Mechanisms of reflex vasodilation: assessment of the role of neural reuptake of norepinephrine and release of histamine.

The mechanisms of reflex vasodilation were studied in an innervated canine hindlimb preparation which was perfused at a constant rate. Reflex vasodilation was produced by suddenly increasing the pressure in the trunk by the intravenous injection of norepinephrine, with consequent stimulation of the baroreceptors. When the basal vasoconstrictor tone exerted by the sympathetic nervous system on the systemic arterial bed was minimized, either by pretreatment with the alpha adrenergic blocking agent phenoxybenzamine or with reserpine, which depletes endogenous catecholamine stores, reflex vasodilation was virtually abolished. Administration of cocaine, a drug which blocks reuptake of norepinephrine by the nerve terminals, significantly reduced reflex vasodilation, the response after cocaine averaging 47% of the vasodilator response in the control period. Cocaine also potentiated the vasoconstriction caused by intra-arterially administered norepinephrine but attenuated the vasoconstriction induced by tyramine. The antihistamine, tripelennamine, had effects similar to those of cocaine. It is suggested, therefore, that reflex vasodilation results from a sudden decrease in the level of norepinephrine at the neuroeffector junction, which is a consequence of the cessation of norepinephrine secretion, together with continued and possibly augmented uptake. When the uptake mechanism is impaired, either by the administration of cocaine or tripelennamine, the magnitude of reflex vasodilation is diminished. It does not appear necessary to postulate active secretion of a vasodilator substance to account for reflex vasodilation.

Reflex cardiovascular depression produced by stimulation of pulmonary stretch receptors in the dog.

To study the possible reflex effects of stimulation of pulmonary stretch receptors on the cardiovascular system, experiments were designed that would allow separate assessment of the responses of the heart, the total peripheral vascular resistance, and the resistance of the innervated hindlimb that was perfused at a constant flow rate. In every experiment, inflation of the lungs to a positive pressure of 20 mm Hg produced significant negative inotropic and chronotropic effects. Heart rate fell an average of 22.3+/-3.8% (SEM) (P < 0.01), pressure recorded from within an isovolumic balloon in animals on total cardiopulmonary bypass fell an average of 14.3+/-4.6% (P < 0.05), dp/dt recorded from within the balloon declined an average of 31.4 +/- 6.0% (P < 0.01), and contractile force measured with a Walton-Brodie strain gauge arch fell an average of 18.6 +/-2.2% (P < 0.01). Similarly, a depressor response to inflation of the lungs was noted in the periphery as manifested by an average decrease in total peripheral vascular resistance of 21.9+/-2.5% in the animals on total cardiopulmonary bypass (P < 0.01), and by an average decrease in perfusion pressure in the isolated hindlimb of 26.0 +/-3.8% (P < 0.01). After bilateral cervical vagotomy, the cardiovascular responses to inflation of the lungs were either abolished or markedly lessened. Thus, sudden expansion of the lungs activates the afferent arm of a depressor reflex, which produces negative inotropic and chronotropic responses, in addition to arterial vasodilation. The receptors are sensitive to stretch and the afferent pathway runs predominantly in the vagus nerves.

Myocardial blood flow distribution in concentric left ventricular hypertrophy.

Regional myocardial blood flow during both control conditions and ischemia-induced vasodilatation was studied in eight chronically instrumented awake dogs. Seven of these animals had coarctation-banding of the ascending aorta performed at 6 wk of age, and the other dog had congenital subvalvular aortic stenosis. The mean left ventricular weight for the group was 157+/-7.6 g, and the left ventricular body weight ratio was 8.76+/-0.47 g/kg. None of the animals exhibited signs of congestive heart failure. During the control state, the mean left ventricular systolic pressure was 249+/-12 mm Hg and the left ventricular end-diastolic pressure was 11.5+/-0.5 mm Hg. The aortic diastolic pressure was 74+/-6 mm Hg. Mean left circumflex coronary artery blood flow was 71+/-6 cm(3)/min. In the animals with coarctation-banding, 52+/-6% of the flow occurred during systole. In the dog with congenital subvalvular aortic stenosis, 5% of the coronary flow was systolic. Mean transmural blood flow during resting conditions was 0.97+/-0.08 cm(3)/min per g, and the ratio of endocardial to epicardial flow (endo/epi) was 0.88+/-0.07. During reactive hyperemia, the mean transmural blood flow increased to 3.5+/-0.30 cm(3)/min per g; however, the endo/epi decreased to 0.52+/-0.06.THESE STUDIES DOCUMENT A DIFFERENCE IN TRANSMURAL BLOOD FLOW DISTRIBUTION BETWEEN THE NORMAL AND THE HYPERTROPHIED LEFT VENTRICLE: during resting conditions, in the normal ventricle, the highest flow occurs in the endocardial layer, whereas in the hypertrophied ventricle, the highest flow is in the middle layers with the endocardial flow less than the epicardial flow. During ischemia-induced vasodilatation, the abnormal endo/epi becomes accentuated markedly. These data demonstrate that, in situations requiring high flow, the endocardial layer of a heart with marked concentric left ventricular hypertrophy may not be perfused adequately.

