Defining The incidence of Cardiac Involvement in Myositis Using Mapping Based Cardiovascular Magnetic Resonance Imaging

Myositis is the name of a group of rare conditions characterised by inflammation and fibrosis of skeletal muscle leading to pain and progressive weakness [1]. In a proportion of patients, extra skeletal muscle manifestations complicate the clinical course. In particular, cardiac muscle involvement is associated with worse outcomes [2, 3]. The pathophysiology of myocardial involvement is inflammation and fibrosis [4] which has proven difficult to identify by traditional investigations. The new techniques of T1 and T2 mapping in cardiovascular magnetic resonance (CMR) allow for assessment of myocardial fibrosis and oedema. Use of T1 and T2 mapping has been shown to offer improved sensitivity for mild and diffuse inflammation as well as subtle focal and diffuse fibrosis in inflammatory myocardial diseases such as viral myocarditis and sarcoidosis. This could help guide therapy and monitor treatment response [5, 6] in myositis.We scanned healthy volunteers to establish normal T1 and T2 values for our particular scanner. Using both healthy volunteers and patients with myositis we devised and validated a novel method of analysing the ventricle following a multi-segment model. The model was based on the 12 basal and mid-level American Heart Association myocardial segments [7]. The apical segments were excluded due to well documented issues around reproducibility [8, 9].Using the above method, we found that patients with myositis had significantly higher T1 and T2 than healthy volunteers, independent of blood troponin. We also found that in patients with myositis, a raised troponin was associated with higher myocardial T1 and T2 values than those patients whose troponin was not elevated.We performed follow -up scans on patients with myositis and demonstrated a reduction in T1 and T2 values over time without any change in overall cardiac function. T2 values returned to baseline over the course of the study whereas T1 values remained significantly higher than that of healthy volunteers.These studies show that measuring myocardial T1 and T2 values in myositis may have a role in both the identification of inflammation or fibrosis and in monitoring the response to treatment. The sample size of the study did not allow for comparison of different treatments to be made.We also undertook mapping of skeletal muscle tissue mapping using the same, gated, cardiac specific un-optimised sequences. The purpose was to look for trends in T1 and T2 values that might suggest a benefit in developing specific sequences to allow researchers or clinicians to reproducibly measure skeletal muscle disease activity non-invasively. We found that, despite large variability in the data set, T2 values decrease over time with treatment suggesting there may indeed be a benefit in working towards dedicated skeletal muscle sequences in the future.<br/

Therapies to limit myocardial injury in animal models of myocarditis:a systematic review and meta-analysis

Current myocarditis guidelines do not advocate treatment to prevent myocardial injury and scar deposition in patients with myocarditis and normal left ventricular ejection fraction. We aimed to ascertain the utility of beta blockers, calcium channel blockers and antagonists of the renin–angiotensin system in ameliorating myocardial injury, scar formation and calcification in animal in vivo models of myocarditis. The project was prospectively registered with the PROSPERO database of systematic reviews (CRD42018089336). Primary outcomes (necrosis, fibrosis and calcification) were meta-analysed with random-effects modelling. 52 studies were systematically reviewed. Meta-analysis was performed compared with untreated controls. In each study, we identified all independent comparisons of treatment versus control groups. The pooled weighted mean difference (WMD) indicated treatment reduced necrosis by 16.9% (71 controlled analyses, 95% CI 13.2–20.7%; P < 0.001), however there was less evidence of an effect after accounting for publication bias. Treatment led to a 12.8% reduction in fibrosis (73 controlled analyses, 95% CI 7.6–18.0%; P < 0.001). After accounting for publication bias this was attenuated to 7.8% but remained significant. Treatment reduced calcification by 4.1% (28 controlled analyses, 95% CI 0.2–8.0%; P < 0.0395). We observed significant heterogeneity in effect size in all primary endpoints, which was predominantly driven by differences between drug categories. Beta blockers and angiotensin-converting enzyme (ACE) inhibitors were the only agents that were effective for both necrosis and fibrosis, while only ACE inhibitors had a significant effect on calcification. This study provides evidence for a role for ACE inhibitors and beta blockers to prevent myocardial injury and scar deposition in in vivo models of myocarditis. There is a need for further well-designed studies to assess the translational application of these treatments

Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans

AIMS: Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity. METHODS AND RESULTS: We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [−2.3 (−0.3, −4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = −32; z = −12; P < 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = −14; y = −56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009]. CONCLUSIONS: These data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease

Coronary Wave Intensity Analysis as an Invasive and Vessel-Specific Index of Myocardial Viability

Coronary angiography and viability testing are the cornerstones of diagnosing and managing ischemic cardiomyopathy. At present, no single test serves both needs. Coronary wave intensity analysis interrogates both contractility and microvascular physiology of the subtended myocardium and therefore has the potential to fulfil the goal of completely assessing coronary physiology and myocardial viability in a single procedure. We hypothesized that coronary wave intensity analysis measured during coronary angiography would predict viability with a similar accuracy to late-gadolinium–enhanced cardiac magnetic resonance imaging. METHODS: Patients with a left ventricular ejection fraction ≤40% and extensive coronary disease were enrolled. Coronary wave intensity analysis was assessed during cardiac catheterization at rest, during adenosine-induced hyperemia, and during low-dose dobutamine stress using a dual pressure-Doppler sensing coronary guidewire. Scar burden was assessed with cardiac magnetic resonance imaging. Regional left ventricular function was assessed at baseline and 6-month follow-up after optimization of medical-therapy±revascularization, using transthoracic echocardiography. The primary outcome was myocardial viability, determined by the retrospective observation of functional recovery. RESULTS: Forty participants underwent baseline physiology, cardiac magnetic resonance imaging, and echocardiography, and 30 had echocardiography at 6 months; 21/42 territories were viable on follow-up echocardiography. Resting backward compression wave energy was significantly greater in viable than in nonviable territories (−5240±3772 versus −1873±1605 W m(−2) s(−1), P<0.001), and had comparable accuracy to cardiac magnetic resonance imaging for predicting viability (area under the curve 0.812 versus 0.757, P=0.649); a threshold of −2500 W m(−2) s(−1) had 86% sensitivity and 76% specificity. CONCLUSIONS: Backward compression wave energy has accuracy similar to that of late-gadolinium–enhanced cardiac magnetic resonance imaging in the prediction of viability. Coronary wave intensity analysis has the potential to streamline the management of ischemic cardiomyopathy, in a manner analogous to the effect of fractional flow reserve on the management of stable angina