Characterisation of cardiovascular involvement in inflammatory arthropathies and systemic rheumatic diseases using multi-parametric cardiovascular magnetic resonance 
Keywords: myocardial fibrosis
myocardial inflammation
Cardiovascular magnetic resonance
magnetic resonance spectroscopy
systemic rheumatic disorders

Inflammatory arthropathies and systemic rheumatic diseases (IASRDs) commonly involve the cardiovascular system, and are associated with high morbidity and mortality. Mechanisms of cardiovascular involvement in these clinical entities are not fully understood. Cardiovascular magnetic resonance (CMR) is the single imaging modality capable of assessing non-invasively cardiac function, strain, ischaemia, altered vascular function, perfusion, oedema/inflammation and fibrosis. Furthermore, magnetic resonance spectroscopy (MRS) can give further insights into the status of myocardial energetics and lipidosis.
The pathophysiological mechanisms and phenotype of cardiovascular disease (CVD) in IASRDs need further clarification. CMR is an ideal tool for the early identification and monitoring of cardiac manifestations in patients with IASRDs. Hence, the aims of this D.Phil project were to (i) utilise CMR and MRS to study disease mechanisms in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and (ii) to assess the role of anti-cytokine therapies in abrogation of cardiovascular complications and effects on cardiovascular function in patients with RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA).
First, we used CMR to assess myocardial structure and function in RA, SLE and SSc patients with no known cardiovascular symptoms. Patients and controls were stratified by the presence of traditional cardiovascular risk factors (CVRFs). Our data demonstrated no differences in overall left ventricular (LV) systolic function, size and mass between patients and matched controls. There were, however, impairments in regional function and myocardial deformation, which is most severe in RA, SLE and SSc patients with CVRFs. We also found evidence of impaired vascular function in RA, SLE and SSc, using pulse wave velocity (PWV) and aortic distensibility, and again, showed that patients with CVRFs demonstrated the most severe aberrations, while patients without CVRFs and controls with CVRFs had an intermediate phenotype. Abnormalities in vascular and regional function were most severe in patients with SSc. Also, we showed that impaired vascular function correlated with abnormal systolic myocardial strain and diastolic strain rate in all groups of IASRDs studied. These data have implications for the clinical care of patients with RA, SLE and SSc and show that there is extensive cardiovascular involvement in asymptomatic patients. These results also suggest that early identification and stratification of CVD in IASRDs, with non-invasive techniques like CMR, may permit earlier intervention, thus potentially reducing the effect of CVD on morbidity and mortality in IASRDs. Lastly, these data highlight the importance of early detection and aggressive management of co-existent traditional CVRFs, as they confer incremental risk of CVD in patients with IASRDs.
Second, we used CMR for comprehensive phenotyping of tissue characteristics in patients with RA, SLE and SSc. Our data confirmed that subclinical myocardial changes are common in patients with IASRDs (even with apparently normal hearts), which can be detected using multiparametric CMR. In addition to focal areas of fibrosis (detected by late gadolinium enhancement [LGE]), there were also areas of focal myocardial oedema or inflammation (detected by T2-weighted imaging). Further, using more sensitive techniques such as native T1 mapping and extracellular volume (ECV) quantification, we were able to demonstrate even more areas of myocardial involvement in IASRD patients than conventional CMR techniques can reveal, with patients showing significantly larger areas of T1 abnormality and expanded ECV, which likely represent a combination of low grade inflammation and diffuse myocardial fibrosis that are well-described disease processes in this cohort. We also found that T1 and ECV measures were associated with subtle myocardial systolic and diastolic dysfunction. The results of this study suggest that CMR, particularly T1 and ECV quantification, can be used for early detection of subclinical myocardial involvement in IASRD patients, potentially serving as an early screening tool before overt LV dysfunction or irreversible myocardial damage occurs.
Third, we utilised CMR to study myocardial perfusion in patients with RA, SLE and SSc. We found that myocardial perfusion was impaired in asymptomatic IASRD with no overt heart disease. Non-segmental, subendocardial perfusion defects consistent with microvascular dysfunction were present in 47%, 31% and 41% of RA, SLE and SSc patients, respectively. Furthermore, there was a significant correlation between MPRI and systolic and diastolic regional function in all groups of patients. In RA and SSc, there was also a correlation between myocardial perfusion reserve index (MPRI) and disease activity. SSc patients had the greatest burden of ECV expansion, and in this group ECV also correlated with MPRI. These data led us to hypothesise that myocardial ischaemia likely leads to impaired myocardial relaxation and diffuse fibrosis, which predate overt dysfunction in contractility.
Fourth, we investigated the effect of TNF-alpha inhibitors on myocardial and vascular function and structure in RA, AS and PsA patients. We confirmed that anti-TNF therapy was associated with improvements in serum inflammatory parameters like CRP and ESR, as well as with improved clinical measures of disease activity. Anti-TNF therapy, however, was not related to a change in left ventricular size, mass and global systolic function. We found that inhibition of TNF-alpha activity does result in better myocardial strain and strain rate, likely reflecting an improvement in myocardial inflammatory burden. Moreover, these findings were also supported by improvements in T2 weighted measures, native T1 values and ECV calculations. There was, however, no significant change in myocardial perfusion following anti-TNF therapy. These results support the hypothesis that during episodes of disease activity, myocardial oedema is present in patients with IASRDS and that by reducing the systemic inflammatory response, improvements in myocardial and vascular function can be achieved.
Finally, we used CMR and MRS in asymptomatic RA and SLE patients (with normal hearts on echocardiography) to investigate cardiac metabolic status in this cohort. We found that myocardial energetics were impaired in patients, despite preserved overall ejection fraction. Interestingly, abnormal myocardial energetics were associated with presence of LGE, decreased myocardial perfusion, expanded ECV, volume fraction of T1 >990ms (which represents >2 standard deviations above the mean T1 value at 1.5T) and left atrial size. We did not find any difference in myocardial and hepatic lipid content between patients and controls. These data clearly demonstrate that abnormalities in cardiac energetics are present in IASRD patients even before the development of overt cardiac dysfunction, and may be driven by microvascular function and fibrosis.