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Sex dependent differences in coronary artery vasoregulation may be due to variations in responses to endogenous vasoactive compounds including endothelin (ET-1) and nitric oxide (NO).Septal coronary arteries (200 μm) from healthy, sexually mature male, female and ovariectomized (i.e. surgical menopause) Sprague-Dawley rats were used. Myogenic tone, measured by pressure myography, was initially determined for all vessel segments studied before and after exposure to the nonselective ETMyogenic tone was 26 ± 7% in male, 20 ± 7% in female (p = 0.04 versus male) and 24 ± 3% in ovariectomized (p = NS versus male/female) vessels. Antagonism of ET-1 receptors produced a greater reduction in myogenic tone in male, compared to female rats over a similar range of intraluminal pressure (20-80 mmHg). Robust constrictor responses to cumulative concentrations of ET-1 were observed in all vessels; however, male rats exhibited greater sensitivity to vasoconstrictor effects of ET-1. After exposure to L-NAME vessel responses to ET-1 were normalized in male and female (not studied in ovariectomized) groups.These findings confirm marked sex differences for myogenic tone and vessel constrictor responses to ET-1 in coronary resistance vessels. Results also suggest greater sensitivity to vasoconstrictor effects of ET-1 in male coronary resistance vessels.

Background: Myocardial ischemia is a dynamic process whereby a cascade of events is initiated to stimulate transition from reversible to irreversible cellular injury. Non-pharmacologic approaches to cellular protection, such as ischemic conditioning, delay onset of cellular injury in most organs in a host of animal species; however the degree of protection is limited to rather short durations of ischemia. In the present study, we examined whether protection afforded by ischemic conditioning could be extended beyond currently established limits of coronary occlusion in an in situ animal model. Methods: Rabbits (n = 106) were exposed to 30-, 60-, 120-, 180-, 240-, or 360-min coronary occlusion followed by 180-min coronary reperfusion (i.e. non-conditioned control groups). Ischemic conditioned rabbits were pre-treated by ischemic conditioning (i.e. 2-cycles of 5-min coronary occlusion and 5-min reperfusion) prior to a prolonged period of ischemia as described above. Area at risk (AR; by fluorescent microparticles) and area of necrosis (AN; by tetrazolium staining) were quantified by planimetry. Serum troponin I levels were assessed at baseline (i.e. before experimental protocol) and at the end of the experiment. Results: Changes in heart rate and hemodyamic indices were similar for all groups regardless of duration of ischemia and regardless of treatment (i.e. non-conditioned vs. ischemic conditioned). Infarcts (as percent AR) were markedly smaller (~35%) in ischemic conditioned rabbits (vs. controls) for the 30-min coronary occlusion group. With longer durations of coronary occlusion (60-, 120-, 180-, 240-min) infarcts were smaller (~20%) in ischemic conditioned groups but protection afforded was not statistically significant. With 360-min coronary occlusion, infarct size was the same for both treatment groups. Serum troponin I levels were greater in relation to infarct size as expected but no differences were detected between treatments regardless of ischemic duration. Conclusions: Ischemic conditioning limits infarct development; however, protection is limited when the duration of ischemia is extended beyond 4 hours. These findings provide further support for the concept that ischemic conditioning can delay, but does not limit myocyte necrosis. Underlying mechanisms for cellular protection remain to be established.

Acute myocardial infarction initiates a cascade of events including loss of protein homeostasis and chronic inflammation that affect overall cellular repair and senescence. This contributes to loss of cardiomyocytes and consequent formation of fibrotic scar. In certain vertebrate species, the heart can completely self-repair or regenerate after myocardial injury; however, this does not appear to be the case for humans. Despite this limitation, studies using novel non-pharmacologic interventions designed to protect against ischemic damage and to improve patient outcomes are ongoing. Remote ischemic conditioning stratagems are used to attenuate ischemia-reperfusion injury in clinical and animal studies; endogenous protective factors that stimulate complex signal transduction pathways are deemed responsible. Some of these factors could conceivably act in concert with those involved in regulating cardiovascular regeneration. Numerous studies have focused on cardiac regenerative interventions using stem-cell based therapies and transplantation of cardiomyocyte (or other cell types) or biocompatible matrices. This review discusses recent progress of pre-clinical and clinical translational studies for cardiac regeneration. In addition, we submit that interventions using cellular adjunctive therapies combined with remote ischemic conditioning may prove to be of interest in the battle to find novel strategies for protection against cardiac injury.

Diffuse coronary artery injury produces a host of physiopathological, structural and metabolic changes in cardiocytes that, if not rectified, result in significant loss of functional myocardium to cause cardiac contractile dysfunction. Restoration of blood perfusion to the infarct-related artery helps to limit the acute effects of myocardial infarction; however, cardiocyte injury may be exacerbated because of the restoration of blood perfusion to the ischemic zone (i.e. reperfusion injury). Various manifestations of reperfusion injury include no-reflow, myocardial stunning or hibernation and ventricular arrhythmias. Consequently, reperfusion of an infarct related artery is often viewed in the context of being a “double-edged sword.” Pharmacologic and non-pharmacologic interventions have been investigated in pre-clinical and clinical studies in the hunt to develop strategies to protect cardiomyocytes against the long-term effects of ischemia, or delay development of necrosis (resulting from ischemia or reperfusion). This book chapter will update current thinking on cardioprotective strategies to improve clinical outcomes in patients with coronary artery disease.

Postischemic accumulation of intracellular Na+ promotes calcium overload and contributes to cellular necrosis. Cardioprotection afforded by pharmacologic blockade of the sodium-hydrogen exchanger subtype 1 (NHE1) is thought to be more remarkable than that obtained by ischemic conditioning (IC). The window of protection provided by IC pretreatment is maintained even when performed up to 48 hours before ischemia. In addition, the perception exists that combined NHE1 inhibition plus IC produces greater than additive protection against ischemic injury. The current study compared the efficacy of NHE1 blockade by N-[2-methyl-4,5-bis(methylsulfonyl)-benzoyl]-guanidine (EMD 87580 5 mg/kg) combined with first- or second-window IC on ischemic tolerance in dogs subject to 90-minute acute ischemia and 180-minute reperfusion. Infarct size (tetrazolium staining), vascular responses, and myocardial perfusion (microspheres) were assessed. EMD 87580 given before ischemia or before reperfusion did not reduce infarct size (compared to vehicle-treated group). Significant protection against tissue necrosis was obtained by both first- and second-window IC, but additive cardioprotection (ie, greater than that afforded by IC) was not observed by treatment with EMD 87580. Vascular reactivity in the infarct-related artery was not preserved after ischemia-reperfusion in any of the experimental groups. Likewise, either the pharmacologic or the nonpharmacologic interventions did not modify myocardial perfusion. These data demonstrate that EMD 87580 did not protect against ischemia-reperfusion injury regardless of the time of drug administration. Combined EMD 87580 and IC did not antagonize protection that was achieved by either first- or second-window IC alone; no additive protection beyond preconditioning was obtained. Further study is necessary to assess the value of NHE1 blockers as protective agents against myocardial injury.

