Reduction In Coronary Flow Research Articles

Ist die Ruheherzfrequenz ein kardiovaskulärer Risikofaktor?

During recent years, resting heart rate was not considered as a cardiovascular risk factor. However, new evidences have showed that resting heart rate is an important prognostic factor for sudden cardiac death and heart failure in the general population, and especially among patients with known cardiac disease. Interestingly, resting heart rate not only predicts cardiac mortality but also all-cause mortality. The most common pathophysiological explanation is related to the fact that increased heart rate increases myocardial oxygen consumption and in parallel reduces coronary blood flow (reduction in the diastolic duration).

Inhibiting matrix metalloproteinase‐2 (MMP‐2 reduces endothelial damage in isolated rat hearts during ischemia‐reperfusion

Previous studies have shown disruption of the coronary endothelium and increase in its permeability during ischemia‐reperfusion (I/R) which can be linked with MMPs activity. Our group has shown that during I/R, increased activity of MMP‐2 is associated with cardiac dysfunction, which can be prevented by MMP inhibitors. Therefore, we hypothesize that MMPs inhibition reduces the MMP‐2 dependent disruption of the coronary endothelium during I/R.Isolated rat hearts were perfused in the Langendorff mode at a constant pressure and subjected to 15‐30 min of no‐flow ischemia followed by 30 min of reperfusion. o‐Phenanthroline (Phen), an inhibitor of MMPs, was used to protect the hearts from dysfunction. Endothelial integrity was evaluated by measuring coronary flow, and by measuring the interstitial albumin and serotransferrin in the effluent. MMP‐2 activity was measured in the hearts by zymography.MMP‐2 activity was increased in heart tissue at the end of ischemia and was correlated with duration of ischemia. The coronary flow was decreased and correlated with the disruption of the endothelial barrier (increased release of albumin and serotransferrin in the coronary effluent). Administration of Phen inhibited both reduction of coronary flow and endothelial barrier disruption.

Haemodynamic impact of the left ventricular pacing site during graded ischaemia in an open-chest pig model

In post-operative setting after cardiac surgery, the choice of the optimal ventricular pacing site remains an issue, particularly in patients with ischaemic cardiomyopathy. We aimed to investigate the impact of the left ventricular (LV) pacing site in an animal model of incremental myocardial ischaemia. Three epicardial LV pacing leads were implanted in 10 pigs [LV1 in the territory of the left anterior descending (LAD) artery, LV2 in the lateral border of this territory, LV3 in an anatomically opposed position]. A two-dimensional strain echocardiogram was performed at baseline and during two levels of incremental ischaemia, corresponding to 30 and 70% reduction of coronary flow in the LAD, during spontaneous sinus rhythm (SR) and during LV1, LV2, LV3, and multi-LV (LV1 + LV2 + LV3) pacing. At baseline (n = 10), LV + dP/dt(max) was decreased (P < 0.01) during LV1, LV2, LV3, and multi-LV pacing compared with SR. At first level of ischaemia (n = 7; 3 animals died from ventricular fibrillation), LV1 pacing (ischaemic area) induced a significant decrease in LV + dP/dt(max) compared with SR, LV2, LV3, and multi-LV pacing (P < 0.05). At second level of ischaemia (n = 6), LV1 pacing induced a significant decrease in LV + dP/dt(max) associated with an increase in the extent of myocardium with echocardiographic post-systolic shortening compared with SR, LV2, LV3, or multi-LV pacing (P < 0.05). In contrast, multi-LV pacing induced a significant haemodynamic improvement compared with SR, LV1, LV2, and LV3 (P < 0.05). Pacing within an ischaemic area has detrimental impact on acute global and regional LV function. More studies are needed to assess the impact of multi-LV pacing in chronic ischaemic conditions.

Hemodynamic diagnostics of epicardial coronary stenoses: in-vitro experimental and computational study.

