RESEARCH LETTER
Cardiac amyloidosis results from extracellular deposition of insoluble abnormal fibrillar proteins, including transthyretin (TTR), in the cardiac chambers. Much attention has been paid toward understanding the relationship of common, inherited amyloidogenic variants and heart failure (HF) risk, particularly the V122I (p.V142I) variant which is present in 3–4% of Black Americans (1). However, the expanding treatment armamentarium has heightened interest in identifying additional and/or earlier phenotypes of TTR-associated cardiac amyloidosis.
Beyond HF, the amyloidogenic V122I variant may lead to other clinically important cardiovascular events, including atrial fibrillation (AF) and ischemic stroke. AF is particularly common in cardiac amyloidosis and marks a highly thrombogenic state (2), associated with a high incidence of ischemic stroke (3). The relationship between V122I and these cardiovascular outcomes in an unselected population has not been well defined.
We studied 3,856 Black Atherosclerosis Risk in Communities (ARIC) participants with V122I TTR genotyping. Longitudinal outcomes included AF and ischemic stroke. At visit 5 (2011–2013), we studied the relationship between genotype and cerebral infarcts on brain magnetic resonance imaging (MRI) in an ancillary study (4). The institutional review board at each participating site approved the study protocol, and informed consent was obtained at each examination.
We performed age- and sex-stratified Cox proportional hazards models to assess the relationship between the variant and adverse outcomes (1). Since the risk for AF may relate to an increased risk for HF, we assessed for an interaction between genotype and time-updated heart failure status. Using ischemic stroke as the outcome, we similarly analyzed interactions between genotype and time-updated 1) AF status, 2) HF status, and 3) CHADS2VASC score. Among participants attending the visit 5 brain MRI, we used age and sex-adjusted logistic regression to analyze the association between genotype and prevalence of infarcts.
The mean age at visit 1 was 54.0±5.8 years, 38% were men, 56% had hypertension, 19.7% had diabetes, 6.7% had prevalent HF, 2.9% had a previous stroke, and 0.1% had AF. The average CHADS2-VASC score was 1.6±1.1. Participant characteristics were balanced across V122I carrier status.
Over 23.2±8.7 years of follow-up, there were 549 cases of AF and 469 cases of ischemic strokes. V122I carrier status was associated with a significantly increased risk for AF (HR 1.86, 95% CI 1.26, 2.74, p=0.002) (Figure). No difference was detected for the risk for AF between those with and without time-updated HF (p-interaction=0.87). V122I carrier status was also associated with an increased risk for ischemic stroke (HR 1.58, 95% CI 1.01, 2.46, p=0.04) (Figure). There was no difference in the risk for ischemic stroke across CHADS2VASC score (p-interaction=0.99), among those with and without time-updated HF (p-interaction=0.15), or with and without time-updated AF (p-interaction=0.36).
Figure 1: Cumulative Incidence Curves for Atrial Fibrillation and Ischemic Stroke by V122I Carrier Status.
Cumulative incidence curves for each of the study outcomes by genotype status. AF, atrial fibrillation; CI, confidence interval; HR, hazard ratio.
Among the 526 participants attending the brain MRI ancillary study, 21 (4.0%) were V122I carriers. The average CHADS2-VASC scores at visit 5 were 3.8±1.3 (non-carriers) and 3.9±1.7 (carriers) (p=0.68). The V122I variant was associated with increased odds of cortical infarcts (6/21 (28.6%) vs. 61/505 (12.1%), odds ratio 3.11, 95% CI 1.15–8.38, p=0.025). There were non-statistically significant increases in subcortical (OR 2.00, p=0.15) and lacunar infarcts (OR 2.12, p=0.12).
In a large study of unselected self-identified Black participants with nearly 25 years of follow-up, we found that V122I carriers were at significantly increased risk for AF and ischemic stroke. The heightened risk for AF was consistent among those with and without HF, and the increased risk for ischemic stroke was similar across CHADS2VASC score. On cross-sectional analysis at visit 5 during late-life, V122I carriers were 3 times more likely to have cortical infarcts than non-carriers. Since the V122I variant is relatively common in Black Americans, our findings indicate a significantly underappreciated burden of the variant on non-HF clinical events. Specifically, these data suggest that AF, ischemic stroke, and cerebral infarcts may be markers of transthyretin amyloidosis among some self-identified Black patients with the V122I variant, irrespective of underlying HF. Whether earlier identification and treatment of V122I carriers at increased risk for these events improve these clinical outcomes warrants further investigation.
ACKNOWLEDGEMENTS
The authors thank the staff and participants of the ARIC study for their important contributions.
SOURCES OF FUNDING
The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). Additionally, this research was supported by R01 HL126637 (Chen), and R01HL135008, R01HL143224, R01HL150342, R01HL148218 and K24HL152008 (Shah). The authors thank the staff and participants of the ARIC study for their important contributions.
DISCLOSURES
Dr. Selvaraj receives research support from the Doris Duke Charitable Foundation (Physician Scientist Fellowship Award 2020061), the Measey Foundation, Institute for Translational Medicine and Therapeutics (Junior Investigator Preliminary/Feasibility Grant Program award and Translational Bio-Imaging Center award) and the American Society of Nuclear Cardiology (Institute for the Advancement of Nuclear Cardiology award). Dr. Minamisawa received support from the Japanese Circulation Society, the Japanese Society of Echocardiography, and the Uehara Memorial Foundation Overseas Research Fellowship. Dr. Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent.
ACRONYMS AND ABBREVIATIONS
- AF
atrial fibrillation
- ARIC
Atherosclerosis Risk in Communities
- HF
heart failure
- MRI
magnetic resonance imaging
- TTR
transthyretin
REFERENCES
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