Subclinical Cardiovascular Disease in early Rheumatoid Arthritis and established Giant Cell Arteritis: Insights from Cardiovascular Magnetic Resonance Imaging

Immune-mediated inflammatory diseases (IMID) are a group distinguished by specific pathways of immune-dysregulation that lead to inflammation, organ damage and dysfunction, of which Rheumatoid Arthritis (RA) and Giant Cell Arteritis (GCA) are two examples. An increased risk of cardiovascular disease (CVD) is observed in patients with IMID. Inflammation plays an important role in atherosclerosis. The inflammatory process has confounding effects on lipid and glucose metabolism, blood pressure and haemostatic factors. RA is a chronic inflammatory arthritis and one of the most common systemic autoimmune diseases affecting approximately 1% of the UK population. In RA, the risk of myocardial infarction (MI) is independent of, and incremental to, traditional CVD risk factors. CVD, as a direct result of the IMID process and independent of atherosclerosis can be an additional insult and seen in GCA. GCA is associated with an increased mortality mainly due to CVD, including aortic syndromes. Aortic involvement in GCA may manifest clinically as a syndrome of systemic inflammation without specific symptoms, or even be asymptomatic until aortic dissection or rupture supervenes with life-threatening consequences. The early identification of disease can benefit patients clinically by initiation of earlier disease modifying therapy, potentially reducing morbidity and mortality. Determining disease phenotype is important to develop effective screening strategies. This thesis aims to identify subclinical cardiovascular (CV) change using cardiovascular magnetic resonance (CMR) in the IMIDs of RA and GCA. It is also tested whether therapeutic interventions can modulate surrogate markers of CV outcomes in RA. Using CMR, this thesis demonstrates the presence of CV abnormalities in early RA (ERA) and established GCA. Changes in vascular function, myocardial tissue composition and ventricular geometry/performance are present in ERA, inferring an increased risk of CVD at the earliest stages of the RA disease continuum. There are thoracic aortic structural changes in established, treated, GCA. Dilatation of the thoracic aorta is common in GCA, with polymyalgic symptoms a possible risk factor. Patients with GCA also had increased aortic arterial stiffness than controls. CMR is able to detect subclinical CV change in asymptomatic ERA and established GCA patients without known CVD. Surrogate markers of CV events can be modulated in ERA with early aggressive RA therapy and CMR can identify silent aortic dilatation, associated with adverse outcomes, in GCA. CMR can aid the early and appropriate diagnosis of disease and complications, and potentially identify those at the highest risk of adverse outcomes

Myocardial strain and symptom severity in severe aortic stenosis: insights from cardiovascular magnetic resonance

Background: Symptomatic severe aortic stenosis (AS) is a class I indication for replacement in patients when left ventricular ejection fraction (LVEF) is preserved. However, symptom reporting is often equivocal and decision making can be challenging. We aimed to quantify myocardial deformation using cardiovascular magnetic resonance (CMR) in patients classified by symptom severity. Methods: Forty-two patients with severe AS referred to heart valve clinic were studied using tagged CMR imaging. All had preserved LVEF. Patients were grouped by symptoms as either “none/mild” (n=21, NYHA class I, II) or “significant” (n=21, NYHA class III, IV, angina, syncope) but were comparable for age (72.8±5.4 vs. 71.0±6.8 years old, P=0.345), surgical risk (EuroSCORE II: 1.90±1.7 vs. 1.31±0.4, P=0.302) and haemodynamics (peak aortic gradient: 55.1±20.8 vs. 50.4±15.6, P=0.450). Thirteen controls matched in age and LVEF were also studied. LV circumferential strain was calculated using inTag© software and longitudinal strain using feature tracking analysis. Results: Compared to healthy controls, patients with severe AS had significantly worse longitudinal and circumferential strain, regardless of symptom status. Patients with “significant” symptoms had significantly worse peak longitudinal systolic strain rates (−83.352±24.802%/s vs. −106.301±43.276%/s, P=0.048) than those with “no/mild” symptoms, with comparable peak longitudinal strain (PLS), peak circumferential strain and systolic and diastolic strain rates. Conclusions: Patients with severe AS who have no or only mild symptoms exhibit comparable reduction in circumferential and longitudinal fibre function to those with significant symptoms, in whom AVR is clearly indicated. Given these findings of equivalent subclinical dysfunction, reportedly borderline symptoms should be handled cautiously to avoid potentially adverse delays in intervention

Acute Infarct Extracellular Volume Mapping to Quantify Myocardial Area at Risk and Chronic Infarct Size on Cardiovascular Magnetic Resonance Imaging

