Coronary Vascular Bed Research Articles

Noninvasive imaging of atheromatous carotid plaques

Atherothrombosis is a systemic disease of the arterial wall that affects the carotid, coronary, and peripheral vascular beds, and the aorta. This condition is associated with complications such as stroke, myocardial infarction, and peripheral vascular disease, which usually result from unstable atheromatous plaques. The study of atheromatous plaques can provide useful information about the natural history and progression of the disease, and aid in the selection of appropriate treatment. Plaque imaging can be crucial in achieving this goal. In this Review, we focus on the various noninvasive imaging techniques that are being used for morphological and functional assessment of carotid atheromatous plaques in the clinical setting.

The Suppression of Proinflammatory Cytokines Improves Heart Function From Non-Heart-Beating Donors Following Transplantation in a Canine Model

We evaluated the effectiveness of a suppressant of the production of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha on a canine heart transplantation model with non-heart-beating donors (NHBDs).Adult mongrel dogs were divided into 3 groups of 5: a control group; FR-1 in which donors were given FR167653, a potent suppressant of IL-1beta and TNF-alpha production; and FR-2 in which both donors and recipients were given FR167653. After measuring the baseline hemodynamic parameters, including cardiac output (CO), left ventricular pressure (LVP), and maximum and minimum rates of increase in LVP (+/- LVdp/dt), FR167653 was administered continuously for 30 minutes before ischemia in the FR-1 and FR-2 groups. Cardiac arrest was obtained by rapid exsanguination from the abdominal aorta and inferior vena cava. The organ was left in the cadaver for 30 minutes. The coronary vascular beds were washed out with 4 degrees C Celsior solution, and then the donor heart was preserved in 4 degrees C Celsior solution for 4 hours. The donor heart was transplanted orthotopically with cardiopulmonary bypass (CPB). FR167653 was administered intravenously from 15 minutes before aortic-cross clamping until the end of the experiment in the FR-2 group. The recipient was weaned from CPB 1 hour after reperfusion. We compared the hemodynamic parameters at 3 hours after reperfusion with the preoperative values in donor animals with the right atrial pressure at 10 mmHg and a 5 microg/kg/min dopamine infusion. Histopathological analysis was also performed.There were no significant differences in the recovery rates of the hemodynamic parameters between the control and FR-1 groups and between the FR-1 and FR-2 groups. However, the recovery rates of CO and -LVdp/dt in the FR-2 group were significantly (P < 0.05) higher than those in the control group. Histopathological analysis showed that myofilaments were better preserved in the FR-2 group compared with the control group.The administration of a suppressant of proinflammatory cytokines before both ischemia and reperfusion effectively preserves donor heart function after transplantation with NHBDs.

Role of oxidative and nitrosative stress biomarkers in chronic heart failure

In this review, we present recent insights on chronic heart failure (CHF) and the potential role of tumor necrosis factor (TNF)-alpha, interleukins, myeloperoxidase (MPO), and nitrosative stress in the progression of this disease process. Reactive oxygen species (ROS) are produced as a consequence of aerobic metabolism. Under physiologic conditions, their unfavourable effect in causing oxidative damage is counteracted by antioxidants. An imbalance in favour of oxidants leads to oxidative stress, and contributes to myocyte apoptosis, direct negative inotropic effects, and reduced bioavailability of nitric oxide (NO). Together, these effects lead to impaired vasodilatation of the coronary, pulmonary and peripheral vascular beds. In patients with moderate to severe forms of CHF, TNF-alpha leads to the formation of nitrotyrosine and consumption of nitric oxide by virtue of activation of myeloperoxidase. Further studies are required to better elucidate the complex interaction of oxidative stress, endothelial dysfunction and inflammatory activation in CHF. Such insights would likely lead to development of better strategies for the assessment of the disease severity by monitoring of new bio-humoral indices and better treatment approaches.

