Effects of altered site of electrical activation on myocardial performance during inotropic stimulation

The effects of altering the site of electrical activation on responses to isoproterenol (ISO) and treadmill exercise were examined in mongrel dogs instrumented for long-term measurement of left ventricular pressure, left ventricular dP/dt, coronary blood flow, cardiac output, left ventricular diameters, and mean arterial pressure and O2 content in the coronary sinus and aorta. During spontaneous rhythm, 0.2 micrograms/kg/min ISO increased heart rate by 90 +/- 7 beats/min, left ventricular dP/dt by 2479 +/- 301 mm Hg/sec, cardiac output by 3.5 +/- 0.9 liters/min, coronary blood flow by 30.4 +/- 3.9 ml/min, and myocardial oxygen consumption (MVO2) by 3.91 +/- 0.84 ml/min. During right atrial pacing at 193 +/- 7 beats/min, the effects of ISO were not different from the effects during spontaneous rhythm, with the exception of a lesser increase in coronary blood flow and lesser reductions in coronary resistance and left ventricular end-diastolic diameter and pressure. During right ventricular pacing at an identical rate, ISO increased left ventricular dP/dt (1140 +/- 158 mm Hg/sec) and cardiac output (2.2 +/- 0.5 liters/min) significantly less (p less than .025) than during either sinus rhythm or right atrial pacing, while MVO2 rose to a higher value. During right ventricular pacing the changes in mean arterial pressure and left ventricular end-diastolic diameters with ISO were not significantly different from those during right atrial pacing. Treadmill exercise induced significantly smaller (p less than .025) increases in left ventricular dP/dt during right ventricular pacing as compared with during either right atrial pacing or sinus rhythm, while MVO2 rose to a higher value.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preservation of left ventricular performance with reduced ischemic dysfunction by intravenous nisoldipine

The effect of intravenous nisoldipine on cardiac performance was examined during pacing-induced ischemia in 14 patients with coronary artery disease. The relative contributions of afterload reduction or prevention of myocardial ischemia were assessed using load-independent global (peak-systolic pressure/end-systolic volume) and regional (peak-systolic pressure/end-systolic radial length) "contractile" indexes. Nisoldipine decreased aortic pressure (predrug, 109 +/- 14 vs postdrug, 88 +/- 13 mm Hg, p less than 0.01) and prevented elevation of left ventricular end-diastolic pressure during rapid atrial pacing (predrug, 7.9 +/- 5.7 vs postdrug, -0.5 +/- 4.9 mm Hg, p less than 0.001). Resting cardiac index (predrug, 3.3 +/- 0.6 vs postdrug, 4.2 +/- 0.7 liters/min/m2, p less than 0.05), and left ventricular ejection fraction (predrug, 68.1 +/- 9.0 vs postdrug, 74.2 +/- 9.4%, p less than 0.05) increased after nisoldipine, which also prevented the deterioration in left ventricular ejection fraction (predrug, -8.1 +/- 7.9 vs postdrug, -1.0 +/- 3.7%, p less than 0.05) and fractional radial shortening (predrug, -8.7 +/- 13.1 vs postdrug, 3.7 +/- 16.4%, p less than 0.01) during rapid atrial pacing. Under these conditions, nisoldipine preserved myocardial function, as determined by global peak-systolic pressure/end-systolic volume (predrug, -0.82 +/- 0.39 vs postdrug, 0.17 +/- 1.54 mm Hg/ml, p less than 0.05) and regional (peak-systolic pressure/end-systolic radial length, predrug, -23.8 +/- 36.1 vs postdrug, 12.7 +/- 36.3 mm Hg/cm, p less than 0.01) "contractile" indexes. Intravenous nisoldipine maintains ventricular performance during rapid atrial pacing via a combination of systemic vasodilation and amelioration of ischemic myocardial dysfunction.     

