Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

Summary Contractile dysfunction of reversibly injured, reperfused myocardium can be enhanced by inotropic interventions. A decrease in the Ca-sensitivity of contractile proteins with slow recovery during reperfusion has been suggested as a potential mechanism underlying this postischemic dysfunction. We therefore tested the effects of the cardiotonic agent AR-L 57 (1 mg/kg i.v.) in six anesthetized, vagotomized dogs during constant atrial pacing at 192±6 beats/min. Before ischemia, AR-L 57 increased left ventricular pressure from 131±22 to 138±21 mm Hg and maximum dP/dt from 3,022±1,427 to 4,337±2,608 mm Hg/s. Mean systolic thickening velocity of the posterior myocardium was increased from 8.9±1.1 to 11.7±1.1 mm/s. After release of a 15 min LCX-occlusion which caused complete regional akinesia, baseline function in the posterior myocardium was severely depressed and only gradually returned towards control values over 8 h of reperfusion. AR-L 57 increased systolic thickening velocity at 10 min, 4 and 8 h reperfusion to a similar extent as before ischemia. With reference to a purported Ca-sensitizing mechanism underlying the positive inotropic action of AR-L 57, our data suggest no change in the Ca-sensitivity of reperfused myocardium.     

Sex differences in the tolerance of immature rat myocardium to global ischemia

Summary Currently there is considerable interest in the metabolism of the immature myocardium and in particular the mechanisms underlying its greater tolerance to ischemia than that of the adult heart. In order to investigate whether this tolerance is sex-related, we compared the recovery of function in isolated hearts from male and female neonatal rats (three to five days old) following 60 min of normothermic global ischemia and 30 min of reperfusion (n=8 per group). The female hearts exhibited significantly better (p<0.05) recovery of rate (81±5% vs. 65±5%) and the rate-pressure product (73±9% vs. 37±8%), and a tendency towards better recovery of contractile function (left ventricular developed pressure, 89±9% vs. 59±12%; dP/dt, 84±12% vs. 54±13%). This evidence for greater resistance of female hearts to ischemic injury was supported by a delayed onset of contracture (mean time to onset, 29.4±2.7 min vs. 24.9±2.6 min). The loss in left ventricular compliance during ischemia and reperfusion was also smaller in the female hearts (increase in left ventricular end diastolic pressure, 6.5±1.2 mm Hg vs. 13.6±3.8 mm Hg). These results suggest that there may be sex-related differences in the tolerance of immature hearts to ischemia, a factor which should be taken into account in the design and interpretation of experimental studies.     

Cardiovascular response to sudden strenuous exercise

Summary Cardiac responses to sudden strenuous exercise were studied in seven dogs instrumented to measure cardiac output (Q), stroke volume (SV), left ventricular (LV) pressure, aortic pressure and circumflex coronary blood flow (CBF). The dogs were run on a treadmill at 12.9 km/h, 20% grade for 15s without prior warm-up. During the first 10s of the run, HR and Q increased rapidly. By 2s, myocardial O₂ requirements, as estimated from either the tension time index (TTI) or calculated wall tension, had increased significantly above resting values. Simultaneously, mean CBF fell 13% and stroke CBF fell 49% below resting values at the onset of sudden exercise (2s) and was associated with 17% and 21% decreases in positive and negative LV dP/dt, a 9% decrease in (dP/dt)/P and an 11% decrease in SV. After the initial decrease at 2s, these variables then increased rapidly as the run continued except for stroke CBF which never reached resting levels. HR. Q, and LV dP/dt reached near maximal values for this level of exercise by 10s after the start of exercise. In contrast, mean CBF was still increasing when the run was terminated.These data show that sudden strenuous exercise results in a transient decrease in myocardial O₂ delivery at a time when myocardial O₂ requirements are rapidly increasing. This imbalance between myocardial O₂ supply and demand is due to a transient decrease in coronary blood flow followed by a delay in metabolic regulation of CBF.     

