Patients with rheumatoid arthritis (RA) are at increased risk for ischemic and non-ischemic heart disease, secondary to subclinical pathological changes in heart muscle and in coronary vessels, according to a review published in Rheumatic & Musculoskeletal Diseases. Systemic inflammation is a risk factor for cardiovascular disease (CVD) and treatment with conventional and biologic antirheumatic medications may have a significant impact on cardiovascular (CV) outcomes.1

Previous studies have established RA is an independent risk factor for premature atherosclerosis and reported that patients with RA are at an increased risk for CV events and cardiac mortality, compared with the general population.2-4 Chronic systemic inflammation secondary to rheumatic diseases is an important contributor for the increased CV risk among patients with RA and is associated with arterial stiffness, lipid-salvage mechanisms, and destabilization of plaques.4

Disease activity significantly affects CV risk, as each period of increased joint disease activity is associated with a 7% increased CV risk, while a low disease activity reduces the CV risk.5,6 Several proinflammatory cytokines have been associated with inflammation in RA and with pathogenesis of heart disease, including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6 and IL-17.1 While the contribution of inflammation to atherosclerosis and ischemic heart disease is well described, the mechanisms responsible for non-ischemic heart disease is less well understood.

In addition to inflammation, traditional CV risk factors, including hypertension, diabetes, dyslipidemia, obesity, smoking, family history and physical inactivity, may be more common among patients with RA, compared with the general population.7


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Patients with RA were found to be at increased risk for myocardial infarction, major CV events and all-cause mortality, regardless of the presence of coronary artery disease (CAD). RA may precipitate CV events beyond CAD and in those with CAD may exacerbate the clinical risk of CV events.9

Heart disease in patients with RA can be classified to ischemic and non-ischemic heart disease. Ischemic heart disease refers to CAD with endothelial dysfunction, atherosclerosis, aortic stiffness and vulnerable plaques resulting in angina and myocardial infarction. Non-ischemic heart disease refers to heart abnormalities occurring in the absence of CAD, including inflammation in the myocardium or pericardium, myocardial fibrosis, systolic or diastolic dysfunction, conduction defects, and valvular abnormalities, resulting in dilated or inflammatory cardiomyopathy. Both ischemic and non-ischemic heart disease can potentially result in cardiogenic shock, cardiac arrhythmia and sudden cardiac death.1

Cardiac involvement in patients with RA can range from subclinical and asymptomatic changes in the hearts to clinical manifestations of heart failure.

Subclinical changes may involve the myocardium and the coronary system and include evidence for cardiac fibrosis or inflammation on imaging or reduced left ventricle function, reported in up to 50% of patients with RA and no history of CVD.9,10 Furthermore, cardiac microvascular dysfunction was reported in a third of patients with RA.11 These subclinical changes may result in ischemic and non-ischemic complications.1

Davis and colleagues reported that both the clinical presentation and the outcome of heart failure are significantly different in patients with RA, compared with those without the rheumatic disease. Patients with RA have a more subtle presentation, as signs and symptoms of heart failure are less common and preserved ejection fraction is more frequent in those with RA, compared with patients without RA. Mortality risk was reported to be almost 2-fold greater for those with RA, compared with non-RA patients.12

A systematic review and meta-analysis aimed to compare the CV outcomes in patients with CAD and RA reported that among patients with CAD, a diagnosis of RA was associated with a 40-50% increased risk for all-cause mortality, cardiac death, and congestive heart failure.13 Similarly, patients with RA were reported to have a 2-fold increased risk for sudden cardiac death.14

According to a study by Nicola and colleagues, the mortality risk associated with either heart failure or ischemic heart disease was not significantly different between patients with RA and patients without the rheumatic disease. Their conclusion was that increased incidence of congestive heart failure, rather than ischemic heart disease, plays an important role in the excess overall mortality among patients with RA.15

Treatment with aspirin, statins, folic acid, angiotensin converting enzyme inhibitors and angiotensin II receptor blockers may be used to prevent CVDs in patients with RA.1 Medications used to treat RA may also have a major impact on the CV risk. Treatment with conventional synthetic, biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) is important in patients with RA, and modern treatment strategies, specifically the treat-to-target approach, may be responsible for the recent decline in cardiovascular mortality among patients with RA.16 

Conventional synthetic DMARDs, including hydroxychloroquine, methotrexate, sulfasalazine and leflunomide, were reported to have a cardioprotective effect in most studies, although in some cases a potential harm was suggested.1,17 Using corticosteroids or non-steroidal anti-inflammatory drugs may increase the cardiovascular risk.17