BackgroundThe severity of epicardial coronary stenosis can be assessed by invasive measurements of trans-stenotic pressure drop and flow. A pressure or flow sensor-tipped guidewire inserted across the coronary stenosis causes an overestimation in true trans-stenotic pressure drop and reduction in coronary flow. This may mask the true severity of coronary stenosis. In order to unmask the true severity of epicardial stenosis, we evaluate a diagnostic parameter, which is obtained from fundamental fluid dynamics principles. This experimental and numerical study focuses on the characterization of the diagnostic parameter, pressure drop coefficient, and also evaluates the pressure recovery downstream of stenoses.MethodsThree models of coronary stenosis namely, moderate, intermediate and severe stenosis, were manufactured and tested in the in-vitro set-up simulating the epicardial coronary network. The trans-stenotic pressure drop and flow distal to stenosis models were measured by non-invasive method, using external pressure and flow sensors, and by invasive method, following guidewire insertion across the stenosis. The viscous and momentum-change components of the pressure drop for various flow rates were evaluated from quadratic relation between pressure drop and flow. Finally, the pressure drop coefficient (CDPe) was calculated as the ratio of pressure drop and distal dynamic pressure. The pressure recovery factor (η) was calculated as the ratio of pressure recovery coefficient and the area blockage.ResultsThe mean pressure drop-flow characteristics before and during guidewire insertion indicated that increasing stenosis causes a shift in dominance from viscous pressure to momentum forces. However, for intermediate (~80%) area stenosis, which is between moderate (~65%) and severe (~90%) area stenoses, both losses were similar in magnitude. Therefore, guidewire insertion plays a critical role in evaluating the hemodynamic severity of coronary stenosis. More importantly, mean CDPe increased (17 ± 3.3 to 287 ± 52, n = 3, p < 0.01) and mean η decreased (0.54 ± 0.04 to 0.37 ± 0.05, p < 0.01) from moderate to severe stenosis during guidewire insertion.ConclusionThe wide range of CDPe is not affected that much by the presence of guidewire. CDPe can be used in clinical practice to evaluate the true severity of coronary stenosis due to its significant difference between values measured at moderate and severe stenoses.

Embolic protection: the FilterWire EZ™ Embolic Protection System

The field of interventional cardiology has grown dramatically over the past 30 years, including recent advances in the area of peripheral vascular intervention. The phenomenon of no-reflow, characterized by a reduction in coronary blood flow during vascular intervention, has been associated with adverse outcomes in both saphenous vein graft and carotid artery interventions. Distal embolic protection devices, such as the FilterWire EZ™ System, have been shown to reduce the incidence of no-reflow and adverse cardiac events in patients undergoing saphenous vein graft interventions. Recently approved indications for the FilterWire EZ System include carotid artery stenting. With the definite reduction in adverse events from the use of distal protection, future advancements will focus on improved deliverability of such devices.

Impact of irrigated energy application on the right coronary artery hemodynamics: FFR measurement in patients who underwent ablation of common type atrial flutter

The purpose of this first in vivo study was to assess the incidence of thermal influence to the right coronary artery (RCA) during ablation of common type atrial flutter (Aflu) by measuring the fractional flow reserve (FFR) in the vessel before, under and after ablation. In thirty three patients ablated we performed coronary angiography (CA) before and at the end of the procedure. The FFR wire was positioned in the distal, the isthmus underlying, part of the RCA. Before and after the procedure FFR measurement was done at baseline and during adenosine administration. During the whole ablation procedure FFR measurement was continuously carried on, to monitor a transient thermal impact to the RCA. Of the 33 patients observed, 25 males, 8 females, mean age 58 +/- 9.5 years, none with CAD, all patients, except one with unidirectional block, were successfully ablated. The FFR at rest and under medication with adenosine before and after ablation was 0.985/0.949 and 0.981/0.942, respectively (p = ns). The CA of the RCA did not reveal any morphological change. The mean FFR while ablation declined from 0.94 to 0.904 (p = ns). Twenty-six patients (78.8%) had no or moderate decrease in FFR, seven patients (21.2%) demonstrated a substantial decrease [five patients (15.2%), FFR < 0.9 and >0.75] or significant change [two patients (6.1%)], FFR < 0.75 consistent with a remarkable or significant reduction of coronary flow. Ablation of AFlu did not alter RCA morphology; simultaneous FFR measurement showed severe depression of the FFR in a few patients, consistent with impairment in myocardial perfusion.