Changes in intramyocardial tissue pressure modulate the relationship between coronary pressure and flow during the cardiac cycle. The present study compared the relation between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero flow in anesthetized dogs after modulation of either coronary sinus (i.e. Fogarty catheter) or left ventricular intracavity (i.e. volume loading) pressure. Experiments were conducted in anesthetized, instrumented dogs; coronary pressure flow relations were constructed during pharmacologic vasodilatation and intramyocardial tissue pressure was measured using micromanometer pressure sensors. Elevated coronary sinus pressures did not affect subendocardial pressure-flow relations signifying that diastolic tissue pressure within this layer is the effective coronary back pressure. Higher left ventricular intracavity pressure did not affect either diastolic subendocardial tissue pressure or pressure flow relations within this layer. Results show a direct linear relation (y = 1.106x - 0.652; r2 = 0.59. P = 0.001) between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero-flow over a wide range of pressures after either LV systemic or coronary sinus pressure modulation. Knowledge of back pressure in the subendocardium is useful for the evaluation of efficacy of cardiac interventions on myocardial perfusion particularly at the level of the microcirculation.

Platelet activation and aggregation during ischemia influence reperfusion-related myocyte necrosis, myocardial perfusion at the microvascular level, and thereby eventual recovery of cardiac performance. Inhibition of platelet activity therefore represents a worthwhile target to reduce cellular injury. The current study examined the effects of MK383 (tirofiban), a potent inhibitor of platelet aggregation, on infarct size and myocardial perfusion in canine subjects to either reocclusion (ie, 120-minute + 60-minute ischemia with intervening reperfusion) or prolonged occlusion (ie, 3 hours) followed by reperfusion (180 minutes). Platelet aggregation, infarct size (tetrazolium staining), coronary blood flow (flow probe), coronary vascular reserve, and myocardial perfusion (microspheres) were evaluated. MK383, administered at the time of reperfusion, produced a modest reduction of tissue necrosis (compared to saline-treated controls) in the reocclusion and prolonged occlusion studies. Blood flow in the infarct-related artery after coronary occlusion was comparable between treatment groups, as was myocardial perfusion in the deeper layers of the ischemic region; coronary vascular reserve decreased progressively during reperfusion. Of note, compensatory changes in blood flow within the adjacent nonischemic myocardium were not observed. In conclusion, we report that that limiting platelet aggregation during reperfusion impacted infarct development. Continued investigation into the mechanisms by which inhibition of platelet activity protects myocardium against ischemia–reperfusion injury and improves clinical outcomes is necessary.

The present study investigated the role of cardiac nerves on homeometric autoregulation in anesthetized dogs during acute volume loading. Ventricular pressure-volume loops (conductance catheter method) were constructed during acute volume loading with intact cardiac nerves (ICN) and after cardiac decentralization (DCN; bilateral ablation of thoracic vagosympathetic complexes, stellate ganglia and anterior and posterior ansae subclavia). Arterial pressure increased as expected after volume loading but no significant changes were observed for heart rate and other hemodynamic parameters. Coronary sinus venous oxygen content was also higher regardless of nerve status in response to the overall increase in cardiac work. Pressure-volume catheter data showed markedly higher end-systolic volumes after volume loading under ICN and DCN conditions; stroke volume (mL/beat) and stroke work (mL/mm Hg) were not changed but LV ejection fraction was significantly lower. End-diastolic volume and cardiac output did not change. In addition, systemic vascular resistance and tau were higher with volume loading but no differences between ICN and DCN were observed. These findings show that acute volume loading produces an immediate influence on LV function independent of cardiac nerve status.

Background: Cardiac complications after myocardial infarction are believed to be worse in the presence of comorbidities; we tested whether experimentally induced prolonged uremia exacer-bated myocardial necrosis in a rabbit preparation of ischemia-reperfusion injury. In addition, we examined if treatment with an angiotensin converting enzyme inhibitor (Enalapril, ENA, 3 mg/Kg, IV) could reduce post-ischemic myocardial damage. Methods: Prolonged uremia was induced by a two-stage subtotal nephrectomy and confirmed by marked increases in serum creatinine and urea levels; after 5 weeks, four groups of rabbits were exposed to 45-min acute coronary occlusion followed by 180-min reperfusion. In treated animals, ENA was administered 5-min before onset of coronary reperfusion. All data from uremic animals were compared with time-matched controls. Results: Cardiac hemodynamics was similar for all groups during the development of kidney failure; heart rate in uremic rabbits was significantly lower for the duration of ischemia-reperfusion. In this animal model, the absence of coronary collateral circulation provides a stable ischemic substrate for evaluation of cellular necrosis. Infarct size (expressed as percent risk zone size) was: control, 48 ± 16; uremia, 36 ± 5; control + ENA, 51 ± 19; and uremia + ENA, 41 ± 16; risk zone size was similar for all animals. Conclusion: The present findings are inconsistent with the view that post-ischemic cardiac injury is greater in animals with pre-existent uremia. In addition, we were unable to show a significant beneficial effect with an angiotensin converting enzyme inhibitor on infarct size in either control or uremic rabbits. It remains to be proven in animal models with comorbidities such as manifest kidney disease that ischemic tolerance can be substantially reduced by either pharmacologic or non-pharmacologic interventions.

Inter-organ crosstalk plays an essential role in the physiological homeostasis of the heart and other organs, and requires a complex interaction between a host of cellular, molecular, and neural factors. Derangements in these interactions can initiate multi-organ dysfunction. This is the case, for instance, in the heart or kidneys where a pathological alteration in one organ can unfavorably affect function in another distant organ; attention is currently being paid to understanding the physiopathological consequences of kidney dysfunction on cardiac performance that lead to cardiorenal syndrome. Different cardiorenal connectors (renin–angiotensin or sympathetic nervous system activation, inflammation, uremia, etc.) and non-traditional risk factors potentially contribute to multi-organ failure. Of these, inflammation may be crucial as inflammatory cells contribute to over-production of eicosanoids and lipid second messengers that activate intracellular signaling pathways involved in pathogenesis. Indeed, inflammation biomarkers are often elevated in patients with cardiac or renal dysfunction. Epigenetics, a dynamic process that regulates gene expression and function, is also recognized as an important player in single-organ disease. Principal epigenetic modifications occur at the level of DNA (i.e., methylation) and histone proteins; aberrant DNA methylation is associated with pathogenesis of organ dysfunction through a number of mechanisms (inflammation, nitric oxide bioavailability, endothelin, etc.). Herein, we focus on the potential contribution of inflammation in pathogenesis of cardiorenal syndrome.

Background/Aims: Chronic kidney disease (CKD) increases cardiovascular risk possibly due to coronary microvessel dysfunction and impaired myocardial flow reserve. This study investigated the effects of CKD on the regulation and transmural distribution of myocardial blood flow along with oxygen demand during intravenous dobutamine-induced increases in cardiac work. Methods: CKD was produced in dogs by a two-stage subtotal nephrectomy (kidney ablation-infarction model). Serum creatinine and blood urea nitrogen were evaluated during the development of CKD along with systemic blood pressure (tail-cuff plethysmography). After 5 weeks, the CKD dogs were staged according to the International Renal Interest Society staging system; all dogs were anesthetized and surgically prepared for blood flow studies. Data analyses were performed between sham control (CTR) and stage 1 and 2 CKD dogs. Results: At baseline, myocardial blood flow and diastolic aortic pressure were similar for all groups. During intravenous dobutamine, myocardial blood flow was markedly higher than CTR even though hematocrit levels declined with the severity of CKD. In the CTR dogs, myocardial blood flow increased in direct relation to cardiac work. However, in the CKD dogs (stage 1 and 2), maximum blood flow was achieved with low-dose dobutamine, indicating that coronary autoregulation is more readily exhausted with minimal increases in cardiac work during CKD. Conclusion: We report that CKD markedly impairs coronary vascular reserve and myocardial blood flow regulation which could contribute to greater cardiovascular risk and poor clinical outcomes in CKD patients.

