myocardial-infarction-and-functional-outcome-assessment-in-pigs

Myocardial Infarction and Functional Outcome Assessment in Pigs

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One ...

an-injectable-drug-loaded-supramolecular-hydrogel-for-local-catheter

An Injectable and Drug-loaded Supramolecular Hydrogel for Local Catheter Injection into the Pig Heart

Regeneration of lost myocardium is an important goal for future therapies because of the increasing occurrence of chronic ischemic heart failure and the ...

University Medical Center Utrecht

Interuniversity Cardiology Institute of the Netherlands

During acute myocardial infarction and in the reperfused heart, loss of cardiomyocytes is mostly caused by apoptosis and necrosis. As apoptosis was considered as the only form of regulated cell death for many years, initial studies investigating cardiomyocyte cell death mainly focused on direct inhibition of apoptosis. However, it has become clear that ischemic conditioning protocols--the application of alternating periods of non-lethal ischemia and reperfusion--can reduce necrotic cell death in the reperfused heart. Research on the signal-transduction pathways responsible for this phenomenon resulted in the discovery of many pharmacological targets to limit cell death after reperfusion, in which the activation of survival kinases and inhibition of mitochondrial permeability transition pore (MPTP) play an important role. Very recently, a regulated form of necrotic cell death (called 'necroptosis') was identified together with potential pharmacological inhibitors, which may also protect the myocardium from lethal reperfusion injury. This review highlights the role of apoptosis and necrosis in the reperfused hearts, including its execution and regulation and the emerging role of programmed necrosis (necroptosis). Furthermore, we will focus on the results of pharmacological interventions in experimental studies as well as relevant proof-of-concept clinical trials trying to limit apoptosis, necrosis and necroptosis in the reperfused heart. Although the list of cardioprotective compounds is promising, large multi-centre clinical trials, with enough statistical power, will be necessary to determine whether they can improve clinical outcome and can be applied in patients as adjuvant therapy next to reperfusion.

Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection.

Stem cell therapy is a new strategy for chronic ischaemic heart disease in patients. However, no consensus exists on the most optimal delivery strategy. This randomized study was designed to assess cell delivery efficiency of three clinically relevant strategies: intracoronary (IC) and transendocardial (TE) using electromechanical mapping guidance (NOGA) compared to surgical delivery in a chronic pig model of ischaemic cardiomyopathy. Twenty-four animals underwent delivery of 10(7) autologous Indium-oxine-labelled bone marrow-derived mesenchymal stem cells (MSC) 4 weeks after infarction and were randomized to one of three groups (n = 8 each group): IC, TE or surgical delivery (reference group). Primary endpoint was defined as percentage (%) of injected dose per organ and assessed by in vivo gamma-emission counting. In addition, troponin and coronary flow were assessed before and after MSC injection. Blinded endpoint analysis showed no significant difference in efficiency after surgical (16 ± 4%), IC (11 ± 1%) and TE (11 ± 3%) (P = 0.52) injections. IC showed less variability in efficiency compared with TE and surgical injection. Overall, TE injection showed less distribution of MSC to visceral organs compared with other modalities. Troponin rise and IC flow did not differ between the percutaneous groups. This randomized study showed no significant difference in cell delivery efficiency to the myocardium in a clinically relevant ischaemic large animal model between IC and TE delivery. In addition, no differences in safety profile were observed. These results are important in view of the choice of percutaneous cell delivery modality in future clinical stem cell trials.

Transendocardial cell injection is not superior to intracoronary infusion in a porcine model of ischaemic cardiomyopathy: a study on delivery efficiency.

Cardiac regenerative therapy is still not used in daily clinical practice. A reason for this might be the modest effect on relevant global clinical endpoints [i.e. ejection fraction (EF)] in preclinical studies. To introduce proper improvement strategies, it is important to extend the focus from clinical endpoints to more detailed local measures of cardiac function. In this review, we discuss the measurement principles of all invasive and non-invasive techniques that are used to assess the local effects of cardiac regenerative therapy in order to improve feedback to researchers unravelling the dominant pathways that lead to effective cardiac regeneration. Generally adopted mechanisms of cardiac regenerative therapy are: (i) vasculogenesis, (ii) cardiomyogenesis, and (iii) matrix-assisted myocardium stabilization. Since direct in vivo measures of these mechanisms do not exist, we discuss the measurement techniques of local microvascular resistance, myocardial perfusion, viability, fibrosis, and deformation imaging. The ability of these techniques to reflect the mechanism of cardiac regenerative therapy, and the results of applications in stem cell studies are discussed, and critically commented upon. Special attention is given to applications of deformation imaging, since this has recently been suggested and used as a potential new technique to assess local changes of cardiac biomechanics, which requires special knowledge about cardiac physiology. We conclude that besides the clinically relevant EF measurements, detailed measures of local cardiac function provide information about the local changes induced by cardiac regenerative therapy. In particular, combination of deformation imaging, by ultrasound or magnetic resonance imaging, with simultaneously measured local geometry and pressure measurements is a promising approach to assess the effects of cardiac regenerative therapy on local cardiac biomechanics. This approach provides information about local tissue contractility, stiffness, and thereby remodelling. We recommend that researchers use this comprehensive approach in future studies.

Advanced measurement techniques of regional myocardial function to assess the effects of cardiac regenerative therapy in different models of ischaemic cardiomyopathy.

