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- Anttila, V., et al.
(författare)
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Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
- 2023
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Ingår i: Molecular Therapy. - : Elsevier BV. - 1525-0016. ; 31:3, s. 866-874
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool. © 2022
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| 4. |
- Michaëlsson, Erik, et al.
(författare)
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Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.
- 2023
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Ingår i: JACC. Heart failure. - 2213-1787. ; 11:7, s. 775-87
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Tidskriftsartikel (refereegranskat)abstract
- Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n=86, n=216, and n=242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With HeartFailure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n=41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge database.TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.
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