Acute Administration of Epirubicin Induces Myocardial Depression in Isolated Rat Heart and Production of Radical Species Evaluated by Electron Spin Resonance Spectroscopy

The aim of our study was to evaluate the acute effect of epirubicin (EPI), an anthracycline anticancer drug, on the evolution of cardiac functional parameters and production of reactive oxygen/nitrogen species (RONS). Isolated perfused rat hearts were subjected to 70 minutes of EPI (10.3 microM) infusion and to 5 minutes of isoproterenol (ISO, 0.1 microM) at the end of the protocol. Coronary flow (CF), left ventricular developed pressure (LVDP), and lactate dehydrogenase (LDH) release in the coronary effluents were evaluated throughout the protocol. RONS were detected in the coronary effluents by electron spin resonance spectroscopy with a spin probe, 1-hydroxy-3-carboxy-pyrrolidine (CP-H, 0.1 mM). EPI induced a reduction in CF and in LVDP (P < 0.001). ISO infusion enhanced CF and RPP in the control group; in the EPI group, these increases were significantly impaired. Release of LDH was significantly increased during EPI infusion (P < 0.001). RONS was 2.5 times greater in the EPI group than in the control group (P < 0.05). In conclusion, a significant deterioration in cardiac function was observed after EPI perfusion and was associated with cellular injury and the generation of myocardial RONS. Further investigations are now needed to determine whether new cardioprotective agents targeting oxidative stress may reduce the incidence of anthracycline-induced cardiotoxicity.

(n-3) Long Chain PUFA Dose-Dependently Increase Oxygen Utilization Efficiency and Inhibit Arrhythmias after Saturated Fat Feeding in Rats

Fish oil (FO) modifies cardiac membrane phospholipid fatty acid composition to confer increased efficiency of oxygen utilization and antiarrhythmic effects. We tested the capacity of low-dose increments of FO, rich in (n-3) PUFA, to reverse the detrimental pro-arrhythmic and inefficient oxygen usage effects of dietary saturated fat (SAT) [including high ratio of (n-6) PUFA:(n-3) PUFA] during ischemia and reperfusion. Wistar rats were fed an SAT-enriched diet (15.3% fat, including 12% SAT, added by weight) for 6 wk and were then divided into 4 groups (n = 10/group) fed that diet or a 12% fat diet containing 3, 6, or 12% FO in place of SAT for 6 wk. Paced (300/min), erythrocyte-perfused isolated working hearts were subjected to low coronary flow ischemia (15 min) and were then reperfused. At normoxic baseline, external work capacity increased marginally at 6 and 12% FO; however, marked dose-related reductions in oxygen consumption were evident due to FO-dependent reduction in oxygen-energy utilization efficiency and associated reductions in coronary flow and oxygen extraction. Postischemic recovery resulted in lower oxygen consumption, greater oxygen-energy utilization efficiency, reduced coronary release of creatine kinase, and reduced incidence of arrhythmias in all FO groups compared with the SAT group. FO at a dose as low as 3% of total fat dietary supplement effectively reversed the high oxygen requirements and pro-arrhythmic effects of a SAT-rich diet even with continued consumption of SAT (9%) in this ex vivo animal model.

Nandrolone Potentiates Arrhythmogenic Effects of Cardiac Ischemia in the Rat

Anabolic steroid abuse has been associated with thrombosis and arteriosclerosis, both of which predispose to myocardial ischemia and infarction. However, there are reports of sudden cardiac death in the absence of thrombus and atheroma following anabolic steroid use. Although treatment with the commonly abused steroid, nandrolone, has been shown to decrease recovery of systolic function following ischemia in isolated rat hearts, it is unknown whether anabolic steroids can increase the incidence of fatal arrhythmia associated with cardiac ischemia. Anesthetized male Sprague-Dawley rats were administered vehicle or nandrolone (10-160 microg/kg/min iv) 10 min prior to 15-min occlusion of the left anterior descending coronary artery followed by 10-min reperfusion. Nandrolone, in this dose range, did not significantly change heart rate, blood pressure, or cardiac rhythm in the absence of ischemia. However, the fraction of rats surviving ischemia was significantly (p < 0.05) decreased by nandrolone at both 40 and 160 microg/kg/min, while survival time during ischemia was decreased significantly (p < 0.001) by nandrolone 160 microg/kg/min. An increase (p < 0.05) in the duration of ventricular fibrillation was noted at the highest compared to the lowest dose of nandrolone, corresponding to a significant increase in the fraction of rats experiencing ventricular fibrillation (p < 0.01). Nandrolone had no effect on the frequency or duration of ventricular fibrillation or survival time during reperfusion. Although the mechanisms underlying these effects are currently unclear, they indicate that exposure to anabolic steroids in combination with transient reductions in coronary blood flow may explain some reports of sudden cardiac death in anabolic steroid users.