Transcription rates of SERCA and phospholamban genes change in response to chronic stimulation of skeletal muscle.

Chronic low frequency stimulation of predominantly fast-twitch skeletal muscles decrease the levels of SERCA1 (fast-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) mRNA, and increase the levels of SERCA2 (slow-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) and phospholamban mRNAs. To assess the role of transcription in these changes in mRNA levels, nuclei were isolated from chronically stimulated canine latissimus dorsi muscles and transcription rates were estimated by nuclear run-on assays. Decreases in the rates of SERCA1 gene transcription matched the fall in its mRNA level and increases in the rates of SERCA2 and phospholamban gene transcription matched the increases in their mRNAs.

Outlet strut fracture of the Björk-Shiley 60 degrees Convexo-Concave valve: current information and recommendations for patient care.

Mechanical failure of artificial heart valves can be a catastrophic event. The problem of outlet strut fracture of the Björk-Shiley 60 degrees Convexo-Concave tilting disc prosthesis has received much attention in the medical literature and generated both concern and confusion among patients and physicians. Analysis of current data from the manufacturer, as well as a review of the medical literature, suggests that the overall risk of outlet strut fracture is low and that elective explantation of a well functioning Björk-Shiley 60 degrees Convexo-Concave valve prosthesis is not warranted. Diagnostic features of outlet strut fracture can be seen with overpenetrated chest X-ray films so that diagnosis can be established promptly. Early operation to replace the fractured prosthesis is essential for patient survival.

Ca-ATPase isozyme expression in sarcoplasmic reticulum is altered by chronic stimulation of skeletal muscle.

Chronic stimulation of a predominantly fast skeletal muscle enhanced the expression of type I (slow muscle) Ca-ATPase and suppressed the expression of the type II (fast muscle) Ca-ATPase. Monoclonal antibodies IID8 and IIH11 against type I (slow) and type II (fast) isozymes respectively, were used to type the Ca-ATPases of the isolated SR (sarcoplasmic reticulum) by Western blots, and the Ca-ATPases of the muscle fibers by immunohistochemistry. Of the fibers from control muscles 80% stained for the type II isozyme and 20% for the type I isozyme. Following chronic stimulation all fibers stained for type I isozyme and none stained for type II isozyme. Ca-ATPase isozyme distribution in isolated SR confirmed this effect of chronic stimulation. The calcium uptake activities of homogenates of stimulated muscles were 22% of the control muscles. The Ca-ATPase and calcium-uptake activities of the isolated SR from stimulated muscles were, respectively, 32 and 45% of the control muscles.

Myocardial depression by anesthetic agents (halothane, enflurane and nitrous oxide): quantitation based on end-systolic pressure-dimension relations.

The end-systolic pressure-diameter relation of the left ventricle was used to examine the effect of halothane, enflurane and nitrous oxide on left ventricular (LV) contractility in 10 dogs chronically instrumented with dimension transducers to measure LV diameter and micromanometers to measure LV transmural pressure. Contractility was assessed by the slope (EES) of the end-systolic pressure-diameter relation. A new index that identifies the dose of anesthetic necessary to depress the inotropic state by 20% (ID20) was calculated to be 0.63% for halothane and 1.55% for enflurane, indicating a greater apparent myocardial depressant effect of halothane than enflurane. However, when these agents were compared at equi-anesthetic concentrations by normalizing the ID20 to the minimal alveolar concentration of each drug, they had comparable degrees of myocardial depressant effects. This measurement technique was used in 7 patients undergoing coronary artery bypass grafting conducted under narcotic anesthesia showing that halothane induced a similar depression of contractility. The use of ID20 should allow reclassification of anesthetic agents according to their myocardial depressant effects.

