Background: Ventricular arrhythmias (VA) are a common cause of sudden death after myocardial infarction (MI). Therefore, developing new therapeutic methods for the prevention and treatment of VA is of prime importance. Methods: Human bone marrow derived CD271⁺ mesenchymal stem cells (MSC) were tested for their antiarrhythmic effect. This was done through the development of a novel mouse model using an immunocompromised Rag2^−/− γc^−/− mouse strain subjected to myocardial “infarction-reinfarction”. The mice underwent a first ischemia-reperfusion through the left anterior descending (LAD) artery closure for 45 min with a subsequent second permanent LAD ligation after seven days from the first infarct. Results: This mouse model induced various types of VA detected with continuous electrocardiogram (ECG) monitoring via implanted telemetry device. The immediate intramyocardial delivery of CD271⁺ MSC after the first MI significantly reduced VA induced after the second MI. Conclusions: In addition to the clinical relevance, more closely reflecting patients who suffer from severe ischemic heart disease and related arrhythmias, our new mouse model bearing reinfarction warrants the time required for stem cell engraftment and for the first time enables us to analyze and verify significant antiarrhythmic effects of human CD271⁺ stem cells in vivo.

Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells (MSC) showed their potential in MI therapy. Our study aimed to investigate the effects of MSC injection on post-infarction arrhythmia. We used our murine double infarction model, which we previously established, to more closely mimic the clinical situation and intramyocardially injected hypoxic pre-conditioned murine MSC to the infarction border. Thereafter, various types of arrhythmias were recorded and analyzed. We observed a homogenous distribution of all types of arrhythmias after the first infarction, without any significant differences between the groups. Yet, MSC therapy after double infarction led to a highly significant reduction in simple and complex arrhythmias. Moreover, RNA-sequencing of samples from stem cell treated mice after re-infarction demonstrated a significant decline in most arrhythmias with reduced inflammatory pathways. Additionally, following stem-cell therapy we found numerous highly expressed genes to be either linked to lowering the risk of heart failure, cardiomyopathy or sudden cardiac death. Moreover, genes known to be associated with arrhythmogenesis and key mutations underlying arrhythmias were downregulated. In summary, our stem-cell therapy led to a reduction in cardiac arrhythmias after MI and showed a downregulation of already established inflammatory pathways. Furthermore, our study reveals gene regulation pathways that have a potentially direct influence on arrhythmogenesis after myocardial infarction.

BACKGROUND: Time to mechanical thrombectomy (MT) is a critical predictor of functional outcomes in large vessel occlusion stroke. This study compares 2 large vessel occlusion stroke treatment approaches: the one-stop management approach (OSM), in which patients are directly transferred to the angiosuite for flat detector computed tomography and MT, versus the conventional approach, which includes multidetector CT before MT. METHODS: Between March 2014 and December 2019, 205 patients with acute ischemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score of ≥7 and symptom onset ≤4.5 hours underwent large vessel occlusion stroke-treatment using the OSM approach at the University Medical Center Göttingen, Germany. After confirmation of LVO, eligible patients received intravenous thrombolysis followed by MT. Ordinal regression corrected for all confounders. Primary end points included door-to-groin and door-to-reperfusion times, NIHSS at discharge, NIHSS improvement, and modified Rankin Scale at 90 days. Propensity score matching accounted for age, sex, NIHSS, thrombolysis, Thrombolysis in Cerebral Ischemia score, and post-MT intracranial hemorrhage. Treatment times were noncensored. RESULTS: Compared with 2470 patients from the German Stroke Registry treated conventionally (non-OSM group), OSM patients had significantly shorter door-to-groin (33.33±±17.91 versus 95.73±±158.33 minutes; P <0.001) and door-to-reperfusion (78.06±±30.33 versus 147.47±±165.32 minutes; P <0.001) times. While baseline NIHSS was similar, OSM patients showed greater NIHSS improvement and better modified Rankin Scale at 90 days (OR, 2.26 [95% CI, 1.16–4.42]; P <0.05). CONCLUSIONS: In this observational trial, direct angiosuite transfer for large vessel occlusion stroke treatment reduces periprocedural times and is associated with improved functional outcomes compared with a conventional approach using multidetector CT before MT. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03356392.

Objective: Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited peripheral neuropathy, results from PMP22 gene duplication and presents with progressive motor and sensory deficits. Despite well-defined genetics, therapeutic development is hindered by the lack of sensitive clinical outcome assessments (CAO) given slow disease progression and variable severity. This study aimed to identify robust transcriptomic biomarkers from blood which may serve as surrogate outcome measures for monitoring disease progression. Methods: A cohort of 139 genetically confirmed CMT1A patients was longitudinally assessed over 2 years using standardized clinical tests and blood RNA sequencing at 3 expert sites across Germany. Parallel analyses were conducted in a Pmp22-overexpressing rat model over 12 weeks. Differential expression analysis, cross-species comparisons, and integration with functional data were employed to identify candidate biomarkers associated with disease severity and progression. Results: Over the two-year follow-up, we confirm deterioration of the Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) (0.32 (95%-CI [0.05; 0.59]) per year (p = 0.019). Out of a pool of consistently upregulated disease markers in CMT1A patients and CMT rats (vs.controls) based on RNA Seq data sets at baseline, 9 regulated genes were validated via Real-Time Quantitative PCR (RT-PCR). Transcriptional expressions of Actb, E2F2, MFAP, SAMD14, SEMA5A and SPI1 show a significant increase over time, whereas UQCRB declined over time. Interpretation: Transcriptomic profiling revealed several blood-derived mRNA candidates in CMT1A patients correlate with longitudinal changes in CAOs and overlap with findings from the CMT rat model. These markers may offer a minimally invasive, scalable tool for disease monitoring in future clinical trials.