Evaluation of multiorgan protection strategies against ischemic injury in humans is essential to improve quality of life and reduce mortality. Over the past 40 years a host of pharmacologic and non-pharmacologic interventions have been evaluated with the aim of limiting cell damage produced by ischemia-reperfusion injury. Different conditioning strategies, such as remote conditioning, are documented to mitigate ischemic injury in animal and human studies and may have remarkable clinical promise. However, successful clinical application of these interventions remains questionable since protection is known to be compromised in humans with comorbidities either with or without medications. Regardless, ongoing studies continue to examine the underlying mechanisms involved in this endogenous cytoprotective phenomenon to further its successful implementation in the clinical setting. In this review, we examine recent findings in support of remote conditioning stratagems for organ protection and their relevance for translation to clinical use.

Clinical management of patients with acute myocardial infarction for the most part involves re-opening of an infarct-related coronary vessel by the use of clot-busting pharmacologic treatment or percutaneous coronary interventions. While blood flow in the epicardial coronary vessel is restored downstream, effects remain largely unexplored; progressive injury at the microvessel level has significant repercussions on restoration of cardiocyte viability and the ventricular blood flow and contractile function relationship. This review focuses on the cardiac microcirculation and the fact that it should be a principle target of future studies to permit improvement of clinical outcomes in patients presenting with evolving myocardial infarction.

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Aims Remote ischaemic preconditioning (rIPC) protects cardiac and non-cardiac tissues against ischaemic injury. Although there is increased demand to investigate its potential clinical applicability, fundamental mechanisms responsible for rIPC-mediated protection remain unresolved. We examined in isoflurane-anaesthetized dogs whether an intact cardiac nervous system was necessary to mediate rIPC protection against ischaemic injury. Methods and results Dogs were randomly allocated to six groups: 1, control (CON, no-rIPC); 2, rIPC (4 × 5 min renal artery occlusion/reperfusion); 3, autonomic ganglionic blockade with hexamethonium (HEX, no-rIPC; 20 mg/kg iv); 4, HEX + rIPC; 5, cardiac decentralization by surgical ablation of extracardiac nerves (DCN, no-rIPC); and 6, DCN + rIPC. All dogs underwent 60 min coronary occlusion and 180 min reperfusion; cardiac haemodynamic parameters were monitored. Regional blood flow (microspheres) in the heart and kidneys was assessed. Necrotic tissue was visualized using triphenyltetrazolium staining and related to anatomic risk zone size (area at risk; P = NS between groups) and coronary collateral blood flow. Infarct size (% AAR) was 29 ± 5 (mean ± 1 SD) in CON and 15 ± 4 in rIPC dogs ( P = 0.001 vs. CON); 24 ± 3 in HEX vs. 12 ± 2 in HEX + rIPC ( P = 0.001 vs. HEX); and 20 ± 2 in DCN vs. 12 ± 4 in DCN + rIPC ( P = 0.001 vs. DCN). In CON dogs, infarct size was inversely related to coronary collateral flow; this relation was shifted downwards in all groups pre-treated with rIPC. Conclusion We report robust myocardial protection by rIPC against ischaemic injury in canines that was not abrogated by either pharmacological or surgical decentralization of cardiac nerves.

Background/Aims: Cardiovascular events are common in patients with renocardiac syndrome. A direct link between endothelial dysfunction and increased cardiovascular events has not been established for this syndrome; however, a causal role could be attributed to modulations of Cytochrome P450-mediated (CYP450) eicosanoid metabolites including Epoxyeicosatrienoic (EETs), Dihydroxyeicosatrienoic (DHET) and 20-Hydroxyeicosatetraenoic acids (20-HETE). In this study we investigated inter-organ variations in CYP450-mediated eicosanoids in key organs from dogs with renal insufficiency. Methods: Renal insufficiency was induced by two-stage subtotal nephrectomy (SNx). Biochemical markers (serum creatinine, blood urea nitrogen) and cardiac hemodynamics were measured weekly. After 5 weeks, arachidonic acid CYP450-metabolites in heart, remnant kidney and liver biopsies were analyzed. Results: Serum creatinine and blood urea nitrogen were significantly higher in the SNx group (versus timematched sham controls); hematocrit, body weight and creatinine clearance were significantly reduced. The lymphocyte:monocyte ratio, a biomarker of vascular risk, was lower (p=NS) in SNx dogs. Cardiac hemodynamics were similar for both groups. Cardiac levels of 20-HETE were markedly lower (p=0.014) in SNx dogs; however, 14, 15-DHET, a biomarker of soluble epoxide hydrolase levels were unchanged. The 20-HETE/14, 15-DHET ratio was lower in these dogs (p=0.003) and could help to explain a loss of autoregulation in this experimental model. In kidney and liver biopsies from SNx dogs 20-HETE tended to be higher and 14, 15-DHET lower (p=NS) versus time-matched controls; no change was observed for 20-HETE/14, 15-DHET. Conclusion: A marked reduction of cardiac 20-HETE and 20-HETE/14, 15-DHET levels occurred in dogs with kidney injury but no change in these CYP450-metabolites was observed in kidney or liver biopsies. As such, kidney injury appears to trigger significant alterations in CYP450-metabolites that may initiate endothelial dysfunction and vascular inflammation even in distant organs. Manipulating these pathways may eventually constitute a potential pharmacologic target to limit vessel dysfunction in the setting of renocardiac syndrome.

The present article reviews pertinent contributions from the Coronary Physiology Research Group at the Quebec Heart Institute to the understanding of coronary physiology in health and disease. Mechanisms that contribute to regulation of coronary blood flow and its distribution across the ventricular wall are discussed. Data from animal studies of ischemia-reperfusion injury are also presented and discussed in the context of current concepts regarding postischemic myocardial protection strategies. Future research directions regarding the cardiac nervous system and its importance in the regulation of coronary blood flow, cardiac function and myocyte injury during acute myocardial infarction are also discussed.

Impaired renal function is associated with an increased risk for cardiovascular events and death, but the pathophysiology is poorly defined. The hypothesis that coronary blood flow regulation and distribution of ventricular blood flow could be compromised during acute renal failure (ARF) was tested. In two separate groups (n = 14 each) of dogs with ARF, (1) coronary autoregulation (pressure-flow relations), vascular reserve (reactive hyperemia), and myocardial blood flow distribution (microspheres) and (2) coronary vessel responses to intracoronary infusion of select endothelium-dependent and -independent vasodilators were evaluated. In addition, coronary pressure-flow relations and vascular reserve after inhibition of nitric oxide and prostaglandin release were evaluated. Under resting conditions, myocardial oxygen consumption increased in dogs with ARF compared with no renal failure (NRF; 11.8 +/- 9.2 versus 5.0 +/- 1.5 ml O(2)/min per 100 g; P = 0.01), and the autoregulatory break point of the coronary pressure-flow relation was shifted to higher diastolic coronary pressures (60 +/- 17 versus 52 +/- 8 mmHg in NRF; P = 0.003); the latter was shifted further rightward after inhibition of both nitric oxide and prostaglandin release. The endocardial/epicardial blood flow ratio was comparable for both groups, suggesting preserved ventricular distribution of blood flow. In dogs with ARF, coronary vascular conductance also was reduced (P = 0.001 versus NRF), but coronary zero-flow pressure was unchanged. Vessel reactivity to each endothelium-dependent/independent compound also was blunted significantly. In conclusion, under resting conditions, coronary vascular tone, reserve, and vessel reactivity are markedly diminished with ARF, suggesting impaired vascular function. Consequently, during ARF, small increases in myocardial oxygen demand would induce subendocardial ischemia as a result of a limited capacity to increase oxygen supply and thereby contribute to higher risk for adverse coronary events and mortality.