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Nucleoside trapping during reperfusion prevents ventricular dysfunction, "stunning," in absence of adenosine. Possible separation between ischemic and reperfusion injury.

A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.

Intermittent aortic crossclamping prevents cumulative adenosine triphosphate depletion, ventricular fibrillation, and dysfunction (stunning): is it preconditioning?

This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocardium becomes preconditioned after the first episode of ischemia in canine models in vivo. The role of adenosine triphosphate catabolism and subsequent release of purines on reperfusion-mediated postischemic ventricular dysfunction and arrhythmias was assessed with the use of selective inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBMPR), and a specific adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA). Thirty-two anesthetized dogs were instrumented to monitor left ventricular contractility, off bypass, by sonomicrometry. During cardiopulmonary bypass dogs were treated before ischemia with either saline solution (control group, n = 8) or EHNA (100 mumol/L) and NBMPR (25 mumol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of reperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of adenosine triphosphate and induced reperfusion-mediated ventricular fibrillation and severe left ventricular dysfunction in the control group. EHNA/NBMPR treatment augmented myocardial adenosine trapping during ischemia, attenuated ventricular fibrillation, and enhanced left ventricular functional recovery, despite similar depletion of adenosine triphosphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant adenosine triphosphate depletion, ventricular fibrillation, and left ventricular stunning in both control and drug-treated groups. The prevalence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0.05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group (p < 0.05 versus control). Subsequent episodes of ischemia prevented ventricular fibrillation and did not cause cumulative left ventricular stunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adenosine triphosphate, limited purine release, and prevented ventricular fibrillation and cumulative stunning. These results suggest that intermittent ischemia and reperfusion augmented the endogenous protective mechanism or mechanisms of "preconditioning." Nucleoside trapping improved functional recovery after sustained or repetitive ischemia. It is concluded that adenosine triphosphate preservation or blockade of nucleoside transport may play an important role in the activation of endogenous myocardial protective mechanisms that "precondition" against subsequent ischemic stress.

Delayed myocardial preconditioning by alpha1-adrenoceptors involves inhibition of apoptosis.

OBJECTIVE: Previous studies have demonstrated that alpha1-adrenoceptor activation increases myocardial resistance to ischemic injury 24 hours later. Here we tested the hypothesis that delayed protection is associated with limited infarction and involves altered expression of pro-apoptotic and/or anti-apoptotic proteins. METHODS: Rabbits were treated with phenylephrine or an equivalent volume of vehicle (n = 6 per group). Twenty-four hours after pretreatment, isolated hearts were perfused with a bovine erythrocyte suspension in modified Krebs solution, subjected to 45 minutes of global ischemia (37 C), and reperfused for 120 minutes. Infarct size was determined by triphenyltetrazolium chloride staining. Apoptosis was quantified by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling. Left ventricular tissue from separate groups of animals (n = 5 per group), 24 hours after pretreatment with phenylephrine or vehicle but without ischemia and reperfusion, was analyzed by Western blotting for content of the anti-apoptotic protein, bclx, and pro-apoptotic protein, bax. RESULTS: Isolated hearts after phenylephrine pretreatment had increased end-reperfusion developed pressures (56.8 +/- 4.9 vs 36.2 +/- 3.9 mm Hg for vehicle, P =.008) and decreased elevated end-diastolic pressures (26.7 +/- 4.5 vs 42.3 +/- 5.0 mm Hg for vehicle, P =.04). Phenylephrine pretreatment abrogated infarction (9.9 +/- 2.4% vs 42.6 +/- 6.3% for vehicle, P =.002) and reduced the number of apoptotic nuclei (24 +/- 4.8 vs 51 +/- 4.6 for vehicle, P = .038). Analysis by Western blotting showed that the ratio of bclx to bax protein increased in phenylephrine-pretreated hearts (2.65 +/- 0.5 vs 1.0 +/- 0.1 for vehicle, P =.008). CONCLUSION: Delayed myocardial protection to infarction mediated by alpha1-adrenoceptor activation involves an increased bclx/bax ratio, thereby limiting apoptotic cell death.

Effects of methoxamine on the coronary circulation during cardiopulmonary bypass.

