Safety of combination therapy with milrinone and esmolol for heart protection during percutaneous coronary intervention in acute myocardial infarction.

PURPOSE: Ischemia/reperfusion injury remains an untreated clinical problem in patients with acute myocardial infarction (AMI) despite significant advances in emergent revascularization through percutaneous coronary intervention (PCI). Pharmacological intervention for infarct size reduction is unavailable. We have identified that the medications milrinone and esmolol, when administered together at the beginning of the reperfusion, significantly decrease infarct size via reducing reperfusion injury in an experimental model. The present study tested the safety of combination therapy of milrinone and esmolol (M + E) in patients with AMI. METHODS: Sixteen subjects with AMI requiring PCI were consecutively recruited. M + E was intravenously infused simultaneously for 10 min started at 5 min before anticipated angioplasty balloon inflation. Another 16 consecutively recruited AMI patients requiring PCI served as a placebo arm treated per routine clinical protocol. Blood pressure (BP) and heart rate (HR) were monitored continuously during PCI. RESULTS: M + E combination therapy resulted in a trend of non-significant reduction in BP compared with a control group. There was a modest but significant increase in HR at the later phase of M + E infusion compared with a control group. No significant cardiac arrhythmia was induced during M + E infusion. CONCLUSIONS: The combination therapy with M + E produces a minimal change in hemodynamics and appears safe as an adjunctive therapy to PCI in AMI patients. Further studies are warranted.

Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion.

INTRODUCTION: The present study determined whether late-ischemia/early reperfusion therapy with the ß(1)-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). METHODS AND RESULTS: In an ischemia/reperfusion rat model (30-min ischemia/4-hr reperfusion), esmolol, milrinone or esmolol + milrinone were intravenous (IV) infused over 10 min (from the last 5 min of ischemia to the first 5 min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline, esmolol, milrinone, and esmolol + milrinone, respectively (n = 12/group). Esmolol + milrinone further reduced LV-IS compared with esmolol or milrinone alone (p < 0.05). LV-IS-reduction induced by esmolol + milrinone was eliminated in the presence of protein kinase A-(PKA)-inhibitor (Rp-cAMPS) or Akt-inhibitor (AKT 1/2 kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of esmolol, milrinone or esmolol + milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by esmolol + milrinone was abrogated in the presence of PKA-inhibitor or Akt-inhibitor. Esmolol, milrinone or esmolol + milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of Rp-cAMPS on myocytes was identified in a purified myocyte preparation during hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of esmolol, milrinone or esmolol + milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This esmolol + milrinone induced pAkt activation was abolished in the presence of PKA inhibitor. Esmolol, milrinone and esmolol + milrinone reduced myocyte apoptosis rates by 22%, 37% and 60%, respectively, compared with saline (p < 0.01). CONCLUSIONS: Late-ischemia/early reperfusion therapy with esmolol + milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway.

Identification and characterization of syntenin binding protein in the black tiger shrimp Penaeus monodon.

Shrimp exhibit a diverse response to viral infection that is manifested in drastic up- and down-regulations of a variety of genes. In our previous work, we identified syntenin of the shrimp Penaeus monodon (Pm) as a dynamic responder to white spot syndrome virus (WSSV) infection, its message being greatly upregulated in the acute phase of the infection. In order to further explore the link between Pm-syntenin and viral infection, we performed a yeast two-hybrid screening of a P. monodon cDNA library, using Pm-syntenin as bait. One of the molecules that specifically interacted with Pm-syntenin was the receptor-binding domain of alpha-2-macroglobulin (alpha2M). A GST pull-down assay showed that GST-alpha2M, but not GST alone, was capable of co-precipitating syntenin. Another GST pull-down assay showed that GST-syntenin, but not GST alone, was capable of co-precipitating alpha2M. In addition, mutant analyses showed that the N-terminal 131 amino acids of syntenin were both necessary and sufficient to bind the C-terminus receptor-binding domain of alpha2M. Furthermore, WSSV-infected Pm showed a significant upregulation of the alpha2M message, suggesting that both syntenin and its protein partner alpha2M are upregulated in the acute phase of a WSSV infection. Taken together with a previous report showing the co-localization of alpha2M and syntenin in the exosome of a dendritic cell line, it is likely that syntenin, through its interaction with alpha2M, plays an important role in the immune defense mechanisms of viral infections of shrimps.

Delta-opioid augments cardiac contraction through ß-adrenergic and CGRP-receptor co-signaling.

Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist DPDPE (100 µg/kg) with or without 10-min pretreatment with either ß-adrenergic receptor (ß-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 µg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36 ± 18% (p<0.001) increase of the LVFS, which continues to increase to 51 ± 24% (p<0.0001) by 10 min, and 68 ± 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11 ± 6% (p<0.001) by 15 min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 ± 8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9 ± 9%, p=0.03) decrease in SBP that was not apparent until 20 min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP(8-37), or combined propranolol+CGRP(8-37). Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced ß-AR and CGRPR co-signaling.

Cardiac allograft vasculopathy: advances in diagnosis.

Cardiac allograft vasculopathy (CAV), characterized by diffuse intimal thickening and luminal narrowing in the arteries of the allograft, is the leading cause of morbidity and mortality in cardiac transplant recipients. Many transplant centers perform routine annual surveillance coronary angiography. However, angiography can underdiagnose or miss CAV due to its diffuse nature. Intravascular ultrasound (IVUS) is more sensitive than angiography. IVUS provides not only accurate information on lumen size, but also quantification of intimal thickening, vessel wall morphology, and composition. IVUS has evolved as a valuable adjunct to angiography and the optimal diagnostic tool for early detection. Noninvasive testing such as dobutamine stress echocardiography and nuclear stress test have shown considerable accuracy in diagnosing significant CAV. Computed tomographic imaging and cardiac magnetic resonance imaging are promising new modalities but require further study. This article reviews the diagnostic methods that are currently available.

Reducing ischaemia/reperfusion injury through delta-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.

Vascular access site complications with the use of closure devices in patients treated with platelet glycoprotein IIb/IIIa inhibitors during rescue angioplasty.

The objective of this study was to evaluate the effectiveness of two different closure devices in patients undergoing rescue percutaneous coronary intervention (PCI) using IIb/IIIa inhibitors and to compare it with patients undergoing elective PCI. One hundred sixty-two patients undergoing rescue PCI treated with IIb/IIIa inhibitors underwent vascular access site closure (6 Fr Perclose, n = 92, or 6 Fr Angioseal, n = 70). Vascular complications were compared with a sex- and age-matched group (n = 100) of patients undergoing manual compression after sheath removal and a similar group of patients undergoing elective PCI (n = 196). The incidence of access site complications was not significantly different between the three groups undergoing rescue PCI and was not higher than in patient receiving GP IIb/IIIa inhibitors without fibrinolysis (RR = 0.95; 95% CI = 0.88-1.01). In patients undergoing rescue PCI and receiving IIb/IIIa inhibitors, closure devices allow early sheath removal and are associated with similar outcomes compared with manual compression and elective PCI regardless of the type of closure device used.