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)     

Alterations in left ventricular relaxation during atrioventricular pacing in humans

To determine whether the asynchronous left ventricular contraction-relaxation sequence that exists during right ventricular pacing alters left ventricular relaxation, measurements of both the maximal rate of decline of left ventricular pressure (peak negative dP/dt) and the time constant of left ventricular relaxation were obtained during atrial and atrioventricular (AV) pacing in 25 patients referred for diagnostic cardiac catheterization. Heart rate was maintained at 10 to 15 beats/min above the sinus rate at rest, and relaxation was assessed during atrial pacing, AV pacing and repeat atrial pacing. The patients were classified into two groups. Group 1 included 10 patients with normal left ventricular systolic function at rest (ejection fraction greater than 0.55) and without evidence of prior myocardial infarction. Group 2 included 15 patients with a depressed left ventricular ejection fraction or akinesia of one or more left ventricular segments on the contrast ventriculogram, or both. Heart rate, peak left ventricular systolic pressure, end-systolic pressure and end-diastolic pressure remained constant during atrial, AV pacing and repeat atrial pacing in all patients. In group 1 patients, the decrease in peak negative dP/dt (1,507 +/- 200 versus 1,424 +/- 187 mm Hg/s) and the increase in the time constant of left ventricular relaxation (48 +/- 11 versus 51 +/- 11 ms) during AV pacing was not significantly different when compared with values during atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of increasing heart rate on left ventricular performance in patients with normal cardiac function

The influence of an increase in heart rate on left ventricular (LV) contractile performance was assessed in patients with normal LV function. In 19 patients (3 men, 16 women) ages 55 +/- 9 years (mean +/- standard deviation) with normal global and segmental LV function and normal coronary arteries, LV dP/dt max was measured at baseline heart rate and during atrial pacing at baseline +5, baseline +25 and baseline +45 beats/min. In 10 of the patients, intravascular volume was not altered during pacing and, as a result, echocardiographically measured LV end-diastolic dimension decreased (5.4 +/- 0.4 at baseline vs 4.9 +/- 0.5 cm at baseline +45 beats/min, p less than 0.05). In these patients, LV dP/dt max increased modestly (1,571 +/- 237 at baseline vs 1,760 +/- 199 mm Hg/s at baseline +45 beats/min, p less than 0.05). In the other 9 patients, intravascular volume was expanded rapidly (by saline infusion) during pacing and, as a result, LV end-diastolic dimension was held constant (5.2 +/- 0.6 at baseline vs 5.1 +/- 0.6 cm at baseline +45 beats/min, difference not significant). In these patients, LV dP/dt max increased substantially with pacing (1,505 +/- 228 at baseline vs 2,050 +/- 258 mm Hg/s at baseline +45 beats/min, p less than 0.05). Thus, an increase in heart rate induces a modest increase in LV dP/dt max in patients in whom LV preload (as reflected by end-diastolic dimension) is allowed to decrease; in contrast, it causes a marked increase in LV dP/dt max in those in whom LV preload is maintained constant.     

Effects of verapamil and nifedipine on rate of left ventricular relaxation in coronary arterial disease patients

We have evaluated the effects of nifedipine and verapamil on rate of left ventricular relaxation in 26 patients having coronary arterial disease with normal ejection fraction and normal left ventricular contractility. None of the patients had myocardial infarction. All patients showed normal contractile indices and abnormally high values of T constant, neg, dP/dt and left ventricular protodiastolic pressure, suggesting an impairment of left ventricular relaxation. Nifedipine, injected intravenously (15 micrograms/kg) in 14 patients induced a significant reduction of afterload parameters and an increase of contractility. Nifedipine also improved left ventricular relaxation, as it induced a reduction of the T constant from 42 +/- 2 msec to 33 +/- 2 msec (P less than 0.01). It induced a tendency to a reduction of negative dP/dt and protodiastolic pressure without reaching statistical significance. Verapamil, injected intravenously in the remaining 12 patients (0.1 mg/kg as a bolus followed by chronic infusion of 0.005 mg/kg/min for 3 min) induced a reduction of the T constant from 43 +/- 10 to 37 +/- 6 msec (P less than 0.01). It reduced the negativity of dP/dt from 2302 +/- 273 to 2021 +/- 252 mm Hg/sec (P less than 0.05) and of left ventricular protodiastolic pressure from 3.2 +/- 1.4 to 1.5 +/- 1.1 mm Hg (P less than 0.01). Verapamil, like nifedipine, reduced the afterload parameters although to a lesser extent. It did not substantially affect the left ventricular contractility. These data suggest that abnormalities of left ventricular relaxation may precede changes in systolic function and that nifedipine and verapamil favourably modify the indices of left ventricular diastolic function in patients with coronary arterial disease.     