Effects of perfusion pressure augmentation with methoxamine on transmural distribution and adequacy of coronary blood flow during cardiopulmonary bypass were investigated. Flow in normal, nonworking canine hearts was measured with tracer microspheres and electromagnetic flow probes while heart rate, myocardial oxygen consumption, left ventricular contractility and epicardial ST-segment stability were monitored. Measurements during normotensive cardiopulmonary bypass were compared with values during intraoperative hypotension and subsequent normotension achieved following methoxamine infusion. Total and regional coronary blood flow returned to levels not different from normotensive controls after methoxamine infusion with a redistribution of flow to the subendocardium. We conclude that elevating perfusion pressure during cardiopulmonary bypass with methoxamine infusion increases total coronary and subendocardial blood flow by means of peripheral and selective subepicardial alpha adrenergic vasoconstriction.

Reperfusion of inflow-limited myocardium following hypothermic potassium-induced cardioplegia.

Previous studies have shown that transmural reperfusion patterns may be markedly abnormal following periods of ischemia. The present study was done to elucidate the effects of hypothermic potassium cardioplegia on pressure-flow characteristics during reperfusion of myocardial regions with chronically compromised arterial inflow. Prior to cardiopulmonary bypass studies. Ameroid constrictors were placed on the circumflex coronary artery of 10 adult dogs to create a myocardial region subserved by inflow-restricting collaterals. Subsequently, during cardiopulmonary bypass at 80 mm Hg, 10 minutes of ischemic arrest was induced with hypothermic potassium cardioplegia (15 degrees C, pH 7.4, potassium chloride 25 mEq/L). Transmural myocardial flow was measured in normal and collateral-dependent regions during control conditions and at 1, 5, and 10 minutes of reperfusion. Also, retrograde circumflex pressures were monitored as an additional index of perfusion of the collateral regions. A normal endocardial/epicardial flow ratio was maintained in the normal regions at 1, 5, and 10 minutes of reperfusion. In contrast, a marked decrease in endocardial/epicardial flow ratio occurred transiently in the collateral regions at 1 minute of reperfusion (0.28 +/- 0.05). Simultaneously, retrograde circumflex pressures fell from 55 +/- 3.5 mm Hg to 42 +/- 3.0 mm Hg (p less than 0.001). By 5 minutes of reperfusion, retrograde circumflex pressure, mean flow, and transmural endocardial/epicardial ratios returned to normal in collateral regions. These data suggest that, even with optimal myocardial protection, changes in transmural flow occur very early during reperfusion and are exaggerated in inflow-restricted myocardial regions. Mechanisms responsible for these changes may include refilling of epicardial vessels emptied during the cross-clamp period or an early epicardial hyperemic response. Despite these alterations, normal transmural flow patterns are reestablished rapidly. Thus, when detailed attention is paid to adequate myocardial protection, abnormal reperfusion characteristics are obviated, and this is particularly important in myocardium supplied by inflow-compromised coronary vessels.

Immediate versus delayed coronary grafting after streptokinase treatment. Postoperative blood loss and clinical results.

Of all patients with acute evolving myocardial infarction treated surgically at Duke University Medical Center between 1984 and 1986, 27 patients given high doses (greater than 1.5 million units) of streptokinase preoperatively were studied. Eleven patients who received streptokinase had coronary bypass grafting 12 hours after thrombolytic therapy (early hours), eight patients between 12 and 72 hours (delayed), and eight patients beyond 72 hours (late hours). Seventeen patients who underwent coronary bypass grafting within 6 hours of the onset of symptoms, without preoperative streptokinase, were included as control patients. Only the patients having early operation had significantly greater postoperative blood loss; postoperative use of red blood cells; fresh-frozen plasma; cryoprecipitate; prolonged postoperative prothrombin time; and prolonged partial thromboplastin time. Patients having delayed or late operations did not differ significantly from patients not receiving streptokinase. Only the interval between time of streptokinase administration and operation could account for the coagulopathy and the postoperative bleeding complications in the early group. Patients in the early group had a higher in-hospital mortality (27% versus 6% for the non-streptokinase group) and major noncardiac morbidity (36% versus 12% for the non-streptokinase group). Patients in the delayed and late groups had minimal postoperative complications and no mortality. Observations were not explained by differences in total ischemic time, number of angioplasty failures, or number of patients with cardiogenic shock between the early group and the non-streptokinase group. Postoperative bleeding and massive use of blood products seemed to be contributory factors: Two of three deaths in the patients having early operations were associated with clinical suspicion of tamponade. Patients undergoing coronary bypass grafting within 12 hours of streptokinase therapy appear to be a high-risk group in a more emergent, uncontrolled clinical setting and require aggressive monitoring and correction of coagulopathy.

