Causal association between venous thromboembolism and cardiovascular disease risks: a two-sample bidirectional Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

XU Ruining ¹ , ZHU Wenjuan ¹ , YANG Ying ¹ , ZHI Hong ² ,  WANG Lina ¹

1. Department of Epidemiology and Statistics, School of Public Health, Southeast University, Nanjing 210009, P. R. China;
2. Department of Cardiovascular Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, P. R. China;

Corresponding author：

WANG Lina, Email: lnwang@seu.edu.cn

Keywords：

Venous thromboembolism; Cardiovascular diseases; Mendelian randomization; Cause-effect; Genome-wide association study

DOI：

10.7507/1672-2531.202406043

Video：

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Objective To explore the causal association between venous thromboembolism and cardiovascular disease risks using a two-sample bidirectional Mendelian randomization study. Methods The single-nucleotide polymorphism (SNP) data associated with venous thromboembolism (VTE) and cardiovascular diseases (CVD) from genome-wide association studies were obtained as instrumental variables. Inverse variance weighted (IVW) was used as the main Mendelian randomization method and other methods were used as supplementary methods. Cochran's Q test, the intercept term of MR-Egger, and MR-PRESSO were used to assess pleiotropy and heterogeneity to ensure the robustness of the results. Results The IVW method suggested a causal association between venous thromboembolism and atrial fibrillation (OR=1.033, 95%CI 1.009 to 1.058, P=0.008), but no association was identified between VTE and coronary artery disease (OR=0.994, 95%CI 0.974 to 1.023, P = 0.551), heart failure (OR=1.021, 95%CI 0.992 to 1.050, P=0.159) and myocardial infarction (OR=1.012, 95%CI 0.971 to 1.055, P=0.568). The results of Cochran's Q test showed that there was no heterogeneity in the MR analyses of VTE and CVD. The MR-Egger intercept analysis and the MR-PRESSO global testing did not detect potential horizontal pleiotropy, and the results were robust. Reverse Mendelian randomization analysis was used to verify the presence of reverse causal associations. The reverse MR analysis demonstrated that reverse causal associations between venous thromboembolism and cardiovascular diseases were not evidenced. Conclusion The results of the Mendelian randomization study demonstrated a causal association between venous thromboembolism and atrial fibrillation, but not with CAD, HF, or MI, providing a new perspective on the prevention and treatment of atrial fibrillation.

