Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 µg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Therapeutic synergy and complementarity for ischemia/reperfusion injury: ß1-adrenergic blockade and phosphodiesterase-3 inhibition.

The ß1-blocker when administered before reperfusion activates myocyte prosurvival signaling via ß2-adrenergic receptor (ß2-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 ß2-adrenopeptide receptor activation. I/R triggers cardiac epinephrine and neuropeptide calcitonin gene-related peptide (CGRP) release. Cardiac ß1- and ß2-AR stimulation mediates pro- and anti-apoptotic cell signaling, respectively. Removal of myocardial ß1-AR-derived proapoptotic force with ß1-AR blockade unmasks the dominance of ß2-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 ß2-adrenopeptide neuroparacrine signaling mechanisms involved in I/R injury protection. While ß2-adrenopeptide-mediated cardioprotection is important, age-related ß2-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-ß1-AR-mediated PKA activation activates multiple prosurvival signaling pathways eventually leading to Akt activation. Combination therapy with ß1-blocker esmolol and PDE3 inhibitor milrinone additively reduced infarct-size in preclinical studies. Concurrent ß1-AR blockade and PDE3 inhibition provides complementary synergy with promising therapeutic potential in patients with acute myocardial infarction and beyond.

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.

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.

Prolonged survival in 2 nonagenarians with heart failure and severe aortic stenosis.

The prevalence of severe aortic stenosis is 6% in persons 85 to 86 years of age according to a Finnish population-based report. In the United States, the population over 80 years old is projected to rise from the current 7 million to 25 million by the year 2050. Thus, aortic stenosis in aging adults, and the management questions it poses, will be increasingly common. We report herein the cases of 2 nonagenarian patients with severe symptomatic aortic stenosis who far outlived the natural history of this disease. We suspect that we are seeing a change in the prognosis of senile aortic stenosis as a result of advances in the geriatric care and management of advanced heart failure. Furthermore, the unusual longevity of these patients was made possible by the remarkable holistic care given by a dedicated, altruistic caregiver who had training in psychology, theology, and nursing.

The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation.

BACKGROUND: Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. HYPOTHESIS: CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction. METHODS: Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride. RESULTS: Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 +/- 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 +/- 7%). CONCLUSIONS: ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.

Mediating delta-opioid-initiated heart protection via the beta2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell.

Stimulation of cardiac beta(2)-adrenergic receptor (beta(2)-AR) or delta-opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that delta-opioid-initiated cardioprotection is mediated by the intrinsic cardiac adrenergic (ICA) cell via enhanced epinephrine release. Using immunohistochemical and in situ hybridization methods, we detected in situ tyrosine hydroxylase (TH) mRNA and TH immunoreactivity that was colocalized with DOR immunoreactivity in ICA cells in human and rat hearts. Western blot analysis detected DOR protein in ICA cells isolated from rat ventricular myocytes. The physiology of DOR expression was examined by determining changes of cytosolic Ca(2+) concentration ([Ca(2+)](i)) transients in isolated rat ICA cells using fluorescence spectrophotometry. Exposing the selective delta-opioid agonist D-[Pen(2,5)]enkephalin (DPDPE) to ICA cells increased [Ca(2+)](i) transients in a concentration-dependent manner. Such an effect was abolished by the Ca(2+) channel blocker nifedipine. HPLC-electrochemical detection demonstrated a 2.4-fold increase in epinephrine release from ICA cells following DPDPE application. The significance of the ICA cell and its epinephrine release in delta-opioid-initiated cardioprotection was demonstrated in the rat myocardial infarction model and ICA cell-ventricular myocyte coculture. DPDPE administered before coronary artery occlusion or simulated ischemia-reperfusion reduced left ventricular infarct size by 54 +/- 15% or myocyte death by 26 +/- 4%, respectively. beta(2)-AR blockade markedly attenuated delta-opioid-initiated infarct size-limiting effect and abolished delta-opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, delta-opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that delta-opioid-initiated myocardial infarct size reduction is primarily mediated via endogenous epinephrine/beta(2)-AR signaling pathway as a result of ICA cell activation.

Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin.

We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI(2) production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x kg(-1) x day(-1)) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n=8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 +/- 1.4% of the AR) compared with controls (31.0 +/- 2.2%). Intravenous ASA alone did not affect IS (29.0 +/- 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 +/- 0.9%, 22.0 +/- 1.6%, and 23.7 +/- 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 +/- 0.90 pg/mg; ATV, 75.85 +/- 1.08 pg/mg; ATV + ASA5, 34.39 +/- 1.48 pg/mg; ATV + ASA10, 19.87 +/- 1.10 pg/mg; and ATV + ASA20, 9.36 +/- 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.

Oxidative stress and apoptosis in cardiomyocyte induced by high-dose alcohol.

Binge drinking of alcohol causes cardiac dysfunction in some people. The mechanism remains unclear. This study was designed to investigate high doses of alcohol-induced oxidative stress and apoptosis in cardiomyocytes and protective effects of antioxidants. Cardiomyocytes isolated from 1- to 2-day-old Sprague-Dawley rats were treated with ethanol at doses of 0 mM, 50 mM, 100 mM, and 200 mM for 24 hours. Vitamin E (1 mM) and vitamin C (0.2 mM) were added to medium 1 hour before addition of ethanol. Results showed typical apoptosis: chromatin condensation, membrane blebbing, shrinkage, and cytoplasm condensation. Apoptosis is concentration-dependent in the range of 0 to 100 mM ethanol (apoptosis rates were respectively 0.68%, 2.03%, and 9.66% at ethanol concentration of 0 mM, 50 mM, and 100 mM). Necrotic cells became greatly increased in the 200 mM ethanol-treated group. Intracellular production of reactive oxygen intermediates increased as mitochondrial membrane potential decreased after ethanol treatment. Cytochrome c was found to be greater in the cytosol of the ethanol-treated groups. Activity of caspase-3 was higher in ethanol-treated groups (P < 0.05). Both vitamin E and vitamin C inhibited oxidative stress and myocyte apoptosis in ethanol-treated groups (P < 0.05). In conclusion, our data indicated that acute high-dose ethanol treatment primarily induces cardiomyocyte apoptosis at concentration up to 100 mM while necrosis is predominate at 200 mM. The underlying mechanism appears to involve mitochondrial damage via an increase in oxidative stress and releasing cytochrome c, which activates caspases that initiate chromatin fragmentation and apoptosis. Antioxidants, to a large extent, inhibit oxidative stress and apoptosis induced by ethanol.

Paradoxical effect of prostacyclin infusion in a patient with primary pulmonary hypertension-a case report.

Prostacyclin treatment successfully delays the need for lung transplantation in many patients with progressive primary pulmonary hypertension by vasodilating pulmonary arteries. However, the treatment of pulmonary hypertension with prostacyclin may cause a paradoxical increase in pulmonary artery pressure, as shown in this case.

Severe obstruction of the left main coronary artery by mycotic aortic psuedoaneurysm following orthotopic heart transplantation.

Mycotic aneurysm of the ascending aorta is a rare complication following orthotopic heart transplantation. This article describes a case of mycotic pseudoaneurysm caused by Candida albicans that developed shortly after orthotopic heart transplantation. The pseudoaneurysm compressed the left main coronary artery, which led to the development of congestive heart failure symptoms mimicking sub-acute transplant rejection. The heart failure signs and symptoms resolved completely with resection of the aneurysm. This case reiterates that early diagnosis and complete resection of the aneurysm is associated with good prognosis.