Three-dimensional analysis of regional mechanical function,blood flow and electrophysiological parameters during early myocardial ischemia in dogs

Summary Ventricular arrhythmias are primarily responsible for sudden cardiac death early after the onset of acute myocardial ischemia. We designed an experimental model to simultaneously characterize regional myocardial function, myocardial blood flow, and electrophysiological parameters, and to determine predisposing factors for the development of early ventricular arrhythmias (EVA).The left circumflex coronary artery was occluded in six anesthetized (n=2 piritramide/N₂O, n=4 chloralose/urethane) mongrel dogs. Systolic wall thickening (% WT) in a control zone and in the central ischemic zone was measured with sonomicrometry and regional myocardial blood flow (RMBF) with colored microspheres. Excitability and relative refractory period at the stimulus electrode and conduction times to all other electrodes were determined with a three-dimensional transmural multi(16)-electrode array using a computer algorithm.In three of six dogs spontaneous EVA occurred 4 to 6 min after coronary occlusion, degenerating to ventricular fibrillation in two of these dogs. The three dogs developing EVA were not distinguished from those not developing EVA, neither by the kind of anesthesia nor by ischemic % WT (–6.6±3.8 [SD] vs –7.8±1.6, ns). Also, dogs with and without EVA did not differ significantly in excitability and relative refractory period. In contrast, dogs with EVA were characterized by a greater mass of severely ischemic myocardium, i.e., exhibiting a RMBF reduction to less than 0.1 ml/(min · g) (18±3 g vs 7±4 g, p<0.05), and by an increase in subendocardial conduction times of greater than 100% above the respective pre-ischemic values (120±18% vs 66±9%, p<0.05). Dogs with and without EVA were not as clearly distinguished by the increases in subepicardial (81±22% vs 46±15%, ns) and transmural (98±31% vs 67±14%, ns) conduction times.The development of EVA is associated with a greater mass of severely ischemic myocardium and a greater increase in subendocardial conduction times.Dedicated to Prof. Dr. Werner Meesmann on the occasion of his 68th birthday     

Effect of dopamine on regional myocardial function and oxygen consumption in experimental left ventricular hypertrophy

Summary We investigated the hypothesis that the capacity of left ventricular myocardium to respond to an inotropic challenge by dopamine would be diminished in left ventricular hypertrophy induced by plication of the aortic valve. Seven mongrel dogs (LVH group) aged 6–8 weeks and weighing 4–6 kg, were subjected to preliminary surgery in which the noncoronary sinus of Valsalva was plicated. Six months later these animals, as well as a control group of dogs, were subjected to acute experiments in which the effect of dopamine (7.5 and 15 g/kg/min) on regional and global myocardial function and oxygen consumption was studied. Myocardial segment length was measured with ultrasonic dimension transducers, and left ventricular and aortic blood pressures were recorded from catheter-tip transducers. Regional coronary blood flow was determined with radioactive microspheres, and regional oxygen saturation in small arteries and veins was measured using microspectrophotometry. Regional myocardial O₂ consumption was calculated from these parameters. Heart weights were significantly elevated in the LVH group, and a pressure gradient of about 25 mm Hg was observed across the aortic valve. In both groups, dopamine infusion produced a dose-dependent increase in heart rate, left ventricular pressure, and LV dP/dt_max. Prior to dopamine infusion, percent shortening per beat was greater in the LVH group (13.97 ± 1.2 %) than in the control group (9.49 ± 1.07 %). Although the maximum speed of segment shortening was elevated by dopamine in both groups, percent shortening was not elevated in the LVH group. Stimulation by the high dose of dopamine produced a threefold elevation in regional coronary blood flow in both groups. Oxygen extraction was unchanged; the proportion of small veins with low O₂ saturation was not elevated in LVH hearts, even during dopamine stimulation. Regional myocardial O₂ consumption was elevated by dopamine (15 g/kg/min) to about the same extent in both the control and LVH groups (19.1 ± 2.3 and 17.5 ± 2.3 ml O₂/min/100 g) respectively. It is concluded that, in dogs with six months of aortic stenosis, dopamine does not exhaust functional reserve and the relationship between O₂ supply and consumption is not significantly impaired.This study was supported in part by PHS research grant HL40320     

Different responses of left ventricular systolic function to changes in right ventricular volume and shortening —comparison between aorto-femoral vein and aorto-left atrium shunts in dog hearts