Differential ventricular ischemic injury: an experimental model of right ventricular failure with a variable degree of left ventricular dysfunction.

The hemodynamic manifestations of right ventricular dysfunction after ischemic injury depend not only on the severity of injury but also on the degree of coexistent left ventricular dysfunction. A better understanding of right ventricular failure and of optimal therapies has been hindered in part by lack of suitable experimental models of selective and differential ventricular injury. Therefore, we developed a technique of differential ventricular myocardial protection during a period of global cardiac ischemia and examined the effect of such an injury on intrinsic right and left ventricular myocardial function, metabolism, and regional blood flow. Twenty-six dogs were subjected to 30 minutes of ischemia while being supported by cardiopulmonary bypass. During ischemia, right and left ventricular myocardial temperatures were independently varied by selective ventricular endomyocardial thermal regulation. Nine dogs underwent right and left ventricular normothermic ischemia, eight underwent right and left ventricular hypothermic ischemia, and nine underwent right ventricular normothermic and left ventricular hypothermic ischemia. In both ventricles, normothermic ischemia resulted in greater depression of ventricular ability to generate stroke work as a function of end-diastolic dimension (p less than 0.05), greater depletion of myocardial adenine nucleotide content (p less than 0.05), and greater subendocardial reperfusion hyperemia (p less than 0.05). Myocardial temperature of the contralateral ventricle during ischemia had no effect (p = not significant) on intrinsic ventricular functional, metabolic, or regional blood flow response to injury. For a given degree of right ventricular injury assessed by these parameters, the degree of left ventricular injury could be independently varied by as much as 50%. This is a particularly suitable model for the investigation of acute right ventricular failure.

Dynamic right ventricular dimension. Relation to chamber volume during the cardiac cycle.

Whereas the left ventricle has been analyzed extensively, the apparent complexity of right ventricular geometry and contraction has hindered analysis of right ventricular performance by an assessment of instantaneous ventricular dimensions and volume during the cardiac cycle. To address this issue, we examined the temporal and quantitative relation between dynamic right ventricular free wall dimension, rate of pressure development (dP/dt), and pulmonary artery flow in the open-chest dog. Right ventricular free wall chord dimension was recorded by sonomicrometry, right ventricular pressure by micromanometer-tipped catheter, and pulmonary flow by electromagnetic probe. The point of peak positive right ventricular dP/dt closely correlated with the end of isovolumic contraction and initiation of ejection, occurring within 10 +/- 25 msec of initiation of pulmonary flow. Right ventricular dimension at peak positive dP/dt differed from dimension at initiation of chord shortening by less than 3%. Peak negative dP/dt correlated with end ejection, occurring within 10 +/- 25 msec of cessation of pulmonary flow. Right ventricular dimension at peak negative dP/dt differed from minimal dimension by less than 1%. In all dogs, volume ejected from the right ventricular chamber during each cardiac cycle was directly related to the change in right ventricular dimension during the same period (mean r = 0.969). This relationship between right ventricular stroke volume and dimensional change remained linear and was not changed (p = NS) by increases in right or left ventricular afterload induced by constricting the pulmonary artery or descending aorta. Right ventricular stroke work, calculated as the integral of instantaneous right ventricular pressure and dimension, correlated well (mean r = 0.980) with directly measured global right ventricular stroke work over a wide range; it was also not changed (p = NS) by changes in afterload. Accurate assessments of beat-to-beat right ventricular chamber volume and stroke work can be obtained by analysis of dynamic right ventricular chord dimension.

Coronary bypass grafting after failed elective and failed emergent percutaneous angioplasty. Relative risks of emergent surgical intervention.