The efficacy of intermittent coronary sinus occlusion in the absence of coronary artery collaterals

The purpose of this study was to evaluate the efficacy of time-controlled intermittent coronary sinus occlusion (ICSO) in preserving regional and global mechanical function during acute ischemia in an animal preparation without significant arterial collateral vessels. Seventeen (eight control, nine ICSO) swine heart preparations undergoing extracorporeal coronary perfusion in situ were subjected to ligation of the left anterior descending coronary artery (LAD) distal to the first major diagonal branch. Data were obtained before and immediately after coronary artery ligation in both animal groups. ICSO, 15 sec of occlusion alternating with 5 sec of release, was then begun in the treatment group. Additional data were obtained in both control and treatment groups at 15 min intervals for 1 hr starting immediately after coronary artery ligation. Global left ventricular function was assessed by shifts in left ventricular end-diastolic pressure and left ventricular dP/dt with left ventricular systolic pressure maintained at about 100 mm Hg. Regional mechanical function was evaluated with transmurally placed ultrasonic crystals. Pressure was also measured directly in the coronary sinus and LAD distal to the ligature. Regional myocardial blood flow was measured in the ischemic bed using 9 micron diameter radiolabeled microspheres injected before, immediately after, and 60 min after coronary artery ligation in both treated and control animals. LAD mean pressure measured distal to the ligation (less than 16 mm Hg) and ischemic bed myocardial blood flow (less than 0.01 ml/g/min) confirmed the absence of significant arterial-arterial collaterals in this preparation. Mean coronary sinus pressure increased significantly (p less than .001) in treated animals during ICSO (e.g., 11.2 +/- 1.6 to 66.2 +/- 10.0 mm Hg at 15 min after coronary ligation). Mean LAD pressure distal to the coronary ligature also increased during ICSO (14.2 +/- 1.2 to 26.8 +/- 1.6 mm Hg), with a similar but delayed rate of pressure rise. No significant differences in left ventricular end-diastolic pressure or left ventricular dP/dt were noted between control or treated animals after coronary ligation. Ischemic bed systolic wall thickening, present before coronary ligation, was not present after occlusion and was not improved during intermittent coronary sinus occlusion in the treatment group. We conclude that in an animal preparation without significant collateral circulation, intermittent coronary sinus occlusion is incapable of restoring regional or global left ventricular mechanical function during conditions of acute ischemia.     

Effects of acute K-strophantidin administration on left ventricular relaxation and filling phase in coronary artery disease.

In 10 patients with coronary artery disease, preserved left ventricular (LV) performance and absence of previous myocardial infarction, the effects of an acute intravenous administration of k-strophantidin (0.005 mg/kg over 10 minutes) on selected parameters of both LV systolic and diastolic function, including relaxation, were evaluated. An increase in positive first derivative of LV pressure (dP/dt) and in the ratio between dP/dt and the pressure developed (dP/dt/P) (1,530 +/- 287) 1,600 +/- 329 mm Hg/s [p less than 0.05], and 30 +/- 6 to 34 +/- 8 s-1 [p less than 0.05], respectively) demonstrated the inotropic effect of k-strophantidin, whereas volumetric parameters of systolic function (end-systolic and stroke volume indexes, and ejection fraction) did not show any significant change. However, LV relaxation was impaired by k-strophantidin injection; in fact, mean values of T constant were significantly increased from 50 +/- 12 to 55 +/- 13 ms (p less than 0.01). Lowest LV and end-diastolic pressures increased from 8 +/- 4 to 11 +/- 4 mm Hg (p less than 0.05) and from 17 +/- 6 to 20 +/- 8 mm Hg (p less than 0.05), respectively. The end-diastolic volume and maximal rate of volumetric increase during the early and late filling phases were not modified by k-strophantidin. Mean aortic pressure increased from 110 +/- 10 to 120 +/- 12 mm Hg (p less than 0.001). Therefore, in patients with coronary artery disease and LV preserved performance, an acute intravenous administration of k-strophantidin appears to stimulate contractility and to worsen relaxation, and minimal LV and end-diastolic pressures.     

Effect of ischemia and reperfusion on sarcoplasmic reticulum calcium uptake.

