Reduction In Cardiac Work Research Articles

Prevention of Ischemic Myocardial Contracture Through Hemodynamically Controlled DCD

PurposeIschemic myocardial contracture (IMC) or “stone heart” is a condition with rapid onset following circulatory death. It inhibits transplantability of hearts donated upon circulatory death (DCD). We investigate the effectiveness of hemodynamic normalization upon withdrawal of life-sustaining therapy (WLST) in a large-animal controlled DCD model, with the hypothesis that reduction in cardiac work delays the onset of IMC.MethodsA large-animal study was conducted comprising of a control group (n=6) receiving no therapy upon WLST, and a test group (n=6) subjected to a protocol for fully automated computer-controlled hemodynamic drug administration. Onset of IMC within 1 h following circulatory death defined the primary end-point. Cardiac work estimates based on pressure-volume loop concepts were developed and used to provide insight into the effectiveness of the proposed computer-controlled therapy.ResultsNo test group individual developed IMC within {1} text { h}, whereas all control group individuals did (4/6 within {30}{text { min}}).ConclusionAutomatic dosing of hemodynamic drugs in the controlled DCD context has the potential to prevent onset of IMC up to {1}{text { h}}, enabling ethical and medically safe organ procurement. This has the potential to increase the use of DCD heart transplantation, which has been widely recognized as a means of meeting the growing demand for donor hearts.

Do β-Blockers Decrease the Hypermetabolic State in Critically Ill Children With Severe Burns?

Severe burns result in a hypermetabolic state that is associated with increased morbidity and mortality. We reviewed the literature to determine if there is strong evidence that short-term β-blockers reduce the hypermetabolic state or mortality and length of stay (LOS) compared with no therapy in patients with severe burns. A literature search of PubMed, Embase, the Cochrane Database of Systematic Reviews, and BestBETs was conducted on the use of adrenergic β-antagonists in burn patients. Six randomized controlled trials met the inclusion criteria. Five pediatric trials found that β-blockers reduced the hypermetabolic state (as defined by reduction of cardiac work, rate pressure product, resting energy expenditure, central deposition of fat, and bone mineral loss) and were associated with an improvement in lean muscle mass in patients with severe burns. However, there was no change in LOS or mortality in these children. One adult study in burn patients found shorter LOS in patients treated with β-blockers but no difference in mortality rate. β-blockers were relatively well tolerated, with no differences in adverse effects reported. β-blockers seem to reduce the hypermetabolic state in pediatric patients with burns, but there is insufficient evidence to suggest they have an impact on mortality rates or LOS.

Intra-aortic balloon pump for high-risk percutaneous coronary intervention.

The intra-aortic balloon pump (IABP) was first introduced into clinical practice in 1968.1 Early experimental and clinical trials suggested that intra-aortic balloon counterpulsation could provide circulatory assistance to a failing left ventricle.2,3 Counterpulsation—balloon inflation during diastole and deflation in systole—augments the intrinsic Windkessel effect, whereby potential energy stored in the aortic root during systole is converted to kinetic energy with the elastic recoil of the aortic root. Counterpulsation leads to a decline in afterload, a reduction in cardiac work, and therefore myocardial oxygen requirements of the ventricle. Augmentation of diastolic pressure when the balloon is fully inflated together with reduction in left ventricular (LV) filling pressures contribute to improved coronary perfusion (Figures 1 and 2).4 This proposed improvement in myocardial energetics has been further supported by a significant reduction in systemic lactate.5 These physiological enhancements are thought to be of particular benefit after acute myocardial infarction (AMI), supported by animal studies, which have shown a reduction in infarct size when counterpulsation is used.6,7 Figure 1. Coronary perfusion. Coronary flow is predominantly diastolic and further enhanced by counterpulsation, which augments diastolic blood flow and thus coronary perfusion. In addition, aortic recoil during diastole further improves efficiency of the left ventricle. Figure 2. Systemic arterial pressure waveform on introduction of intra-aortic balloon pump–assisted diastolic augmentation. The intra-aortic balloon pump inflates at the dicrotic notch, leading to peak-augmented diastolic pressure. As the balloon deflates, assisted end diastolic pressure is seen to be lower than unassisted end diastolic pressure and assisted systolic pressure is lower than unassisted systolic pressure. Peak diastolic augmentation should be greater than the unassisted systolic pressure and both assisted pressures should be less than the unassisted pressures. Intra-aortic balloon counterpulsation was initially used as a means of supporting patients undergoing surgical revascularization. Percutaneous delivery …