Emergency coronary artery bypass grafting after failed elective percutaneous transluminal coronary angioplasty can be performed with acceptable complication rates. Recently, however, a new class of patients with unsuccessful angioplasty has evolved with the use of thrombolytic therapy and emergent angioplasty as treatment for developing acute myocardial infarction. The efficacy of surgical intervention after failure of angioplasty in this setting has not been demonstrated. This report compares the results of coronary bypass done emergently after either failed elective or failed emergent angioplasty. Between March 1984 and September 1986; 1350 angioplasty procedures were performed at our institution, 393 for acute myocardial infarction. Of the 111 patients who came to operation, 42 had had unsuccessful elective angioplasty and 69 unsuccessful angioplasty done in the clinical setting of an evolving acute myocardial infarction detected by electrocardiographic criteria. Twenty-one of the 42 patients having unsuccessful elective angioplasty (group I) and 32 of the 69 with unsuccessful emergent angioplasty (group II) underwent emergency coronary artery bypass grafting. A retrospective nonparametric statistical comparison of the two groups was performed. Age, preoperative ejection fraction, distribution of vessels undergoing angioplasty, and number of vessels bypassed were not statistically different. All group II patients received thrombolytic therapy, and a reperfusion catheter was used in over half the patients in each group. Three group I and six group II patients required a preoperative balloon pump, and half the patients in each group required postoperative inotropic support. One patient in group I (4.7%) and two patients in group II (6.2%) died (no significant difference). Only five patients in group I (23.8%) and 11 in group II (34.3%) had enzymatic and electrocardiographic evidence of an acute myocardial infarction at discharge. Six patients in group II (15.6%) required reexploration for bleeding, versus none in group I (p = 0.04). Nonhemorrhagic complication rates, mean in-patient and acute care days, total hospital charges, and blood product utilization rates were not statistically different. These data indicate that emergency coronary artery bypass grafting can be performed when necessary in the setting of failed emergent percutaneous transluminal coronary angioplasty with results comparable to coronary bypass after failed elective angioplasty.

Microvascular dysfunction after myocardial ischemia.

Endothelium-mediated relaxation and smooth muscle function in large coronary arteries are resistant to prolonged global ischemia. We used a small-vessel myograph to test the hypothesis that small intramyocardial artery endothelium and smooth muscle function have greater sensitivity to ischemic injury than large artery endothelium and smooth muscle. Normothermic global ischemia was induced in 15 porcine hearts. Intramyocardial arterial ring segments were assessed at 0, 30, 60, 90, and 120 minutes of ischemia in vitro with a small-vessel myograph. Potassium determined smooth muscle contraction, bradykinin endothelium-mediated relaxation, and sodium nitroprusside direct smooth muscle relaxation. Endothelium-mediated relaxation after 30 minutes of ischemia was similar to control (56% versus 66%) but was impaired at 60, 90, and 120 minutes of ischemia (32%, 11%, and 6%). Smooth muscle contraction was unchanged at 30 and 60 minutes compared with control (56 and 53 versus 63 mm Hg) but was significantly decreased at 90 and 120 minutes (33 and 13 mm Hg). Direct smooth muscle relaxation was significantly decreased at 120 minutes of ischemia compared with control (58% versus 95%). In a previous study, epicardial coronary artery endothelium-mediated smooth muscle vasodilation and direct smooth muscle vasodilation were preserved until 160 minutes of ischemia. After 160 minutes of ischemia, endothelium-mediated relaxation was lost and only direct smooth muscle vasodilation was preserved. In contrast to vasodilation, vasoconstriction was significantly reduced at 140 minutes of ischemia. These data indicate a greater and earlier adverse effect of ischemia on intramyocardial arterial endothelium-mediated relaxation than smooth muscle contraction or relaxation. These data support the hypothesis that there is an early functional endothelial cell injury associated with global ischemia. Relaxation that is endothelium-dependent in intramyocardial arteries is more sensitive to ischemic injury than in epicardial arteries. Unique to this study was the evaluation of small intramyocardial arteries (281 +/- 29 microns) that are the primary sites of coronary vascular resistance. Microvascular endothelial dysfunction after ischemia, therefore, may contribute to the "no-reflow phenomenon" seen during reperfusion injury.

Elective cardiac arrest with a hyperpolarizing adenosine triphosphate-sensitive potassium channel opener. A novel form of myocardial protection?