Contrasting effect of exercise and angiotensin II hypertension on in vivo and in vitro cardiac angiogenesis in rats

Cardiac vessel density (beta-actin immunolabeling) and angiogenic capacity of coronary artery explants (culture in collagen gel) was determined in hypertrophied heart obtained by exercise training (10 wk) or ANG II infusion for 10 days. A group of rats received ANG II the last 10 days of training. The heart weight index was similarly elevated after exercise, and ANG II-hypertension compared with controls (3.16 +/- 0.09 and 3.11 +/- 0.11 vs. 2.68 +/- 0.08 mg/g, respectively), whereas tail cuff pressure (TCP) increased only in sedentary rats infused with ANG II. Vessel density was increased by 36% in trained rats and reduced by 30% in ANG II-infused rats. The number of sprouts generated by coronary rings was reduced by 50% in ANG II-infused rats and increased by 50% in exercise trained rats compared with controls (35 +/- 4 and 113 +/- 5 vs. 71 +/- 1 sprouts per ring, respectively). Exercise-training partly prevented the hypertensive effect of ANG II (TCP of 141 +/- 5 mmHg), whereas heart weight index (3.66 +/- 0.06 mg/g body wt) was not lowered. Myocardial vessel density was normalized, and sprouting from coronary rings increased by 50% in trained rats infused with ANG II compared with sedentary normotensive rats. Cardiac VEGF (Western blot analysis) was higher in hypertensive rats and not affected by exercise. Facing a similar increase in cardiac mass, intense training, but not ANG II hypertension, is accompanied by an increase in vascular density of the heart. The effect of training is unlikely related to changes in resting VEGF and may represent enhanced angiogenic capacity of the coronary vascular bed.

Rebuttal from Drs. Thijssen and Hopman

POINT-COUNTERPOINTRebuttal from Drs. Thijssen and HopmanPublished Online:01 Sep 2008https://doi.org/10.1152/japplphysiol.90570.2008cMoreSectionsPDF (33 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Reading through Drs. Green, Maiorana, and Cable's argument, we hit on another of Oscar Wilde's wisdoms: “The truth is rarely pure and never simple.”In a series of experiments, Dr. Green and colleagues demonstrated that typical changes in shear pattern, characterized by an increase in retrograde flow, are linked with endothelial NO release in the nonactive regions (4). Although it might be tempting to relate vascular adaptation in inactive regions to alterations in shear pattern, we believe that the truth is not that simple. In nonactive vascular beds during exercise, an enhanced release of vasoconstrictors is present, such as endothelin-1 (5), angiotensin II (7), and vasopressin (8). The actions of these local vasoconstrictors, combined with enhanced activity of the sympathetic nervous system (2), likely outweigh the beneficial effects of NO.The role for shear rate in exercise-induced vascular adaptations is well recognized, but shear rate is not the only factor involved; unfortunately the truth is never simple. Hypoxia, through release of growth factors such as VEGF, importantly contributes to exercise-induced vascular adaptations (6). Notably, hypoxia and VEGF also contribute to the release and homing of circulating bone marrow-derived endothelial progenitor cells (1). These progenitor cells predict the occurrence of cardiovascular events and death (9), possibly through their capability for endothelial repair, arteriogenesis, and angiogenesis. Appreciating a key role for hypoxia in exercise-induced vascular adaptations casts doubt on vascular adaptations in nonactive muscles during exercise where this essential physiological stimulus is absent (3).Interestingly, blood flow and related shear patterns vary markedly among different locations and sizes of arteries at rest and during exercise. The prominent retrograde component in the nonactive brachial artery blood flow pattern is hypothesized to result from an increased downstream vasoconstriction (4). In contrast, arteries supplying highly metabolic tissues (i.e., heart and legs) have marked vasodilation and will therefore not demonstrate this blood flow pattern. Therefore, one may question whether findings in the brachial artery during leg exercise can be extrapolated to the coronary vascular bed, since shear rate as well as other physiological stimuli will be markedly different.Taken together, the central question in this discussion is which stimuli are obligatory, either alone or in combination with others, to result in exercise-induced vascular adaptations in the active and nonactive regions. We enjoyed discussing this topic and hope we presented our arguments in line with Oscar Wilde's “One should always play fairly when one has the winning cards.”REFERENCES1 Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967, 1997.Crossref | PubMed | ISI | Google Scholar2 Buckwalter JB, Clifford PS. The paradox of sympathetic vasoconstriction in exercising skeletal muscle. Exerc Sport Sci Rev 29: 159–163, 2001.Crossref | PubMed | Google Scholar3 Calbet JA, Gonzalez-Alonso J, Helge JW, Sondergaard H, Munch-Andersen T, Boushel R, Saltin B. Cardiac output and leg and arm blood flow during incremental exercise to exhaustion on the cycle ergometer. J Appl Physiol 103: 969–978, 2007.Link | ISI | Google Scholar4 Green DJ, Bilsborough W, Naylor LH, Reed C, Wright J, O'Driscoll G, Walsh JH. Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide. J Physiol 562: 617–628, 2005.Crossref | PubMed | ISI | Google Scholar5 Maeda S, Miyauchi T, Sakane M, Saito M, Maki S, Goto K, Matsuda M. Does endothelin-1 participate in the exercise-induced changes of blood flow distribution of muscles in humans? J Appl Physiol 82: 1107–1111, 1997.Link | ISI | Google Scholar6 Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training? J Appl Physiol 97: 1119–1128, 2004.Link | ISI | Google Scholar7 Stebbins CL, Symons JD. Role of angiotensin II in hemodynamic responses to dynamic exercise in miniswine. J Appl Physiol 78: 185–190, 1995.Link | ISI | Google Scholar8 Stebbins CL, Symons JD. Vasopressin contributes to the cardiovascular response to dynamic exercise. Am J Physiol Heart Circ Physiol 264: H1701–H1707, 1993.Link | ISI | Google Scholar9 Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. New Engl J Med 353: 999–1007, 2005.Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 105Issue 3September 2008Pages 1007-1007 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.90570.2008cHistory Published online 1 September 2008 Published in print 1 September 2008 Metrics