The 'gold standard' radioactive microsphere (RM) technique for measurement of organ blood flow under various experimental conditions is inaccessible to many researchers due to increasing environmental concerns regarding safety and disposal of low-level radioactive waste materials. A new method using neutron activated microspheres (NAM) has recently been described.We compared regional myocardial blood flows using the new formulation STERIspheres (NAM; 15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) with RM (15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) under different experimental conditions during acute ischemia-reperfusion injury in dogs. Random paired combinations of four different RM and NAM were co-injected into the left atrium during autoregulation, coronary occlusion and flow-mediated hyperemia (reperfusion) in the same animal. The left ventricle was divided into non-ischemic and ischemic regions and further subdivided into endocardial, mid-myocardial and epicardial portions. After gamma-counting, blood and myocardial tissue samples (n = 180) were dried and then shipped to a core facility for neutron activation and analysis. NAM-RM blood flow data were directly compared by ANOVA and regression analysis; Bland and Altman analysis was also performed to assess mean differences in blood flow with NAM-RM.A direct relation for blood flow between NAM-RM was observed; the slope of the relation (1.17 RM +/- 0.04 [SEE]) was different from unity but the intercept (0.06 +/- 0.06 [SEE]) was not different from the origin. Intermethod mean differences were minimal between NAM-RM in the low to normal range of blood flow and were increased at the higher blood flow levels the latter being of minor physiological consequence. A direct relation for endo/epicardial blood flow ratios between NAM-RM was also observed; the slope of the relation (0.98 RM +/- 0.04 [SEE]) and the intercept (0.03 +/- 0.06 [SEE]) were not different from unity or the origin, respectively.RESULTS show that in addition to limiting production of radioactive waste materials, NAM accurately measure myocardial blood flow, endocardial/epicardial and ischemic/non-ischemic blood flow distributions over a wide range. We compared myocardial blood flows using paired combinations of neutron activated (NAM) and the 'gold standard' radiolabeled microspheres (RM) co-injected during autoregulation, coronary occlusion and flow-mediated hyperemia in an in situ canine ischemia-reperfusion preparation. A direct relation for blood flow and endo/epicardial blood flow ratios between NAM-RM was observed; intermethod mean differences between NAM-RM were minimal in the low to normal blood flow range but increased at higher blood flow levels. These results indicate that NAM accurately measure myocardial blood flow and its transmural distribution in addition to limiting unnecessary production of radioactive laboratory waste products.

In humans with hypertension and LV hypertrophy, beneficial effects of angiotensin inhibition may be associated with preserved autoregulatory capacity. We studied the effect of acute angiotensin converting enzyme (ACE) inhibition on coronary autoregulatory pressure-flow relations and transmural distribution of blood flow in sham and LV hypertrophy dogs. Heart/body weight ratio increased (p = 0.001) from 5.5 +/- 0.7 in sham to 6.9 +/- 0.5 in LV hypertrophy dogs. The lower coronary pressure limit (LPL) on the pressure-flow relation was 47 +/- 2 mmHg in sham and 57 +/- 6 mmHg (p = 0.001) in LV hypertrophy dogs; after acute ACE-inhibition the LPL was reduced to 40 +/- 5 mmHg and 49 +/- 6 mmHg (p = 0.001), respectively. Transmural distribution of blood flow was preserved at the LPL in both groups before and after acute ACE-inhibition. Concomitant blockade of prostaglandin and nitric oxide release and bradykinin catabolism had no additional effects on the LPL and distribution of blood flow. After acute ACE-inhibition in LV hypertrophy dogs, distribution of blood flow across the LV wall was preserved and subendocardial vascular reserve was maintained even though the LPL was significantly lower. Preservation of autoregulatory capacity by ACE inhibitors contributes to beneficial outcome in patients with hypertension and LV hypertrophy.

Coronary blood flow regulation was studied in dogs with an intact or chronically decentralized intrinsic cardiac nervous system. We also examined the effect of angiotensin-converting enzyme inhibition (ACEI) on coronary autoregulatory pressure–flow relations and distribution of blood flow since the renin–angiotensin system may play a critical role in vasoregulation. Myocardial oxygen demand was reduced in the chronic decentralized dogs compared to the control dogs. The lower pressure limit of the autoregulatory pressure–flow relation was similar for the control and chronic decentralized dogs (47±2 and 44±7 mm Hg, respectively; p=NS). After ACEI, the lower pressure limit shifted leftward to 40 mm Hg (p=0.001) in both groups. Concomitant blockade of cyclooxygenase, bradykinin catabolism and nitric oxide synthase had no further effect on the lower pressure limit. Total myocardial blood flow was lower (p=0.001) in the chronic decentralized dogs compared to the control dogs, while transmural distribution of blood flow was preserved in both groups. The results show that even though myocardial oxygen requirements are lower in the chronically decentralized heart compared to controls, coronary autoregulation is maintained at levels observed in normally innervated hearts. The present findings indicate that intrinsic cardiac neurons contribute to coronary autoregulatory control and myocardial blood flow distribution even in the absence of cardiac connections to the central nervous system. In addition, in the chronic decentralized dog, ACEI allows the heart to work at lower coronary perfusion pressures while myocardial blood flow distribution is preserved.

The sympathetic nervous system and nitric oxide (NO) contribute to regulation of vascular tone, blood flow regulation and cardiac function. Intrinsic cardiac neurons are tonically influenced by locally released NO and exogenous NO donors; however, the role of intact central neural connections remains controversial. We investigated the effects of S -nitroso- N -acetylpenicillamine (SNAP) administered into an intracoronary artery near the ventral interventricular ganglionated plexus (VIVGP) to evaluate distribution of myocardial blood flow (MBF) and ventricular function in normal and acute cardiac decentralized dogs. MBF was measured with microspheres during infusion of SNAP (100 μM, IC) after systemic administration of 7-nitroindazole (nNOS blocker) followed by N ω -nitro-L-arginine methyl ester (LN; non-selective NOS blocker). Cardiac dynamics were not significantly affected by cardiac decentralization; several of these parameters (aortic systolic and diastolic pressures) were significantly increased after systemic administration of LN. Overall SNAP administered to the VIVGP increased blood flow in the anterior LV wall (vs. posterior LV wall) without affecting other cardiodynamic factors. In cardiac decentralized dogs subepicardial blood flow to the anterior LV wall during LN + SNAP was diminished resulting in a significantly higher inner:outer blood flow ratio (index of blood flow uniformity across the LV wall). LV function was not affected by acute cardiac decentralization; however, LV ejection fraction decreased markedly after LN (reduced NO bioavailability). These results validate earlier claims that reduced NO bioavailability imposes an upper limit on myocardial blood flow regulation and its transmural distribution. These effects are exacerbated after disconnection of intrinsic cardiac neurons from intact central neuron connections.