BACKGROUND: Hyperkalemic depolarized cardiac arrest has been the cornerstone of myocardial protection during cardiac surgery for more than 30 years. Many of the advances in myocardial protection seek to minimize the cellular damage and to reduce the ongoing metabolic processes occurring as a direct consequence of the depolarized state. Ideally, cardiac arrest at hyperpolarized cellular membrane potentials--the natural resting state of the heart--will meet all the requirements of modern cardioplegia, namely, electromechanical asystole and cardiac relaxation, while preserving the vital integrity of the heart itself. METHODS AND RESULTS: To determine whether activation of adenosine triphosphate-sensitive potassium channels by pharmacologic agents could produce hyperpolarized cardiac arrest, we tested the ability of aprikalim, a known adenosine triphosphate-sensitive potassium channel opener, to arrest the intact beating heart. In a normothermic (37 degrees C) isolated rabbit heart preparation, aprikalim was found to rapidly shorten the action potential duration and produce cardiac asystole that was maintained during 20 minutes of "no-flow" global ischemia without a rise in end-diastolic pressure. Cardiac rhythm and function were fully restored by reperfusion alone (developed pressure was 100.6% +/- 7.9% of prearrest value after 30 minutes of reperfusion). In contrast, 20 minutes of unprotected normothermic global ischemia resulted in a 2.7 +/- 0.55 mmHg rise in end-diastolic pressure and only 58.2% +/- 3.8% recovery of developed pressure after 30 minutes of reperfusion. By way of comparison, 20 minutes of standard hyperkalemic depolarized normothermic rest was accompanied by a 1.2 +/- 0.6 mmHg rise in end-diastolic pressure and only 80.8% +/- 2.6% recovery of developed pressure after 30 minutes of reperfusion. To directly compare hyperkalemic depolarized cardiac arrest to hyperpolarized cardiac arrest induced by potassium channel openers and to better define the characteristics of such hyperpolarized arrest, we studied a fixed (4 mmHg rise in end-diastolic pressure--contracture) ischemic injury model. The time to development of the contracture was prolonged by hyperkalemic arrest (35.8 +/- 1.7 minutes) and significantly more so by hyperpolarized arrest (47.0 +/- 3.3 minutes) when compared with that of unprotected hearts (24.0 +/- 1.2 minutes). Moreover, aprikalim resulted in significantly better postischemic recovery of function (developed pressure was 69.0% +/- 6.7% of prearrest value after 30 minutes of reperfusion) than after no cardioplegia (45.4% +/- 7.5%) or standard hyperkalemic cardioplegia (44.3% +/- 5.7%). CONCLUSIONS: Pharmacologic activation of adenosine triphosphate-sensitive potassium channels can result in predictable and sustainable hyperpolarized cardiac arrest that is reversible by reperfusion. This method of myocardial protection was found to fully preserve cardiac electromechanical function after a 20-minute period of global normothermic ischemia. Furthermore, hyperpolarized arrest induced by potassium channel openers significantly prolonged the period to the development of contracture and afforded a significantly better postischemic recovery of function than obtained in either hearts protected with hyperkalemic depolarized arrest or those not protected by any form of cardioplegia.

Diastolic ventricular properties in patients during coronary revascularization. Intermittent ischemic arrest versus cardioplegia.

Left ventricular diastolic properties were examined in 24 patients undergoing coronary revascularization with either 32 degrees C intermittent ischemic arrest (IA) or 4 degrees C potassium cardioplegia (CP) for myocardial protection. The ages, numbers of grafts, and preoperative cardiac function were similar for the two groups of patients. For compliance data, hearts were filled passively during bypass perfusion to diastolic pressures between 0 and 20 mm Hg by clamping the left ventricular vent. Simultaneously, minor axis dimensions were measured with 8 mm epicardial ultrasonic crystals. End-diastolic lengths (EDL), normalized to a Lagrangian strain definition (epsilon), were compared at each pressure (P) by the nonlinear regression equation, P = alpha(e beta epsilon-1). Both elastic constants, alpha and beta, as well as linear regression slopes (k) of pressure-strain data were compared as indices of ventricular stiffness. Prior to determinations, the EDL at 0 mm Hg transmural pressure was defined as l0. At each filling pressure, a leftward shift in the compliance curve developed following IA but not CP. Moreover, shifts in alpha, beta, and k constants occurred with IA alone, l0 did not change in either group. Therefore, stiffening did not occur when CP was used for protection, despite ischemic durations twice those of IA (31 versus 15 minutes). These data confirm CP to be a superior method of cardiac protection during coronary bypass grafting and show diastolic ventricular properties to be a sensitive indicator of subclinical ischemic injury.