Can exercise training enhance the repeated remote ischaemic preconditioning stimulus on peripheral and cerebrovascular function in high-risk individuals?

BACKGROUND: Repeated exposure to remote ischaemic preconditioning (rIPC; short bouts of non-lethal ischaemia) enhances peripheral vascular function within 1 week; whereas, longer periods of rIPC (~ 1 year) may improve cerebral perfusion. Increasing the 'dose' of rIPC may lead to superior effects. Given the similarities between exercise and rIPC, we examined whether adding exercise to the rIPC stimulus leads to greater adaptation in systemic vascular function. METHODS: Nineteen individuals with increased risk for cardiovascular disease (CVD) were randomly allocated to either 8 weeks of rIPC (n = 9) or 8 weeks of rIPC + exercise (rIPC + Ex) (n = 10). rIPC was applied three times per week in both conditions, and exercise consisted of 50 min (70% heart rate max) of cycling 3 times per week. Peripheral endothelial function was assessed using flow-mediated dilation (FMD) before and after ischaemia-reperfusion (IR). Cerebrovascular function was assessed by dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity (CVR), and cardio-respiratory fitness (VO2peak) using a maximal aerobic capacity test. RESULTS: FMD% increased by 1.6% (95% CI, 0.4, 2.8) following rIPC + Ex and by 0.3% (- 1.1, 1.5) in the only rIPC but this did not reach statistical significance (P = 0.65). Neither intervention evoked a change in dCA or in CVR (P > 0.05). VO2peak increased by 2.8 ml/kg/min (1.7, 3.9) following the rIPC + Ex and by 0.1 ml/kg/min (- 1.0, 1.4) following the rIPC only intervention (P = 0.69). CONCLUSION: Combining exercise with rIPC across an 8-week intervention does not lead to superior effects in cerebrovascular and peripheral vascular function compared to a repeated rIPC intervention in individuals at risk of CVD.

Diagnostic utility of electrocardiogram for screening of cardiac injury on cardiac magnetic resonance in post-hospitalised COVID-19 patients: a prospective multicenter study.

BACKGROUND: The role of ECG in ruling out myocardial complications on cardiac magnetic resonance (CMR) is unclear. We examined the clinical utility of ECG in screening for cardiac abnormalities on CMR among post-hospitalised COVID-19 patients. METHODS: Post-hospitalised patients (n = 212) and age, sex and comorbidity-matched controls (n = 38) underwent CMR and 12­lead ECG in a prospective multicenter follow-up study. Participants were screened for routinely reported ECG abnormalities, including arrhythmia, conduction and R wave abnormalities and ST-T changes (excluding repolarisation intervals). Quantitative repolarisation analyses included corrected QT (QTc), corrected QT dispersion (QTc disp), corrected JT (JTc) and corrected T peak-end (cTPe) intervals. RESULTS: At a median of 5.6 months, patients had a higher burden of ECG abnormalities (72.2% vs controls 42.1%, p = 0.001) and lower LVEF but a comparable cumulative burden of CMR abnormalities than controls. Patients with CMR abnormalities had more ECG abnormalities and longer repolarisation intervals than those with normal CMR and controls (82% vs 69% vs 42%, p < 0.001). Routinely reported ECG abnormalities had poor discriminative ability (area-under-the-receiver-operating curve: AUROC) for abnormal CMR, AUROC 0.56 (95% CI 0.47-0.65), p = 0.185; worse among female than male patients. Adding JTc and QTc disp improved the AUROC to 0.64 (95% CI 0.55-0.74), p = 0.002, the sensitivity of the ECG increased from 81.6% to 98.0%, negative predictive value from 84.7% to 96.3%, negative likelihood ratio from 0.60 to 0.13, and reduced sex-dependence variabilities of ECG diagnostic parameters. CONCLUSION: Post-hospitalised COVID-19 patients have more ECG abnormalities than controls. Normal ECGs, including normal repolarisation intervals, reliably exclude CMR abnormalities in male and female patients.

Cerebral blood flow velocity and oxygenation in neonatal aortic arch repair at two perfusion temperatures.

OBJECTIVES: (i) To monitor cerebral blood flow velocity (CBFv) throughout aortic arch repair surgery and during the recovery period. (ii) To examine the relationship between transcranial doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) during cardiac surgery. (iii) To examine CBFv in patients cooled to 20°C and 25°C. METHODS: During aortic arch repair and after surgery, measurements of TCD, NIRS, blood pH, pO2, pCO2, HCO3, lactate, Hb, haematocrit (%) and temperature (core and rectal) were recorded in 24 neonates. General linear mixed models were used to examine differences over time and between two cooling temperatures. Repeated measures correlations were used to determine the relationship between TCD and NIRS. RESULTS: CBFv changed during arch repair (main effect of time: P = 0.001). During cooling, CBFv increased by 10.0 cm/s (5.97, 17.7) compared to normothermia (P = 0.019). Once recovering in paediatric intensive care unit (PICU), CBFv had increased from the preoperative measurement by 6.2 cm/s (0.21, 13.4; P = 0.045). CBFv changes were similar between patients cooled to 20°C and 25°C (main effect of temperature: P = 0.22). Repeated measures correlations (rmcorr) identified a statistically significant but weak positive correlation between CBFv and NIRS (r = 0.25, P≤0.001). CONCLUSIONS: Our data suggested that CBFv changed throughout aortic arch repair and was higher during the cooling period. A weak relationship was found between NIRS and TCD. Overall, these findings could provide clinicians with information on how to optimise long-term cerebrovascular health.

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study.

Background: 'Long COVID' describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased ß-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. Methods: Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] -4.30, 95% confidence interval (95% CI) -7.14, -1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation. Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. Funding: Axcella Therapeutics.