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2.	Zhao D, Liu J, Wang M, et al. Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol, 2019, 16(4): 203-212.
3.	Ventura HO, Elagizi A, Lavie CJ. Optimal prevention of cardiovascular diseases: the earlier the better. J Am Coll Cardiol, 2023, 81(12): 1162-1164.
4.	Lutsey PL, Zakai NA. Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol, 2023, 20(4): 248-262.
5.	中国健康促进基金会血栓与血管专项基金专家委员会. 静脉血栓栓塞症机械预防中国专家共识. 中华医学杂志, 2020, 100(7): 484-492.
6.	Hu M, Gong Z, Yang Y. Mendelian randomization study does not support a bidirectional link between atherosclerosis and venous thromboembolism. J Atheroscler Thromb, 2023, 30(9): 1265-1275.
7.	Prandoni P, Bilora F, Marchiori A, et al. An association between atherosclerosis and venous thrombosis. N Engl J Med, 2003, 348(15): 1435-1441.
8.	Hald EM, Enga KF, Løchen ML, et al. Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study. J Am Heart Assoc, 2014, 3(1): e000483.
9.	Lutsey PL, Norby FL, Alonso A, et al. Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the atherosclerosis risk in communities study. J Thromb Haemost, 2018, 16(4): 670-679.
10.	Akrivou D, Perlepe G, Kirgou P, et al. Pathophysiological aspects of aging in venous thromboembolism: an update. Medicina (Kaunas), 2022, 58(8): 1078.
11.	Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow's triad in 2020. Heart, 2020, 106(19): 1463-1468.
12.	Barra SN, Paiva LV, Providência R, et al. Atrial fibrillation in acute pulmonary embolism: prognostic considerations. Emerg Med J, 2014, 31(4): 308-312.
13.	Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation, 2008, 117(1): 93-102.
14.	Noumegni SR, Didier R, Mansourati V, et al. Risk factors for major adverse cardiovascular events and major adverse limb events after venous thromboembolism: a large prospective cohort study. Semin Thromb Hemost, 2022, 48(4): 465-480.
15.	Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
16.	Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease. Int J Epidemiol, 2003, 32(1): 1-22.
17.	van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res, 2018, 122(3): 433-443.
18.	Hartiala JA, Han Y, Jia Q, et al. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction. Eur Heart J, 2021, 42(9): 919-933.
19.	Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet, 2018, 50(9): 1234-1239.
20.	Shah S, Henry A, Roselli C, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun, 2020, 11(1): 163.
21.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
22.	Burgess S, Zuber V, Gkatzionis A, et al. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid. Int J Epidemiol, 2018, 47(4): 1242-1254.
23.	Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
24.	Chang WT, Chang CL, Ho CH, et al. Long-term effects of unprovoked venous thromboembolism on mortality and major cardiovascular events. J Am Heart Assoc, 2017, 6(5): e005466.
25.	Sørensen HT, Horvath-Puho E, Pedersen L, et al. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet, 2007, 370(9601): 1773-1779.
26.	Adamo A, Spiezia L, Dalla VF, et al. Potential association between distal deep vein thrombosis and asymptomatic atherosclerosis. TH Open, 2021, 5(4): e585-e590.
27.	Lind C, Småbrekke B, Rinde LB, et al. Impact of venous thromboembolism on the formation and progression of carotid atherosclerosis: the tromsø study. TH Open, 2017, 1(1): e66-e72.
28.	MacDonald CJ, Madika AL, Lajous M, et al. Association between cardiovascular risk-factors and venous thromboembolism in a large longitudinal study of French women. Thromb J, 2021, 19(1): 58.
29.	龚伟, 刘婷婷, 郑杨. 静脉血栓形成与心血管疾病危险因素. 中华心血管病杂志, 2018, 46(5): 407-410.
30.	Mahmoodi BK, Cushman M, Anne Næss I, et al. Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies. Circulation, 2017, 135(1): 7-16.
31.	Shahjehan RD, Sharma S, Bhutta BS. Coronary artery disease. StatPearls, 2024.
32.	Alkarithi G, Duval C, Shi Y, et al. Thrombus structural composition in cardiovascular disease. Arterioscler Thromb Vasc Biol, 2021, 41(9): 2370-2383.
33.	Chernysh IN, Nagaswami C, Kosolapova S, et al. The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli. Sci Rep, 2020, 10(1): 5112.
34.	Migliacci R, Becattini C, Pesavento R, et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica, 2007, 92(6): 812-818.
35.	Mahmoodi BK, Gansevoort RT, Veeger NJ, et al. Microalbuminuria and risk of venous thromboembolism. JAMA, 2009, 301(17): 1790-1797.
36.	Yap ES, Lijfering WM, Timp JF, et al. Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: a cohort study. EJHaem, 2023, 4(1): 3-12.
37.	Spronk HM, De Jong AM, Verheule S, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J, 2017, 38(1): 38-50.
38.	Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J, 2019, 54(3): 1901647.
39.	Sista AK, Miller LE, Kahn SR, et al. Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: systematic review with meta-analysis. Vasc Med, 2017, 22(1): 37-43.
40.	Rafaqat S, Gluscevic S, Patoulias D, et al. The association between coagulation and atrial fibrillation. Biomedicines, 2024, 12(2): 274.
41.	Kukla P, McIntyre WF, Koracevic G, et al. Relation of atrial fibrillation and right-sided cardiac thrombus to outcomes in patients with acute pulmonary embolism. Am J Cardiol, 2015, 115(6): 825-830.
42.	Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol, 2017, 4(2): e83-e93.