Effects of angiotensin II and its metabolites in the rat coronary vascular bed: Is angiotensin III the preferred ligand of the angiotensin AT 2 receptor?

Aminopeptidases metabolize angiotensin II to angiotensin-(2–8) (= angiotensin III) and angiotensin-(3–8) (= angiotensin IV), and carboxypeptidases generate angiotensin-(1–7) from angiotensin I and II. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 (AT 1) receptor blockers affect the concentrations of these metabolites, and they may thus contribute to the beneficial effects of these drugs, possibly through stimulation of non-classical angiotensin AT receptors. Here, we investigated the effects of angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1–7) in the rat coronary vascular bed, with or without angiotensin AT 1 — or angiotensin II type 2 (AT 2) receptor blockade. Results were compared to those in rat iliac arteries and abdominal aortas. Angiotensin II, angiotensin III and angiotensin IV constricted coronary arteries via angiotensin AT 1 receptor stimulation, angiotensin III and angiotensin IV being ≈ 20- and ≈ 8000-fold less potent than angiotensin II. The angiotensin AT 2 receptor antagonist PD123319 greatly enhanced the constrictor effects of angiotensin III, starting at angiotensin III concentrations in the low nanomolar range. PD123319 enhanced the angiotensin II-induced constriction at submicromolar angiotensin II concentrations only. Angiotensin-(1–7) exerted no effects in the coronary circulation, although, at micromolar concentrations, it blocked angiotensin AT 1 receptor-induced constriction. Angiotensin AT 2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of the angiotensin metabolites in these vessels were identical to those in the coronary vascular bed. In conclusion, angiotensin AT 2 receptor activation in the rat coronary vascular bed results in vasodilation, and angiotensin III rather than angiotensin II is the preferred endogenous agonist of these receptors. Angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1–7) do not exert effects through non-classical angiotensin AT receptors in the rat coronary vascular bed, iliac artery or aorta.

Demonstration of aortocoronary venous bypasses using digital subtraction angiography

In 43 patients with a total of 86 aortocoronary bypass grafts digital subtraction angiography was employed in the early post-operative period. Contrast injection into the aortic root allowed in all instances a definitive answer whether the aortocoronary bypass was free or obstructed. The method makes it possible also to assess distal anastomoses and their connected coronary vascular bed.

