprilysin inhibitors (ARNi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Indeed, SGLT2is may have an important role as the use of high-dose loop diuretics are associated with worse outcomes in patients with ATTR-CA¹⁰ and affected patients can develop a cardiorenal syndrome, which may be ameliorated using SGLT2is. Second, as patients live longer, electrical manifestations including atrial fibrillation and the need for and type of permanent pacing, will require further investigation. While rhythm control strategies, including antiarrhythmics and ablation, have not been shown to affect hard clinical outcomes, with earlier diagnosis such strategies may be beneficial and should be tested. Questions raised include: Is there a role for ablation of atrial fibrillation to maintain sinus rhythm and improve functional capacity and outcomes in patients with ATTR-CA? Do left atrial appendage occlusion devices have efficacy in ATTR-CA patients who have high thromboembolic potential but are also at increased risk for bleeding complications? Is there a benefit from biventricular pacing to maintain ventricular synchrony in ATTR-CA patients who are often pacemaker dependent and have markedly reduced stroke volumes that could decline with chronic right ventricular pacing?

Earlier diagnosis is to be lauded but will impact the development and testing of new therapies. With a lower event rate among those being diagnosed earlier, trial duration may need to be longer and cost for the conduct of such trials may increase. Cost of therapies for ATTR-CA are already too high and further escalations will pose a significant obstacle to widespread and equitable administration. Focusing trial recruitment on more advanced patients with enhancement by demographic, clinical or physiologic parameters is one potential approach. To evaluate the value and cost effectiveness of combination therapy, collaboration using real world, high quality, longitudinal registry data will be invaluable and likely the only way for the amyloidosis community to determine what sequence or combination of therapies is best. Whether cardiac biomarkers or imaging parameters can be leveraged as surrogates to allow for more rapid approval of safe and effective therapies is of intense interest.

Given successes to date, is even earlier diagnosis possible and will it be beneficial?

Efforts in implementation science and emerging screening / active ascertainment programs¹¹ have already begun to facilitate efforts at even earlier diagnosis and have provided invaluable information to inform patients and clinicians. A recently delineated simple clinical score¹² that relies on demographic, clinical, and echocardiographic features, can be leveraged to determine who should be referred for nuclear scintigraphy. Among those with high scores, modeling predicts that 1 in 4 to 5 subjects who have high scores will have ATTR-CA. How the score will perform outside of expert centers and in non-referral populations with a lower pretest probability of disease and among under-represented minorities who are at highest risk of disease because of the Val122Ile variant will require additional prospective study. Additionally, use of deep learning and artificial intelligence in imaging may facilitate earlier diagnosis.¹³ Screening for ATTR-CA among at-risk populations seems appropriate, as many of the World Health Organization criteria¹⁴, have been met, except cost-effectiveness. A recent report¹¹ shows that among older adults who underwent bilateral carpal tunnel surgery (CTS) 5–15 years previously, 4.8% (95% CI: 2.5%−8.2%) had ATTR-CA which was higher in males [8.8% (95% CI: 4.5%−15.2%)] than females. Notably, among males >70 years of age who were not obese (BMI <30 kg/m2) and had no explanation for their CTS, 21.2% (95% CI: 11.1%−34.7%) had ATTR-CA and all who were identified using this approach had early phase disease. Would similar or even better results be obtained for screening programs focused on patients with lumbar spinal stenosis in whom amyloid deposits appear to be more common than among those with CTS?¹⁵ Can routine pathologic examination of explanted orthopedic tissue with Congo Red staining and if positive, laser dissection with mass spectrometry, better identify those who require further evaluation? Or does pathologic assessment add cost without improving the diagnostic yield? Among ATTR-CA patients with early-stage disease, can stabilizers such as diflunisal, which is relatively inexpensive, be safe and effective in treating affected patients? Can we envision the day when we can prevent the development of ATTR-CA through pharmacologic manipulation of transthyretin with stabilizers or gene editing? The field of cardiac amyloidosis is accelerating at a rapid pace, and we have collectively made significant progress, but there is still more to do. We look forward to collaboratively working on the clinical issues that have grown out of our early and recent success. Our patients and their families deserve nothing less.