key: cord-0896524-r01tni1o
authors: Singal, Aayush Kumar; Bansal, Raghav; Singh, Avinainder; Dorbala, Sharmila; Sharma, Gautam; Gupta, Kartik; Saxena, Anita; Bhargava, Balram; Karthikeyan, Ganesan; Ramakrishnan, Sivasubramanian; Bisoi, Akshay Kumar; Hote, Milind Padmakar; Rajashekar, Palleti; Chowdhury, Ujjwal Kumar; Devagourou, Velayoudam; Patel, Chetan; Ray, Ruma; Arawa, Sudheer Kumar; Mishra, Sundeep
title: Concomitant Transthyretin Amyloidosis and Severe Aortic Stenosis in Elderly Indian Population: A Pilot Study
date: 2021-10-19
journal: JACC CardioOncol
DOI: 10.1016/j.jaccao.2021.08.008
sha: 2bb22fcdeac81a2f881473ac2e53f5395226a17e
doc_id: 896524
cord_uid: r01tni1o

BACKGROUND: Prevalence of both degenerative severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR-CA) increases with age. Dual disease (AS+myocardial ATTR-CA) occurs in significant proportion of patients undergoing surgical aortic valve replacement (SAVR). OBJECTIVES: This study aimed to determine the prevalence of ATTR-CA in severe AS in the Indian population, identify noninvasive predictors of its diagnosis, and understand its impact on prognosis. METHODS: Symptomatic severe AS patients aged ≥65 years undergoing SAVR were enrolled. ATTR-CA diagnosis was based on preoperative 99m-technetium pyrophosphate (PYP) scan and intraoperatively obtained basal interventricular septum biopsy for myocardial ATTR-CA, and excised native aortic valve for isolated valvular ATTR-CA. Primary amyloidosis was excluded by serum/urine protein electrophoresis with serum immunofixation. RESULTS: SAVR was performed in 46 AS patients (age 70 ± 5 years, 70% men). PYP scan was performed for 32 patients, with significant PYP uptake in 3 (n = 3 of 32, 9.4%), suggestive of myocardial ATTR-CA. On histopathological examination, none of the interventricular septum biopsy specimens had amyloid deposits, whereas 33 (71.7%) native aortic valves showed amyloid deposits, of which 19 (57.6%) had transthyretin deposition suggestive of isolated valvular amyloidosis. Noninvasive markers of dual disease included low myocardial contraction fraction (median [interquartile range], 28.8% [23.8% to 39.1%] vs 15.3% [9.3% to 16.1%]; P = 0.006), deceleration time (215 [144 to 236] ms vs 88 [60 to 106] ms; P = 0.009) and global longitudinal strain (-18.7% [-21.1% to -16.9%] vs -14.2% [-17.0% to -9.7%]; P = 0.030). At 1-year follow-up, 2 patients died (4.3%); 1 each in myocardial ATTR-CA negative and positive groups (3.4% vs 33.3%; P = 0.477). CONCLUSIONS: Dual disease is not uncommon in India. Isolated valvular amyloidosis in severe AS is much more common.

T he prevalence of both degenerative severe aortic stenosis (AS) and transthyretin (TTR) cardiac amyloidosis (ATTR-CA) increases with age (severe AS in w3% of patients aged >75 years and ATTR-CA in w25% of those >80 years) (1) (2) (3) . Multiple studies suggest that ATTR-CA may act as a disease and prognosis modifier in patients with severe AS (4) (5) (6) (7) . The prevalence of ATTR-CA is notably higher in patients with severe AS, especially among those with lowflow, low-gradient (LfLg) AS. Up to 6% of those undergoing surgical aortic valve replacement (SAVR) and 15% of those undergoing transcatheter aortic valve replacement (TAVR) have been shown to have ATTR-CA (5, 6) . Presence of ATTR-CA influences the management and clinical course of AS by distorting the severity assessment of AS and also by worsening the prognosis (5, 8) .

Whether this is by chance or there is a cause-andeffect relationship is not clear as of now. However, it appears that this coexistence leads to worsening of symptoms and a less-than-expected response to standard therapy. These patients tend to fare poorly as compared to those with lone AS, despite aortic valve replacement (TAVR or SAVR).

With the advent of TAVR, the number of patients undergoing aortic valve replacement (AVR) is increasing, thus making it pertinent that this group of patients with dual disease (AS þ ATTR-CA) is identified preoperatively by noninvasive methods so that beyond AVR for severe AS, these patients are also considered for medications directed against the accumulating myocardial TTR deposits.

ATTR-CA is a disease with known racial and ethnic variations in its distribution and prevalence (9) .

Considering the lack of data regarding concomitant existence of ATTR-CA and severe AS in the Asian/ Indian context, we planned this study to determine the prevalence rate of this dual disease in India, identify noninvasive predictors of its diagnosis, and study its impact on prognosis. Taking into consideration the burden of senile severe AS in India which merits AVR, even a small relative percentage would amount to a large absolute number of patients with ATTR-CA. Because no research work in this field was previously reported from low and low-middle-income countries such as ours, this was designed as a pilot study, targeting a sample size of 50 patients. By the time the coronavirus disease-2019 pandemic began, 46 patients had been recruited, and the study was stopped at that point. Figure 1 were acquired with heart in the center of field of view.