1. McClellan M, Brown N, Califf RM, et al. Call to action: urgent challenges in cardiovascular disease: a presidential advisory from the American Heart Association. Circulation, 2019, 139(9): e44-e54.
2. Zhao D, Liu J, Wang M, et al. Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol, 2019, 16(4): 203-212.
3. Ventura HO, Elagizi A, Lavie CJ. Optimal prevention of cardiovascular diseases: the earlier the better. J Am Coll Cardiol, 2023, 81(12): 1162-1164.
4. Lutsey PL, Zakai NA. Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol, 2023, 20(4): 248-262.
5. 中国健康促进基金会血栓与血管专项基金专家委员会. 静脉血栓栓塞症机械预防中国专家共识. 中华医学杂志, 2020, 100(7): 484-492.
6. Hu M, Gong Z, Yang Y. Mendelian randomization study does not support a bidirectional link between atherosclerosis and venous thromboembolism. J Atheroscler Thromb, 2023, 30(9): 1265-1275.
7. Prandoni P, Bilora F, Marchiori A, et al. An association between atherosclerosis and venous thrombosis. N Engl J Med, 2003, 348(15): 1435-1441.
8. Hald EM, Enga KF, Løchen ML, et al. Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study. J Am Heart Assoc, 2014, 3(1): e000483.
9. Lutsey PL, Norby FL, Alonso A, et al. Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the atherosclerosis risk in communities study. J Thromb Haemost, 2018, 16(4): 670-679.
10. Akrivou D, Perlepe G, Kirgou P, et al. Pathophysiological aspects of aging in venous thromboembolism: an update. Medicina (Kaunas), 2022, 58(8): 1078.
11. Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow's triad in 2020. Heart, 2020, 106(19): 1463-1468.
12. Barra SN, Paiva LV, Providência R, et al. Atrial fibrillation in acute pulmonary embolism: prognostic considerations. Emerg Med J, 2014, 31(4): 308-312.
13. Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation, 2008, 117(1): 93-102.
14. Noumegni SR, Didier R, Mansourati V, et al. Risk factors for major adverse cardiovascular events and major adverse limb events after venous thromboembolism: a large prospective cohort study. Semin Thromb Hemost, 2022, 48(4): 465-480.
15. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
16. Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease. Int J Epidemiol, 2003, 32(1): 1-22.
17. van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res, 2018, 122(3): 433-443.
18. Hartiala JA, Han Y, Jia Q, et al. Genome-wide analysis identifies novel susceptibility loci for myocardial infarction. Eur Heart J, 2021, 42(9): 919-933.
19. Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet, 2018, 50(9): 1234-1239.
20. Shah S, Henry A, Roselli C, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun, 2020, 11(1): 163.
21. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
22. Burgess S, Zuber V, Gkatzionis A, et al. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid. Int J Epidemiol, 2018, 47(4): 1242-1254.
23. Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
24. Chang WT, Chang CL, Ho CH, et al. Long-term effects of unprovoked venous thromboembolism on mortality and major cardiovascular events. J Am Heart Assoc, 2017, 6(5): e005466.
25. Sørensen HT, Horvath-Puho E, Pedersen L, et al. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet, 2007, 370(9601): 1773-1779.
26. Adamo A, Spiezia L, Dalla VF, et al. Potential association between distal deep vein thrombosis and asymptomatic atherosclerosis. TH Open, 2021, 5(4): e585-e590.
27. Lind C, Småbrekke B, Rinde LB, et al. Impact of venous thromboembolism on the formation and progression of carotid atherosclerosis: the tromsø study. TH Open, 2017, 1(1): e66-e72.
28. MacDonald CJ, Madika AL, Lajous M, et al. Association between cardiovascular risk-factors and venous thromboembolism in a large longitudinal study of French women. Thromb J, 2021, 19(1): 58.
29. 龚伟, 刘婷婷, 郑杨. 静脉血栓形成与心血管疾病危险因素. 中华心血管病杂志, 2018, 46(5): 407-410.
30. Mahmoodi BK, Cushman M, Anne Næss I, et al. Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies. Circulation, 2017, 135(1): 7-16.
31. Shahjehan RD, Sharma S, Bhutta BS. Coronary artery disease. StatPearls, 2024.
32. Alkarithi G, Duval C, Shi Y, et al. Thrombus structural composition in cardiovascular disease. Arterioscler Thromb Vasc Biol, 2021, 41(9): 2370-2383.
33. Chernysh IN, Nagaswami C, Kosolapova S, et al. The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli. Sci Rep, 2020, 10(1): 5112.
34. Migliacci R, Becattini C, Pesavento R, et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica, 2007, 92(6): 812-818.
35. Mahmoodi BK, Gansevoort RT, Veeger NJ, et al. Microalbuminuria and risk of venous thromboembolism. JAMA, 2009, 301(17): 1790-1797.
36. Yap ES, Lijfering WM, Timp JF, et al. Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: a cohort study. EJHaem, 2023, 4(1): 3-12.
37. Spronk HM, De Jong AM, Verheule S, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J, 2017, 38(1): 38-50.
38. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J, 2019, 54(3): 1901647.
39. Sista AK, Miller LE, Kahn SR, et al. Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: systematic review with meta-analysis. Vasc Med, 2017, 22(1): 37-43.
40. Rafaqat S, Gluscevic S, Patoulias D, et al. The association between coagulation and atrial fibrillation. Biomedicines, 2024, 12(2): 274.
41. Kukla P, McIntyre WF, Koracevic G, et al. Relation of atrial fibrillation and right-sided cardiac thrombus to outcomes in patients with acute pulmonary embolism. Am J Cardiol, 2015, 115(6): 825-830.
42. Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol, 2017, 4(2): e83-e93.

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Latest ArticlesCausal association between venous thromboembolism and cardiovascular disease risks: a two-sample bidirectional Mendelian randomization study

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