Summary It has been reported that left ventricular end-systolic volume decreases during arteriovenous shunt and increases during subclavian artery-left atrium shunt at a constant end-systolic pressure. The mechanism of the opposing changes in end-systolic volume during the two types of shunt is not clear. One possible cause is that left ventricular pump function with enhanced right ventricular ejection differs from that without enhancement. To investigate this hypothesis, we studied the two types of shunt (Aorto-femoral vein shunt, AoFV; aorto-left atrium shunt, AoLA) with matched reduction of systemic vascular resistance in open-chest dogs with -blockade. Both right and left ventricular volumes and shortenings were assessed from short-axis views by two-dimensional (2D)-echocardiogram. Left ventricular end-systolic short-axis area decreased from 76 ± 3 to 62 ± 3% in AoFV shunt (p < 0.05), but tended to increase in AoLA shunt (76 ± 4 in control state vs 81 ± 5% in AoLA, NS) in spite of a similar reduction in left ventricular end-systolic pressure. There was no difference in left ventricular shortening, but significant differences were observed in right ventricular shortening (50 ± 8 in AoFV vs 24 ± 7% in AoLA, p < 0.05) and right ventricular short-axis area at end-diastole (142 ± 6 in AoFV vs 96 ± 3% in AoLA, p < 0.01), and at end-systole (92 ± 8 in AoFV vs 73 ± 7% in AoLA, p < 0.05) between the two types of shunt. We conclude that the different changes in left ventricular end-systolic short-axis area found in the two shunts are not caused by the different left ventricular shortenings, but by the different right ventricular mechanical actions. These findings suggest that left ventricular pumping action in the high output state changes, depending on whether it is accompanied by augmented ejection of the right ventricle or not.     

Quantitative Doppler tissue imaging as a correlate of left ventricular contractility

Doppler tissue imaging is a new noninvasive imaging modality that allows quantitation of the low intensity, high amplitude Doppler shifts in the range of myocardial tissue motion. This study was performed to test the hypothesis that Doppler tissue imaging may provide unique information reflecting left ventricular systolic function, and to test the relationship between myocardial tissue velocity and noninvasive measures of ventricular contractility. Nine patients with mild or moderate mitral insufficiency and no regional wall motion abnormality were studied during dobutamine stress echocardiography. Left ventricular ejection fraction and peak systolic velocity of the sub- endocardial left ventricular posterior wall were quantified at baseline and at peak stress and compared with estimated peak dP/dt. During dobutamine infusion, ejection fraction increased from 41.7±22.2 (range 14 to 70) % to 56.6±27.9 (range 17 to 84) % (p=0.001), peak systolic velocity increased from 22.7±4.2 (range 18 to 28) mm/sec to 35.3±10.1 (range 20 to 47) mm/sec (p=0.004), and dP/dt increased from 1050±322 (range 613 to 1574) mm Hg/sec to 1766±768 (range 936 to 3000) mm Hg/sec (p=0.01). Although there were good correlations between left ventricular dP/dt and both ejection fraction (R=0.75) and peak systolic velocity (R=0.81), the correlation between change in dP/dt and change in myocardial velocity (R=0.75) was better than that between change in dP/dt and change in ejection fraction (R=0.36). These data support the hypothesis that myocardial velocity determined with Doppler tissue imaging reflects myocardial contractility, and that catecholamine- induced alteration in contractility is better reflected by changes in myocardial velocity than by changes in ejection fraction.     

