Detection, assessment and modulation of myocardial inflammation

Coronary atherosclerosis and plaque rupture leads to acute coronary thrombosis and myocardial infarction. Current treatment involves re-establishing vessel patency, but no treatments have been developed to target post-infarction inflammatory pathways. Such treatments may reduce cardiomyocyte injury, attenuate adverse remodelling and improve clinical outcome. Inflammation within the infarcted myocardium is associated with chemotaxis of neutrophils and monocytes to the site of injury. Early reperfusion therapy amplifies this inflammatory cell influx. Neutrophil release a variety of pro-inflammatory factors, including human neutrophil elastase (HNE). HNE has a wide range of substrates. Preclinical studies have demonstrated that neutrophil depletion or inhibition of neutrophil elastase attenuates post-ischemic inflammatory reperfusion injury within the myocardium. Recruitment of monocytes into the infarcted myocardium is followed by maturation and differentiation into macrophages. Macrophages play a key role in orchestrating inflammation and repair. Therapeutic manipulation of this healing process will only come from understanding mechanisms and targeting reparative pathways. “Ultrasmall superparamagnetic iron oxide particles” (USPIOs) extravasate through capillaries and are phagocytosed by tissue inflammatory cells. These cells are predominately macrophages, but neutrophils have also been shown to take up USPIOs. USPIO-enhanced MRI can identify areas of inflammation in models inflammation in various tissues. Therefore we hypothesised that USPIO enhanced MRI could identify and assess cellular inflammation of the myocardium. During coronary artery bypass graft surgery (CABG), the myocardium receives an immediate ischaemic insult that is exacerbated by post-ischaemic reperfusion inflammatory responses leading to increased myocardial injury. CABG surgery can therefore be used as a clinical model of myocardial infarction and inflammation. We investigated this with blood markers of inflammation, MRI scanning and USPIO. Elafin inhibits the destructive and inflammatory HNE enzyme. Beyond this elafin inhibits inflammatory cytokines and modulates the innate and adaptive immune systems. In preclinical studies elafin treatment is associated with reduced myocardial injury. As such, elafin has a marked potential for the treatment of cardiovascular disease involving inflammation. Therefore, we hypothesised that elafin will reduce perioperative ischaemic myocardial injury and inflammation in patients undergoing elective coronary artery bypass graft surgery. We demonstrated for the first time that USPIOs are taken up by the infarct tissue in patients with recent myocardial infarction and by the peri-infarct myocardium to a lesser degree. This represents a novel non-invasive method to further study cardiac inflammation and therapeutic interventions. All patients undergoing CABG surgery demonstrated >10-fold elevation above the 99th centile of cardiac troponin by high sensitivity assay (hs-cTnI) indicating the current universal definition of type 5 myocardial infarction lacks specificity. A peak hs-cTnI at 6 hours following CABG surgery appears to be related to the surgical process and non-specific myocardial injury whilst a continuing increase at 24 hours suggests myocardial infarction. We would suggest hs-cTnI sampling at 6 and 24 hours post CABG surgery together with ECG assessment for the routine detection and diagnosis of type 5 MI. Differing levels of humoral makers inflammation post CABG surgery occurred, and did not correlate directly with the length of cardiopulmonary bypass time or hs-cTnI release. For the first time we identified differing levels of inflammatory cell infiltrate into the myocardium post CABG. This varied from none to levels similar to infarcted myocardial tissues. Elafin did not attenuate myocardial ischemia-reperfusion injury and inflammation. Post-hoc analysis identified reduced cTnI concentrations at 6 hours in Elafin treated patients and it is possible that a bigger dose would have conferred protection out to 48 hours. Elafin did not attenuate the cellular infiltration into the myocardium post CABG surgery, but did appear to reduce inflammation in renal tissue. USPIO enhanced CMR holds major promise in the non-invasive assessment of myocardial inflammation post surgery

CardiOvaScular Mechanisms In Covid-19: methodology of a prospective observational multimodality imaging study (COSMIC-19 study)

Background: 8-28% of patients infected with COVID-19 have evidence of cardiac injury, and this is associated with an adverse prognosis. The cardiovascular mechanisms of injury are poorly understood and speculative. We aim to use multimodality cardiac imaging including cardiac magnetic resonance (CMR) imaging, computed tomography coronary angiography (CTCA) and positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography (18F-FDG-PET/CT) to identify the cardiac pathophysiological mechanisms related to COVID-19 infections. Methods: This is a single-centre exploratory observational study aiming to recruit 50 patients with COVID-19 infection who will undergo cardiac biomarker sampling. Of these, 30 patients will undergo combined CTCA & 18F-FDG-PET/CT, followed by CMR. Prevalence of obstructive and non-obstructive atherosclerotic coronary disease will be assessed using CTCA. CMR will be used to identify and characterise myocardial disease including presence of cardiac dysfunction, myocardial fibrosis, myocardial oedema and myocardial infarction. 18F-FDG-PET/CT will identify vascular and cardiac inflammation. Primary endpoint will be the presence of cardiovascular pathology and the association with troponin levels. Discussion: The results of the study will identify the presence and modality of cardiac injury associated COVID-19 infection, and the utility of multi-modality imaging in diagnosing such injury. This will further inform clinical decision making during the pandemic

A multimodality cross-validation study of cardiac perfusion using MR and CT.