Upregulation of the endothelin (ET) system, following coronary ischemia-reperfusion injury, may contribute to coronary vasospasm and congestive heart failure. Because endothelin-1 (ET-1) is rapidly cleared from the circulation, the levels of its inactive precursor big ET-1 and the ET-1/big ET-1 ratio may constitute better ways to assess the activation of the ET system in both venous and arterial beds. Anesthetized dogs (n = 6-12) were subjected to two successive coronary artery occlusions (with intervening 60 min reperfusion) over 6 h. Cardiac hemodynamics and electrocardiogram (ECG) were recorded and blood samples were drawn simultaneously from the internal thoracic artery and coronary sinus (venous blood). Under basal conditions at t = -20 min, arterial plasma levels of ET-1 and big ET-1 were 2.05 +/- 0.21 and 2.00 +/- 0.51 pg/ml (ratio: 1.00; n = 12); venous values were 2.29 +/- 0.25 and 3.14 +/- 0.77, respectively (ratio: 0.73, n = 12). Both arterial and venous plasma levels of ET-1 increased (by 46 and 56%) after 5 and 15 min of reperfusion, respectively, following the initial 120 min ischemic period compared to baseline values, and returned to near baseline values after 60 min reperfusion. Both arterial and venous values for big ET-1 increased steadily by 2.2 and 2.3 times maximum, respectively, during the initial 60 min reperfusion period; these values increased by 3.4 and 3.2 times, respectively by the end of the second 120 min reperfusion period. ET-1/big ET-1 ratios dropped to 0.39, in arterial, and 0.21, in venous plasma, at the end of the second reperfusion period. In conclusion, plasma ET-1 levels increase significantly but transiently after the first ischemic injury; the increased plasma big ET-1 levels were more pronounced in both the arterial and venous circulation along with ischemia-reperfusion injuries. These results suggest an upregulation of the ET system that was easily monitored by increased production of big ET-1. During ischemia-reperfusion injuries, the conversion to the active mature peptide ET-1 is either impaired, or ET-1 is more rapidly degraded.

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mmHg (1 mmHg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.Key words: autoregulation, coronary artery pressure-flow relations, myocardial blood flow distribution, left ventricular pressure, left ventricular volume.

Objectives. This study characterized the attenuation of myocardial ischemia observed with re-exercise to determine whether: 1) a differing exercise intensity modifies this attenuation; 2) it could be explained by contractile down-regulation or stunning; 3) it is mediated by activation of ATP-sensitive potassium channels (K+-ATP). Background. Subjects with ischemic heart disease (IHD) frequently note less angina with re-exercise after a brief rest. Potential mechanisms of this ‘warm-up’ phenomenon have been little explored. Methods. IHD subjects with a positive exercise test were studied. Groups I and II (12 subjects each) underwent 2 successive Naughton protocol exercise echocardiography tests (with 1 min instead of 2 min stages for Group II). Group D (10 subjects) had type II diabetes, were on ≥10 mg daily of the K+-ATP blocker, glibenclamide, and underwent the group I exercise protocol. The ischemic threshold or rate-pressure product at 1 mm ST segment depression, ST depression corresponding to the peak rate-pressure product of the first exercise (maximum ST depression equivalent), and left ventricular wall motion indexes before and immediately after each exercise were analyzed. Results. Exercise-induced myocardial ischemia with re-exercise was similarly attenuated in groups I, II, and D. The ischemic threshold was raised by nearly 20% with re-exercise (p = 0.001, p = 0.02, and p = 0.02, respectively) and the maximum ST depression equivalent was nearly halved on re-exercise (p = 0.005, p = 0.006, and p = 0.001, respectively). Exercise-induced wall motion dysfunction was attenuated with re-exercise. In group I, wall motion returned to the initial baseline score prior to exercise 2, whereas in the more intense protocol of group II, wall motion dysfunction persisted prior to exercise 2. Conclusions. Thus, the attenuation of myocardial ischemia observed with re-exercise appears to be independent of the intensity of the exercise protocol and is not explained by down-regulation of myocardial contractility induced by the initial ischemic stimulus. Since results were similar in diabetic subjects on robust doses of glibenclamide, this phenomenon does not appear to be mediated by K+-ATP activation.

La pression tissulaire intramyocardique peut influencer la distribution du debit sanguin ventriculaire et la dynamique durant le cycle cardiaque. Les pressions tissulaires sous-endocardiques et sous-epicardiques de la paroi anterieure du ventricule gauche ont ete mesurees simultanement au moyen de deux micromanometres a semi-conducteurs (transducteurs de pression modele P19 de Konigsberg Instruments et modele SPR-230 de 5F Millar) et ont ete comparees a la pression de la cavite ventriculaire gauche. Les pressions systoliques enregistrees par les transducteurs de Konigsberg et de Millar etaient similaires lorsque la surface des capteurs faisait face a la cavite ventriculaire gauche tant au niveau de l'endocarde que de l'epicarde. Les pressions diastoliques de l'epicarde etaient plus elevees que la pression de la cavite ventriculaire gauche. Lorsque les transducteurs de Konigsberg et de Millar etaient inseres dans l'epicarde, et que les capteurs de pression etaient places en direction de l'epicarde, le signal de sortie du transducteur Millar etait dephase par rapport au signal du transducteur de Konigsberg et des pressions de la cavite ventriculaire gauche. Les resultats indiquent que les signaux de sortie des pressions intramyocardiques varient selon la direction du capteur de pression de Konigsberg ou de Millar dans la paroi ventriculaire gauche. Ainsi, les signaux de sortie des pressions varient selon la surface du capteur, la flexibilite relative des câbles de connexion et l'orientation de la surface du capteur par rapport a l'anatomie ventriculaire gauche.

Neural elements of the intrinsic cardiac nervous system transduce sensory inputs from the heart, blood vessels and other organs to ensure adequate cardiac function on a beat-to-beat basis. This inter-organ crosstalk is critical for normal function of the heart and other organs; derangements within the nervous system hierarchy contribute to pathogenesis of organ dysfunction. The role of intact cardiac nerves in development of, as well as protection against, ischemic injury is of current interest since it may involve recruitment of intrinsic cardiac ganglia. For instance, ischemic conditioning, a novel protection strategy against organ injury, and in particular remote conditioning, is likely mediated by activation of neural pathways or by endogenous cytoprotective blood-borne substances that stimulate different signalling pathways. This discovery reinforces the concept that inter-organ communication, and maintenance thereof, is key. As such, greater understanding of mechanisms and elucidation of treatment strategies is imperative to improve clinical outcomes particularly in patients with comorbidities. For instance, autonomic imbalance between sympathetic and parasympathetic nervous system regulation can initiate cardiovascular autonomic neuropathy that compromises cardiac stability and function. Neuromodulation therapies that directly target the intrinsic cardiac nervous system or other elements of the nervous system hierarchy are currently being investigated for treatment of different maladies in animal and human studies.