To investigate the mechanism underlying postischemic cardiac dysfunction (myocardial stunning), contractility and adenine nucleotide metabolism were studied in three groups of isolated perfused rabbit hearts (control, ischemic, and reperfused), whereas Ca2+ uptake by the sarcoplasmic reticulum (SR) was measured in homogenates obtained from them. The hearts were Langendorff-perfused under constant pressure with Krebs-Henseleit solution at 37 degrees C. Global normothermic ischemia was produced by closing the perfusion line. In the reperfused group, after 15 minutes of ischemia, Krebs-Henseleit solution was perfused for 10 minutes. Developed left ventricular pressure (control, 104 +/- 6.3 mm Hg) and left ventricular dP/dt (2,063 +/- 256.6 mm Hg.sec-1) were significantly decreased in reperfused hearts (left ventricular pressure, 78 +/- 5.9 mm Hg; left ventricular dP/dt, 1,339 +/- 216.3 mm Hg.sec-1). Myocardial ATP content (control, 13.6 +/- 0.98 mumol/g dry wt) decreased during ischemia (4.5 +/- 1.23 mumol/g) but was restored to control level on reperfusion (11.8 +/- 0.68 mumol/g). Maximum velocity of Ca2+ uptake by the SR (Vmax) (control, 49.3 +/- 2.54 nmol.min-1 x mg-1) was significantly depressed by ischemia (36.3 +/- 1.94 nmol.min-1 x mg-1) but was restored to the control value after a 10-minute reperfusion (45.3 +/- 0.79 nmol.min-1 x mg-1). Apparent dissociation constant KCa and the Hill coefficient for Ca2+ uptake were not different between control, ischemia, and reperfusion. To test for the possible role of the SR Ca(2+)-release channel in the effect of ischemia and reperfusion, we measured Ca2+ uptake after incubation of homogenates with 610 microM ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)     

The dependence of myocardial ultrasonic integrated backscatter on contractile performance

We have recently shown that the cardiac cycle-dependent variation in myocardial ultrasonic integrated backscatter is blunted with regional ischemia in dogs. To determine if global and intramural regional myocardial contractile performance can be quantified by integrated backscatter, we analyzed ultrasonic responses after induction of increased and decreased contractility in five dogs. A recently developed analog data-acquisition system for measuring integrated backscatter in real time was used to sample radiofrequency signals gated from subepicardial or subendocardial regions. Base-line recordings of integrated backscatter, left ventricular pressure, left ventricular dP/dt, and wall thickness were made at 12 left ventricular sites for both intramural regions. Contractility was modified subsequently by either paired pacing or propranolol to produce significantly elevated or depressed values for maximum left ventricular dP/dt compared with baseline (1083 +/- 289 to 3001 +/- 570 mm Hg/sec; p less than .01 for all). The amplitude of the cyclic variation of integrated backscatter was 50% greater (arithmetically) in subendocardial than in subepicardial regions for all treatments (7.6 +/- 0.3 vs 6.0 +/- 0.5 dB, p less than .001). The maximum rate of change in integrated backscatter waveforms during isovolumetric contraction was faster with paired pacing and slower with propranolol than at baseline for all regions (56 +/- 6 to 74 +/- 6 to 82 +/- 5 dB/sec, p less than .005). The maximum rate of change in integrated backscatter also was greater in subendocardial than subepicardial regions (p less than .001). Thus, both regional and global differences in myocardial contractile performance are manifest quantitatively in integrated backscatter waveforms. We propose that the physiologic determinants of these differences may depend on regional and global variations in myofibril elastic characteristics.     

Altered left ventricular diastolic properties during pacing-induced angina in patients with aortic stenosis

An increase in left ventricular diastolic pressure has been repeatedly observed during angina in patients with coronary artery stenoses and regional demand ischemia, but the role of relaxation abnormalities versus left ventricular segmental dyssynchrony is controversial. In contrast, patients with angina due to aortic stenosis are likely to have diffuse rather than segmental ischemia and thus may provide an alternative model for examining the diastolic physiology of angina in man. Accordingly, we examined the hemodynamic manifestations of angina in eight patients with aortic stenosis without significant coronary artery disease. Angina was induced by pacing tachycardia, and hemodynamic and echocardiographic variables were measured in the control period and during angina in the beats immediately after cessation of pacing. Heart rate (control vs angina, 69 +/- 12 vs 70 +/- 11 beats/min, p = NS) and left ventricular peak systolic pressure (207 +/- 39 vs 222 +/- 22 mm Hg, p = NS) were similar in the control and postpacing angina periods. Left ventricular end-diastolic pressure, on the other hand, was significantly higher during postpacing angina (15 +/- 7 vs 28 +/- 8 mm Hg, p less than .01). The time constant of left ventricular pressure decline during isovolumetric relaxation (TL), calculated as the slope of a linear fit of the natural log of pressure vs time, increased from 44 +/- 5 to 51 +/- 7 msec (p less than .05); the time constant TD, derived from the slope of a linear fit of dP/dt vs pressure, also increased slightly, although the change was not statistically significant (69 +/- 5 vs 75 +/- 5 msec, p = .06).(ABSTRACT TRUNCATED AT 250 WORDS)     