Distal Embolic Protection for Renal Arterial Interventions

Distal or embolic protection has intuitive appeal for its potential to prevent embolization of materials generated during interventional procedures. Distal protection devices (DPDs) have been most widely used in the coronary and carotid vascular beds, where they have demonstrated the ability to trap embolic materials and, in some cases, to reduce complications. Given the frequency of chronic kidney disease in patients with renal artery stenosis undergoing stent placement, it is reasonable to propose that these devices may play an important role in limiting distal embolization in the renal vasculature. Careful review of the literature reveals that atheroembolization does occur during renal arterial interventions, although it often goes undetected. Early experience with DPDs in the renal arteries in patients with suitable anatomy suggests retrieval of embolic materials in approximately 71% of cases and renal functional improvement/stabilization in 98% of cases. The combination of platelet inhibition and a DPD may provide even greater benefit. Given the critical importance of renal functional preservation, it follows that everything that can be done to prevent atheroembolism should be undertaken including the use of DPDs when anatomically feasible. The data available at this time support a beneficial role for these devices.

NO metabolite flux across the human coronary circulation

The theory of a red blood cell derived nitric oxide (NO) reserve conserving NO bioactivity and delivering NO as a function of oxygen demand has been the subject of much interest. We identified the human coronary circulation as an ideal model system in which to analyse NO metabolites because of its large physiological oxygen gradient. Our objective was to identify whether oxygen drove apportion between various NO metabolite species across a single vascular bed. Plasma and red blood cell NO metabolites were assessed from the left main coronary artery, coronary sinus and pulmonary artery (providing cross heart and cross pulmonary analysis) of healthy subjects under resting conditions and following administration of an inhibitor of NO biosynthesis. Physiological parameters and angiographic data were monitored throughout the study. Under baseline conditions we observed significant metabolite flux upon the transit of blood across the coronary and pulmonary vascular beds. Whilst there was no net loss of NO through the coronary circulation (p=0.0759), plasma nitrite/protein NO (excluding nitrate) (p=0.0279) and red blood cell sulphanilamide labile signal (p=0.0143) decreased whereas haemoglobin-bound NO increased three-fold (p=0.005). These changes across the coronary circulation were reversed through the pulmonary circuit with red blood cell sulphanilamide labile signal (p=0.0143) and plasma nitrite/protein NO (p=0.0279) increasing and haemoglobin-bound NO decreasing. Blockade of NO synthesis increased mean arterial blood pressure (p<0.01) and reduced coronary artery diameter (p<0.05), however we observed similar apportion of NO metabolites across the heart and lung with no net loss or gain in total NO metabolites. For the first time in human subjects across the resting coronary circulation we reveal significant re-apportionment of NO between metabolite species which correlate with haemoglobin oxygen saturation. These changes occur even within the transit time of blood across this single vascular bed. We demonstrate no net loss/gain of NO from the total metabolite pool across the coronary circulation even where NO biosynthesis is inhibited.

Association between Systemic Calcified Atherosclerosis and Bone Density

Both atherosclerosis and osteoporosis are responsible for significant morbidity and mortality, are independent predictors of cardiovascular disease (CVD) events, and may share common regulatory mechanisms as well as histopathology. Multiple reports of weak or null relationships between traditional CVD risk factors and calcified atherosclerosis have heightened interest in novel predictors of arterial calcium. One such hypothesis is for an inverse relationship between bone mineral density (BMD) and calcified coronary atherosclerosis. Although contrary findings have been reported, the majority of cross-sectional and all prospective studies have demonstrated a significant inverse association between arterial calcium deposits and BMD. The few studies that include men are equivocal, and, to date, no study has investigated the relationship between BMD and systemic arterial calcium. The aim of this study was to test the hypothesis that lumbar BMD is significantly associated with the presence of arterial atherosclerotic calcium in the carotid, coronary, and iliac vascular beds as well as the aorta.