The oxygen consumption paradox of “stunned myocardium” in dogs

Summary The contractile state of the heart is a major determinant of myocardial oxygen consumption. Since regional myocardial contractility can be severely impaired following a transient coronary occlusion, post-ischemic myocardium is frequently assumed to consume less oxygen. To test this assumption, regional myocardial function and oxygen consumption were studied in ancsthetized dogs during 2 h of myocardial reperfusion following either a 15-min (Group I) or 4-h (Group II) left anterior descending coronary artery occlusion. Both groups developed similar post-ischemic regional dysfunction characterized by paradoxical motion (negative shortening). Measured as a percent of baseline segment shortening, anterior wall function in Group I (n=8) and Group II (n=5) at 30 min of reperfusion was –33±11% and –34±16% (p=NS) and at 120 min was –23±9% and –40±16% (p=NS). However, the two groups showed a marked difference in regional myocardial oxygen consumption during reperfusion. Despite the abnormal wall motion, regional oxygen consumption in Group I at 30 and 120 min of reperfusion was unchanged from pre-ischemic levels as measured as a percent of bascline: 104±20% (p=NS) and 111±21% (p=NS). In contrast, regional oxygen consumption in Group II was markedly depressed from bascline at 30 and 120 min of reperfusion: 42±7% (p<.01) and 40±8% (p<.01). To determine whether the dissociation between regional myocardial oxygen consumption and function in Group I was related to mitochondrial uncoupling, six additional dogs were studied. Tissue samples were obtained from post-ischemic myocardium after 120 min of reperfusion following a 15-min coronary artery occlusion, and compared to non-ischemic myocardium. There were no differences in the in vitro mitochondrial respiratory rates or oxidative phosphorylation capacity between the post-ischemic and non-ischemic myocardium. Therefore, in the post-ischemic myocardium, significant depressions in regional contractility may not be associated with falls in oxygen consumption. Following a 15-min coronary artery occlusion, the injured myocardium maintains a paradoxically high oxygen consumption with normal mitochondrial function despite decreased contractility and abnormal wall motion.Grant Support: Dr. Dean was a Fellow of the American Heart Association. Dr. Nicklas is supported by the NIH Clinical Investigator Award, HL 011170.     

Attenuation of the systemic and coronary hemodynamic effects of cocaine in conscious dogs: propranolol versus labetalol

Summary The interaction of cocaine with myocardial and vascular adrenoceptors is incompletely understood. The systemic and coronary hemodynamic effects of intravenous cocaine (1.5 mg/kg) were examined in dogs with and without pretreatment with propranolol (2 mg/kg i.v.) or labelatol (5 mg/kg i.v.) on different days. A total of 24 experiments was completed (three sets of experiments) using eight dogs chronically instrumented for measurement of aortic and left-ventricular pressure, left-ventricular dP/dt, subendocardial segment length, coronary blood flow, and cardiac output. Myocardial oxygen consumption was estimated from the pressure work index (PWI). Cocaine significantly (p<0.05) increased heart rate (+51±17 bpm), mean arterial pressure (+72±10 mm Hg), left-ventricular systolic and end-diastolic pressures (+56±9 and +14±6 mm Hg, respectively), coronary blood flow (+32±10 ml/min) and the PWI (+10.0±2.3 ml O₂/min/100 g). Significant reductions in stroke volume (–9±5 ml) and percent segment shortening (–7.1±1.7) were observed. These changes returned to control after 30 min. After pretreatment with propranolol, the cocaine-mediated increases in mean arterial pressure, left-ventricular systolic pressure, rate-pressure product, and the pressure work index (4.4±0.7 ml O₂/min/100 g) were significantly (p<0.05) less than those observed with cocaine alone. Cocaine also reduced contractility [dP/dt₅₀ (–341±80 mm Hg/s)] and increased systemic vascular resistance (+2703±339 dyn·s·cm^–5) in the resence of propranolol. Labetalol abolished the cocainemediated increases in heart rate and coronary blood flow and significantly attenuated the increases in mean arterial pressure, left-ventricular systolic pressure, cardiac output, rate-pressure product, and calculated myocardial oxygen consumption when compared to results obtained with cocaine alone. The results demonstrate that a portion of the basic dynamic effects of cocaine is mediated by stimulation of alpha and beta adrenoceptors. Combined alpha and beta adrenergic blockade reduces the hemodynamic effects of cocaine more than beta blockade alone. During antagonism of the sympathomimetic response of cocaine, direct negative inotropic actions of this drug are unmasked.This work was supported by US PHS grants HL 36144 and HL 32911, Anesthesiology Research Training Grant GM 08377, and VA Medical Research Funds.     

Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts

Summary It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dt_max) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dt_max (4196±74 mm Hg s^–1) and beating rate (322±8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p<0.001) than those of the euthyroid hearts (3267±115 mm Hg s^–1 and 260±6 beats/min at an external Ca²⁺ of 2.5 mM). At 2.5 mM Ca²⁺, the working hyperthyroid hearts again displayed enhanced contractility (5636±179 mm Hg s^–1 vs 4508±172 mm Hg s^–1; p<0.001) but the spontaneous beating rate (275±7 beats/min) was not significantly different from euthyroid (261±8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p<0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H₂O to 120 cm H₂O caused significant changes in left ventricular pressure and dP/dt_max in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H₂O; hyperthyroid, 294±9 beats/min; euthyroid, 224±10 beats/min; p<0.001). Alteration of the preload (10 to 25 cm H₂O) and afterload (75 to 105 cm H₂O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dt_max but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.     

Regional and global biventricular function during dipyridamole stress testing

This study assesses the relation between regional ventricular performance (using 2-dimensional echocardiography) and global systolic and diastolic indexes of biventricular myocardial function (using hemodynamic monitoring) during dipyridamole stress testing. Simultaneous 2-dimensional echocardiographic and biventricular hemodynamic monitoring during dipyridamole infusion (0.56 mg/kg over 4 minutes) was performed in 19 patients. All patients had a normal resting function. Eleven of the 19 patients had a positive echocardiography test (new wall motion dyssynergy with dipyridamole) and they formed group 1. Eight patients had a negative echocardiography test (group 2). During baseline conditions, no significant differences were found in the 2 groups: rate pressure product (107 +/- 16 vs 108 +/- 13 mm Hg x beats/min x 1/100), positive left ventricular (LV) dP/dt (1,950 +/- 473 vs 2,262 +/- 430 mm Hg/s), negative LV dP/dt (-2,069 +/- 620 vs -2,205 +/- 245), LV end-diastolic pressure (8.2 +/- 4.4 vs 9.6 +/- 4.0 mm Hg), right ventricular positive dP/dt (368 +/- 133 vs 400 +/- 190 mm Hg/s) and negative dP/dt (-281 +/- 89 vs -383 +/- 147). At peak dipyridamole, the 2 groups were different for LV end-diastolic pressure (20 +/- 10 vs 8 +/- 5 mm Hg, p less than 0.01), LV positive dP/dt (2,100 +/- 688 vs 3,013 +/- 851 mm Hg/s, p less than 0.01) and negative dP/dt (-1,868 +/- 518 vs -2,564 +/- 272, p less than 0.01). At peak ischemia, LV positive dP/dt increased slightly, but not significantly, while negative dP/dt decreased significantly (p less than 0.01) in comparison with resting values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium metabolism and depressed contractility in isolated human and porcine heart muscle

Summary Contractility is often depressed in isolated heart muscle. To analyze this phenomenon, we measured the derivative of left ventricular pressure (dP/dt) in intact and in isolated, blood perfused pig hearts, and peak force (F) or stress (F/mm²) in ventricular trabeculae of man and pig. When the heart was in the steady state at a priming frequency of 2 Hz an extrasystolic interval of 0.3 s was interposed, followed by four postextrasystolic intervals of 0.8 s. In the case of isolated trabeculae the priming frequency was 0.2 Hz, the extra interval 0.4 s, and the post-extrasystolic intervals were 5 s. The exponential decay of potentiation is characterized by the constant D: a low value of D indicates a rapid decay of potentiation. DP/dt was about 1000 mm Hg/s in the intact hearts, but within 1 h after isolation dP/dt decreased to about 700 mm Hg/s, and this was associated with a decrease in D from 0.63 to 0.40. Developed stress in the isolated trabeculac was about 2 mN/mm² and D was about 0.20 under standard, in vitro conditions (a.o. 1.5 mM Ca²⁺, 0.2 Hz stimulus frequency). This stress is only 10% of the calculated stress in the intact heart. An increase of priming frequency, or of [Ca²⁺], or addition of 30 nM isoproterenol to the perfusate caused a marked increase in F and D. Properties of human and porcine trabeculae were quantitatively similar. The strong correlation between dP/dt, or F, and D suggests a causal relationship. This is consistent with the current model of e-c coupling in heart muscle, in which the activity of the Ca²⁺ pump of the sarcoplasmic reticulum determines the decay of potentiation and the amount of releasable Ca²⁺ in the reticulum determines force of contraction. Since isoproterenol stimulates the Ca²⁺ pump in the reticulum, the increase in D and F induced by this drug is consistent with the model. We conclude, that the decreased dP/dt, F, and D in isolated preparations was due to impaired sarcoplasmic reticulum function. The role of this phenomenon in the stunned heart syndrome, species differences and possible causes are discussed.     

Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy

Simultaneous biventricular pacing improves left ventricular (LV) function in patients with heart failure and LV asynchrony. Proper timing of the interventricular pacing interval (VV interval) may further optimize LV function. We investigated the acute hemodynamic response of changing the VV interval using maximum LV dP/dt (LV dP/dt_max) as a parameter for LV function. A biventricular pacemaker was implanted in 53 patients with severely impaired LV function, New York Heart Association class III and IV heart failure, left bundle branch block, LV asynchrony, and a QRS interval >150 ms. Optimization of the atrioventricular and VV intervals was based on measurement of LV dP/dt_max by a 0.014-in sensor-tipped pressure guidewire. Measurement of LV dP/dt_max was obtained without complications in all patients. In patients in sinus rhythm with ischemic cardiomyopathy or idiopathic dilated cardiomyopathy, mean improvements by simultaneous biventricular pacing were 17% and 18%, respectively. Patients in atrial fibrillation showed an improvement of 21%. Optimizing the VV interval resulted in further absolute increases of 8%, 7%, and 3%, respectively, in dP/dt_max in the 3 groups. Maximum dP/dt was achieved with LV pacing first in 44 patients, simultaneous right and left ventricular pacing in 6 patients, and right ventricular pacing first in 3 patients. The mean optimal VV intervals were 37 ± 32 ms in the atrial fibrillation group, 28 ± 30 ms in the idiopathic dilated cardiomyopathy group, and 52 ± 31 ms in the ischemic cardiomyopathy group. Optimization of the VV interval significantly increased LV dP/dt_max compared with simultaneous biventricular pacing, and such optimization could be easily, accurately, and reliably evaluated by a 0.014-in sensor-tipped pressure guidewire.     

Contribution of left ventricular contraction to the generation of right ventricular systolic pressure in the human heart

To determine whether left ventricular (LV) contraction contributes to the generation of right ventricular (RV) systolic pressure in humans, LV and RV pressures and their first derivative (dP/dt) were recorded simultaneously with micromanometer-tipped catheters in 11 conscious subjects. Seven subjects had normal LV and coronary angiograms. Four subjects had moderate LV dysfunction (resting ejection fraction 0.40 to 0.50), and three of these had coronary artery disease. During normal sinus rhythm, LV contraction slightly preceded RV contraction (mean 20 msec), and LV and RV dP/dt recordings showed single positive systolic peaks that were coincident. During endocardial pacing of the RV free wall, RV contraction preceded LV contraction (mean 23 msec) and two systolic RV dP/dt peaks were recorded, the first (peak I) occurring significantly before (mean +/- SD = 67 +/- 23 msec, p less than .01), and the second (peak II) coincident with the single systolic LV dP/dt peak. RV ectopic beats produced a similar RV dP/dt pattern, with peak I occurring 63 +/- 11 msec (p less than .01) before, and peak II coincident with the single LV dP/dt peak. Conversely, during LV ectopic beats, LV contraction preceded RV contraction (mean 63 msec) and two systolic RV dP/dt peaks were recorded, but peak I was coincident with the single LV dP/dt peak, while peak II occurred significantly later (63 +/- 26 msec, p less than .01). In two subjects right bundle branch block produced similar findings. In three subjects left bundle branch block produced little ventricular asynchrony (mean 14 msec), but did delay the development of peak LV dP/dt after LV contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis

Inotropic reserve, demonstrated with administration of sympathomimetic amines, is characteristic of hibernating myocardium. The goal of this study was to determine whether inotropic reserve was present following chronic coronary artery constriction in the pig, which is one potential model of hibernating myocardium. The effects of isoproterenol were examined in five conscious pigs 21±2.1 days after ameroid implantation on the left circumflex coronary artery on measurements of left ventricular (LV) pressure, LV dP/dt, and regional wall thickening in the ameroid-dependent zone (posterior wall) and contralateral non-ischemic zone (anterior wall). Isoproterenol, 0.1 g/kg/min, increased LV dP/dt by 96±11%, heart rate by 43±13 beats/min, and normalized systolic wall thickening, slightly, but not significantly more in the ameroid-dependent zone (+1.57±0.31 mm) than in the contralateral non-ischemic zone (+1.04±031 mm), although the baseline wall thickening was reduced significantly in the ameroid-dependent zone. This occurred at a time when baseline myocardial blood flow was preserved and myocardial perfusion in the ameroid-dependent zone was derived in part from the native coronary circulation and also through collateral channels. Two weeks later histological evidence of lesions characteristics of hibernating myocardium, i.e., myofibrolysis and increased glycogen deposition, were observed. Thus, these histological changes and the confluence of chronically depressed regional function and residual inotropic reserve in the conscious pig with chronic ameroid-induced coronary constriction support this model for further study of hibernating myocardium.Supported in part by USPHS grants HL 33065, 33107 and 38070     

Independent mechanisms for the chronotropic and inotropic responses in hyperthyroidism

Summary We established a hyperthyroid rat model and compared the hemodynamic responses of the hypertrophied rat heartin vivo andin vitro. Heart rate (557±26 beats/min), systolic blood pressure (162±5 mm Hg) and dry heart mass (230±11 mg) in hyperthyroid rats were significantly greater than in control animals (408±12 beats/min, 140±5 mm Hg and 193±4 mg respectively).In vitro studies were performed in order to eliminate neurohumoral and peripheral circulatory factors which are presentin vivo. In thein vitro working heart preparation, there was no significant difference between the heart rates of L-thyroxine-treated (263±9 beats/min) and control (258±10 beats/min) animals, implying that the tachycardia of hyperthyroidism is partly mediated byin vivo factors. Consistent with this hypothesis was the observation that the hyperthyroid heart was more sensitive to the chronotropic effects of physiological concentrations of the synthetic catecholamine, isoproterenol (10^–8M, 10^–7 M) than the control heart. The maximum rate of left ventricular pressure rise (dP/dt_max) was used as an index of myocardial contractility.In vitro values for dP/dt_max were significantly greater in hearts from hyperthyroid rats (5338±228 mm Hg/s) than in control hearts (4583±158 mm Hg/s), suggesting that the increased contractile response of hyperthyroidism is intrinsic to the heart itself. Although persistence of the inotropic response of the hyperthyroid heartin vitro was associated with an increase in heart mass, this factor alone did not account entirely for the enhanced contractility. It appears that intrinsicfunctional changes also contribute to the inotropic response of the hyperthyroid heart.     

Mechanical catecholamine responsiveness and myosin isoenzyme pattern of pressure-overloaded rat ventricular myocardium

Summary Pressure-overloaded cardiac hypertrophy was induced by abdominal aortic constriction in 10-week-old male Wistar rats. 24–26 weeks after aortic constriction, the hearts were excised and a myocardial mechanical study was performed using isolated left ventricular papillary muscles. There was no significant difference in isometric developed tension (T) between sham-operated control and aortic constriction (AC) rats (control vs AC rats=2.9±0.6 vs 2.7±0.7 g/mm²). dT/dt_max of AC rats, on the other hand, was significantly lower than that of controls (controls vs AC rats=32.8±7.5 vs 26.3±6.1 g/mm²sp<0.05). Myocardial mechanical responses to isoproterenol (10^–7 mol/l) were depressed in the group with aortic constriction compared with the control group (T:18.5±6.7 vs 12.1±4.9%,p<0.05, dT/dt: 25.2±6.2 vs 17.5±5.8%,p<0.02). Responses of the parameters to dibutyryl cyclic AMP (10^–5 mol/l) were also smaller in the AC group than in the control group (T: 18.0±5.6 vs 13.3±4.0%,p<0.05, dT/dt: 20.4±6.9 vs 14.7±4.1%,p<0.05). Left ventricular myosin isoenzyme pattern, revealed by pyrophosphate gel electrophoresis, shifted towards VM-3 under pressure overload. The present study demonstrates that post-membrane processes may be mainly responsible for the decreased myocardial mechanical catecholamine responsiveness in pressure-overloaded cardiac hypertrophy.Supported by Tanaka Memorial Medical Research Fund     

Can coronary systolic-diastolic flow differences be predicted by left ventricular pressure or time-varying intramyocardial elastance?