Abstract 19569: Inhibition of Cardiac Actin-Myosin Interaction by Blebbistatin Delays Onset of Ventricular Fibrillation during Myocardial Ischemia

Sudden cardiac death in the context of coronary heart disease is most commonly the result of the occurrence of ventricular fibrillation (VF) following a new episode of myocardial ischemia. The electrophysiological disturbances that create a substrate for the development of VF in myocardial ischemia can be traced back to depletion of cellular ATP resulting from ATP consumption outstripping supply. Reducing cardiac ATP consumption may thus delay or inhibit the development of VF in ischemia. Therefore, we determined the effect of blebbistatin, a selective inhibitor of contraction that will reduce ATP consumption via reducing cardiac work, on the incidence and time of onset of ventricular fibrillation (VF) in an established model of regional myocardial ischemia. Isolated male rat hearts (n=12 per group) were randomized to one of 4 groups: control (vehicle 0.01% v/v), 0.1µM blebbistatin, 1µM blebbistatin, or 10µM blebbistatin. The ECG and left ventricular developed pressure (LVDP) were recorded in each heart. Hearts were perfused with test solution for 15 min, after which regional myocardial ischemia was induced by tightening a snare occluder placed around the left main coronary artery. Ischemia was maintained for 30 min. As expected, prior to myocardial ischemia, blebbistatin reduced LVDP (p>0.05 vs control), abolishing it at the 1µM and 10µM concentrations. Compared to control, the incidence of VF during ischemia was not affected at blebbistatin concentrations of 0.1µM and 1µM (83% and 92% respectively vs 83% in controls) and was reduced only as a trend with 10µM blebbistatin (67%; p<0.05). However, there was a concentration-dependent prolongation in the mean time to onset of VF with blebbistatin, which was significantly longer than the mean time to VF onset in controls at a concentration of 10µM (1367±113s vs 924±80s; p<0.05). This effect of blebbistatin was associated with a trend to increased ATP content in myocardial tissue samples taken from the ischemic zone as measured by luciferase luminescence assay. In conclusion, a reduction in cardiac work by inhibition of the cardiac contractile machinery can delay the onset of VF during myocardial ischemia, most likely as a consequence of delaying the depletion of myocardial ATP.

Effect of antihypertensive therapy on ventricular-arterial mechanics, coupling, and efficiency

To investigate the effect of antihypertensive therapy on ventricular-arterial mechanics, coupling, and efficiency in early-stage hypertension. We studied 527 participants from two clinical trials assessing the effect of blood pressure lowering on diastolic function. Participants were aged ≥45 years with early-stage hypertension, no heart failure, ejection fraction (EF) ≥50%, and diastolic dysfunction using Doppler echocardiography. Effective arterial afterload and its components were assessed along with measures of left ventricular (LV) structure and function prior to and after 24-38 weeks of antihypertensive therapy. Systolic blood pressure decreased from 154 ± 18 to 137 ± 15 mmHg at follow-up. Blood pressure reduction was associated with decreases in ventricular and arterial stiffness, improvements in systemic arterial compliance and resistance, enhanced LV ejection, and reduction in cardiac work (all P < 0.001). Changes in Ea/Ees ratio were inversely correlated with those in EF (r = -0.25; P < 0.001), stroke work index (r = -0.13; P = 0.007), and LV efficiency (r = -0.98; P < 0.001); and directly related to changes in mitral E/e' (r = 0.12; P = 0.01). Adjusting for age and blood pressure change, women and obese individuals had less enhancement in ventricular-arterial coupling and efficiency compared with men and non-obese individuals (P = 0.04 and 0.007, respectively). Antihypertensive therapy reduces arterial and ventricular stiffness, enhances ventricular-arterial coupling, reduces cardiac work, and improves LV efficiency, systolic, and diastolic function. Attenuated responses in women and among obese subjects suggest that structure-function changes may be less reversible in these groups, possibly explaining their greater susceptibility to ultimately develop heart failure.

