See article vol. 28: 241–248
Atrial fibrillation (AF) has been recognized as an intervenable risk factor for incident cardioembolic stroke in various studies. Today, patients with AF receive oral anticoagulation therapy to prevent future thromboembolic events, based on clinical risk scores such as the CHADS21) and CHA2DS2-VASc2). Both scores incorporate risk factors such as age, sex, hypertension, diabetes mellitus, congestive heart failure, previous stroke, and other vascular diseases that incrementally increase the likelihood of incident stroke events, particularly among the Caucasian population. Similarly, in a joint cohort of five representative AF registries in Japan, previous stroke, advanced age, hypertension, low body mass index, and persistent/permanent AF were identified as independent risk factors for ischemic stroke3). Since the majority of the cerebro-cardiovascular events have been shown to be experienced by AF patients with one or more stroke risk factors, their prognosis in the absence of these features has been long believed to be benign. In their latest article, Sairenchi et al. indicated that AF patients with and without traditional cerebrovascular stroke risk factors had higher risk of dying due to cerebrocardiovascular events, in an extensive cohort of 90,629 individuals with 20 years of follow-up4). Their observation has reinforced the underestimated risk of what has commonly been known as lone AF, that is, AF without overt cardiovascular disease or precipitating illness.
Reported prevalence of lone AF has been known to vary widely depending on the definition and cardiovascular testing modalities used to screen for subclinical heart disease at the study baseline. The 1948 Framingham Heart Study reported the prevalence of 0.8% (43/5,209) using the absence of coronary heart disease, congestive heart failure, rheumatic heart disease, and hypertensive cardiovascular disease as a definition. Moreover, incidence of stroke was significantly higher in the lone AF group as compared to the matched controls5). The 1950 Olmsted County Study that also found higher risk of stroke during a 30-year follow-up and showed that lone AF was present in 2.7% (97/3,623) of those aged ≤ 60 years6). In the 1993 Ibaraki Prefectural Health Study, a community-based large cohort study including individuals aged 40–79 years living in Ibaraki prefecture, lone AF was found in 0.03% (31/90,629) of the total cohort, using the definition of the absence of either hypertension, dyslipidemia, diabetes mellitus, habitual smoking, or heavy drinking. As stated in their article, patients with lone AF were at increased risk for long-term mortality, and this included both genders.
Future directions of this field are likely to involve (1) performing a more sophisticated biomarker, cardiac imaging, or genetic testing; and (2) combining various digital health data collected from various sources at serial occasions overcoming the limitations of epidemiological cohorts that rely on baseline individual evaluation. Since much of the detrimental events occur decades after an initial diagnosis of lone AF, determining the optimal strategy to recapture these patients with lone AF during the course of their lives as they transition into a higher-risk state (e.g., elevated blood pressure, glucose, structural changes of their heart chambers or valves) is crucial.
For example, a recent NIPPON DATA 2010 study showed that a subtle increase in serum B-type natriuretic peptide (BNP) was linked to electrocardiographic P-wave terminal force in lead V1 observed at baseline7). The linkage between electrocardiographic P-wave terminal force in lead V1 and long-term outcomes remains to be confirmed. In the Japanese general population, an echocardiographic assessment utilizing speckled tracking showed that left atrial reservoir strain is an independent predictor of elevated serum BNP levels, with both possibly being markers of increased risk of heart failure in older adults8). In a regional case registration of Japanese patients with lone AF, seven rare variants in KCNA5, KCNQ1, KCNH2, and SCN5A, involved in cardiac ion channels, and SCN1B genes in eight patients with lone AF, were identified as a possible contributor to the development of lone AF9). Digital health is still at its infancy; however, there is a growing interest with increasingly wearable devices now capable of detecting biometric information such as electrocardiograms, blood pressure, and blood glucose. Validation studies that can ascertain the credibility of digital health data are required prior to data-oriented health decision making of individuals such as in the case of the Apple Heart Study10).
Conflict of Interest
Dr. M.S. received clinical research funding from Takeda Pharma outside of the submitted work.
References
- 1). Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA, 2001; 285: 2864-2870 [DOI] [PubMed] [Google Scholar]
- 2). Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest, 2010; 137: 263-272 [DOI] [PubMed] [Google Scholar]
- 3). Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, Hayashi K, Sawano M, Goya M, Yamashita T, Fukuda K, Ogawa H, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Miyata H, Okamura T, Sasahara Y. Risk Factors Associated With Ischemic Stroke in Japanese Patients With Nonvalvular Atrial Fibrillation. JAMA Netw open, 2020; 3: e202881 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4). Sairenchi T, Yamagishi K, Iso H, Irie F, Koba A, Nagao M, Umesawa M, Haruyama Y, Takaoka N, Watanabe H, Kobashi G and Ota H. Atrial Fibrillation With and Without Cardiovascular Risk Factors and Stroke Mortality. J Atheroscler Thromb Thromb, 2021; 28: 241-248 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5). Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study. JAMA, 1985; 254: 3449-3453 [PubMed] [Google Scholar]
- 6). Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DRJ, Ilstrup DM, Frye RL. The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med, 1987; 317: 669-674 [DOI] [PubMed] [Google Scholar]
- 7). Shoji S, Kohsaka S, Sawano M, Okamura T, Hirata A, Sugiyama D, Ohkubo T, Nakamura Y, Watanabe M, Kadota A, Ueshima H, Okayama A, Miura K. Electrocardiographic Left Atrial Abnormality and B-Type Natriuretic Peptide in a General Japanese Population: NIPPON DATA2010. J Atheroscler Thromb, 2020; 1-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8). Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, Sawada N, Hirokawa M, Kaneko H, Nakao T, Mizuno Y, Morita H, Di Tullio MR, Homma S, Komuro I. Alteration of Cardiac Performance and Serum B-Type Natriuretic Peptide Level in Healthy Aging. J Am Coll Cardiol, 2019; 74: 1789-1800 [DOI] [PubMed] [Google Scholar]
- 9). Hayashi K, Konno T, Tada H, Tani S, Liu L, Fujino N, Nohara A, Hodatsu A, Tsuda T, Tanaka Y, Kawashiri M, Ino H, Makita N, Yamagishi M. Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation. Circ Arrhythm Electrophysiol, 2015; 8: 1095-1104 [DOI] [PubMed] [Google Scholar]
- 10). Perez M V, Mahaffey KW, Hedlin H, Rumsfeld JS, Garcia A, Ferris T, Balasubramanian V, Russo AM, Rajmane A, Cheung L, Hung G, Lee J, Kowey P, Talati N, Nag D, Gummidipundi SE, Beatty A, Hills MT, Desai S, Granger CB, Desai M, Turakhia MP. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med, 2019; 381: 1909-1917 [DOI] [PMC free article] [PubMed] [Google Scholar]