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Localized targeting of biomaterials following myocardial infarction: a foundation to build on.

ABSTRACT: Acute coronary syndromes can give rise to myocardial injury infarction (MI), which in turn promulgates a series of cellular and extracellular events that result in left ventricular (LV) dilation and dysfunction. Localized strategies focused upon interrupting this inexorable process include delivery of bioactive molecules and stem cell derivatives. These localized treatment strategies are often delivered in a biomaterial complex in order to facilitate elution of the bioactive molecules or stem cell engraftment. However, these biomaterials can impart significant and independent effects upon the MI remodeling process. In addition, significant changes in local cell and interstitial biology within the targeted MI region can occur following injection of certain biomaterials, which may hold important considerations when using these materials as matrices for adjuvant drug/cell therapies.

SUBMITTER: Shuman JA

PROVIDER: S-EPMC3773006 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Localized targeting of biomaterials following myocardial infarction: a foundation to build on.

Shuman James A JA Zurcher Jonathan R JR Sapp Ashley A AA Burdick Jason A JA Gorman Robert C RC Gorman Joseph H JH Goldsmith Edie C EC Spinale Francis G FG

Trends in cardiovascular medicine 20130606 8

Acute coronary syndromes can give rise to myocardial injury infarction (MI), which in turn promulgates a series of cellular and extracellular events that result in left ventricular (LV) dilation and dysfunction. Localized strategies focused upon interrupting this inexorable process include delivery of bioactive molecules and stem cell derivatives. These localized treatment strategies are often delivered in a biomaterial complex in order to facilitate elution of the bioactive molecules or stem ce ...[more]

PMID: 23746937

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Project description:BackgroundPreclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Methods and resultsOverall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.ConclusionsThe presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:BACKGROUND:In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS:Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS:Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0?±?2.3% vs 30.7?±?1.7% in vehicle-treated MI heart, p?<?0.05) and limited adverse remodelling (LV mass: 129?±?7 vs 176?±?14 mg in vehicle-treated MI hearts, p?<?0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661?±?192 vs 924?±?165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p?<?0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3? pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374?±?27 vs 183?±?41 µmol g protein-1 in vehicle-treated MI hearts, p?<?0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ?-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS:mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.

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Localized targeting of biomaterials following myocardial infarction: a foundation to build on.

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Localized targeting of biomaterials following myocardial infarction: a foundation to build on.

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