Contractile and relaxation reserve of the left ventricle. IV. Patients with coronary heart disease (author's transl)

51 patients with coronary heart disease had exercise tests on a bicycle ergometer (86 +/- 32 watts). Compared to a normal control group, only 13 patients had normal contractile reserve (group 4.1). In 32 patients the increase in contractility during exercise was reduced (max dP/dt below 3200 mm Hg/s, group 4.2). Patients with reduced contractile reserve were graded according to the height of left ventricular enddiastolic pressure during exercise: In patients with grade 1, enddiastolic pressure was normal. In patients with grade 2, enddiastolic pressure increased between + 4 and + 15 mm Hg and in the patients with grade 3a a above + 15 mm Hg. Contractile and relaxation reserve decreased along with a rise in enddiastolic pressure and an increase in the complaints of the patients. Severe chest pain led to termination of exercise in patients of grade 3b. Enddiastolic pressure increased above + 15 mm Hg. During ischemia, peak-measured velocity of contractile elements (dP/dt/P) and the maximal rate of left ventricular pressure fall (min dP/dt) decreased. In conclusion, with increasing chest pain a decrease of contractile reserve was observed. Left ventricular enddiastolic pressure rose excessively. This has to be taken as a sign of myocardial failure due to ischemic dyskinesia and impeded relaxation.     

Beta-adrenergic stimulation with isoproterenol enhances left ventricular diastolic performance in hypertrophic cardiomyopathy despite potentiation of myocardial ischemia. Comparison to rapid atrial pacing

Impaired left ventricular relaxation and filling is an important pathophysiologic mechanism in hypertrophic cardiomyopathy. To determine whether isoproterenol, known to improve relaxation in isolated cardiac muscle, could favorably modify this effect, we assessed simultaneous left ventricular volume and regional systolic asynchrony (by radionuclide angiography), left ventricular pressure (by micromanometer catheters), and lactate metabolism in 12 patients with hypertrophic cardiomyopathy. Pressure-volume relations were studied during atrial pacing stress to induce myocardial ischemia and during isoproterenol infusion to similar heart rates. Angina occurred in 10 patients with pacing and in 11 patients during isoproterenol infusion; lactate consumption was reduced in nine patients during isoproterenol compared with pacing, including five patients who produced lactate with isoproterenol. During isoproterenol compared with pacing, peak left ventricular pressure was higher (205 +/- 33 vs. 142 +/- 21 mm Hg, p less than 0.001), ejection fraction was higher (77 +/- 10% vs. 71 +/- 12%, p less than 0.02), and regional systolic nonuniformity was diminished. Despite ischemia, these changes in load and nonuniformity during isoproterenol were associated with enhanced diastolic function compared with pacing tachycardia: isoproterenol reduced T 1/2, the half-time of pressure decline after peak negative dP/dt (from 46 +/- 10 to 33 +/- 6 msec, p less than 0.001), shifted the diastolic pressure-volume curve downward and rightward in 10 of 12 patients, and increased end-diastolic volume (from 77 +/- 18% to 100 +/- 11% of control values, p less than 0.001) with no change in end-diastolic pressure (19 +/- 7 to 19 +/- 5 mm Hg, p = NS). Thus, despite ischemia, isoproterenol improved left ventricular relaxation and filling compared with tachycardia in the absence of beta-adrenergic stimulation. Although isoproterenol is detrimental in hypertrophic cardiomyopathy by provoking ischemia, these data suggest that the adverse effects of ischemia on ventricular relaxation and distensibility may be alleviated by beta-adrenergic stimulation, possibly as a result of enhanced inactivation and restored load sensitivity.     