Changes in cardiac performance during hypoxic exposure in the grass shrimpPalaemonetes pugio

In hearts of higher invertebrates as well as vertebrates, the work performed by the ventricle is a function of both rate and contractility. Decapod crustaceans experience a hypoxia-induced bradycardia that is thought to result in an overall reduction in cardiac work; however, this hypothesis has not yet been tested and is the primary purpose of this study. In the grass shrimp Palaemonetes pugio, cardiac pressure and area data were obtained simultaneously, and in vivo, under normoxic (20.2 kPa O(2)) and hypoxic (6.8 or 2.2 kPa O(2)) conditions and integrated to generate pressure-area (P-A) loops. The area enclosed by the P-A loop provides a measure of stroke work and, when multiplied by the heart rate, provides an estimate of both cardiac work and myocardial O(2) consumption. Changes in intra-cardiac pressure (dp/dt) are correlated to the isovolemic contraction phase and provide an indication of stroke work. At both levels of hypoxic exposure, intra-cardiac pressure, dp/dt, stroke work and cardiac work fell significantly. The significant decrease in intra-cardiac pressure provides the primary mechanism for the decrease in stroke work, and, when coupled with the hypoxia-induced bradycardia, it contributes to an overall fall in cardiac work. Compared with normoxic P-A loops, hypoxic P-A loops (at both levels of hypoxia) become curvilinear, indicating a fall in peripheral resistance (which might account for the reduction in intra-cardiac pressure), which would reduce both stroke work and cardiac work and ultimately would serve to reduce myocardial O(2) consumption. This is the most direct evidence to date indicating that the hypoxia-induced bradycardia observed in many decapod crustaceans reduces cardiac work and is therefore energetically favorable during acute exposure to conditions of low oxygen.

Effect of elastic-band-based resistance training on leg blood flow in elderly women

The age-related decline in basal limb blood flow appears to be related to the pathogenesis of metabolic syndrome, noninsulin-dependent diabetes, and cardiovascular disease. Resistance training improves basal limb blood flow and vascular conductance in middle-aged men and women, but it is unknown whether similar vascular effects of training occur in the elderly. This study aimed to examine the effects of a 12-week progressive resistance training program using elastic bands on basal leg blood flow, vascular conductance, and functional performance in postmenopausal elderly women. Sixteen healthy postmenopausal females (age, 67± 5 years) were randomly assigned to a control (n = 8) or resistance training (n = 8) group, where they underwent 2 supervised strength sessions per week for 12 weeks. Prior to and at completion of this 12-week period, functional and strength performance and leg haemodynamic responses were measured. The training intervention produced significant increases in basal leg blood flow (31%), vascular conductance (34%), and a significant reduction in cardiac work (i.e., rate pressure product) at rest, as well as significant improvements in the 3 functional ability tests performed (30-s bicep curl, 30-s sit to stand, and back scratch). Haemodynamic or functional performance responses were not altered after the 12 weeks in the control group. This study demonstrates that a resistance training program using elastic bands elicits significant improvements in basal leg blood flow in postmenopausal elderly women.

Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.

Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action. In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, L-propranolol and D-propranolol, which compared to L-isomer is approximately 50-fold less potent as a beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker. Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P < 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of L-propranolol. Left ventricular hypertrophy was also prevented by D-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of L-propranolol on LVH are not related to a reduction in cardiac work load. In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

Heart failure: update on treatment and prognosis

HF is a prevalent and debilitating disease, affecting nearly 5 million patients and perhaps an equal number with asymptomatic left ventricular dysfunction who are at high risk of atrial fibrillation developing. An estimated 550,000 new cases occur every year. HF is the most common diagnosis in hospitalized patients aged 65 and over and is a major cause of death. The median survival after onset is 1.7 years in men and 3.2 years in women. The majority of cardiac deaths in patients with HF are sudden and arrhythmogenic: the rest are due to progressive hemodynamic deterioration. A significant advance in the past decade has been the recognition of the importance of inhibiting the neurohormonal action in HF with the use of beta-blockers, angiotensin receptor, and aldosterone antagonists. In addition, a new concept in HF therapy has evolved. The view that chronic HF is an irreversible, end-stage process is being supplanted by the fact that it is possible to effect biological improvement in the intrinsic defects of function and structure in hearts afflicted with chronic HF. Reversibility of HF has been reported by (1) unloading the failing heart using an LVAD, (2) the sophisticated use of diuretic combinations and neurohormonal blocking drugs, or (3) employing continuous arteriovenous hemofiltration. Thus it is now possible to reverse a process that has long been considered irreversible. Exercise programs designed for patients with HF that have been advocated recently can be difficult to apply. Fine tuning of an exercise regimen is required because a reduction in cardiac work is mandatory when treating HF, where the concern is that the heart may not be capable of supplying the metabolic needs of the body, even in resting states. Finally, although not emphasized in the recent literature on HF, the use of diuretics and sodium restriction continue to be the mainstays of therapy without which compensation of HF is not possible.