Acute myocardial infarction leads to irreversible loss of cardiac myocytes, thereby diminishing the pump function of the heart. As a result, the strenuous workload imposed on the remaining cardiac myocytes often gives rise to subsequent cell loss until the vicious circle ends in chronic heart failure (CHF). Thus, we are in need of a therapy that could ameliorate or even reverse the disease progression of CHF. Endogenous regeneration of the mammalian heart has been shown in the neonatal heart, and the discovery that it may still persist in adulthood sparked hope for novel cardioregenerative therapies. As the basis for cardiomyocyte renewal, multipotent cardiac stem/progenitor cells (CSCs) that reside in the heart have been shown to differentiate into cardiac myocytes, smooth muscle cells, and vascular endothelial cells. These CSCs do have the potential to actively regenerate the heart but clearly fail to do so after abundant and segmental loss of cells, such as what occurs with myocardial infarction. Therefore, it is vital to continue research for the most optimal therapy based on the use or in situ stimulation of these CSCs. In this review, we discuss the current status of the cardioregenerative field. In particular, we summarize the current knowledge of CSCs as the regenerative substrate in the adult heart and their use in preclinical and clinical studies to repair the injured myocardium.

Concise review: heart regeneration and the role of cardiac stem cells.

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model.

A fast pH-switchable and self-healing supramolecular hydrogel carrier for guided, local catheter injection in the infarcted myocardium.

Dilated cardiomyopathy (DCM) is the most common form of nonischemic cardiomyopathy worldwide and can lead to sudden cardiac death and heart failure. Despite ongoing advances made in the treatment of DCM, improvement of outcome remains problematic. Stem cell therapy has been extensively studied in preclinical and clinical models of ischemic heart disease, showing potential benefit. DCM is associated with a major health burden, and few studies have been performed on cell therapy for DCM. In this systematic review we aimed to provide an overview of preclinical and clinical studies performed on cell therapy for DCM.

Cell therapy, a novel remedy for dilated cardiomyopathy? A systematic review.

Pre-clinical studies aimed at treating ischemic heart disease (i.e. stem cell- and growth factor therapy) often consider restoration of the impaired microvascular circulation as an important treatment goal. However, serial in vivo measurement hereof is often lacking. The purpose of this study was to evaluate the applicability of intracoronary pressure and flow velocity as a measure of microvascular resistance in a large animal model of chronic myocardial infarction (MI). Myocardial infarction was induced in Dalland Landrace pigs (n = 13; 68.9 ± 4.1 kg) by a 75-min. balloon occlusion of the left circumflex artery (LCX). Intracoronary pressure and flow velocity parameters were measured simultaneously at rest and during adenosine-induced hyperemia, using the Combowire (Volcano) before and 4 weeks after MI. Various pressure- and/or flow-derived indices were evaluated. Hyperemic microvascular resistance (HMR) was significantly increased by 28% in the infarct-related artery, based on a significantly decreased peak average peak flow velocity (pAPV) by 20% at 4 weeks post-MI (P = 0.03). Capillary density in the infarct zone was decreased compared to the remote area (658 ± 207/mm(2) versus 1650 ± 304/mm(2) , P = 0.017). In addition, arterioles in the infarct zone showed excessive thickening of the alpha smooth muscle actin (αSMA) positive cell layer compared to the remote area (33.55 ± 4.25 μm versus 14.64 ± 1.39 μm, P = 0.002). Intracoronary measurement of HMR successfully detected increased microvascular resistance that might be caused by the loss of capillaries and arteriolar remodelling in the chronic infarcted pig heart. Thus, HMR may serve as a novel outcome measure in pre-clinical studies for serial assessment of microvascular circulation.

Assessment of coronary microvascular resistance in the chronic infarcted pig heart.

Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-guided intramyocardial injections of IGF-1/HGF (GF: both 0.5 μg/mL, n = 5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μg/mL, n = 5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ventricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC population was increased almost fourfold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardiac function in chronic MI and that effect size could be further increased by using UPy hydrogel.

Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart.

Placebo in autologous cell-based interventions: hard pill to swallow?

In rodents, it has previously been shown that necrostatin-1 (Nec-1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec-1 in a large animal model, we assessed the effects of Nec-1 in a porcine I/R model, relevant to human disease.

ArticleTotal : 2	Year
Publication title Cited by 52	2014
Publication title Cited by 21	2015

Article	Year
Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection. International journal of cardiology\| PubMed ID: 22459400	2013
Transendocardial cell injection is not superior to intracoronary infusion in a porcine model of ischaemic cardiomyopathy: a study on delivery efficiency. Journal of cellular and molecular medicine\| PubMed ID: 22697212	2012
Advanced measurement techniques of regional myocardial function to assess the effects of cardiac regenerative therapy in different models of ischaemic cardiomyopathy. European heart journal cardiovascular Imaging\| PubMed ID: 22707453	2012
Concise review: heart regeneration and the role of cardiac stem cells. Stem cells translational medicine\| PubMed ID: 23658251	2013
A fast pH-switchable and self-healing supramolecular hydrogel carrier for guided, local catheter injection in the infarcted myocardium. Advanced healthcare materials\| PubMed ID: 23788397	2014
Cell therapy, a novel remedy for dilated cardiomyopathy? A systematic review. Journal of cardiac failure\| PubMed ID: 23834925	2013
Assessment of coronary microvascular resistance in the chronic infarcted pig heart. Journal of cellular and molecular medicine\| PubMed ID: 23910946	2013
Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart. Journal of cardiovascular translational research\| PubMed ID: 24395494	2014
Placebo in autologous cell-based interventions: hard pill to swallow? Journal of the American College of Cardiology\| PubMed ID: 24794125	2014
Necrostatin-1 alleviates reperfusion injury following acute myocardial infarction in pigs. European journal of clinical investigation\| PubMed ID: 25496079	2015

Stefan Koudstaal

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