Abstract:
AIMS: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 ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia 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, 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. TRANSLATIONAL PERSPECTIVE:Serial cardiac magnetic resonance (CMR) evaluation of a highly translatable large animal model of anthracycline-induced cardiotoxicity (AIC) shows that cumulative exposure to doxorubicin results in significantly reduced LVEF and extensive mitochondrial fragmentation. Remote ischemic preconditioning (RIPC) applied before each doxorubicin cycle preserved cardiac contractility and LVEF in long-term CMR exams. RIPC prevented doxorubicin-induced irreversible mitochondrial fragmentation and dysregulated autophagy. RIPC is as an attractive strategy for testing in clinical trials in AIC.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Galán-Arriola C,Villena-Gutiérrez R,Higuero-Verdejo MI,Díaz-Rengifo IA,Pizarro G,López GJ,de Molina-Iracheta A,Pérez-Martínez C,García RD,González-Calle D,Lobo M,Sánchez PL,Oliver E,Córdoba R,Fuster V,Sánchez-González J,Idoi
10.1093/cvr/cvaa181subject
Has Abstractpub_date
2020-06-29 00:00:00eissn
0008-6363issn
1755-3245pii
5864719pub_type
杂志文章abstract:AIMS:Crosstalk between cardiomyocytes and fibroblasts in physiological conditions and during disease remains poorly defined. Previous studies have shown that fibroblasts and myocytes interact via paracrine communication, but several experimental confounding factors, including the use of immature myocytes and the induct...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu264
更新日期:2015-03-01 00:00:00
abstract:OBJECTIVE:Previously we observed that a large reduction in infarct size was attained by cooling the risk region of the heart, either before or early after the onset of a 30-min coronary artery occlusion. While this is a standard duration of ischemia used in the rabbit model of infarction, it may not reflect the situati...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00191-6
更新日期:1998-12-01 00:00:00
abstract:OBJECTIVE:Hemodynamic stresses are considered to be important regulators of gene expression in vascular cells. In this study, we have investigated the role of shear stress on ACE expression in cultured rat vascular cells, and focused on the regulation of ACE expression in smooth muscle cells. METHODS:Rat aortic endoth...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(99)00269-2
更新日期:2000-01-14 00:00:00
abstract:OBJECTIVE:It has been shown that cGMP content is reduced in post-ischemic myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte hypercontracture and cell death in vitro. This study was aimed at determining whether administration of the natriuretic peptide urodilatin (URO) at the time of reperfusion ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00242-5
更新日期:2001-08-15 00:00:00
abstract:OBJECTIVE:Mechanoelectric Feedback, a mechanical intervention inducing an electrical change, is gaining credence as a cause of cardiac arrhythmia in the clinical situation. However, the precise mechanism is unknown. To elucidate this we investigated mechanical and chemical modulation of stretch-induced premature ventri...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00314-3
更新日期:1998-04-01 00:00:00
abstract:OBJECTIVE:The heart contains proteins of the annexin family, a unique group of calcium binding proteins. This study was aimed at identifying the major cardiac annexins and determining their distribution in the rat heart. METHODS:Annexins were isolated by affinity chromatography and purified by ion exchange high pressu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.7.1359
更新日期:1993-07-01 00:00:00
abstract:OBJECTIVE:The factors involved in restenosis after balloon angioplasty are poorly characterized but the local concentration of the potent mitogens angiotensin II (AII) and thrombin is known to be increased at sites of vascular injury. We investigated the possibility of a synergistic interaction between AII and thrombin...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00296-4
更新日期:1998-04-01 00:00:00
abstract:OBJECTIVE:The aim was to investigate the ventricular/vascular coupling of the intact right heart under conditions of normal operation and acute pulmonary hypertension. METHODS:Right ventricular contractility was obtained by calculating the end systolic pressure-volume relationship (Ees) and the effective pulmonary art...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.9.839
更新日期:1992-09-01 00:00:00
abstract:OBJECTIVE:The aims were: (1) to evaluate whether differences in absolute and cyclic echocardiographic image amplitude exist in different layers (subendocardium and subepicardium) and regions (septal, anterior, lateral, inferior wall) of the canine left ventricle; (2) to assess the dependence of these variables upon loc...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.2.279
更新日期:1993-02-01 00:00:00
abstract::The progress made in our understanding of the pathophysiology and treatment of congestive heart failure (CHF) would not have been possible without a number of animal models of heart failure and hypertrophy, each one having unique advantages as well as disadvantages. The species and interventions used to create CHF dep...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(98)00110-2
更新日期:1998-07-01 00:00:00
abstract::The effects of repeated (10 X), brief Ca2+-free perfusions (20 to 120 s) on myocardial contractility, coronary flow and release of cellular constituents of isolated rat heart were investigated. Ten successive Ca2+-deprivations of 20 or 40 s had no irreversible influences on cardiac performance. Ca2+-deprivations, howe...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/17.8.476
更新日期:1983-08-01 00:00:00
abstract::Myocardial ischaemia/reperfusion (I/R)-induced remodelling generally includes cell death (necrosis and apoptosis), myocyte hypertrophy, angiogenesis, cardiac fibrosis, and myocardial dysfunction. It is becoming increasingly clear that microRNAs (miRNAs or miRs), a group of highly conserved small (∼18-24 nucleotide) no...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvr291
