Is the Left Ventricle a Backroom Fixer of Left Atrial Thrombus?

Atrial fibrillation (AF) is the most common arrhythmia seen in routine clinical practice, and it substantially increases the risk of various adverse events, including thromboembolism, heart failure and death. The prevalence of AF is gradually increasing in Japan as the population ages, and it is now estimated to be ≈1% of the general population in Japan.¹

Article p 1790

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder defined by left ventricular (LV) hypertrophy primarily caused by sarcomere gene mutations.² Although the disease course is variable, HCM is also associated with a high risk of adverse events, including heart failure, arrhythmias, and sudden cardiac death. The prevalence of HCM is reported to be ≈0.2% in Japan, according to a nationwide epidemiological survey.³

However, there is limited information on the association of AF and HCM, and the clinical profile of patients with both has not been fully described. In this issue of the Journal, Tsuda et al investigate the clinical backgrounds and outcomes of patients with AF and concomitant HCM, using data from the Hokuriku-Plus AF registry, a multicenter prospective survey of AF patients enrolled in Kanazawa University and its alumni institutions in the Hokuriku-region.⁴

Prevalence of HCM in AF Patients

The prevalence of HCM in AF patients is reportedly low. In the Fushimi AF registry, a community-based all-comer cohort study of AF patients in Japan, the prevalence of cardiomyopathy was 3.0%, with HCM only 1.2%.⁵ In the ANAFIE registry, a prospective observational study of >30,000 Japanese AF patients aged ≥75 years, the prevalence of cardiomyopathy was 3.7%, despite not showing data about HCM.⁶ A Korean nationwide cohort study of AF patients reported 1.1% incidence of HCM.⁷ In contrast, the prevalence of HCM in this Hokuriku-Plus AF registry was exceptionally high at 5.2%. As stated in the Discussion, there may have been a selection bias because >50% of patients were registered from 3 cardiovascular centers that examine many AF patients with structural heart disease. Furthermore, it is possible that other cardiac diseases exhibiting LV hypertrophy, such as cardiac amyloidosis, Fabry disease, and hypertensive heart disease, were included in the HCM group.

However, AF is the most common sustained arrhythmia in patients with HCM, and several studies of HCM have reported that ≈25% of the patients had documented AF.⁸ A recent report from the SHaRe registry (Sarcomeric Human Cardiomyopathy Registry), an international database of 4,591 patients with HCM, showed that 20% of the patients had AF.⁹

Event Risk of Patients With AF and HCM

Of the total 1,396 AF patients enrolled in the Hokuriku-Plus AF registry, 72 (5.2%) had HCM. During a median follow-up of 5 years, both thromboembolic events and heart failure events occurred more frequently in the HCM group as compared with the non-HCM group, and the presence of HCM was an independent risk factor for both events after adjustment for various confounders (hazard ratio for thromboembolic events and heart failure: 2.63 and 2.81, respectively). In contrast, neither all-cause death nor bleeding differed between HCM and non-HCM. From these observations, the authors conclude that HCM predicts thromboembolism and heart failure in patients with AF. The higher risk of heart failure in these patients is as expected, but the higher risk of thromboembolism is noteworthy.