Modern advances in magnetic resonance (MR) and computed tomography (CT) perfusion imaging techniques have developed methods for myocardial perfusion assessment. However, individual imaging techniques present limitations that are possible to be surpassed by a multimodality cross-validation of perfusion imaging and analysis. We calculated the absolute myocardial blood flow (MBF) in MR using a Fermi function and the transmural perfusion ratio (TPR) in CT perfusion data in a patient with coronary artery disease (CAD). Comparison of MBF and TPR results showed good correlation emphasizing a promising potential to continue our multimodality perfusion assessment in a cohort of patients with CAD

Diagnostic performance of myocardial blood flow quantification in coronary artery disease by magnetic resonance.

Background Mathematical modelling of magnetic resonance (MR) perfusion imaging data allows myocardial blood flow (MBF) quantification and can potentially improve the diagnosis and prognostication of obstructive coronary artery disease (CAD). The diagnostic performance of distributed parameter (DP) modelling in detecting obstructive CAD has not yet been assessed. A model assessment in per vessel against per patient analysis has not been fully assessed yet in a single MR study. This work compares the diagnostic performance of DP modelling against the standard Fermi modelling, for the detection of obstructive CAD, in per vessel against per patient analysis. Methods After informed consent, a pilot cohort of 28 subjects with known or suspected CAD underwent adenosine stress-rest magnetic resonance perfusion imaging at 3T. Data were analysed using Fermi and DP modelling against invasive coronary angiography and fractional flow reserve, acquired in all subjects. Obstructive CAD was defined as luminal stenosis of ≥70% alone, or luminal stenosis ≥50% and fractional flow reserve ≤0.80. Results On ROC analysis, the diagnostic performance of all methods was improved in per patient analysis. DP modelling outperformed the standard Fermi model, in per vessel and per patient analysis. In per patient analysis, DP modelling-derived MBF at stress demonstrated the highest sensitivity and specificity (0.96, 0.92) in detecting obstructive CAD, against Fermi modelling (0.78, 0.88) and visual assessments (0.79, 0.88), respectively. Conclusions DP modelling consistently outperformed Fermi modelling and showed that it may have merit for robustly stratifying patients with at least one vessel with obstructive CA

Assessment of Cardiac, Vascular, and Pulmonary Pathobiology In Vivo During Acute COVID‐19

Background: Acute COVID‐19–related myocardial, pulmonary, and vascular pathology and how these relate to each other remain unclear. To our knowledge, no studies have used complementary imaging techniques, including molecular imaging, to elucidate this. We used multimodality imaging and biochemical sampling in vivo to identify the pathobiology of acute COVID‐19. Specifically, we investigated the presence of myocardial inflammation and its association with coronary artery disease, systemic vasculitis, and pneumonitis. Methods and Results: Consecutive patients presenting with acute COVID‐19 were prospectively recruited during hospital admission in this cross‐sectional study. Imaging involved computed tomography coronary angiography (identified coronary disease), cardiac 2‐deoxy‐2‐[fluorine‐18]fluoro‐D‐glucose positron emission tomography/computed tomography (identified vascular, cardiac, and pulmonary inflammatory cell infiltration), and cardiac magnetic resonance (identified myocardial disease) alongside biomarker sampling. Of 33 patients (median age 51 years, 94% men), 24 (73%) had respiratory symptoms, with the remainder having nonspecific viral symptoms. A total of 9 patients (35%, n=9/25) had cardiac magnetic resonance–defined myocarditis. Of these patients, 53% (n=5/8) had myocardial inflammatory cell infiltration. A total of 2 patients (5%) had elevated troponin levels. Cardiac troponin concentrations were not significantly higher in patients with and without myocarditis (8.4 ng/L [interquartile range, IQR: 4.0–55.3] versus 3.5 ng/L [IQR: 2.5–5.5]; P=0.07) or myocardial cell infiltration (4.4 ng/L [IQR: 3.4–8.3] versus 3.5 ng/L [IQR: 2.8–7.2]; P=0.89). No patients had obstructive coronary artery disease or vasculitis. Pulmonary inflammation and consolidation (percentage of total lung volume) was 17% (IQR: 5%–31%) and 11% (IQR: 7%–18%), respectively. Neither were associated with the presence of myocarditis. Conclusion: Myocarditis was present in a third patients with acute COVID‐19, and the majority had inflammatory cell infiltration. Pneumonitis was ubiquitous, but this inflammation was not associated with myocarditis. The mechanism of cardiac pathology is nonischemic and not attributable to a vasculitic process