Background—Late gadolinium enhancement (LGE) imaging overestimates acute infarct size. The main aim of this study was to investigate whether acute extracellular volume (ECV) maps can reliably quantify myocardial area at risk (AAR) and final infarct size (IS). Methods and Results—Fifty patients underwent cardiovascular magnetic resonance imaging acutely (24–72 hours) and at convalescence (3 months). The cardiovascular magnetic resonance protocol included cines, T2-weighted imaging, native T1 maps, 15-minute post-contrast T1 maps, and LGE. Optimal AAR and IS ECV thresholds were derived in a validation group of 10 cases (160 segments). Eight hundred segments (16 per patient) were analyzed to quantify AAR/IS by ECV maps (ECV thresholds for AAR is 33% and IS is 46%), T2-weighted imaging, T1 maps, and acute LGE. Follow-up LGE imaging was used as the reference standard for final IS and viability assessment. The AAR derived from ECV maps (threshold of >33) demonstrated good agreement with T2-weighted imaging–derived AAR (bias, 0.18; 95% confidence interval [CI], −1.6 to 1.3) and AAR derived from native T1 maps (bias=1; 95% CI, −0.37 to 2.4). ECV demonstrated the best linear correlation to final IS at a threshold of >46% (R=0.96; 95% CI, 0.92–0.98; P<0.0001). ECV maps demonstrated better agreement with final IS than acute IS on LGE (ECV maps: bias, 1.9; 95% CI, 0.4–3.4 versus LGE imaging: bias, 10; 95% CI, 7.7–12.4). On multiple variable regression analysis, the number of nonviable segments was independently associated with IS by ECV maps (β=0.86; P<0.0001). Conclusions—ECV maps can reliably quantify AAR and final IS in reperfused acute myocardial infarction. Acute ECV maps were superior to acute LGE in terms of agreement with final IS. IS quantified by ECV maps are independently associated with viability at follow-up

Myocardial effects of aldosterone antagonism in heart failure with preserved ejection fraction

Background: Spironolactone may have prognostic benefit in selected patients with heart failure with preserved ejection fraction. This study assessed the myocardial tissue effects of spironolactone in heart failure with preserved ejection fraction. Methods and Results: A 1:1 randomized controlled study of 6 months of spironolactone versus control in heart failure with preserved ejection fraction. The primary outcome was change in myocardial extracellular volume fraction by cardiovascular magnetic resonance as a surrogate of diffuse fibrosis. Of 55 randomized patients, 40 (20 women; age, 75.2±5.9 years) completed follow-up (19 treatment, 21 control). A significant change in extracellular volume over the study period was not seen (treatment, 28.7±3.7% versus 27.7±3.4% [P=0.14]; controls, 27.6±3.4% versus 28.3±4.4% [P=0.14]); however, the rate of extracellular volume expansion was decreased by spironolactone (−1.0±2.4% versus 0.8±2.2%). Indexed left ventricular mass decreased with treatment (104.4±26.6 versus 94.0±20.6 g/m 2; P=0.001) but not in controls (101.4±29.4 versus 104.0±32.8 g/m 2; P=0.111). Extracellular mass decreased by 13.8% (15.1±4.8 versus 13.0±3.4 g/m 2; P=0.003), and cellular mass decreased by 8.3% (37.6±10.0 versus 34.3±7.9 g/m 2; P=0.001) with spironolactone, but was static in controls. Conclusions: Spironolactone did not lead to significant change in extracellular volume. However, spironolactone did decrease rate of extracellular expansion, with a decrease in the mass of both cellular and extracellular myocardial compartments. These data point to the mechanism of action of spironolactone in heart failure with preserved ejection fraction, including a direct tissue effect with a reduction in rate of myocardial fibrosis

Relationship between cardiac deformation parameters measured by cardiovascular magnetic resonance and aerobic fitness in endurance athletes

Background: Athletic training leads to remodelling of both left and right ventricles with increased myocardial mass and cavity dilatation. Whether changes in cardiac strain parameters occur in response to training is less well established. In this study we investigated the relationship in trained athletes between cardiovascular magnetic resonance (CMR) derived strain parameters of cardiac function and fitness. Methods: 35 endurance athletes and 35 age and sex matched controls underwent CMR at 3.0T including cine imaging in multiple planes and tissue tagging by spatial modulation of magnetization (SPAMM). CMR data were analysed quantitatively reporting circumferential strain and torsion from tagged images and left and right ventricular longitudinal strain from feature tracking of cine images. Athletes performed a maximal ramp-incremental exercise test to determine the lactate threshold (LT) and maximal oxygen uptake (V̇O2max). Results: LV circumferential strain at all levels, LV twist and torsion, LV late diastolic longitudinal strain rate, RV peak longitudinal strain and RV early and late diastolic longitudinal strain rate were all lower in athletes than controls. On multivariable linear regression only LV torsion (beta=-0.37, P=0.03) had a significant association with LT. Only RV longitudinal late diastolic strain rate (beta=-0.35, P=0.03) had a significant association with V̇O2max. Conclusions: This cohort of endurance athletes had lower LV circumferential strain, LV torsion and biventricular diastolic strain rates than controls. Increased LT, which is a major determinant of performance in endurance athletes, was associated with decreased LV torsion. Further work is needed to understand the mechanisms by which this occurs