Carvedilol: molecular and cellular basis for its multifaceted therapeutic potential.

Carvedilol is a unique cardiovascular drug of multifaceted therapeutic potential. Its major molecular targets recognized to date are membrane adrenoceptors (beta 1, beta 2, and alpha 1), reactive oxygen species, and ion channels (K+ and Ca2+). Carvedilol provides prominent hemodynamic benefits mainly through a balanced adrenoceptor blockade, which causes a reduction in cardiac work in association with peripheral vasodilation. This drug assures remarkable cardiovascular protection through its antiproliferative/atherogenic, antiischemic, antihypertrophic, and antiarrhythmic actions. These actions are a consequence of its potent antioxidant effects, amelioration of glucose/lipid metabolism, modulation of neurohumoral factors, and modulation of cardiac electrophysiologic properties. The usefulness of carvedilol in the treatment of hypertension, ischemic heart disease, and congestive heart failure is based on a combination of hemodynamic benefits and cardiovascular protection.

Role of fatty acids in the recovery of cardiac function during resuscitation from hemorrhagic shock.

This study tested the hypothesis that removal of fatty acids as a fuel source would improve cardiac efficiency at the expense of reduced cardiac contractile function in the isolated working heart after hemorrhage-retransfusion. Non-heparinized male Sprague-Dawley rats were anesthetized with ketamine-xylazine and were hemorrhaged to a mean arterial blood pressure of 40 mmHg for 1 h. Two-thirds volume of shed blood was reinfused together with 0.9% NaCl in a volume equal to 2.3 times the shed blood volume, followed by continuous infusion of 0.9% NaCl at 10 mL/kg per h for 3 h. Hearts were removed and perfused in closed, recirculating working mode for 60 min to measure hydraulic work and cardiac efficiency. Rates of glycolysis and glucose oxidation were assessed with [5-3H/U-14C] glucose (11 mM) in the absence or presence of 0.4 mM palmitate. Compared to baseline measurements, hemorrhage-retransfusion significantly reduced arterial blood glucose (228+/-7 versus 118+/-12 mg/dL) and non-esterified fatty acid concentrations (0.36+/-0.01 versus 0.30+/-0.02 mM), while elevating blood lactate (0.8+/-0.1 versus 2.5+/-0.4 mM). Perfusion of sham hearts with glucose-only did not alter cardiac work compared to shams perfused with glucose plus palmitate. However, shocked hearts perfused with glucose-only demonstrated a significant reduction in cardiac work compared to shocked hearts perfused with glucose plus palmitate and compared to sham hearts perfused with glucose only (P < 0.05, repeated measures ANOVA). Shocked hearts perfused with glucose plus palmitate showed no reduction in cardiac work compared to shams. Shocked hearts perfused with glucose-only had increased glucose oxidation rates compared to shams perfused with glucose plus palmitate. In sham hearts perfused with glucose-only, myocardial glycogen and triacylglycerol contents were significantly reduced compared to hearts freeze-clamped in situ. These endogenous fuels were not decreased in shocked hearts. These data indicate that hemorrhagic shock renders the heart unable to mobilize endogenous fuels, and suggest that withdrawal of fatty acid oxidation will impair myocardial energy metabolism during resuscitation.

Age-related decline of PCr/ATP-ratio in progressively hypertrophied hearts of spontaneously hypertensive rats.

Although the ultimate cause for the myocardial dysfunction of hypertensive heart disease is still unclear, a crucial role of the myocardial energy metabolism has been suggested. Therefore, the aim of the present study was to investigate whether age-related myocardial dysfunction in hearts of spontaneously hypertensive rats (SHR) is associated with an impaired myocardial energy metabolism. Isolated hearts of SHR and Wistar Kyoto rats (WKY) aged about 40, 60, and 80 weeks, respectively (each n = 4-5), were perfused according to the working heart technique. Cardiac work and coronary flow were monitored online. Myocardial energy metabolism was evaluated by calculating the ratio of phosphocreatine (PCr) and adenosine triphosphate (ATP) which were measured by nuclear magnetic resonance (31P-NMR) spectroscopy. All hearts were subjected to work for 30min at baseline conditions (low afterload), followed by another 30min under a moderate pressure load (high afterload). Each SHR group showed a higher heart weight/body weight ratio than the age-matched WKY controls. The SHR showed a progressive age-dependent reduction of cardiac work (40 weeks = 5.1+/-0.3, 60 weeks = 4.0+/-0.3, 80 weeks = 3.8+/-0.2 (mW/g) at baseline conditions) and PCr/ATP-ratio (40 weeks = 1.82+/-0.06, 60 weeks = 1.69+/-0.05, 80 weeks = 1.59+/-0.09 (PCr/ATP) at baseline conditions). Similar results were found for hearts of SHR at high afterload. In WKY no significant decline in cardiac work or PCr/ATP-ratio was found under either low or under high afterload. The cardiac work capacity of hearts of SHR progressively decreases with increasing age and left ventricular hypertrophy. This myocardial dysfunction is closely associated with an impaired PCr/ATP-ratio, suggesting a decreased energy reserve.