Unrecognized Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery as a Cause of Ventricular Fibrillation After Patent Ductus Arteriosus Ligation in an Infant

We present a case of an infant who developed ventricular fibrillation after patent ductus arteriosus (PDA) ligation. The infant had unrecognized anomalous origin of the left coronary artery from the pulmonary artery before PDA ligation. Acute reduction in systemic pulmonary artery pressures after PDA ligation resulted in an abrupt reduction in left main coronary artery blood flow. After prompt resuscitation, cardiac catheterization confirmed the diagnosis of anomalous origin of the left coronary artery from the pulmonary artery. The infant subsequently underwent coronary artery translocation and recovered uneventfully.

Physiologically Tolerable Insulin Reduces Myocardial Injury and Improves Cardiac Functional Recovery in Myocardial Ischemic/Reperfused Dogs

This study was designed to examine whether physiologically tolerable insulin, which maintains lower blood glucose, can protect the myocardium against ischemia/reperfusion (I/R) injury in a preclinical large animal model. Adult dogs were subjected to 50 minutes of myocardial ischemia (80% reduction in coronary blood flow) followed by 4 hours of reperfusion and treated with vehicle, glucose-insulin-potassium (GIK; glucose, 250 g/L; insulin, 60 U/L; potassium, 80 mmol/L), GK, or low-dose insulin (30 U/L) 10 minutes before reperfusion. Treatment with GIK exerted significant cardioprotective effects as evidenced by improved cardiac function, improved coronary blood flow, reduced infarct size, and myocardial apoptosis. In contrast, treatment with GK increased blood glucose level and aggravated myocardial I/R injury. It is interesting that treatment with insulin alone at the dose that reduced blood glucose to a clinically tolerable level exerted significant cardioprotective effects that were comparable to that seen in the GIK-treated group. This low-dose insulin had no effect on coronary blood flow after reperfusion but markedly reduced coronary reactive hyperemia and switched myocardial substrate uptake from fat to carbohydrate. Our results suggest that lower glucose supply to the ischemic myocardium at early reperfusion may create a "metabolic postconditioning" and thus reduce myocardial ischemia/reperfusion injury after prolonged reperfusion.

Abstract 602: Repetitive Coronary Stenosis Induces a Third Window of Ischemic Preconditioning

The mechanisms responsible for the 1 st and 2 nd window of protection following ischemic preconditioning (IPC) have been studied in detail. We tested the hypothesis that chronic myocardial ischemia (repetitive bouts of coronary stenosis, CS) may induce IPC mediated by different mechanisms. To study this, 6 episodes of 90 min chronic CS (reduction in coronary blood flow, &gt;35% from baseline), followed by reperfusion every 12 hrs were examined in conscious pigs chronically instrumented to measure left ventricular (LV) pressure and regional wall thickness. Infarct size/area at risk (IF/AAR) was assessed in all groups after 60 min of coronary artery occlusion (CAO) followed by 4 days of reperfusion. This resulted in IF/AAR of 42±5% in control pigs without IPC (n=5). Following repetitive CS, IF/AAR was markedly decreased (p&lt;0.05) (4±6%, n=4). The 2 nd window of IPC was induced in 5 pigs by two 10 min periods of CAO. 24 hrs later, the 60 min of CAO also resulted in reduced IF/AAR of 16±4%. In 6 pigs, 24 hrs after IPC without 60 min of CAO, the IPC myocardium was found to have significant, p&lt;0.05, 2– 4-fold increases in iNOS, Cox-2, phosphorylated PKC and AMPK. None of these proteins was elevated in myocardium subjected to repetitive CS. Pretreatment with an NO synthase inhibitor, L-NNA, prevented the 2 nd window of IPC as expected, since iNOS was elevated, but failed to prevent the ischemic protection following repetitive CS, where iNOS was not elevated. Following repetitive CS, genomic microarray analysis revealed upregulation of cytoprotective genes, e.g., IAP, H11 kinase, αB-crystallin, Akt 1, Bcl-2. These cytoprotective genes were also found to be upregulated in samples from patients with chronic coronary artery disease and hibernating myocardium. Thus, repetitive CS induces powerful protection against lethal myocardial ischemia, with mechanisms radically different from that observed in the 2 nd window of IPC, suggesting a novel “third window” of IPC, which could also be involved in the protection inherent to hibernating myocardium.

