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  • 1
    Online-Ressource
    Online-Ressource
    Coronary microcirculation damage in anthracycline cardiotoxicity
    Oxford University Press (OUP) ; 2022
    In:  Cardiovascular Research Vol. 118, No. 2 ( 2022-01-29), p. 531-541
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 118, No. 2 ( 2022-01-29), p. 531-541
    Kurzfassung: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. Methods and results Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. Conclusion Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.
    Materialart: Online-Ressource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvab053
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2022
    ZDB Id: 1499917-1
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Remote ischaemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
    Oxford University Press (OUP) ; 2021
    In:  Cardiovascular Research Vol. 117, No. 4 ( 2021-03-21), p. 1132-1143
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 117, No. 4 ( 2021-03-21), p. 1132-1143
    Kurzfassung: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
    Materialart: Online-Ressource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvaa181
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2021
    ZDB Id: 1499917-1
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
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