Introduction It has been proven that blood supply to the heart can include blood from noncoronary collateral circulation. Whether this network can somehow be augmented to provide an alternative therapy for ischemic patients is an intriguing hypothesis with no clear answer yet due to the challenging nature of this research field. In an attempt to enhance noncoronary collateral blood flow, we experimented with left internal thoracic artery ligature and angiogenic growth factors in a canine model. Materials and methods Eight dogs weighing between 20 and 29 kg were scheduled for three operations each. Neutron-activated microspheres were used for blood flow measurement throughout the study. The first operation was a left thoracotomy for ameroid constrictor positioning at the proximal segment of the circumflex coronary artery. Three weeks later the left internal thoracic artery was ligatured distally. A micro-pump was positioned in the mediastinum, connected with a small catheter inserted in the proximal segment of the left internal thoracic artery for slow delivery of vascular endothelial growth factor. The protocol called for a coronary angiography 4 weeks later, sacrifice of the animals, and explantation of the heart for microsphere analysis. Results Four of the dogs failed to tolerate ameroid constrictor positioning by thoracotomy and died after the first operation. The remaining four dogs underwent a second operation to ligate their left internal thoracic arteries and implant micro-pumps with catheters. The implant was a success, but only one dog survived in the postoperative period. When the last dog was voluntarily sacrificed after a third operation, coronary angiography showed no neovascularization, nor did heart slice analysis reveal microspheres. Conclusions Despite the technical challenge of building research protocols to exactly quantify blood from noncoronary arteries, there are many historical, anatomical, physiopathological, clinical, radiological, and surgical indications suggesting that blood flow from extracardiac structures may play an important role in ischemic heart disease. Our preliminary investigation combining internal thoracic artery occlusion and angiogenic growth factors was unsuccessful for several reasons, the main one being it was too heavy a protocol for the dogs. Despite this, we think that noncoronary collateral blood flow represents an intriguing research field worthy of debate and further study.

The internal thoracic arteries (ITAs) are a source of "noncoronary collateral circulation" (NCCC), or "noncoronary collateral blood flow" (NCCBF). The hypothesis herein is that enhancement of NCCC may represent an alternative means of myocardial blood supply: (1) Ligature of the ITAs creates a local hypertensive status and increases the perfusion pressure within the channels leading to the heart; (2) Myocardial ischemic stimulus diverts most ITA-related collateral flow to the heart rather than to the chest wall; (3) The ITAs may develop neo-collaterals owing to their ischemia-related plastic potential; (4) Angiogenic growth factor administration within the ITAs enhances neo-collateral development. These elements may pave the way for a new field of cardiovascular research aimed at enhancing NCCC as a new therapeutic option for ischemic heart disease.

Background— The objective of this study was to identify the impact of diabetes and related comorbidities, namely chronic renal failure, peripheral vascular disease, and low ejection fraction ( Methods and Results— A unicenter study was conducted on 9125 survivors of isolated coronary artery bypass graft surgery between 1992 and 2002. There were 6581 nondiabetic patients and 2544 diabetics, including 1809 patients with noninsulin-dependent diabetes mellitus and 735 patients with insulin-dependent diabetes mellitus. Cardiac-specific survival at 5 and 10 years was lower in insulin-dependent diabetes mellitus compared with both nondiabetic mellitus patients and patients with noninsulin-dependent diabetes mellitus ( P P =0 0.08) after surgery and was significantly lower thereafter ( P =0.004). Cardiac-specific survival after coronary artery bypass graft surgery in patients with one or more comorbidities was comparable ( P =0.4) for both nondiabetes mellitus patients and patients with noninsulin-dependent diabetes mellitus, but was significantly lower for those requiring insulin therapy ( P P =0.41); however, insulin-dependent diabetes mellitus, chronic renal failure, peripheral vascular disease, and low ejection fraction were all independent risk factors for late cardiac death (all P Conclusions— Noninsulin-dependent diabetes is not an independent predictor of late cardiac death after coronary artery bypass graft surgery, because cardiac-related survival is similar to that of nondiabetic patients for 6 years after surgery. In diabetic and nondiabetic patients, cardiac survival is adversely affected by the need for insulin therapy and/or the presence and number of comorbidities such as chronic renal failure, peripheral vascular disease, and low ejection fraction.

ObjectivesThis open-label canine study assessed whether n-3 polyunsaturated fatty acids (PUFAs) prevent vagally induced atrial fibrillation (AF) and influence atrial tissue expression levels of connexins (CXs).Backgroundn-3 polyunsaturated fatty acids in fish oils protect against sudden cardiac death and reduce postoperative AF. Changes in spatial organization of gap junctions or cellular CX levels have been linked to arrhythmogenesis.MethodsVagally induced AF was studied. Eight dogs were given fish oil daily for 14 days. Eight control dogs had reproducibly induced AF and were re-evaluated after intravenous administration of fish oil. Atrial fibrillation was compared, and n-3 PUFA, CX40, and CX43 protein levels were assessed in atrial biopsies.ResultsAtrial tissue n-3 PUFA levels increased in oral treatment dogs (5.78 ± 0.71% vs. 2.49 ± 0.46% in control animals, p < 0.001). No difference was observed for atrial refractory periods or hemodynamic or electrocardiographic parameters. Incidence of AF in oral treatment dogs decreased 79% with the extra stimulus technique (10.5% vs. 48.9%, p = 0.003) and 42% with burst induction (22.5% vs. 38.8%, p = 0.038). Both CX40 and CX43 levels were lower in oral treatment dogs (60% [p = 0.019] and 42% [p = 0.038] lower, respectively); protection against AF was mostly related to reduced CX40 expression levels (p = 0.02). In dogs that were given intravenous n-3 PUFAs, AF inducibility by the extra stimulus technique was reduced from 75.0% to 28.6% (p = 0.002).ConclusionsOral treatment with fish oils increased atrial n-3 PUFA levels and reduced vulnerability to induction of AF in this dog model. Modulation of cardiac CX by n-3 PUFAs probably contributes to the antiarrhythmic effects of fish oils.

Electrical excitation of the dorsal aspect of the rostral thoracic spinal cord imparts long-term therapeutic benefits to patients with angina pectoris. Such spinal cord stimulation also induces short-term suppressor effects on the intrinsic cardiac nervous system. The purpose of this study was to determine whether spinal cord stimulation (SCS) induces long-term effects on the intrinsic nervous system, particularly in the presence of myocardial ischaemia. The activity generated by right atrial neurons was recorded in 10 anesthetized dogs during basal states, during prolonged (15 min) occlusion of the left anterior descending coronary artery, and during the subsequent reperfusion phase. Neuronal activity and cardiovascular indices were also monitored when the dorsal T1-T4 segments of the spinal cord were stimulated electrically (50 Hz; 0.2 ms) at an intensity 90% of motor threshold (mean 0.32 mA) for 17 min. SCS was performed before, during and after 15-min periods of regional ventricular ischaemia. Occlusion of a major coronary artery, one that did not perfuse investigated neurons, resulted in their excitation. Ischaemia-induced neuronal excitatory effects were suppressed (-76% from baseline) by SCS. SCS suppression of intrinsic cardiac neuronal activity persisted during the subsequent reperfusion period; after terminating 17 min of SCS, at least 20 min elapsed before intrinsic cardiac neuronal activity returned to baseline values. It is concluded that populations of intrinsic cardiac neurons are activated by inputs arising from the ischaemic myocardium. Ischaemia-induced activation of these neurons is nullified by SCS. The neuronal suppressor effects that SCS induces persist not only during reperfusion, but also for an extended period of time thereafter. These long-term effects may account, in part, for the fact that SCS imparts clinical benefit to patients with angina of cardiac origin not only during its application, but also for a time thereafter. (C) 2002 Elsevier Science B.V. All rights reserved.