Biologic DMARDs include anti-tumor necrosis factor-alpha that can effectively suppress inflammation and prevent disease progression. In patients with preserved heart function, anti-tumor necrosis factor-alpha may have beneficial effects, including reduced atherosclerosis and improved heart function, contributing to reduced CV risk. However, in patients with chronic heart failure, the use of these medications may adversely exacerbate heart failure and is potentially associated with increased mortality risk. Abatacept and rituximab, another class of biologic DMARDs, showed a CV safety profile comparable to anti-tumor necrosis factor-alpha treatments.1 

Targeted synthetic DMARDs, tofacitinib or baricitinb, have no significant cardioprotective effect despite of their anti-inflammatory properties. While these medications may negatively affect lipid profile, the treatment is not associated with increased CV risk.1

“Future studies should be more focused on targeted, cardioprotective therapies tailored for these patients with RA with high disease activity and those with established heart failure. Achievement of these goals requires a better understanding of RA-related pathophysiological processes promoting heart failure,” wrote the researchers.

References

  1. Błyszczuk P, Szekanecz Z. Pathogenesis of ischaemic and non-ischaemic heart diseases in rheumatoid arthritis. RMD Open. 2020;6(1):e001032. doi:10.1136/rmdopen-2019-001032
  2. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303-7. doi:10.1161/01.cir.0000054612.26458.b2
  3. Solomon DH, Avorn J, Katz JN, et al. Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(12):3790-8. doi:10.1002/art.22255
  4. Mahtta D, Gupta A, Ramsey DJ, et al. Autoimmune rheumatic diseases and premature atherosclerotic cardiovascular disease: an analysis from the VITAL registry. Am J Med. 2020;133(12):1424-1432.e1. doi:10.1016/j.amjmed.2020.05.026
  5. Myasoedova E, Chandran A, Ilhan B, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Ann Rheum Dis. 2016;75(3):560-5. doi:10.1136/annrheumdis-2014-206411
  6. Arts EE, Fransen J, Den Broeder AA, van Riel PLCM, Popa CD. Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study. Ann Rheum Dis. 2017;76(10):1693-1699. doi:10.1136/annrheumdis-2016-210997
  7. Jagpal A, Navarro-Millán I. Cardiovascular co-morbidity in patients with rheumatoid arthritis: a narrative review of risk factors, cardiovascular risk assessment and treatment. BMC Rheumatol. 2018;2:10. doi:10.1186/s41927-018-0014-y
  8. Løgstrup BB, Olesen KKW, Masic D, et al. Impact of rheumatoid arthritis on major cardiovascular events in patients with and without coronary artery disease. Ann Rheum Dis. 2020;79(9):1182-1188. doi:10.1136/annrheumdis-2020-217154
  9. Amigues I, Tugcu A, Russo C, et al. Myocardial inflammation, measured using 18-fluorodeoxyglucose positron emission tomography with computed tomography, is associated with disease activity in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(4):496-506. doi:10.1002/art.40771
  10. Cioffi G, Viapiana O, Ognibeni F, et al. Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis. A prospective tissue Doppler echocardiography study. Herz. 2015;40(7):989-96. doi:10.1007/s00059-015-4320-5
  11. Amigues I, Russo C, Giles JT, et al. Myocardial microvascular dysfunction in rheumatoid arthritis quantitation by 13N-ammonia positron emission tomography/computed tomography. Circ Cardiovasc Imaging. 2019;12(1):e007495. doi:10.1161/CIRCIMAGING.117.007495
  12. Davis JM, Roger VL, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. The presentation and outcome of heart failure in patients with rheumatoid arthritis differs from that in the general population. Arthritis Rheum. 2008;58(9):2603-11. doi:10.1002/art.23798
  13. Wang H, Li X, Gong G. Cardiovascular outcomes in patients with co-existing coronary artery disease and rheumatoid arthritis: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(14):e19658. doi:10.1097/MD.0000000000019658
  14. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52(2):402-11. doi:10.1002/art.20853
  15. Nicola PJ, Crowson CS, Maradit-Kremers H, et al. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum. 2006;54(1):60-7. doi:10.1002/art.21560
  16. Provan SA, Lillegraven S, Sexton J, et al. Trends in all-cause and cardiovascular mortality in patients with incident rheumatoid arthritis: a 20-year follow-up matched case-cohort study. Rheumatology (Oxford). 2020;59(3):505-512. doi:10.1093/rheumatology/kez371
  17. Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(3):480-9. doi:10.1136/annrheumdis-2014-206624