Measurement of myocardial blood flow by cardiovascular magnetic resonance perfusion: comparison of distributed parameter and Fermi models with single and dual bolus

Background Mathematical modeling of cardiovascular magnetic resonance perfusion data allows absolute quantification of myocardial blood flow. Saturation of left ventricle signal during standard contrast administration can compromise the input function used when applying these models. This saturation effect is evident during application of standard Fermi models in single bolus perfusion data. Dual bolus injection protocols have been suggested to eliminate saturation but are much less practical in the clinical setting. The distributed parameter model can also be used for absolute quantification but has not been applied in patients with coronary artery disease. We assessed whether distributed parameter modeling might be less dependent on arterial input function saturation than Fermi modeling in healthy volunteers. We validated the accuracy of each model in detecting reduced myocardial blood flow in stenotic vessels versus gold-standard invasive methods. Methods Eight healthy subjects were scanned using a dual bolus cardiac perfusion protocol at 3T. We performed both single and dual bolus analysis of these data using the distributed parameter and Fermi models. For the dual bolus analysis, a scaled pre-bolus arterial input function was used. In single bolus analysis, the arterial input function was extracted from the main bolus. We also performed analysis using both models of single bolus data obtained from five patients with coronary artery disease and findings were compared against independent invasive coronary angiography and fractional flow reserve. Statistical significance was defined as two-sided P value <0.05. Results Fermi models overestimated myocardial blood flow in healthy volunteers due to arterial input function saturation in single bolus analysis compared to dual bolus analysis (P < 0.05). No difference was observed in these volunteers when applying distributed parameter-myocardial blood flow between single and dual bolus analysis. In patients, distributed parameter modeling was able to detect reduced myocardial blood flow at stress (<2.5 mL/min/mL of tissue) in all 12 stenotic vessels compared to only 9 for Fermi modeling. Conclusions Comparison of single bolus versus dual bolus values suggests that distributed parameter modeling is less dependent on arterial input function saturation than Fermi modeling. Distributed parameter modeling showed excellent accuracy in detecting reduced myocardial blood flow in all stenotic vessels

Cardiovascular risk factors and markers of myocardial injury and inflammation in people living with HIV in Nairobi, Kenya: a pilot cross-sectional study

Objectives: To determine the prevalence of cardiovascular disease (CVD) risk factors and explore associations with high-sensitivity cardiac troponin I (hscTnI) and high-sensitivity C-reactive protein (hsCRP) in people living with HIV (PLHIV) in Kenya. Design: Pilot cross-sectional study. Setting: Data were collected from community HIV clinics across two sites in Nairobi, Kenya, from July 2019 to May 2020. Participants: Convenience sample of 200 PLHIV (≥30 years with no prior history of CVD). Outcome measures: Prevalence of cardiovascular risk factors and its association with hsTnI and hsCRP levels. Results: Across 200 PLHIV (median age 46 years, IQR 38–53; 61% women), the prevalence of hypercholesterolaemia (total cholesterol \u3e6.1 mmol/L) and hypertension were 19% (n=30/199) and 30% (n=60/200), respectively. Smoking and diabetes prevalence was 3% (n=5/200) and 4% (n=7/200). HscTnI was below the limit of quantification (\u3c2.5 ng/L) in 65% (n=109/169). High (\u3e3 mg/L), intermediate (1–3 mg/L) and low (\u3c1 mg/L) hsCRP levels were found in 38% (n=75/198), 33% (n=65/198) and 29% (n=58/198), respectively. Framingham laboratory-based risk scores classified 83% of PLHIV at low risk with 12% and 5% at intermediate and high risk, respectively. Older age (adjusted OR (aOR) per year increase 1.05, 95% CI 1.01 to 1.08) and systolic blood pressure (140–159 mm Hg (aOR 2.96; 95% CI 1.09 to 7.90) and \u3e160 mm Hg (aOR 4.68, 95% CI 1.55 to 14) compared with \u3c140 mm Hg) were associated with hscTnI levels. No associations were observed between hsCRP and CVD risk factors. Conclusion: The majority of PLHIV—using traditional risk estimation systems—have a low estimated CVD risk likely reflecting a younger aged population predominantly consisting of women. Hypertension and hypercholesterolaemia were common while smoking and diabetes rates remained low. While hscTnI values were associated with increasing age and raised blood pressure, no associations between hsCRP levels and traditional cardiovascular risk factors were observed