Objectives. Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with angina pectoris refractory to conventional therapeutic strategies. The purpose of this study was to determine whether spinal cord stimulation (SCS) in dogs affects regional myocardial blood flow and left-ventricular (LV) function before and during transient obstruction of the left anterior descending coronary artery (LAD). Methods. In anesthetized dogs, regional myocardial blood flow distribution was determined using radiolabeled microspheres and left-ventricular function was measured by impedance-derived pressure-volume loops. SCS was accomplished by stimulating the dorsal T1-T2 segments of the spinal cord using epidural bipolar electrodes at 90% of motor threshold (MT) (50 Hz, 0.2-ms duration). Effects of 5-min SCS were assessed under basal conditions and during 4-min occlusion of the LAD. Results. SCS alone evoked no change in regional myocardial blood flow or cardiovascular indices. Transient LAD occlusion significantly diminished blood flow within ischemic, but not in non-ischemic myocardial tissue. Left ventricular pressure-volume loops were shifted rightward during LAD occlusion. Cardiac indices were altered similarly during LAD occlusion and concurrent SCS. Conclusions. SCS does not influence the distribution of blood flow within the non-ischemic or ischemic myocardium. Nor does it modify LV pressure-volume dynamics in the anesthetized experimental preparation. (C) 2001 Elsevier Science B.V. All rights reserved.

Estrogen replacement therapy reduces risk of cardiovascular events by altering coronary vasoregulation and distribution of blood flow. Vessel reactivity and blood flow distribution were assessed in anesthetized female rabbits in the following groups: 1) sham, 2) ovariectomy, 3) ovariectomy + 17β-estradiol, and 4) ovariectomy + dehydroepiandrosterone. After a 2-wk treatment, cardiac hemodynamics, vascular reserve, and blood flow were evaluated during the following infusions: 1) NaCl, or vehicle (0.5 ml/min), 2) acetylcholine (2 mg/kg), 3) isoproterenol (2 mg · kg−1 · min−1), and 4) chromonar (8 mg/kg). In hearts from ovariectomized rabbits, autoregulatory blood flow was preserved despite lower diastolic perfusion pressures (55 ± 8 vs. 64 ± 8 mmHg in sham) and rate-pressure product (14.4 ± 0.8 vs. 19.3 ± 0.8 beats/min · mmHg×10−3). Estrogen replacement therapy restored coronary pressure and reserve, and all drugs increased vascular conductance. In conclusion, in hearts from ovariectomized rabbits, vascular reserve declined because coronary pressure was lower; however, blood flow was preserved at a higher level than expected for oxygen demand. Estrogen replacement therapy restores myocardial oxygen supply-demand indices and returns coronary pressure-flow data to levels observed in animals with intact ovaries.

OBJECTIVES This study examined the roles of myocardial perfusion and adenosine in warm-up angina. BACKGROUND In warm-up angina, neither the role of an adenosine-mediated mechanism, as is found in experimental ischemic preconditioning, nor of increased myocardial perfusion is well defined. METHODS In substudy A, a single-photon emission computed tomography (SPECT)-thallium-201 exercise test was performed by 12 subjects with ischemic heart disease on three occasions one week apart. The third test was preceded by a warm-up test. The extent of the thallium deficit and its intensity on the third test were compared with the baseline tests controlling for the heart rate-systolic blood pressure product (RPP) at thallium injection. In substudy B, 12 similar subjects did two successive exercise tests at two separate sessions and received the adenosine antagonist, aminophylline (intravenous 5 mg/kg bolus and 0.9 mg/kg/h infusion) at one session, and equivalent saline at the other session. Change in ischemic threshold (RPP at 1 mm ST segment depression) and in maximum ST depression adjusted for RPP were analyzed. RESULTS In substudy A, despite a significant attenuation of electrocardiogram indexes of myocardial ischemia between the baseline and third (warmed-up) tests, the thallium extent deficits (20.8 ± 15.1% and 16.8 ± 12.4%) and intensity deficits (41.2 ± 12.6% and 39.3 ± 12.6%) did not differ significantly. In substudy B, the increase in ischemic threshold on re-exercise was unaffected by aminophylline. Adjusted maximum ST depression even decreased to a greater extent on re-exercise with aminophylline (by 51 ± 21%) than with saline (by 32 ± 19%) (p = 0.012). CONCLUSIONS While warm-up angina is associated with a significant attenuation of exercise electrocardiogram indexes of ischemia, it is unaccompanied by significant changes in SPECT perfusion and does not appear to be mediated by an adenosine-dependent mechanism since it is not blocked by aminophylline. Thus, its mechanism, which appears distinct from experimental ischemic preconditioning, remains unidentified.

OBJECTIVES We studied the effects of N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate (MK-0852) (platelet GPIIb/IIIa receptor blocker) on peak reactive hyperemia, distribution of blood flow, regional contractile function and infarct size in a canine model of acute ischemia-reperfusion injury. BACKGROUND Platelet activation and formation of platelet microaggregates in coronary vessels could contribute to ischemia-induced myocyte injury. Inhibition of platelet aggregation could reduce ischemia-reperfusion injury. METHODS Three groups of dogs (n = 10/group) were studied; group 1—heparin (HEP) (100 U/kg/h intravenously), group 2—MK-0852 (300 μg/kg intravenous bolus followed by 3 μg/kg/min for 3 h) and group 3—MK-0852 plus HEP. Infarct size after 60 min regional ischemia and 3 h reperfusion was evaluated by tetrazolium staining and normalized to risk area (Monastral blue dye). RESULTS Infarct size in HEP-treated controls was 32.4 ± 2.8%; in MK-0852 without or with HEP groups, infarct size was 17.4 ± 1.9% (p = 0.001) and 23.4 ± 3.0% (p = 0.04), respectively. Cardiac hemodynamics and rate-pressure product were comparable between groups. Multivariate analysis using collateral blood flow as the independent variable confirmed the cytoprotective actions of MK-0852. Postischemic peak reactive hyperemia in the infarct-related artery was depressed in all groups; during reperfusion, transmural distribution of myocardial blood flow returned to near control levels, but severe regional hypokinesia persisted. CONCLUSIONS Diminished infarct size with MK-0852 treatment suggests an additional mechanism of benefit for GPIIb/IIIa blockers beyond stabilization of a “culprit” acute coronary lesion. This cytoprotective effect was unrelated to preservation of coronary vasoreactivity (assessed by reactive hyperemia), restoration of blood flow across the myocardium or acute improvement in contractility.

