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Infarction

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‘Turning the right screw’: targeting the interleukin-6 receptor to reduce unfavourable tissue remodelling after myocardial infarction

Möllmann H et al. Cardiovasc Res (2010) 87(3): 395-396 first published online June 16, 2010 doi:10.1093/cvr/cvq186 - Click here to view the abstract

‘Turning the right screw’: targeting the interleukin-6 receptor to reduce unfavourable tissue remodelling after myocardial infarction

Partial overview of targets and mechanisms involved in LV remodelling after myocardial infarction (MI). Early inhibition of IL-6 signalling using an anti-IL-6 receptor antibody (M16-1) leads to decreased mortality after MI, mainly through reduction of inflammation and extracellular matrix remodelling of the healthy surrounding myocardial tissue. Infarct size and apoptosis were not altered by interference with IL-6 receptor signalling.

Vicious relationship between wall stress and ventricular remodelling to aggravate postinfarction heart failure

Takemura G et al. Cardiovasc Res (2009) 83(2): 269-276 first published online January 28, 2009 doi:10.1093/cvr/cvp032 - Click here to view the abstract

Vicious relationship between wall stress and ventricular remodelling to aggravate postinfarction heart failure

(A) Transverse ventricular sections taken from mouse hearts on Day 3, 7, or 28 postinfarction and stained with Masson's trichrome. Left ventricular remodelling progresses with time following myocardial infarction (MI). (B) Photomicrographs of infarct tissue collected from mouse hearts on Day 3, 7, or 28 post-MI, showing, respectively, acute inflammation, granulation, and scar. (C) With the passage of time after the onset of MI, the infarct length and left ventricular cavity become larger, whereas the infarct wall thickness decreases. Wall stress is proportional to the cavity diameter and intracavitary pressure and inversely proportional to the wall thickness (Laplace's law). Thus, wall stress and ventricular remodelling (dilatation and wall thinning) have a vicious relationship, aggravating one another and exacerbating post-infarction heart failure.

Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4+ stem cells into the ischaemic heart

Huber BC et al. Cardiovasc Res (2011) 90(3): 529-537 doi:10.1093/cvr/cvr014 - Click here to view the abstract

Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4<sup>+</sup> stem cells into the ischaemic heart

Mechanism of PTH-mediated cardioprotection. PTH administration after MI induces mobilization of stem cells from the BM to the peripheral blood. These stem cells circulate to the damaged heart, where they are incorporated by interaction of intact myocardial SDF-1 and the homing receptor CXCR4. PTH inhibits DPP-IV activity and thereby prevents the degradation of intact SDF-1. Thus, an increased amount of SDF-1 improves homing of mobilized CXCR4+ cells. Altogether, PTH reduced cardiac remodelling after MI and enhanced cardiac function by attenuating the development of ischaemic cardiomyopathy.

Contribution of calpains to myocardial ischaemia/reperfusion injury.

Cardiovasc Res (2012) 96(1): 23-31 first published online July 10, 2012 doi:10.1093/cvr/cvs232 - Click here to view the abstract

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Schematic diagram showing the proposed mechanisms by which calpains participate in reperfusion injury and in the cardioprotective effects of preconditioning and postconditioning. NCX, Na+/Ca2+ exchanger; NBC, Na+/HCO3 cotransporter; NHE, Na+/H+ exchanger.

Calcium-mediated cell death during myocardial reperfusion

Cardiovasc Res (2012) 94(2): 168-180 first published online April 11, 2012 doi:10.1093/cvr/cvs116 - Click here to view the abstract

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Mechanisms and consequences of altered Ca2+ handling in cardiomyocytes during initial reperfusion. Main events are connected through black lines, whereas red lines indicate important modulating factors. GCPR, G-coupled protein receptors; IP3, inositol trisphosphate; NOS, nitric oxide synthase; ROS, reactive oxygen species.

The SR–mitochondria interaction: a new player in cardiac pathophysiology

Cardiovasc Res (2010) 88(1): 30-39 first published online July 8, 2010 doi:10.1093/cvr/cvq225 - Click here to view the abstract

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Pathophysiological role of SR–mitochondria functional units on lethal reperfusion injury. Calcium overload and re-energization cause calcium oscillations. ROS favour oscillations and trigger MPT. mNCX, mitochondrial Na/Ca exchanger; MCU: mitochondrial calcium uniporter.

Postconditioning: Reperfusion of “reperfusion injury” after hibernation

Cardiovasc Res (2006) 69(1): 1-3 doi:10.1016/j.cardiores.2005.11.011 - Click here to view the abstract

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Myocardial injury in ischemia–reperfusion develops in two phases. Reperfusion injury adds to the injury developed during initial ischemia (resulting in the red curve). The extent of reperfusion injury can be influenced by protective procedures, such as postconditioning or protective agents, applied during the first minutes of reperfusion (resulting in the blue curve). When the myocardium is not reperfused, it becomes entirely subject to ischemic cell death (broken black curve). While the past dogma was that protection against ischemia–reperfusion injury achieved by the pre-ischemic application of preconditioning is solely achieved by an effect on ischemic injury, it is now thought that this protection is also largely due to an effect on the causes of reperfusion injury (blue arrows).

Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia–reperfusion injury

Cardiovasc Res (2008) 77(2): 325-333 first published online January 1, 2007 doi:10.1093/cvr/cvm062 - Click here to view the abstract

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Scheme summarizing the potential roles of Cx43 in the pathophysiology of ischaemia–reperfusion. Solid lines indicate roles for which there is experimental evidence. Broken lines indicate phenomena for which available evidence has been obtained under conditions other than ischaemia–reperfusion. PK, protein kinases; Src, Src tyrosine kinase.

Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia–reperfusion injury

Cardiovasc Res (2008) 77(2): 325-333 first published online January 1, 2007 doi:10.1093/cvr/cvm062 - Click here to view the abstract

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Potential mechanisms by which mitochondrial Cx43 could participate in ischaemic pharmacological (diazoxide) preconditioning. Monomeric Cx43 (in blue) could modulate mitochondrial K+ATP channels (in brown), but also the effects of diazoxide on the respiratory chain (in dark gray).103 Cx43 hemichannels could favor H+ and K+ leak resulting in protective mild uncoupling104 and swelling.105,106

The sarcoplasmic reticulum as the primary target of reperfusion protection

Cardiovasc Res (2006) 70(2): 170-173 doi:10.1016/j.cardiores.2006.03.010 - Click here to view the abstract

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Scheme of the pathogenesis of acute reperfusion injury. Reperfusion reactivates ATP production in mitochondria (Mito). Recovering energy production (High ATP) activates the Ca2+ pump (SERCA) of the sarcoplasmic reticulum (SR), which clears the cytosol from Ca2+ overload accumulated during ischemia. Repetitive release of Ca2+ through the ryanodine receptor Ca2+ release channel (RyR) and reuptake into the SR leads to Ca2+ oscillations with high cytosolic peak Ca2+ concentrations. This high Ca2+ together with ATP provokes myofibrillar hypercontracture (Ca2+ contracture) and subsequent disruption of cells (Necrosis). Ca2+ uptake through the uniporter into mitochondria causes the opening of mitochondrial permeability transition pores (mPTP) and cytochrome c (Cyt c) release. The former leads to failure of energy production (low ATP), and the latter activates apoptosis. Low ATP induces rigor contracture of the myofibrils, again leading to cell disruption. Protection by reperfusion injury salvage kinase pathways (RISK) may interfere favourably at the SR or at mitochondria.

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