Charles Y. Lui

Phenyl-α-tert-butyl-nitrone and Benzonidazole Treatment Controlled the Mitochondrial Oxidative Stress and Evolution of Cardiomyopathy in Chronic Chagasic Rats

OBJECTIVES The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction. BACKGROUND Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease. METHODS Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-alpha-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats. RESULTS Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, beta-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN +/- BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, alpha-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN +/- BZ-treated chagasic rats. CONCLUSIONS BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.

Reducing ischaemia/reperfusion injury through δ-opioid-regulated intrinsic cardiac adrenergic cells: adrenopeptidergic co-signalling

AIMS The purpose of this study was to determine whether intrinsic cardiac adrenergic (ICA) cells release calcitonin gene-related peptide (CGRP), exerting synergistic adrenopeptidergic cardioprotection. METHODS AND RESULTS In situ hybridization coupled with immunostaining demonstrated that ICA cells exclusively expressed CGRP mRNA and co-expressed CGRP and delta-opioid receptor in human and rat left ventricular (LV) myocardium. Radioimmunoassay detected constitutive CGRP release from ICA cells in human and rat hearts. The delta-opioid agonist [D-Pen(25)]-enkephalin (DPDPE) increased CGRP release from ICA cells in denervated rat heart. In an ischaemia/reperfusion rat model, pre-ischaemic treatment with DPDPE reduced infarct size (IS) by 51 +/- 16% (P < 0.01). Co-infusion of beta(2)-adrenergic receptor (beta(2)-AR) and CGRP receptor (CGRP-R) antagonists increased IS by 62 +/- 23% (P < 0.01) compared with saline and abolished DPDPE-initiated IS reduction. Pre-treatment of ICA cell-myocyte co-culture with the beta(2)-AR/CGRP-R antagonists increased myocyte death rate by 24 +/- 4% (P < 0.01) and abolished DPDPE-initiated myocyte protection against hypoxia/reoxygenation (re-O(2)). In the ICA cell-depleted myocyte culture, DPDPE did not confer myocyte protection. Supplementing ICA cell-depleted myocyte culture with beta(2)-AR/CGRP-R agonists reduced hypoxia/re-O(2)-induced myocyte death by 24 +/- 5% (P < 0.01), simulating endogenous neurohormonal effects of ICA cells. Western blot analysis showed that DPDPE markedly increased phosphorylated myocardial Akt levels. This effect was abolished in the presence of beta(2)-AR/CGRP-R blockade. Terminal dUTP nick-end labelling staining analysis of the LV infarct zone demonstrated that DPDPE reduced myocyte apoptosis by 58 +/- 19% (P < 0.05), an effect that was eliminated in the presence of beta(2)-AR/CGRP-R blockade. Finally, echocardiography showed that DPDPE increased LV contractility in a manner dependent on beta-AR/CGRP-R stimulation. CONCLUSION ICA cells constitute a delta-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through beta(2)-AR/CGRP-R co-signalling, resulting in the activation of an anti-apoptotic pathway during ischaemia/reperfusion.

Distal myocardial protection with intracoronary beta blocker when added to a Gp IIb/IIIa platelet receptor blocker during percutaneous coronary intervention improves clinical outcome†

Objective: The present study tested the hypothesis that intracoronary (IC) propranolol improves clinical outcomes with percutaneous coronary intervention (PCI) when used with background Gp IIb/IIIa receptor blockade. Background: We have previously shown that administration of a relatively large weight‐based IC dose of the beta blocker propranolol before PCI decreases the incidence of post‐PCI myocardial infarction (MI) and improves short‐ and long‐term outcome. It has previously been shown that administration of a Gp IIb/IIIa receptor blocker decreases post‐PCI MI and improves short‐ and long‐term clinical outcome. Methods: Patients undergoing PCI (n = 400) were randomized in a prospective double‐blind fashion to IC propranolol (n = 200) or placebo (n = 200) with eptifibatide administered to all the patients. Myocardial isoform of creatine kinase was measured during the first 24 hr and clinical outcomes at 30 days and 1 year. Results: MI after PCI was seen in 21.5% of placebo and 12.5% of propranolol patients (relative risk reduction 0.42; 95%CI 0.09, 0.63; P = 0.016). At 30 days, the composite end point of death, post‐procedural MI, urgent target lesion revascularization, or MI after index hospitalization occurred in 22.5% of placebo vs. 13.5% of propranolol patients (risk reduction 0.43; 95%CI 0.08, 0.65; P = 0.018). Similar results were observed at 1 year with adverse outcomes in 21.5% of propranolol and 32.5% of placebo patients (P = 0.01). Conclusion: IC propranolol administration with the background Gp IIb/IIIa receptor blockade significantly reduces the incidence of post‐PCI MI and improves the short‐ and long‐term clinical outcome when compared with a Gp IIb/IIIa blocker alone.

Therapeutic synergy and complementarity for ischemia/reperfusion injury: β1-adrenergic blockade and phosphodiesterase-3 inhibition.

The β1-blocker when administered before reperfusion activates myocyte prosurvival signaling via β2-adrenergic receptor (β2-AR) and protein kinase A (PKA)-dependent mechanism during ischemia/reperfusion (I/R). The heart is endowed with powerful self-protective ability executed by endogenous β2-adrenopeptide receptor activation. I/R triggers cardiac epinephrine and neuropeptide calcitonin gene-related peptide (CGRP) release. Cardiac β1- and β2-AR stimulation mediates pro- and anti-apoptotic cell signaling, respectively. Removal of myocardial β1-AR-derived proapoptotic force with β1-AR blockade unmasks the dominance of β2-AR mediated prosurvival cell signaling through the well-defined PKA-Akt dependent mechanism. This review focuses on recent clinical and experimental findings including intrinsic cardiac β2-adrenopeptide neuroparacrine signaling mechanisms involved in I/R injury protection. While β2-adrenopeptide-mediated cardioprotection is important, age-related β2-adrenopeptide receptor decoupling can result in their ineffectiveness in response to the receptor-specific therapies. Accordingly, direct activation of receptor-coupled upstream PKA-dependent signaling may serve as a therapeutic alternative to achieve cardioprotection bypassing adrenopeptidergic receptor decoupling accompanied with aging. Phosphodiesterase-3 (PDE3) inhibitor reduces infarct-size via cAMP-dependent PKA signaling. Non-β1-AR-mediated PKA activation activates multiple prosurvival signaling pathways eventually leading to Akt activation. Combination therapy with β1-blocker esmolol and PDE3 inhibitor milrinone additively reduced infarct-size in preclinical studies. Concurrent β1-AR blockade and PDE3 inhibition provides complementary synergy with promising therapeutic potential in patients with acute myocardial infarction and beyond.

Fractional Flow Reserve–Guided Intervention of Angiographically Nonsignificant Coronary Stenoses

We read with interest the recent DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia) study by Pijls et al. ([1][1]) comparing results of percutaneous coronary intervention (PCI) with medical therapy in patients with stable coronary artery disease and angiographically