Systolic and diastolic changes in human coronary blood flow during Valsalva manoeuvre.

Valsalva manoeuvre is reported to be sometimes successful for the relief of angina pectoris. The present study investigated how haemodynamic changes produced by Valsalva manoeuvre can interact to improve the relationship between cardiac work and coronary blood flow. Ten male subjects aged 53 +/- 12 years (SD) were considered. Blood velocity in the internal mammary artery, previously anastomosed to the left descending coronary artery, was studied with Doppler technique. The subjects performed Valsalva manoeuvres by expiring into a tube connected to a mercury manometer, to develop a pressure of 40 mmHg. The arterial blood pressure curve was continuously monitored with a Finapres device from a finger of the left hand. During expiratory effort, an increase in heart rate and a decrease in arterial pulse pressure were followed by a more delayed and progressive increase in mean and diastolic pressures. Systolic blood velocity markedly decreased along with the reduction in pulse pressure and increase in heart rate. By contrast, diastolic and mean coronary blood velocities did not show any significant change. Since it is known that the Valsalva manoeuvre strongly reduces stroke volume and cardiac output, it is likely that a reduction in cardiac work also takes place. Since in diastole, i.e. when the myocardial wall is better perfused, coronary blood velocity did not show any significant reduction, it is likely that unchanged perfusion in the presence of reduced cardiac work is responsible for the relief from angina sometimes observed during Valsalva manoeuvre. It is also likely that the increase in heart rate prevents the diastolic and mean blood coronary velocity from decreasing during the expiratory strain, when an increased sympathetic discharge could cause vasoconstriction through the stimulation of the coronary alpha-receptors.

Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine

Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Randomized, controlled, prospective study. Laboratory of an urban hospital. Thirty mongrel dogs. Thirty mongrel canines were anesthetized with alpha-chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to +/- 10 mg/dL [+/- 0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 microgram/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-microgram/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. During verapamil titration, the myocardial respiratory quotient increased from 0.84 +/- 0.05 to 1.07 +/- 0.11 (p < .05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p < .05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 +/- 2 vs. 39 +/- 21 microU/mL at 30 mins). Hyperinsulinemia-euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p < .05 vs. other treatments, contrast analysis). Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.

ATP sparing effect of isoflurane during ischaemia and reperfusion of the canine heart

Sustained dysfunction of myocardial contractility after short periods of coronary artery occlusion and reperfusion has been termed "stunned myocardium". Isoflurane may improve the recovery of regional myocardial contractility in stunned myocardium. The purpose of the present study was to determine if isoflurane prevents depletion of high energy phosphates after myocardial ischaemia-reperfusion and if the reduction in cardiac work during isoflurane anaesthesia contributes to the preservation of high energy phosphate metabolism in an acute canine model. Mongrel dogs were allocated to one of three groups: controls, anaesthetized with urethane and chloralose; ISO group, isoflurane administered before ischaemia; and ISOc group, heart rate and mean arterial pressure controlled to approximately match baseline values. The left anterior descending (LAD) coronary artery was occluded for 15 min and then reperfused for 60 min during 1.5% end-tidal isoflurane anaesthesia. Full thickness samples of myocardium were obtained from the reperfused area (supplied by the LAD) and the non-ischaemic area (supplied by the left circumflex coronary artery). The concentrations of adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), creatine phosphate (CP) and lactate in the endocardial portion of the myocardium were measured. Arterial pressure, aortic flow in the ascending aorta and rate-pressure product decreased significantly after isoflurane. Although the concentration of ATP of the reperfused area in the control group showed a significant reduction 60 min after reperfusion, the ISO and ISOc groups had significantly greater concentrations. Isoflurane anaesthesia maintained myocardial high energy phosphate metabolism in reperfused myocardium. We conclude that the reduction in cardiac work played only a minor role in the ATP-sparing effect of isoflurane.

