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Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy.

ABSTRACT: BACKGROUND:Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. METHODS:Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. RESULTS:The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. CONCLUSION:For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

SUBMITTER: Lodi M

PROVIDER: S-EPMC6642576 | biostudies-other | 2019 Jul

REPOSITORIES: biostudies-other

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Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy.

Lódi Mária M Priksz Dániel D Fülöp Gábor Áron GÁ Bódi Beáta B Gyöngyösi Alexandra A Nagy Lilla L Kovács Árpád Á Kertész Attila Béla AB Kocsis Judit J Édes István I Csanádi Zoltán Z Czuriga István I Kisvárday Zoltán Z Juhász Béla B Lekli István I Bai Péter P Tóth Attila A Papp Zoltán Z Czuriga Dániel D

Journal of translational medicine 20190719 1

<h4>Background</h4>Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this ...[more]

PMID: 31324258

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Project description:IntroductionA 2015 Institute Of Medicine statement "Transforming Health Care Scheduling and Access: Getting to Now", has increased concerns regarding patient wait times. Although waiting times have been widely studied, little attention has been paid to the role of patient arrival times as a component of this phenomenon. To this end, we investigated patterns of patient arrival at scheduled ambulatory heart failure (HF) clinic appointments and studied its predictors. We hypothesized that patients are more likely to arrive later than scheduled, with progressively later arrivals later in the day.Methods and resultsUsing a business intelligence database we identified 6,194 unique patients that visited the Cleveland Clinic Main Campus HF clinic between January, 2015 and January, 2017. This clinic served both as a tertiary referral center and a community HF clinic. Transplant and left ventricular assist device (LVAD) visits were excluded. Punctuality was defined as the difference between 'actual' and 'scheduled' check-in times, whereby negative values (i.e., early punctuality) were patients who checked-in early. Contrary to our hypothesis, we found that patients checked-in late only a minority of the time (38% of visits). Additionally, examining punctuality by appointment hour slot we found that patients scheduled after 8AM had progressively earlier check-in times as the day progressed (P < .001 for trend). In both a Random Forest-Regression framework and linear regression models the most important risk-adjusted predictors of early punctuality were: later in the day appointment hour slot, patient having previously been to the hospital, age in the early 70s, and white race.ConclusionsPatients attending a mixed population ambulatory HF clinic check-in earlier than scheduled times, with progressive discrepant intervals throughout the day. This finding may have significant implications for provider utilization and resource planning in order to maximize clinic efficiency. The impact of elective early arrival on patient's perceived wait times requires further study.

Project description:AimsDoxorubicin (DOX)-induced heart failure has a poor prognosis, and effective treatments have not been established. Because DOX shows cumulative cardiotoxicity, we hypothesized that minimal cardiac remodelling occurred at the initial stage in activating cardiac fibroblasts. Our aim was to investigate the initial pathophysiology of DOX-exposed cardiac fibroblasts and propose prophylaxis.Methods and resultsAn animal study was performed using a lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulative dose. Histological analysis was performed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, picrosirius red staining, and immunohistochemical staining. The mechanism was analysed in vitro with a low dose of DOX, which did not induce cell apoptosis. Microarray analysis was performed. Differentially expressed genes were confirmed by enrichment analysis. Mitochondrial damage was assessed by mitochondrial membrane potential. The production of inflammatory cytokines and fibrosis markers was assessed by western blot, quantitative polymerase chain reaction, and ELISA. A phosphokinase antibody array was performed to detect related signalling pathways. Low-dose DOX did not induced cell death, and fibrosis was localized to the perivascular area in mice. Microarray analysis suggested that DOX induced genes associated with the innate immune system and inflammatory reactions, resulting in cardiac remodelling. DOX induced mitochondrial damage and increased the expression of interleukin-1. DOX also promoted the expression of fibrotic markers, such as alpha smooth muscle actin and galectin-3. These responses were induced through stress-activated protein kinase/c-Jun NH2-terminal kinase signalling. A peroxisome proliferator-activated receptor (PPARγ) agonist attenuated the expression of fibrotic markers through suppressing stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, this molecule also suppressed DOX-induced early fibrotic responses in vivo.ConclusionsLow-dose DOX provoked reactive fibrosis through sterile inflammation evoked by the damaged mitochondria.

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Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy.

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Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy.

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