Transient myocardial dysfunction after smoke inhalation

Acute onset, transient (reversible) myocardial contraction abnormality has been described in patients with acute non-cardiac illness and after acute emotional stress. Such reversible myocardial contraction abnormalities may occur via mechanisms other than reduction in epicardial coronary blood flow. We report a case of acute transient cardiomyopathy after smoke exposure. The patient developed acute heart failure without evidence of carbon monoxide poisoning that resolved within 4 days. An association between brief smoke exposure without carbon monoxide poisoning and acute heart failure has not been previously described.

Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, p.o.) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, p.o.) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.

Reduction of coronary flow by non-invasive establishment of a coil in a coronary artery in pigs: a validation study

Reduction of coronary flow by non-invasive establishment of a coil in a coronary artery in pigs: a validation study

Impact of the Coronary Flow Reduction at Rest on Myocardial Perfusion and Functional Indices Derived from Myocardial Contrast and Strain Echocardiography

The severity of the coronary flow reduction that corresponds to myocardial perfusion and functional abnormalities remains unclear. We estimated the impact of various severities of flow-limiting coronary stenosis at rest on myocardial perfusion and functional indices from myocardial contrast echocardiography and tissue strain imaging and characterized the relationship between both the indices. Four levels of flow-limiting stenoses (slight, mild, moderate, severe) of the left circumflex coronary artery were examined in 10 open-chest dogs. In the left circumflex coronary artery area, plateau videointensity and time to plateau (TP) of the replenishment curve from myocardial contrast echocardiography were calculated for perfusion analysis, and peak systolic strain and postsystolic strain index (PSI) from tissue strain imaging were measured for functional analysis. Plateau videointensity and peak systolic strain tended to decrease with increased severity of stenosis, although these differences did not reach the level of statistical significance. TP and PSI were significantly increased in the context of moderate (>or=30-<50%) and severe (>or=50%) flow reduction when compared to baseline values (TP, moderate 1.69 +/- 0.20 and severe 1.77 +/- 0.25 vs baseline 0.93 +/- 0.17, P < .01, respectively; PSI, moderate 0.96 +/- 0.15 and severe 1.28 +/- 0.32 vs baseline 0.59 +/- 0.18, P < .05 and P < .01, respectively). Further, TP and PSI were positively correlated with flow reduction (r = 0.81 and r = 0.84, P < .0001, respectively), and PSI was positively correlated with TP (r = 0.72, P < .0001). In contrast to conventional indices, such as plateau videointensity and peak systolic strain, novel indices, such as TP and PSI, were both able to detect 30% or greater coronary flow reduction at rest.

Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

Chronic angina, a condition that impairs quality of life and is associated with decreased life expectancy, affects &6.4 million Americans.1 Current therapies that reduce angina frequency and nitrate consumption and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include drugs (nitrates, β-blockers, calcium antagonists), exercise conditioning, enhanced external counterpulsation, and coronary revascularization.1–3 Several new investigational drugs are being tested for the treatment of chronic angina.4–9 This review will focus on sustained-release ranolazine, a drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.8–29 Ranolazine was approved on January 27, 2006, in the United States for use in patients with chronic angina who continue to be symptomatic on β-blockers, calcium antagonists, or nitrates. Ranolazine ([(+) N -(2,6-dimethylphenyl)-4(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-1-piperazine acetamide dihydrochloride]) is an active piperazine derivative that was patented in 1986 and is available in an oral and intravenous form (Figure 1). The immediate-release ranolazine (not in current use) had an average terminal elimination half-life ranging from 1.4 to 1.9 hours and a 10-fold peak/trough difference with dosing of 240 to 400 mg 3 times per day.19 Early studies with immediate-release ranolazine provided evidence of antiischemic/antianginal properties in patients with chronic angina without clinically significant changes in heart rate or blood pressure and are reviewed elsewhere.20–24 Unless otherwise stated, the remainder of this review refers to sustained-release ranolazine. Figure 1. Chemical structure and metabolism of ranolazine. Reprinted with permission from J Clin Pharmacol . 2005;45:422–433.17 Ranolazine (Ranexa; CV Therapeutics Inc, Palo Alto, Calif) is manufactured in a sustained-release form that has a prolonged absorption phase with maximal plasma concentrations (Cmax) typically seen 4 to 6 hours after administration. The average terminal elimination half-life is &7 hours after multiple dosing to steady state, and the …

Pharmacological Management of No Reflow During Percutaneous Coronary Intervention

Angiographic no reflow is a recognized phenomenon during percutaneous coronary intervention (PCI). It usually follows successful lesion dilation and, by definition, it represents a reduction in epicardial coronary blood flow in the absence of identifiable dissection, obstruction or distal vessel cut off (indicative of distal embolisation). No reflow appears to be more commonly associated with PCI for acute myocardial infarction and PCI for saphenous vein graft occlusions. While the exact mechanism of no reflow is unknown, theoretical causes include local humoral and microembolic effects leading to microcirculatory dysfunction. As the process is multifactorial, various therapeutic strategies are required in different situations. The present day pharmacological management involves the use of vasodilators including nitrates, verapamil, papaverine, adenosine, nicardipine and sodium nitroprusside, but interestingly a vasoconstrictor like epinephrine may also have a role. Glycoprotein IIb/IIIa platelet receptors antagonist have shown a powerful de-thrombotic effect, and the intracoronary administration appears to be particularly promising. We review the pathogenesis of a reduced epicardial flow during PCI and focus on those drugs that have been studied for the treatment of no reflow. Although no double blind, randomized trial has been conducted to assess any of these agents, or to determine the appropriate dosage, we try to identify some useful conclusions from the published evidence.

Sildenafil Improves Coronary Artery Patency in a Canine Model of Platelet-Mediated Cyclic Coronary Occlusion After Thrombolysis

We sought to assess the effect of sildenafil, a highly-specific type 5 phosphodiesterase (PDE5) inhibitor, on platelet-mediated cyclic coronary flow reductions occurring in a canine model of coronary thrombosis despite aspirin therapy. The PDE5 inhibitors augment the antithrombotic effects of nitric oxide in vitro and in vivo, but it has been proposed that the PDE5 inhibitor sildenafil is prothrombotic. Cyclic coronary flow reductions were induced in the left anterior descending coronary artery by creation of a stenosis, endothelial injury, and thrombus formation followed by treatment with aspirin, heparin, and tissue plasminogen activator. After an initial observation period, dogs were treated with or without sildenafil (100 microg/kg bolus followed by 4 microg/kg/min infusion). Cyclic coronary flow reductions ceased in five of six animals 18 +/- 5 min after initiation of sildenafil but continued in all six control animals. The portion of the observation period during which the coronary artery was patent increased from 52 +/- 9% to 83 +/- 5% after sildenafil administration (p = 0.008) but did not differ between the first and second observation periods in untreated dogs (49 +/- 11% vs. 44 +/- 11%, respectively). Among animals with plasma free sildenafil levels > or =20 nmol/l, cyclic coronary flow reductions were 73 +/- 12% less frequent and the time to cessation of cycling 72 +/- 14% shorter than in animals with levels <20 nmol/l (p < 0.05 for both). Sildenafil transiently decreased blood pressure 7 +/- 1% but did not change heart rate. Sildenafil treatment reduced ex vivo thrombin-induced platelet aggregation by 39 +/- 3% (p < 0.005). Sildenafil improves coronary patency in a canine model of platelet-mediated coronary artery thrombosis, likely via inhibition of platelet aggregation.