Thromboembolic Risk of Patients With AF and HCM

As is well known, AF is an independent risk factor for thromboembolism,¹⁰ and concomitant HCM is reported to further increase this risk. The JCS guidelines for AF management designate “cardiomyopathy” as one of the “other risks” for thromboembolism in addition to the well-validated risk factors in patients with AF. This designation is based on cohort studies in Japan demonstrating cardiomyopathy, especially HCM, as an independent risk factor for stroke.^11,12 The mechanism of the increased risk of thromboembolism in HCM remains undetermined, but those studies suggested the involvement of an activated coagulation system manifested by elevated D-dimer levels. It is also likely that LV hypertrophy, regardless of its cause, may be the underlying mechanism of thrombus formation in the left atrium (LA). A previous study from the Fushimi AF registry demonstrated that a relative increase in the wall thickness of the LV (LV wall thickness divided by LV end-diastolic dimension measured by cardiac echo) was associated with higher risk of thromboembolism in AF patients.¹³ A posthoc analysis of the AFFIRM trial, a randomized clinical trial comparing outcomes in AF patients undergoing rate- vs. rhythm-control therapy, demonstrated that LV hypertrophy was a predictor of stroke in patients with AF, suggesting the possible link between hypertrophic LV geometry and risk of stroke in those patients.¹⁴ LV hypertrophy and diastolic dysfunction can lead to increased LA afterload and subsequent LA enlargement, which promotes blood stasis and thrombus formation. Increased LA stress eventually leads to the development of atrial fibrosis or atrial myopathy.¹⁵ However, it is also likely that LV hypertrophy may simply manifest coexisting morbidities that could predispose to thromboembolism; that is, the presence of LV hypertrophy may be a marker, and not a cause of thromboembolism.

Summary

Thus, the LV may be a “backroom fixer” of LA thrombus formation. Much attention has been paid to the morphology or function of the LA in the pathogenesis of LA thrombus, but the LV may, at least in part, contribute to this process. There has not been a comprehensive report examining the clinical profile of AF patients with concomitant HCM, and the present study provides important information on this important issue. The accumulation of prospective clinical data will be essential for the better management of these patients, especially from the viewpoint of optimization of anticoagulation therapy.

References

• 1.   Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
• 2.   Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: A personal history. Circ Res 2011; 108: 743–750.
• 3.   Miura K, Nakagawa H, Morikawa Y, Sasayama S, Matsumori A, Hasegawa K, et al. Epidemiology of idiopathic cardiomyopathy in Japan: Results from a nationwide survey. Heart 2002; 87: 126–130.
• 4.   Tsuda T, Hayashi K, Kato T, Kusayama T, Nakagawa Y, Nomura A, et al. Hypertrophic cardiomyopathy predicts thromboembolism and heart failure in patients with nonvalvular atrial fibrillation: A prospective analysis from the Hokuriku-Plus AF Registry. Circ J 2023; 87: 1790–1797.
• 5.   Akao M, Chun Y, Wada H, Esato M, Hashimoto T, Abe M, et al. Current status of clinical background of patients with atrial fibrillation in a community-based survey: The Fushimi AF Registry. J Cardiol 2013; 61: 260–266.
• 6.   Koretsune Y, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Baseline demographics and clinical characteristics in the All Nippon AF in the Elderly (ANAFIE) Registry. Circ J 2019; 83: 1538–1545.
• 7.   Jung H, Yang PS, Sung JH, Jang E, Yu HT, Kim TH, et al. Hypertrophic cardiomyopathy in patients with atrial fibrillation: Prevalence and associated stroke risks in a nationwide cohort study. Thromb Haemost 2019; 119: 285–293.
• 8.   Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001; 104: 2517–2524.
• 9.   Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018; 138: 1387–1398.
• 10.   Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–988.
• 11.   Tomita F, Kohya T, Sakurai M, Kaji T, Yokoshiki H, Sato M, et al. Prevalence and clinical characteristics of patients with atrial fibrillation: Analysis of 20,000 cases in Japan. Jpn Circ J 2000; 64: 653–658.
• 12.   Nozawa T, Inoue H, Hirai T, Iwasa A, Okumura K, Lee JD, et al. D-dimer level influences thromboembolic events in patients with atrial fibrillation. Int J Cardiol 2006; 109: 59–65.
• 13.   Tezuka Y, Iguchi M, Hamatani Y, Ogawa H, Esato M, Tsuji H, et al. Association of relative wall thickness of left ventricle with incidence of thromboembolism in patients with non-valvular atrial fibrillation: The Fushimi AF Registry. Eur Heart J Qual Care Clin Outcomes 2020; 6: 273–283.
• 14.   Apostolakis S, Sullivan RM, Olshansky B, Lip GY. Left ventricular geometry and outcomes in patients with atrial fibrillation: The AFFIRM Trial. Int J Cardiol 2014; 170: 303–308.
• 15.   Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication. Europace 2016; 18: 1455–1490.