Update on Cardiovascular Disease Risk in Patients with Rheumatic Diseases

Cardiovascular disease (CVD) is the main cause of death in patients with rheumatoid arthritis (RA). Apart from traditional cardiovascular risk factors, immune dysfunction and chronic inflammation of RA are also risk factors for complex cardiovascular damage. Although methotrexate (MTX) is beneficial to CVD in RA patients by inhibiting inflammation, its adverse effects limit its clinical application. Therefore, it is essential to seek safer and more effective drugs.

We aimed to assess the efficacy of Guanxining Tablet (GXNT) for rheumatoid arthritis complicated with cardiovascular damage.

We will conduct a prospective single-center randomized trial. We will randomly divide 56 eligible patients into two groups. The treatment group will take GXNT and MTX treatment, and the control group will receive MTX and the placebo. The primary outcome measure will be aortic distensibility (AD). Secondary outcome measures will be Cardiac function which will contain right ventricular outflow tract diameter (RVOTD), aortic diameter (AOD), left atrium diameter (LAD), right ventricular end diastolic diameter (RVDD), left ventricular end diastolic diameter (LVDD), ejection fraction (EF%), fractional shortening (FS%), stroke volume (SV). Adverse events will be closely monitored during the entire trial period.

This trial is intended to determine whether the addition of GXNT will improve the prognosis of patients with rheumatoid arthritis and cardiovascular damage without severe adverse reactions. Completing this clinical trial might provide these patients with a novel and effective drug while avoiding adverse reactions similar to methotrexate.

ChiCTR2000030247.

To extend our investigation of cardiovascular diseases (CVD) in rheumatoid arthritis (RA) patients to a follow up of more than 20 years, with a special focus on patients without prevalent CVD.

The CARRÉ study is an ongoing prospective cohort study on CV endpoints in RA patients. Results were compared to those of a reference cohort (n = 2484) enriched for type 2 diabetes mellitus (DM). Hazard ratios (HR) for RA and DM patients compared to non-RA/-DM controls were calculated with cox proportional hazard models, and adjusted for baseline SCORE1 (estimated 10-year CVD mortality risk based on CV risk factors).

238 RA patients, 117 DM patients and 1282 controls, without prevalent CVD at baseline were included. Analysis of events in these patients shows that after adjustment, no relevant ‘RA-specific’ risk remains (HR 1.16; 95%CI 0.88 – 1.53), whereas a ‘DM-specific’ risk is retained (1.73; 1.24 – 2.42). In contrast, adjusted analyses of all cases confirm the presence of an ‘RA-specific’ risk (1.50; 1.19 – 1.89).

In RA patients without prevalent CVD the increased CVD risk is mainly attributable to increased presence of traditional risk factors. After adjustment for these factors, an increased risk attributable to RA only was thus preferentially seen in the patients with prevalent CVD at baseline. As RA treatment has improved, this data suggests that the ‘RA-specific’ effect of inflammation is preferentially seen in patients with prevalent CVD. We suggest that with modern (early) treatment of RA, most of the current increased CVD risk is mediated through traditional risk factors.

The level of circulating interferon-γ (IFNγ) is elevated in various clinical conditions including autoimmune and inflammatory diseases, sepsis, acute coronary syndrome, and viral infections. As these conditions are associated with high risk of myocardial dysfunction, we investigated the effects of IFNγ on 3D fibrin-based engineered human cardiac tissues (“cardiobundles”). Cardiobundles were fabricated from human pluripotent stem cell-derived cardiomyocytes, exposed to 0–20 ng/ml of IFNγ on culture days 7–14, and assessed for changes in tissue structure, viability, contractile force and calcium transient generation, action potential propagation, cytokine secretion, and expression of select genes and proteins. We found that application of IFNγ induced a dose-dependent reduction in contractile force generation, deterioration of sarcomeric organization, and cardiomyocyte disarray, without significantly altering cell viability, action potential propagation, or calcium transient amplitude. At molecular level, the IFNγ-induced structural and functional deficits could be attributed to altered balance of pro- and anti-inflammatory cytokines, upregulation of JAK/STAT signaling pathway (JAK1, JAK2, and STAT1), and reduced expression of myosin heavy chain, myosin light chain-2v, and sarcomeric α-actinin. Application of clinically used JAK/STAT inhibitors, tofacitinib and baricitinib, fully prevented IFNγ-induced cardiomyopathy, confirming the critical roles of this signaling pathway in inflammatory cardiac disease. Taken together, our in vitro studies in engineered myocardial tissues reveal direct adverse effects of pro-inflammatory cytokine IFNγ on human cardiomyocytes and establish the foundation for a potential use of cardiobundle platform in modeling of inflammatory myocardial disease and therapy.