更新日期:2012-05-01 00:00:00
abstract:OBJECTIVES:To characterize the 'anti-ischemic' effects of adenosine metabolism inhibition in ischemic-reperfused myocardium. METHODS:Perfused C57/B16 mouse hearts were subjected to 20 min ischemia 40 min reperfusion in the absence or presence of adenosine deaminase inhibition (50 microM erythro-2-(2-hydroxy-3-nonyl)ad...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00360-1
更新日期:2001-10-01 00:00:00
abstract:OBJECTIVE:To examine whether altered PCO2 or HCO3- at normal pH potentiate agonist-induced vasoconstriction of small pulmonary arteries, and if so to determine the mechanism. METHODS:Small intrapulmonary arteries (IPA) from rats were mounted on a myograph and PGF2alpha (3 microM)-induced tension recorded before and 40...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.10.038
更新日期:2005-02-01 00:00:00
abstract:OBJECTIVE:Anisotropic conduction characteristics, which may be expressed as the ratio of conduction velocities in the longitudinal (Vlong) and transverse (Vtrans) fibre directions, have been shown to stabilise reentry and favour the induction of sustained, uniform ventricular tachycardia. The aim of this study was to i...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)88593-2
更新日期:1995-03-01 00:00:00
abstract:OBJECTIVES:Injury stimulates smooth muscle cell (SMC) migration and proliferation by mechanisms that are incompletely understood. Surgical preparative injury is an important determinant of neointimal thickening in human saphenous vein bypass grafts. We investigate here whether basement-membrane-degrading metalloprotein...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00211-8
更新日期:1997-02-01 00:00:00
abstract::Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed 'ischaemia and no obstructive ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvaa002
更新日期:2020-03-01 00:00:00
abstract:OBJECTIVE:The aim was to examine whether an absolute reduction in energy supply is required for preconditioning against myocardial infarction, and whether an episode of increased adrenergic activity with or without supply-demand imbalance is capable of triggering cardioprotection. METHODS:41 anaesthetised dogs were su...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.11.2071
更新日期:1993-11-01 00:00:00
abstract:STUDY OBJECTIVE:The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis. DESIGN:In 72 male Wistar rats (250-350 g) the transient stimul...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/24.9.741
更新日期:1990-09-01 00:00:00
abstract::Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2007.03.029
更新日期:2008-03-01 00:00:00
abstract:OBJECTIVE:Temporal effects of prolonged hypoxaemia and reoxygenation, on the systemic pulmonary and mesenteric circulations in newborn piglets, were investigated. METHODS:Two groups [control (n = 5), hypoxaemic (n = 7)] of 1-3 day old anaesthetised piglets were instrumented with ultrasound flow probes placed to measur...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00080-7
更新日期:1998-08-01 00:00:00
abstract::To test hypothesis that adrenergic neurotransmission is impaired in acute myocardial ischaemia, we studied contractile function of normal and ischaemic myocardium after coronary artery occlusion. For each area we compared the contractile response to left sympathetic nerve stimulation (LSS) with the response to exogeno...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/14.2.116
更新日期:1980-02-01 00:00:00
abstract:OBJECTIVES:I(Ks), the slow component of the delayed rectifier potassium current, underlies a strong beta-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I(Ks). Recent work has pointed to an opposing biological effect of beta(1)- and beta(3)-adrenoceptors in the heart....
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00601-6
更新日期:2002-12-01 00:00:00
abstract:AIMS:The aim of this work was to use hyperpolarized carbon-13 ((13)C) magnetic resonance (MR) spectroscopy and cine MR imaging (MRI) to assess in vivo cardiac metabolism and function in the 15-week-old spontaneously hypertensive rat (SHR) heart. At this time point, the SHR displays hypertension and concentric hypertrop...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvs164
更新日期:2012-07-01 00:00:00
abstract:OBJECTIVE:In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by block...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00505-3
更新日期:2002-08-15 00:00:00
abstract:AIMS:Doxorubicin (DOX) is widely used in cytostatic treatments, although it may cause cardiovascular dysfunction as a side effect. DOX treatment leads to enhanced free radical production that in turn causes DNA strand breakage culminating in poly(ADP-ribose) polymerase (PARP) activation and mitochondrial and cellular d...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvr246
更新日期:2011-12-01 00:00:00
abstract:AIMS:Notch signalling is essential for blood vessel formation. During angiogenesis, the Notch ligand DLL4 on the leading tip cell activates Notch receptors on the adjacent stalk cells. DLL4-Notch signalling is impaired by the Notch ligand JAG1 in endothelial cells. The Delta/Serrate/Lag2 (DSL) domain of the Notch ligan...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvv151
更新日期:2015-07-01 00:00:00
abstract:OBJECTIVES:Myostatin, a member of the transforming growth factor-beta (TGF-beta) family, plays a key role in skeletal muscle myogenesis by limiting hyperplastic and hypertrophic muscle growth. In cardiac muscle, myostatin has been shown to limit agonist-induced cardiac hypertrophic growth. However, its role in cardiac ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2007.02.023
更新日期:2007-05-01 00:00:00
abstract::A pulsed, range gated, directional, ultrasonic, Doppler blood velocity meter was used to record signals from the pulmonary artery in 52 normal subjects ranging in age from less than 1 week to over 30 years. Signals were obtained from an unfocused transducer in the second or third left intercostal space using a 2.25 MH...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.11.816
更新日期:1986-11-01 00:00:00
abstract:OBJECTIVE:Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00036-4
更新日期:1998-06-01 00:00:00