Can we use surrogate vascular beds for evaluating endothelial function of the coronary vasculature in patients with cardiac allografts?

a landmark study in vascular biology almost 30 years ago described the essential role of the endothelium as a mediator of vasodilator response to acetylcholine ([4][1]). Since then many studies have been performed in an effort to understand this complex organ. Endothelial function plays a pivotal

Dynamics and Source of Endothelin-1 and Interleukin-6 Following Coronary Reperfusion in Patients with Acute Myocardial Infarction

The goals of this study were to determine the source of circulating endothelin-1 (ET-1) and interleukin-6 (IL-6) in acute myocardial infarction (MI) and to study the effects of coronary reperfusion (CR) on plasma levels of ET-1 and IL-6. We serially measured plasma concentrations of ET-1 and IL-6 at different sampling sites before and after CR in patients with acute MI. A femoral vein (FV) catheter, a Swan-Ganz catheter, and a femoral artery (FA) catheter were placed in 25 patients with acute MI who were admitted within 12 hours after onset. For the measurement of ET-1 and IL-6 concentrations, blood samples from the FV, right atrium (RA), pulmonary artery (PA), and FA were collected before and 1 hour, 8 hours, and 24 hours after CR therapy. In 5 of the 25 patients, blood samples were collected through a coronary sinus (CS) catheter. We also assessed the gradient across 3 vascular beds (systemic, pulmonary, and coronary) as indices of the net release of ET-1 and IL-6 from those vascular beds. The maximal serum creatine kinase (CK) levels were assessed as an index of myocardial necrosis. ET-1 levels were higher in the FV than in the RA, PA, or FA. On CR, ET-1 levels peaked after 1 hour and returned to baseline by 24 hours. Calculated net release of ET-1 from the systemic vascular bed (ET-1 at FV-ET-1 at FA) was the highest among the 3 vascular beds. Plasma ET-1 levels correlated with hemodynamic parameters. Plasma IL-6 levels were similar among different sampling sites, whereas calculated net release of IL-6 from the coronary vascular bed was the highest among the 3 vascular beds. IL-6 levels increased throughout 24 hours after coronary reperfusion and closely correlated with maximal CK levels. The present study suggests that, in acute MI, the major source of ET-1 maintaining baseline plasma levels is the systemic vascular bed and that the ET-1 levels presumably reflect the congestion. ET-1 levels peaked 1 hour after CR. IL-6 increased for 24 hours after CR. The major source of IL-6 is the coronary vascular bed. Only a slight correlation was observed between plasma ET-1 and IL-6 levels.

Intermedin (IMD/AM2) dilates the pig coronary vascular bed through release of nitric oxide

The present study was designed to investigate the effects of IMD/AM2 (IMD), an endogenous agonist for calcitonin-like calcitonin receptors (CLCR), on coronary and systemic hemodynamics. Ultrasonic transit time flow probes were placed around the left anterior descending artery in the anesthetized, open-chest pig. Intracoronary arterial bolus injections (IAB) of IMD, hADM13–52 and CGRP increased coronary blood flow in a dose-dependent manner. IMD at the doses studied was more potent than CGRP and hADM13–52 and did not alter systemic arterial pressure, cardiac output and cardiac index. IAB of L-NAME significantly decreased the coronary vasodilatory response (CVR) to IMD. The present data suggest that IMD possesses marked vasodilator activity in the pig coronary vascular bed. The present data further suggest the CVR to IMD in the pig is mediated by release of nitric oxide from endothelial CLCR. The degree of the CVR to IMD may serve as functional marker for the integrity of endothelial cells in resistance segments of the coronary circulation. This study was supported by Gulhane Military School of Medicine (# AR-2006-20).

Relation between transcardiac gradient of VEGF and coronary flow response in humans

Background Angiogenic growth factors, produced in the myocardium and coronary vascular bed, increase myocardial blood flow. This study examined whether plasma levels of vascular endothelial growth factor (VEGF) in coronary circulation may be related to coronary blood flow responses. Methods Blood flow responses in the left anterior descending coronary artery to an intracoronary infusion of acetylcholine (ACh) were measured by an intracoronary flow wire technique in 46 consecutive control subjects with normal coronary angiograms and left ventriculograms. Circulating VEGF levels were measured by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV). Results The transcardiac gradient of VEGF, calculated by the difference in VEGF concentrations between the AIV and AO, showed a positive correlation with the coronary blood flow increase in response to ACh independently of traditional coronary risk factors. In patients with cardiac syndrome X ( n = 17), defined as a positive exercise stress test with a normal coronary angiograms and left ventriculogram, the transcardiac VEGF gradient was significantly lower than in the risk factors-matched control subjects ( n = 21). Conclusions The transcardiac gradient of plasma VEGF was independently and positively correlated with the coronary blood flow increase in response to ACh. A reduced transcardiac VEGF gradient was present in cardiac syndrome X, a condition with a blunted coronary blood flow response.