Summary In six isolated rabbit hearts perfused with a pressure source and Krebs-Henseleit as the perfusion medium, the effect of left ventricular pressure on coronary inflow in the maximally vasodilated bed was studied. This effect was determined from isovolumic beats, low afterloaded isobaric beats (afterload maintained at values below 10 mm Hg) and during cardiac arrest. For isovolumic beats end-diastolic left ventricular pressure was varied by means of an intraventricular balloon between 0–40 mm Hg and systolic left ventricular pressure varied between 90–130 mm Hg. In these ranges diastolic inflow decreased significantly 18±6% (mean±SD) with increasing pressure and systolic inflow could not be shown to depend on pressure (n=6). For isobaric beats, diastolic and systolic inflow remained at values similar to those found for the isovolumic beats (n=6). In the arrested heart inflow diminished 8±2% when the pressure in the left ventricle was increased from 0 to 40 mm Hg (n=3). We conclude that systolic coronary inflow is hardly affected by left ventricular pressure. Systolic inflow decreased by the same amount in the isovolumically and isobarically beating heart, when cardiac contractility was enhanced by epinephrine infusion. We suggest the results can be explained on the basis of the time-varying elastance concept: systolic elastance is the same for isovolumic and isobaric beats but depends on contractility. Models that relate coronary inflow impediment to left ventricular pressure should therefore be reevaluated.This investigation is supported by the Netherlands Organisation for the Advancement of Pure Research (NWO-grant: FHC-5 810-906-005).     

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart

Summary The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and cuthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dt_max) was lower in the hyperthyroid (0.81±0.07 mM) than in the cuthyroid hearts (1.12±0.09 mM, p<0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p<0.01) depression in dP/dt_max after 12 min in the hyperthyroid (50±7%) than in the cuthyroid heart (15±2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.     

Regional myocadial blood flow and cardiac mechanics in dog hearts with CO2 laser-induced intramyocardial revascularization

Summary Laser-induced intramyocardial revascularization (LIR) has been used to promote direct communications between blood within the ventricular cavity and that of the existing myocardial vasculature in an attempt to increase perfusion in patients with ischemic heart discase. This study was conducted to measure the effects of LIR channels on regional myocardial flood flow (microspheres), cardiac mechanics (sonomicrometers), and myocardial tissue pressures in 18 dogs. Under baseline hemodynamic conditions (mean HR=165.2±11.4 bpm, LVP=123.6±22.9/4.0±1.8 mmHg, AoP=112.8±27.1/77.0±22.5 mmHg), myocardial blood flow in laser-treated tissue (mean =1.11±.10 cc/min/gm before laser; .71±.19 cc/min/gm after laser) was reduced as compared to blood flow in control tissue (mean=1.12±.15 cc/min/gm before laser; 1.25±.22 cc/min/gm after laser). Regional myocardial systolic shortening (11.32%±3.82% before laser; 7.49%±2.86% after laser) was decreased by 33%. During simultaneous reversible ligation of the LAD and LCCA for 2 min, when intramyocardial channels represented the only tissue access for the injected microspheres, blood flow in laser-treated tissue was not increased above that of the control non-lasered tissue. However, regional blood flow was greater in laser-treated ischemic tissue (mean=.61±.12 cc/min/gm) than in untreated ischemic areas (mean=.04±.03 cc/min/gm) when left ventricular pressure (LVP) was acutely elevated (mean SLVP=207.0±16.1 mmHg). Using these measurements, a model is proposed to predict regional systolic pressure gradients between the left ventricular cavity and coronary intramyocardial vasculature required to permit restoration of blood flow to ischemic myocardium. We conclude that improved perfusion via laser-induced intramyocardial channels does not occur in otherwise normal myocardium exposed to acute coronary ligation and only small improvements in perfusion are noted when LVP is significantly elevated. Consideration of further clinical application of this approach is seriously cautioned awaiting additional experimental studies.This study was supported by U.S. Public Health Service Grant R01 HL32897-01 from the National Heart, Lung, and Blood Institute, by grants in aid from the American Heart Association, and by the Fulbright-Hays Scholarship Grant.