Glycaemic status and reperfusion injury in patients with ST-segment elevation myocardial infarction

Background Failed myocardial tissue reperfusion due to microvascular injury despite successful culprit lesion percutaneous coronary intervention (PCI) is associated with poor clinical outcome in patients with ST-elevation myocardial infarction (STEMI). A possible influence of dysglycaemia on myocardial reperfusion injury is unclear. Objectives To investigate the association between glycaemic status and microvascular injury determined by magnetic resonance imaging in STEMI patients. Methods This prospective observational cohort study included 260 consecutive STEMI patients undergoing primary PCI between 2016 and 2019. Peripheral venous blood samples for glucose and HbA1c measurements were drawn on admission. Primary microvascular injury endpoint was defined as presence of intramyocardial haemorrhage (IMH) assessed by cardiac magnetic resonance T2* mapping at 4 (interquartile range [IQR]:2–5) days after PCI. Results HbA1c (odds ratio [OR]: 1.73 [95% CI: 1.24–2.40]; p=0.001), pre-diagnosis of diabetes (OR: 2.63 [95% CI: 1.18–5.90]; p=0.02) and glucose concentration (OR: 1.01 [95% CI: 1.00–1.01]; p=0.01) significantly predicted IMH, which was present in 90 (35%) patients. Of these three parameters, only HbA1c remained significantly associated with IMH (OR: 2.12 [95% CI: 1.12–3.99]; p=0.02) after adjusting for total ischemic time, culprit lesion location, pre- and post-interventional TIMI flow and peak biomarker concentrations (troponin, N-terminal pro-B-type natriuretic peptide and C-reactive protein). The rate of IMH was 24% in patients with HbA1c <5.7%, 43% in patients with HbA1c ≥5.7 to 6.4% and 59% in patients with HbA1c ≥6.5% (p<0.001). Conclusions In STEMI patients undergoing primary PCI, admission HbA1c was independently associated with reperfusion injury as determined by IMH. These findings suggest that IMH could represent the underlying pathophysiological link between dysglycaemia and adverse outcomes following STEMI. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): FWF - Austrian Science Fund; ÖKG - Austrian Society of Cardiology Figure 1. This figure illustrates the relation between HbA1c and IMH by two patient examples successfully treated with PCI (intervention with stent implantation schematically shown on the very left side). The first patient (upper line), representing the patient group with HbA1c <5.7% (associated IMH risk 24%), showed an anterior wall STEMI without IMH (T2* mapping on the very right, corresponding schematic picture of the infarct area without IMH next on the left). The second patient (lower line), representing the patients with HbA1c ≥5.7% (associated IMH risk 47%), showed an anterior wall STEMI with large IMH (arrows point to the hypo-intense core on the T2* mapping image and to the corresponding dark-red area in the schematic illustration). The zoomed view of one microvessel indicates the complex pathophysiology of IMH (including endothelial destruction, embolisation of thrombotic material and inflammation). (Created with BioRender)

The association between invasive microvascular function and CMR-derived microvascular injury indicators and left ventricular function and infarct size at 1-month after reperfused STEMI

Background The restoration of the coronary microcirculation in ST-segment elevation myocardial infarction (STEMI) patients remains hampered in up to 50% of the STEMI patients after successful primary percutaneous coronary intervention (PCI). The association between the coronary microvascular function and injury indicators and functional outcome remains debated. Purpose This study aims to investigate the relation between post-PCI invasive microvascular function and cardiovascular magnetic resonance (CMR)-derived microvascular injury indicators and left ventricular (LV) function and infarct size (IS) at 1-month after STEMI. Methods The study was performed in 110 STEMI patients who underwent angiography for primary PCI and at 1-month follow-up. Invasive assessment of coronary microcirculation physiology in the culprit artery was performed during both procedures and included coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR). Data were available for 101 patients. A ratio of >2 for CFR and a value of <25 U for IMR were considered normal. CMR was performed during the acute phase (2 to 7 days after PCI) and at 1-month and provided assessment of LV function, IS and non-invasive information of microvascular injury in 78 patients by microvascular obstruction (MVO) and intra-myocardial hemorrhage (IMH). Results Over 1-month, CFR, IMR, LV function, and IS all significantly improved (p≤0.001). In univariable linear regression analysis, the post-PCI normal index CFR and IMR (both p=0.04), MVO presence, MVO size, IMH presence, IMH size (all, p<0.001) were significantly associated with LV ejection fraction at 1-month. Additionally, the post-PCI index CFR (p=0.04), MVO presence, MVO size, IMH presence, IMH size (all, p<0.001) were all associated with 1-month IS. In a multivariable linear regression analysis model including invasive and non-invasive coronary microcirculation function and injury indicators, MVO presence was identified as the only independent marker related to both 1-month LV ejection fraction and IS (both p<0.001). Conclusion(s) In STEMI patients, CMR-derived coronary microcirculation injury indicators reveal a closer association with 1-month LV function and IS outcome than invasive microcirculatory measurements. MVO presence is independently associated with 1-month LV ejection fraction and IS. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): The REDUCE-MVI study was funded by Astra Zeneca to MvL and NvR.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. Methods In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.