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. III. Influence of basal heart rate

The influence of basal heart rate (HR) on the effects of inotropic (dobutamine infusion) and chronotropic (atrial pacing) stimuli during acute myocardial ischemia was assessed by measurement of intramural carbon dioxide partial pressure (PCO2) in open-chest dogs undergoing transient 10-minute left anterior descending coronary artery occlusions. In protocol I, in 5 dogs anesthetized with pentobarbital alone, HR increased from 153 +/- 10 to 182 +/- 7 beats/min between experimental coronary occlusions, but the increase in ischemic zone intramural carbon dioxide tension (delta PmCO2) was not altered by this significant increase in HR. In protocols II to V, dogs were anesthetized with combinations of morphine, thiamylal and pentobarbital and had a basal average HR of 81 beats/min. Atrial pacing in protocol II (13 dogs) increased HR from 76 +/- 21 to 134 +/- 19 beats/min (p less than 0.001); left ventricular (LV) myocardial oxygen consumption (MVO2) rose from 3.9 +/- 1.6 to 4.9 +/- 1.4 ml/min/100 g (p less than 0.05), and delta PmCO2 rose from 42 +/- 14 to 50 +/- 15 mm Hg (p less than 0.01), indicating more severe ischemic injury during the second experimental coronary occlusion. In protocol III, 11 dogs received 20 micrograms/kg/min of dobutamine before the second experimental occlusion, which significantly (p less than 0.02) increased HR, LV dP/dt and MVO2; delta PmCO2 increased from 46 +/- 13 to 63 +/- 18 mm Hg (p less than 0.01). The 7 dogs in protocol IV received 3.9 +/- 1.9 micrograms/kg/min of dobutamine, titrated such that HR was unchanged (84 +/- 10 vs 81 +/- 15 beats/min), but LV dP/dt increased by 92% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute decrease in left ventricular diastolic chamber distensibility during simulated angina in isolated hearts

It is not clear what factors contribute to the prompt and reversible decrease in left ventricular diastolic chamber distensibility during angina pectoris that is induced by an increase in myocardial energy demand due to exercise or pacing tachycardia. To simulate the demand ischemia that occurs clinically during pacing-induced angina, we used isolated, blood-perfused rabbit hearts with restricted coronary flow and increased myocardial energy demand. A constant left ventricular balloon volume model was used to measure left ventricular diastolic chamber distensibility during 6 minutes of low-flow global ischemia, induced by a reduction in coronary perfusion pressure from 100 to 20 mm Hg. To investigate the influence of different levels of myocardial energy demand, the effects of two different heart rates were studied during low-flow global ischemia; pacing tachycardia (6.4 +/- 0.2 Hz, n = 7) was compared with the rabbit's baseline heart rate of 4 Hz (n = 7). Low-flow ischemia caused a marked decrease in contractile function relative to the baseline preischemic state. In the pacing-tachycardia group, myocardial energy demand, as estimated by the rate X systolic pressure product, was significantly greater than in the constant heart-rate group. When tachycardia was imposed during low-flow global ischemia, there was a transient and reversible increase in isovolumic left ventricular end-diastolic pressure from 14 +/- 1 to 25 +/- 4 mm Hg (measured during long diastoles obtained with transient cessation of pacing) in the pacing-tachycardia group, but there was no increase in left ventricular end-diastolic pressure during low flow ischemia in the constant heart-rate group with lower energy demand (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures

To study the mechanism and hemodynamic significance of myocardial ischemia in hypertrophic cardiomyopathy, 20 patients (nine with resting left ventricular outflow tract obstruction greater than or equal to 30 mm Hg) with a history of angina pectoris and angiographically normal coronary arteries underwent a pacing study with measurement of great cardiac vein flow, lactate and oxygen content, and left ventricular filling pressure. Compared with 28 control subjects without hypertrophic cardiomyopathy, their resting coronary blood flow was higher (91 +/- 27 vs 66 +/- 17 ml/min; p less than .001) and their coronary resistance was lower (1.13 +/- 0.38 vs 1.55 +/- 0.45 mm Hg/ml/min; p less than .001). Left ventricular end-diastolic pressure (16 +/- 6 vs 11 +/- 3 mm Hg; p less than .001) and pulmonary arterial wedge pressure (13 +/- 5 vs 7 +/- 3 mm Hg; p less than .001) were significantly higher in patients with hypertrophic cardiomyopathy. During pacing, coronary flow rose in both groups, although coronary and myocardial hemodynamics differed greatly. In contrast to the linear increase in flow in control subjects up to heart rate of 150 beats/min (66 +/- 17 to 125 +/- 28 ml/min), patients with hypertrophic cardiomyopathy demonstrated an initial rise in flow to 133 +/- 31 ml/min at an intermediate heart rate of 130 beats/min. At this point, 12 of 20 patients developed their typical chest pain. With continued pacing to a heart rate of 150 beats/min, mean coronary flow fell to 114 +/- 29 ml/min (p less than .002), with 18 of 20 patients experiencing their typical chest pain and metabolic evidence of myocardial ischemia. This fall in coronary flow was associated with a substantial rise in left ventricular end-diastolic pressure (30 +/- 9 mm Hg immediately after peak pacing). In the 14 patients whose coronary flow actually fell from intermediate to peak pacing, the rise in left ventricular end-diastolic pressure in the same interval was greater than that of the six patients whose flow remained unchanged or increased (11 +/- 8 vs 2 +/- 2 mm Hg; p less than .01). In addition, despite metabolic and hemodynamic evidence of myocardial ischemia, the arteriovenous O2 difference actually narrowed at peak pacing. Thus most patients with hypertrophic cardiomyopathy achieved maximum coronary vasodilation and flow at modest increases in heart rate. Elevation in left ventricular filling pressure, probably related to ischemia-induced changes in ventricular compliance, was associated with a decline in coronary flow.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion

Prolonged nontransmural ischemia was produced and the early and late effects of reperfusion were studied in 10 conscious dogs instrumented over the long term. Five hours of partial circumflex coronary artery stenosis was produced with a hydraulic occluder, followed by gradual release over 20 min, with measurements of left ventricular pressure, regional myocardial function (systolic wall thickening by sonomicrometry), coronary blood flow velocity (pulsed Doppler), and myocardial blood flow (microspheres). During coronary stenosis the occluder was adjusted frequently to maintain a reduction of systolic wall thickening to 50% to 75% of control (average 62.6% of control). Myocardial blood flow in the ischemic area at 4 hr of partial coronary stenosis was reduced in the inner layers of the myocardium (subendocardium, from 0.81 +/- 0.18 at control to 0.36 +/- 0.08 SD, p less than .01; midwall, from 0.77 +/- 0.20 to 0.46 +/- 0.07 ml/min/g, p less than .01), accompanied by significant ST segment elevation on the subendocardial electrogram (0.83 +/- 0.96 to 4.58 +/- 4.10 mV; p less than .05) and decreased left ventricular dP/dt (3503 +/- 462 to 2991 +/- 339 mm Hg/sec; p less than .01). Within a few minutes after complete release of partial coronary stenosis, ST segments returned to control and myocardial blood flow of the inner layers was increased (subendocardium, 1.37 +/- 0.39, p less than .01; midwall, 0.97 +/- 0.28, p less than .05), but systolic wall thickening and left ventricular dP/dt were significantly depressed and remained reduced at 24, 48, and 72 hr when myocardial blood flow was normal. By seven days, systolic wall thickening and left ventricular dP/dt had returned to control (94.1 +/- 7.0% of control, 3353 +/- 605 mm Hg/sec, respectively; NS). Histologic changes caused by ischemia constituted only 2.7% (average) of the tissue between the crystals in the ischemic wall, but ischemic damage in the posterior papillary muscle, which did not contain crystals, was 31.9%. Thus, regional myocardial dysfunction reduced by nontransmural ischemia for 5 hr persisted for at least 3 days, with only slight damage to the left ventricular free wall but considerable infarction of the posterior papillary muscle. Full recovery of regional and global contractile function of the free wall then occurred within a period of 1 week.     