If blood pool activity was suspected in the images at 1 hour, the scan was repeated at 3 hours post-injection. For subtyping the amyloid detected on congo red staining, immunohistochemistry (IHC) using specific Table 1 . Dual AS + ATTR-CA in Elderly Indian Patients Values are n (%) or median (interquartile range). a Of the total 46 patients who underwent SAVR, only 32 patients underwent a PYP scan (due to logistical constraints). Significant radiotracer uptake was seen in 3 patients (dual AS þ ATTR-CA), and radiotracer uptake was not significant in the remaining 29 patients (isolated AS). (13) . Nine percent of this amounts to w400,000 patients expected to have dual AS-ATTR-CA (range: 90,000 to 1,125,000 considering a 95% confidence interval of 2.0% to 25%).

We found isolated valvular amyloidosis in the aortic valves of 33 (72%) patients. This is similar to the amyloid deposition in aortic valves of patients with calcific AS which has been noted previously, ranging from 75% to 100% (14, 15) . However, the ma- deposition in the calcific aortic valves was previously explained by the atherogenic milieu, and is thought to be promoted by dyslipidemia. This is mainly due to local inflammation within the atherosclerotic plaques in the aortic valve which oxidizes the methionine residues of Apo-A1 and transforms them into amyloidogenic proteins (16) . These amyloid depositions are believed to cause mineralization of calcified aortic valves by promoting apoptosis of valvular interstitial cells (15) . However, there is no benefit of lipid-lowering therapy (statins) on severity or progression of aortic stenosis (17) . TTR deposition may be explained by the shear stress caused by the accelerated flow of blood across the stenosed valve predisposing it to amyloidogenesis. Also, TTR deposition was qualitatively observed more prominently adjacent to high calcific burden sites. In contrast to our study, none of these previous 2 studies studying aortic valves looked at amyloid deposition in the IVS (14, 15) . On the contrary, myocardial amyloidosis, without looking at valvular amyloidosis, has been diagnosed on IVS biopsy by Treibel et al (5) .

No previous study has looked at severe AS patients for concomitant ATTR-CA by performing surgery. This is reflected in the recent studies, all of which have attempted to diagnose ATTR-CA by radionuclide scintigraphic imaging tests instead of using IVS biopsy specimens (6,7,18,19) . These studies are briefly summarized in Supplemental Table 3 (5-8, [18] [19] [20] [21] . In the absence of tissue histopathological examination, red flags from clinical features, ECG, echo, biomarkers (NT-proBNP and troponin), PYP/DPD scan, and cardiac magnetic resonance imaging should guide amyloid screening in these patients (22) .

Radionuclide scintigraphy has become the standard for diagnosis of ATTR-CA as per the guidelines endorsed by ASNC/AHA/ASE (11) . Specifically, grade II or III uptake, in the absence of clonal cell expansion, is considered to be highly specific and sensitive (>95%) for ATTR-CA (23) . In our cohort, this was seen in 3 patients (9.4% of the 32 patients where PYP imaging was performed), suggesting significant myocardial ATTR-CA. There was no difference in our patients with ATTR-CA (grade II or III uptake) versus suspicion of blood pool activity). The scans were visually assessed qualitatively (heart-to-bone ratio, Perugini score) (Supplemental Table 1 ).

Perugini grades II or III were considered as significantly positive for diagnosis of myocardial ATTR-CA. SPECT ¼ single-photon emission computed tomography; other abbreviations as in Figure 1 . shown in previous studies as well (6, 18, 19, 24, 25) . Table 3 ). Black Americans are known to have even higher TTR penetrance (9) .

Before the present study, the distribution of ATTR-CA in an Asian population was unknown. As emphasized above, conservatively estimating a prevalence of dual @Singal_Aayush, @AvinainderSingh, @Dorbala-Sharmila, @bansalrags, @ProfBhargava, @drkar-thik2010, @aiims_newdelhi.

The global burden of aortic stenosis

Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a populationbased autopsy study

Systemic amyloidosis

Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?

Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement

Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement

Coexistence of degenerative aortic stenosis and wildtype transthyretin-related cardiac amyloidosis

Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis

Transthyretin cardiac amyloidosis in black Americans

Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

ASNC/AHA/ ASE/EANM/HFSA/ISA/SCMR/ SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging

Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples

United Nations, Department of Economic and Social Affairs

High prevalence of amyloid in 150 surgically removed heart valves -a comparison of histological and clinical data reveals a correlation to atheroinflammatory conditions

Amyloid substance within stenotic aortic valves promotes mineralization

Myeloperoxidase-mediated methionine oxidation promotes an amyloidogenic outcome for apolipoprotein A-I

Statins for aortic valve stenosis

Light-chain and transthyretin cardiac amyloidosis in severe aortic stenosis: prevalence, screening possibilities, and outcome

Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis

Pathology of transcatheter valve therapy

Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation

How to image cardiac amyloidosis: a practical approach

Non biopsy diagnosis of cardiac transthyretin amyloidosis

Identifying cardiac amyloid in aortic stenosis: ECV quantification by CT in TAVR patients

Prevalence and outcomes of concomitant aortic stenosis and cardiac amyloidosis