Pathophysiology of peripheral arterial disease and risk factors for its development.

Peripheral arterial disease (PAD) is a systemic atherosclerotic process for which the major risk factors are similar to those for atherosclerosis in the carotid, coronary, and other vascular beds. Among the traditional risk factors for PAD, those with the strongest associations are advanced age, smoking, and diabetes mellitus. More recently, a number of nontraditional risk factors for PAD have also been recognized. This article briefly reviews the pathophysiology of PAD and the evidence supporting established and emerging risk factors for its development.

Atherothrombosis at a distance: Contributing role of existing large-burden vascular disease, circulating biosignals and modulating extravascular tissues

The development of coronary atherothrombosis among patients with inflammatory disorders that includes rheumatoid arthritis and the metabolic syndrome, raises important questions concerning contributing mechanisms, vascular bed specificity and predisposition, and the modulation of proinflammatory and prothrombotic stimuli. Similarly, a well-described relationship between atherosclerosis of the abdominal aorta and coronary vascular events, including myocardial infarction and cardiovascular death prompts one to consider the coronary vascular bed as possibly representing a common btarget organ.Q The following review presents a construct of systemic signalling from existing sites of atherothrombosis, which defines coronary atherothrombosis as not merely a coexisting component of multibed vascular disease, but rather the endresult of a thromboinflammatory state originating at remote vascular sites. Because the aorta is the body’s largest vascular structure, an early site of

Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans

Adiponectin, an adipocyte-derived protein, has been shown to have vasculoprotective effects. This study examined the possible relationship between coronary vasomotor function and the transcardiac gradient of adiponectin, reflecting adiponectin utilization and/or accumulation in the coronary vascular bed. The epicardial diameter and blood flow response of the left anterior descending coronary artery to intracoronary infusions of ACh was analyzed in 108 consecutive subjects who had a normal coronary angiogram and left ventriculogram. Adiponectin levels were measured by ELISA in plasma obtained from the aortic root (Ao) and the anterior interventricular vein (AIV). Adiponectin levels in the AIV were lower than levels in the Ao. In multivariate linear regression analysis, the transcardiac gradient of adiponectin (Ao - AIV levels) showed a positive correlation with increases in epicardial coronary diameter and coronary blood flow in response to ACh that was independent of traditional coronary risk factors. The transcardiac gradient of adiponectin was not significantly associated with the coronary dilator response to isosorbide dinitrate and the coronary flow response to sodium nitroprusside. In other groups of patients with coronary spastic angina (n = 41) or microvascular angina (n = 32) who had impaired coronary vasomotor responses, there was no significant gradient of adiponectin between the Ao and AIV. The transcardiac gradient of adiponectin may modulate endothelial vasomotor function in large and resistance coronary arteries and may play a role in the pathogenesis of diseases presenting with coronary vasomotor dysfunction.

Is the Fetal Heart a Hematopoietic Organ?

To the Editor: The article by Tomanek et al1 presents well the in vivo data on the requirement of VEGF family members for tubulogenesis and coronary artery formation. The authors observed that VEGF-Trap (a chimera of R1 and R2), apart from precluding formation of coronary arteries, causes a massive accumulation of erythrocytes in the subepicardium and in the interventricular septum. The important finding of this study was that erythrocytes that are components of blood islands derive from epicardial-derived precursors. The authors assume that proepicardial cells include a hemangioblast population. From this observation a conclusion can be drawn that either the proepicardium or the fetal heart exhibits a hematopoietic activity. Considering the topic of blood island derivation in the embryonic heart I would like to comment that although the derivation of the endothelial cell component in these structures has been proven, the origin of erythrocytes is …