The effect of acute alterations in left ventricular afterload and beta-adrenergic tone on indices of early diastolic filling rate

The effects of an acute increase in left ventricular systolic pressure and the effects of an intravenous isoproterenol infusion on myocardial (segment) lengthening rate and chamber (minor axis dimension) filling rate were examined in 12 anesthetized dogs. Measurements of left ventricular systolic pressure (by micromanometer) and of segment length and chamber dimension transients (by ultrasonic crystals) were made in variably afterloaded beats (three-beat descending aortic cross-clamp) before and during an isoproterenol infusion that raised (+)dP/dt by 40%. During the baseline state, we found an inverse relation between the peak rate of increase in minor axis dimension [(+)dD/dt] and systolic pressure over a wide range of systolic pressures (110-160 mm Hg) and end-systolic dimensions (25-40 mm); peak (+)dD/dt and end-systolic dimension were also inversely related. During isoproterenol infusion, end-systolic dimension fell from 29.7 +/- 3.1 to 28.0 +/- 3.1 mm and (+)dD/dt increased from 79.6 +/- 8.0 to 90.1 +/- 8.7 mm/sec; however, the slope and y intercept of the relation between (+)dD/dt and end-systolic dimension were unchanged. Peak (+)dD/dt at a common end-systolic dimension of 31 mm was nearly equal during baseline and isoproterenol states (64.2 +/- 6.3 vs. 65.1 +/- 6.6 mm/sec). Similar results were found using segment length transients. We interpret these data to indicate that (+)dD/dt is strongly influenced by changes in systolic pressure and dimension and that isoproterenol-induced changes in (+)dD/dt are mediated, at least in part, through changes in systolic pressure and dimension.     

Regional myocardial blood flow and left ventricular diastolic properties in pacing-induced ischemia

The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses, left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing, with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses, indicating decreased regional diastolic distensibility. In dogs without coronary stenoses, the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries, and a decrease in regional vascular resistance. In dogs with coronary stenoses, regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses, regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g, p less than 0.01), as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog

To determine the contribution of transsarcolemmal calcium flux to abnormal diastolic function produced by brief periods of flow-limiting ischemia and reperfusion, we evaluated early and late diastolic function during transient coronary occlusion and reperfusion before and during administration of intravenous nifedipine (NIF) (10 +/- 1 microgram/kg/min) in nine preinstrumented conscious dogs. We also assessed the effects of nitroprusside (NTP) (2 +/- 0.2 micrograms/kg/min) during an identical period of ischemia and reperfusion to independently assess the consequences of altered loading alone on diastolic function. To minimize the effects of temporal dysynchrony and altered ventricular loading conditions on isovolumetric relaxation, we developed a conscious dog preparation of reversible transient (30 to 60 sec) bilateral coronary occlusion (BCO). BCO was characterized by significant systolic depression: maximum (+)dP/dt decreased (from 2617 +/- 600 to 1981 +/- 565 mm Hg/sec, p less than .05), left ventricular transverse dimension shortening diminished (from 20 +/- 5 to 9 +/- 5%, p less than .05), and the left ventricle dilated (42.4 +/- 6.4 to 43.8 +/- 6.3 mm, p less than .05). Concomitantly the time constants of isovolumetric relaxation prolonged (from 22 +/- 3 to 28 +/- 4 msec, p less than .05) and minimal diastolic left ventricular pressure increased (from -3 +/- 6 to 6 +/-6 mm Hg, p less than .05). The passive diastolic pressure-dimension relationship shifted upward and to the right and was associated with increased chamber stiffness (from 0.50 +/- 0.26 to 1.03 +/- 0.53 mm Hg/mm, p less than .05) and increased left ventricular end-diastolic pressure (from 7 +/- 7 to 19 +/- 7 mm Hg, p less than .05). Reperfusion immediately after BCO was characterized by prompt restoration of systolic contractile performance [maximum (+)dP/dt 3220 +/- 530 mm Hg/sec] but persistently abnormal early and late diastolic function (time constant of isovolumetric relaxation 30 +/- 6 msec, left ventricular end-diastolic pressure 20 +/- 7 mm Hg). The effects of drug administration on ventricular function during BCO were then evaluated under matched loading conditions. NTP improved time constant of isovolumetric relaxation (20 +/- 8 vs 28 +/- 4 msec, p less than .05) and minimal diastolic left ventricular pressure (2 +/- 5 vs 6 +/- mm Hg, p less than .05) during BCO, but NIF did not (time constant of isovolumetric relaxation 27 +/- 6 msec, minimal diastolic left ventricular pressure 7 +/- 5 mm Hg).(ABSTRACT TRUNCATED AT 400 WORDS)