Attenuation by R 56865, a novel cytoprotective drug, of regional myocardial ischemia- and reperfusion-induced electrocardiographic disturbances in anesthetized rabbits.

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.

Methimazole treatment reduces cardiac hypertrophy and mortality without a concomitant reduction in blood pressure in established Goldblatt two-kidney one clip hypertension.

The effects of methimazole, an antithyroid drug, on blood pressure and other parameters were evaluated in the established phase of Goldblatt two-kidney one clip (G2K-1C) hypertension. Methimazole was administered via drinking water for five weeks, starting five weeks after hypertension had been induced. After this period of treatment, similarly high blood pressures were observed in methimazole-treated and non-treated G2K-1 C rats, despite the fact that a hypothyroid state had been achieved in methimazole-treated rats. Methimazole-treated G2K-1 C rats showed reductions in heart rate, ventricular weight, ventricular/body weight ratio and mortality in comparison with rats not treated with methimazole. These results clearly demonstrate that hypothyroidism induced by methimazole: a) does not reverse G2K-1 C hypertension, but b) improves the rate of survival and c) reduces relative cardiac hypertrophy, possibly by the reduction in cardiac work observed in Goldblatt hypothyroid rats.

Evaluation of the effect of metoprolol on energy metabolism in the ischaemic myocardium in relation to regional myocardial blood flow.

To evaluate the effect of beta blockade on energy metabolism in ischaemic myocardium metoprolol tartrate in doses of 0.2 or 0.5 mg.kg-1 or saline was injected into 24 anaesthetised dogs 20 min after coronary ligation. Regional myocardial blood flow was measured by the hydrogen gas clearance method, and the heart rate and aortic pressure were recorded. After 60 min coronary occlusion myocardial biopsy specimens were removed from five areas where myocardial blood flow had been recorded to determine their content of adenosine-5'-triphosphate (ATP). Respiratory function and acyl-coenzyme A contents of mitochondria isolated from ischaemic and non-ischaemic myocardium were also measured. In the control group the ATP content in severely ischaemic myocardium where myocardial blood flow was less than 20 ml.min-1.100 g-1 was decreased to 27.5% of that in the non-ischaemic area, whereas the administration of metoprolol 0.5 mg.kg-1 maintained ATP content at 46.3%. In ischaemic myocardium metoprolol inhibited the accumulation of long chain acyl-coenzyme A in mitochondria and significantly preserved their respiratory function. In contrast, metoprolol did not affect myocardial blood flow in myocardium where flow was less than 60 ml.min-1.100 g-1. Heart rate was decreased by metoprolol in proportion to the dose, whereas mean aortic pressure was not changed. These results suggest that beta blockade had beneficial effects on the energy metabolism of ischaemic myocardium and that such effects might be due not only to a reduction in cardiac work but also to a reduction in the vicious circle of fatty acid metabolism in ischaemic myocardium.

Ischemic pain relief in patients with acute myocardial infarction by intravenous atenolol

Pain relieft in acute myocardial infarction (AMI) by the beta-adrenoceptor antagonist, atenolol, was demonstrated by three separate studies. First, 18 patients were randomized to double-blind intravenous atenolol (5 mg) or saline immediately after admission, followed by oral atenolol (50 mg) or placebo 10 minutes later. In patients receiving atenolol, pain relief coincided with reduction in heart rate (HR), systolic blood pressure (SBP), and HR × SBP product ( p < 0.05); however, pain and these parameters were unchanged by placebo. The degree of pain relief was related to the reduction in cardiac work achieved ( r = 0.725; p < 0.001). A second open study involving 22 patients receiving intravenous atenolol (5 to 15 mg) early after AMI showed ischemic pain relief in 17 patients. They achieved a more significant reduction in HR × SBP product than those whose pain remained unchanged ( p = 0.004). Finally, a retrospective study of 163 patients randomized to either atenolol or no beta blockade early after AMI revealed that patients receiving atenolol needed less opiate analgesia after admission ( p < 0.001). The safety of this therapy was illustrated by a decreased incidence of left heart failure and atrial fibrillation and no tendency to second- and third-degree heart block.

Reduction in myocardial ischemia by left ventricular bypass after acute coronary artery occlusion

With the use of an epicardial ST mapping technique, left ventricular bypass (LVB) was shown to reduce effectively the myocardial ischemia associated with coronary artery occlusion in dogs in proportion to the extent of bypass. Pulsatile flow was equally, but not more, effective. A reduction in cardiac work is proposed as the basis for these benefits.