Acute myocardial ischemia initiates a cascade of cellular events that lead to irreversible injury. We previously described the transient nature of heat-shock induced cardioprotection; treatment with a catalase inhibitor abolished the cytoprotective actions without affecting expression levels of HSP71. Repeated, transient ischemic episodes augment the ischemic tolerance of affected myocardium but the fundamental cytoprotective mechanism(s) for both “early” and “delayed” preconditioning remains unclear. Increased cellular induction of protooncogenes, heat shock genes, and downstream effector proteins might play critical roles in the cytoprotection afforded by delayed preconditioning. We measured c-fos, c-jun, c-myc, and hsp70 induction in preconditioned (2 × 5-min ischemia/10-min reperfusion) and control rabbit hearts that either underwent 30- or 120-min coronary occlusion and 60-min reperfusion, or did not undergo subsequent sustained ischemia; the latter hearts were allowed to recover for 0, 1, 3, 6, 24, 48, 72, or 96 hours. Both c-fos and c-jun in ischemic tissue were strongly induced by ischemia-reperfusion injury and preconditioning pretreatment. However, expression levels diminished significantly by 1-h reperfusion and remained depressed during the 96-h recovery period. Hsp70 (inducible) mRNA expression levels were highest primarily in ischemic myocardium after 6-h recovery post-preconditioning; Hsp70 levels in ischemic myocardium were slightly stronger after 48-h recovery but subsequently diminished to barely detectable levels by 96-h post-preconditioning. Induction of c-fos and c-jun preceded that of Hsp70. These findings support the concept that upregulation of immediate early genes and heat shock genes plays an important role in myocardial adaptation to acute ischemic stress.

Objective: Agents which promote increased interstitial adenosine levels may be cardioprotective. The aim of this study was to evaluate the ability of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAr), an adenosine regulating agent, to limit infarct size when given before ischaemia, before coronary reperfusion, or postreperfusion in a rabbit preparation of ischaemia-reperfusion injury. Methods: The left coronary artery was occluded for 30 min and subsequently the ischaemic bed was reperfused for 180 min. Infarct size and risk zone size were delineated by tetrazolium staining and microsphere autoradiography, respectively. Four groups were studied: controls (n = 13), AICAr (2.5 mg·kg−1·min−1 intravenously for 5 min followed by 0.5 mg·kg−1·min−1 for 60 min) beginning either 5 min before coronary occlusion (n = 11), 5 min before coronary reperfusion (n = 11), or at 25 min coronary reperfusion (n = 10). Lignocaine was not given in these experiments. Results: Infarct size, normalised to risk zone, was significantly reduced with AICAr given 5 min before coronary reperfusion, at 35.0(SEM 4.4)% v 51.8(3.9)% in controls; p = 0.03. Cardioprotection was not observed when AICAr was given either 5 min before coronary occlusion [44.2(4.8)%] or 25 min postreperfusion [45.9(3.2)%]. Conclusions: These findings support the hypothesis that adenosine regulating agents, such as AICAr, can modulate infarct size in this rabbit preparation of ischaemia-reperfusion injury. Cardiovascular Research 1994; 28: 1003-1007

This study examined whether the adenosine potentiator, 5-aminoimidazole-4-carboxamide riboside (AICAr), could limit tissue necrosis during acute myocardial infarction in rabbit hearts with minimal coronary collateral flow. Forty-four rabbits underwent 45 min of ischemia with or without coronary reperfusion for 180 min. Five groups were studied. Saline or AICAr (20 mg/kg, i.v.) was administered as a bolus either 10 min before coronary occlusion or 10 min before the onset of coronary reperfusion. The anatomic risk zone size was assessed by radiolabeled microsphere autoradiography and the area of tissue necrosis was defined using the tetrazolium staining method. Coronary collateral flow in the central ischemic zone was assessed using the radiolabeled microsphere technique. No differences were observed for tissue necrosis (normalized to risk zone size) for saline- and AICAr-treated rabbits (66.2 +/- 10.9% vs. 70.8 +/- 19.9%, p = NS) subjected to 45 min of coronary occlusion without reperfusion. Similarly, tissue necrosis in rabbit hearts with 45 min of coronary occlusion followed by 180 min of reperfusion was not significantly reduced when AICAr was administered either 10 min before ischemia or 10 min before reperfusion (79.8 +/- 17.5 and 76.4 +/- 8.1%, respectively) compared to saline-treated controls (68.1 +/- 22.7%). Coronary collateral flow in these hearts was almost nonexistent. The risk zone size and cardiac hemodynamics were similar between the treatment groups. These results demonstrate that AICAr was unable to limit myocyte necrosis when administered either before ischemia or before coronary reperfusion in this experimental preparation of acute myocardial infarction.

It has been suggested that changes in left atrial pressure may mask or mimic left ventricular diastolic function abnormalities detected by Doppler echocardiography. The effect of the Valsalva maneuver on the transmitral flow velocity profile was therefore studied in 28 patients without evidence of coronary artery disease (group 1, mean age +/- standard deviation 50 +/- 8 years) and in 94 patients with evidence of coronary artery disease or systemic hypertension (group 2, mean age 54 +/- 10 years). At baseline, group 2 patients had higher peak late diastolic filling velocity (A), lower peak early (E) to late diastolic filling velocity (E/A) ratio and longer isovolumic relaxation time than group 1, whereas heart rate, E velocity and E deceleration time were similar in both groups. During Valsalva, both groups had similar increases in heart rate and similar decreases in E velocity but E/A ratio decreased significantly only in group 2 because of a lesser decrease in A velocity. The E/A ratio was greater than or equal to 1.0 both before and during Valsalva in all but 1 patient in group 1, whereas in group 2, 32 patients had E/A greater than or equal to 1.0 at rest and during Valsalva, 33 patients had E/A greater than or equal to 1.0 at rest but less than 1.0 both at rest and during Valsalva. Using group 1 as controls, prevalence, specificity and positive predictive value of E/A less than 1.0 in group 2 were 31, 100 and 100% at rest and 66, 96 and 98% during Valsalva.(ABSTRACT TRUNCATED AT 250 WORDS)

The anti-infarct effect of ischemic preconditioning (PC) is partly due to adenosine receptor-mediated opening of KATPchannels. PC-mediated protection may be potentiated by exogenous infusion of adenosine receptor agonists. To test this hypothesis, pentobarbital anesthetized rabbits (n = 8/group) underwent two cycles of 5 min regional ischemia and 5 min coronary reperfusion (REP; i.e., PC) followed by 30 min ischemia and 3 h REP. Rabbits received either adenosine (AD; 0.01 mg/min); cyclopentyladenosine (CP; A1receptor agonist; 0.001 mg/min) or CGS 21680 (CG; A2receptor agonist; 001 mg/min), i.v.for 65 min starting 5 min before onset of REP. KATPchannels were blocked with i.v.glibenclamide (G; 0.15 mg/kg) 10 min before PC in the absence or presence of AD, CP or CG. Infarct and risk (R; cm3) volume was assessed with tetrazolium and microsphere autoradiography. Infarct size (IS) was normalized to R. IS in absolute controls (i.e., no PC) was 51 ± 6% (mean ± SEM). PC G + PC AD G + AD CP G + CP CG G + CG R 1.6 ± 1 1.8 ± 0.2 1.6 ± 0.2 1.4 ± 0.1 1.9 ± 0.1 1.4 ± 0.3 2.0 ± 0.2 1.2 ± 0.1 IS 19 ± 2 39 ± 7† 27 ± 7 37 ± 6† 12 ± 1† 44 ± 9† 22 ± 3 50 ± 5† † P ≤ 0.05: one-way ANOVA and SNK multiple range test Full-size table Table options View in workspace Download as CSV Cardiodynamics were similar for the treatment groups; but heart rate-blood pressure product was lower (p ≤ 0.05) during CP infusion. Conclusions PC markedly reduced IS; 2) PC-mediated protection was not potentiated with exogenous AD, CP or CG; and 3) G abolished PC-mediated protection without/with exogenous AD, CP or CG. These data indicate that adenosine receptor activation and opening of KATPchannels are involved in PC.