Inhibition of Cyclooxygenase-2 Improves Cardiac Function Following Long-Term Preservation

Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid to prostaglandin endoperoxide (PGG(2)). There are two isoforms of COX, namely constitutive COX-1 and inducible COX-2. It has been reported that COX-2 plays an important role in ischemia-reperfusion injury and that COX-2 mRNA and protein expression were up-regulated during cardiac allograft rejection. FK3311 is a suppressor of COX-2 activation. The purpose of this study was to evaluate the effectiveness of inhibiting COX-2 with FK3311 for the minimization of ischemia-reperfusion injury and for the improvement of donor heart function following transplantation in a canine model. Adult mongrel dogs were used. After the measurement of hemodynamic parameters [cardiac output (CO), left ventricular pressure (LVP), and the maximum rates of increase and decrease in LVP (+/-LVdp/dt)], coronary vascular beds were washed out with a hypothermic (4 degrees C) University of Wisconsin (UW) solution following cardiac arrest in response to cold (4 degrees C) glucose-insulin-potassium solution. The heart was then excised and preserved in hypothermic (4 degrees C) UW solution for 12 h. FK3311 (3 mg/kg) was administered intravenously to five dogs prior to reperfusion, while vehicle was administered intravenously to a control group (n = 5). After 3 h of orthotopic transplantation using cardiopulmonary bypass, the hemodynamic parameters were compared with preoperative values of the donor animals under the condition of 10 mm Hg right atrial pressure and 5 mug/kg/min dopamine support. The recovery rates of CO and +/-LVdP/dt were significantly (P < 0.05) higher in the FK-treated dogs than in the controls (CO: 93 +/- 6 versus 66% +/- 4%; +LVdp/dt: 125 +/- 8 versus 77 +/- 10%; and -LVdp/dt: 81 +/- 7 versus 52 +/- 6%; for FK-treated versus control dogs, respectively). The recovery rate of LVP was higher in the FK-treated dogs than in the controls (90 +/- 5 versus 72 +/- 5%), but this difference was not statistically significant. Immunohistochemical staining revealed that COX-2 expression was reduced significantly in the myocardium of FK-treated dogs compared with controls. Hemodynamic parameters following transplantation were improved significantly in dogs treated with FK3311. Therefore, the inhibition of COX-2 improves transplanted cardiac function following long-term preservation.

Degradation of bradykinin, a cardioprotective substance, during a single passage through isolated rat-heart

Angiotensin converting enzyme (ACE) inhibitors have cardioprotective effects in different species including human. This cardioprotective effect is mainly due to the inhibition of bradykinin (BK) degradation rather than inhibition of the conversion of angiotensin I to angiotensin II. Bradykinin, a nonapeptide, has been considered to be the potential target for various enzymes including ACE, neutral endopeptidase 24.11, carboxypeptidase M, carboxypeptidase N, proline aminopeptidase, endopeptidase 24.15, and meprin. In the present study, the coronary vascular beds of Sprague Dawley rat isolated hearts were perfused (single passage) with Krebs solution alone or with different concentrations of BK i.e. 2.75x10(-10), 10(-7), 10(-6) and 10(-5) M solution. Percent degradation of BK was determined by radioimmunoassay. The degradation products of BK after passing through the isolated rat-hearts were determined using RP-HPLC and mass spectroscopy. All the four doses of BK significantly decreased the perfusion pressure during their passage through the hearts. The percentage degradation of all four doses was decreased as the concentration of drug was increased, implying saturation of a fixed number of active sites involved in BK degradation. Bradykinin during a single passage through the hearts degraded to give [1-7]-BK as the major metabolite, and [1-8]-BK as a minor metabolite, detected on HPLC. Mass spectroscopy not only confirmed the presence of these two metabolites but also detected traces of [1-5]-BK and arginine. These findings showed that primarily ACE is the major cardiac enzyme involved in the degradation of bradykinin during a single passage through the coronary vascular of bed the healthy rat heart, while carboxypeptidase M may have a minor role.