Various inflammatory and autoimmune diseases including rheumatoid arthritis, sepsis, lupus erythematosus, Chagas disease, and others, as well as viral infections including H1N1 influenza and COVID-19 show increased systemic levels of a pro-inflammatory cytokine interferon-γ (IFNγ) and are associated with high risk of heart disease. Here we explored for the first time if chronically elevated levels of IFNγ can negatively affect structure and function of engineered human heart tissues in vitro. Our studies revealed IFNγ-induced deterioration of myofibrillar organization and contractile force production in human cardiomyocytes, attributed to decreased expression of multiple sarcomeric proteins and upregulation of JAK/STAT signaling pathway. FDA-approved JAK inhibitors fully blocked the adverse effects of IFNγ, suggesting a potentially effective strategy against human inflammatory cardiomyopathy.

The recognition that patients with rheumatoid arthritis are at a heightened risk of cardiovascular disease (CVD) events and mortality spans more than 2 decades, yet there continues to be debate as to who should screen this population for CVD risk. There are several challenges to regular screening of this population: limited time, the assumption that this problem is being addressed by the rheumatologist, and lack of awareness by primary care providers (PCP) of increased CVD risk. A collaborative approach between PCPs and rheumatologists is necessary to address the increased CVD risk and to treat these risk factors aggressively.

Le risque cardiovasculaire élevé retrouvé dans la polyarthrite rhumatoïde ou l’arthrite psoriasique est en grande partie imputable à l’inflammation systémique. Dans l’arthrose (OA), la survenue d’une inflammation systémique a parfois été rapportée mais l’association entre arthrose et augmentation du risque cardiovasculaire reste à préciser. Cette méta-analyse avait pour objectif d’évaluer l’incidence des infarctus du myocarde (IM) et des accidents vasculaires cérébraux (AVC) mais également les facteurs de risque cardiovasculaire chez les patients OA.

Nous avons effectué une recherche dans les bases de données PubMed, EMBase et Cochrane Library afin de trouver des références d’intérêt publiées jusqu’au mois de juin 2018. Les incidences de l’IM et de l’AVC ont été calculées à l’aide d’une méta-analyse des proportions. Les différences relatives aux facteurs de risque de maladie cardiovasculaire entre les patients OA et les sujets témoins ont été exprimées sous forme de différences moyennes standardisées (DMS) selon la méthode de l’inverse de la variance.

Les études analysées ont rapporté 227 IM chez 3550 patients arthrosiques (incidence, 7,5 % ; IC95 % : 3,0–13,8 %) et 616 IM chez 12 444 sujets témoins (incidence, 6,0 % ; IC95 % : 2,8–10,3 %). La méta-analyse des trois études longitudinales a révélé une augmentation significative du risque d’IM chez les patients OA (RR = 1,22 ; IC95 % : 1,02–1,45). Nous avons également retrouvé un risque d’AVC significativement élevé chez les patients OA (RR = 1,43 ; IC95 % : 1,38–1,48). En ce qui concerne les facteurs de risque de maladie cardiovasculaire, les patients OA affichaient un profil lipidique et glucidique pro-athérogène se traduisant par une élévation des concentrations en glucose, cholestérol total et LDL-cholestérol ainsi qu’un indice de masse corporel (IMC) élevé. S’agissant des marqueurs de l’athérosclérose, les patients OA montraient une majoration du risque de syndrome métabolique et une élévation de la vitesse de l’onde de pouls (VOP).

Les résultats de notre méta-analyse ont révélé un risque cardiovasculaire plus élevé chez les patients arthrosiques. Ces observations soulignent l’importance de la prise en charge des facteurs de risque cardiovasculaire dans l’arthrose.

Higher cardiovascular risk found in rheumatoid arthritis or psoriatic arthritis is largely due to systemic inflammation. In osteoarthritis (OA), occurrence of systemic inflammation has already been sometimes reported, but the possible association between OA and increased cardiovascular risk remains unclear. In this meta-analysis, we aimed to assess the incidences of myocardial infarction (MI) and stroke, and the cardiovascular risk factors in OA patients.

We searched PubMed, EMBase, and the Cochrane Library to find references of interest up to June 2018. MI and stroke incidence were calculated using meta-proportion analysis. Differences in cardiovascular risk factors between OA patients and controls were expressed as standardized mean differences using the inverse of variance method.

The reviewed studies reported 227 MIs in 3550 OA patients (incidence, 7.5%; 95% CI: 3.0–13.8%) and 616 MIs among 12,444 control subjects (incidence, 6.0%; 95% CI: 2.8–10.3%). Meta-analysis of the three longitudinal studies revealed a significantly increased MI risk among OA patients (RR = 1.22; 95% CI: 1.02–1.45). We also found a significantly increased stroke risk in OA patients (RR = 1.43; 95% CI: 1.38–1.48). Concerning cardiovascular risk factors, OA patients exhibited a pro-atherogenic lipid and glycemic profile including high levels of fasting glucose, total cholesterol, and LDL cholesterol and a high body mass index. Concerning atherosclerosis markers, OA patients exhibited a higher risk of metabolic syndrome, and increased pulse wave velocity.

Our meta-analysis results revealed higher cardiovascular risk in OA patients. This highlights the importance of cardiovascular risk factor management in OA.