Thomas Patrick

Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure.

We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.

Left Ventricular Response to Severe Exertion in Untethered Dogs

The left ventricular response to severe exercise was studied by telemetering direct measurements of left ventricular diameter (D) and pressure (P) and aortic blood flow from healthy dogs running at speeds up to 30 mph in the field. Severe exercise increased cardiac output from 101 to 478 ml/kg per min, heart rate from 95 to 297 beats/min, stroke volume from 31 to 44 ml, left ventricular isolength (iso) systolic pressure from 120 to 186 mm Hg, left ventricular end diastolic pressure from 6 to 18 mm Hg, and left ventricular end diastolic diameter from 58.9 to 60.1 mm, while end systolic diameter decreased from 53.0 to 52.2 mm. Two indices of myocardial contractility, (dP/dt)/P increased from 37 to 92 sec(-1), while dD/dt, the velocity of myocardial fiber shortening at isolength, rose from 54 to 119 mm/sec. All of these changes were statistically significant. When, in resting dogs, heart rate was first raised to exercise levels by electrical stimulation, severe exercise subsequently increased left ventricular end diastolic diameter more profoundly, from 55.7 to 59.7 mm, while end systolic diameter remained constant and the increases in left ventricular pressure, (dP/dt)/P and velocity(iso) were roughly comparable to those occurring during exercise in spontaneous rhythm. After propranolol, 1.0 mg/kg, severe exercise resulted in significantly smaller increases in cardiac output (from 82 to 240 ml/kg), in heart rate (from 87 to 186 beats/min), in left ventricular pressure(iso) (from 122 to 150 mm Hg), in (dP/dt)/P (from 32 to 44 sec(-1)), in velocity(iso) (from 47 to 59 mm/sec), and in slightly greater increases in end diastolic diameter, from 59.8 to 62.0 mm and pressure from 8 to 22 mm Hg, while end systolic diameter did not change significantly.Thus, the left ventricle responds to severe exercise with near maximal increases in heart rate and contractility, while significant increases in end diastolic diameter (Frank-Starling mechanism) and stroke volume occur as well. When heart rate was held constant severe exercise produced similar increases in contractility but end systolic size failed to diminish and the increases in end diastolic size were greater. Beta adrenergic receptor blockade interfered with the chronotropic and particularly the inotropic response to severe exercise and while the participation of the Frank-Starling mechanism was somewhat greater, the latter was not sufficient to increase cardiac output normally.

Effects of Catecholamines, Exercise, and Nitroglycerin on the Normal and Ischemic Myocardium in Conscious Dogs

The effects of isoproterenol, norepinephrine, dobutamine, exercise, and nitroglycerin on left ventricular diameter, pressure, velocity of shortening, dP/dt, dP/dt/P, arterial pressure, left circumflex coronary blood flow, and coronary vascular resistance were examined in healthy conscious dogs with normal coronary perfusion and in the same animals after moderate global ischemia had been induced by partial occlusion of the left main coronary artery. In the normal nonischemic heart, all interventions improved left ventricular performance, as evidenced by increases in dP/dt/P and velocity at the same or lower left ventricular end-diastolic diameter. Interventions, which in the normal heart caused large increases in heart rate and myocardial contractility, e.g. isoproterenol and exercise, or which decreased coronary perfusion pressure, e.g. nitroglycerin or isoproterenol, elicited paradoxical responses in moderate global ischemia, i.e., left ventricular enddiastolic diameter and pressure rose, and dP/dt/P and velocity fell substantially. On the other hand, norepinephrine, which increased coronary perfusion pressure along with myocardial contractility but did not increase heart rate, improved left ventricular function. Dobutamine, which did not alter heart rate or arterial pressure substantially while improving myocardial contractility, produced an intermediate response between that of norepinephrine and isoproterenol in the presence of moderate global myocardial ischemia. Thus, interventions that increase myocardial O(2) requirements, by increasing heart rate and myocardial contractility without augmenting coronary perfusion pressure, can produce a paradoxical depression of ventricular function in the presence of global myocardial ischemia.

The peripheral vascular response to severe exercise in untethered dogs before and after complete heart block

The peripheral vascular response to severe exercise was studied in 11 healthy conscious dogs instrumented with Doppler ultrasonic flow probes on the mesenteric, renal, and iliac arteries, and miniature pressure gauges in the aorta. The response to severe exercise was restudied in six of these dogs after recovery from a second operation producing complete heart block by the injection of formalin into the atrioventricular (AV) node. Three of these dogs also exercised while their ventricles were paced at rates of 100/min and 200/min. The untethered normal dogs ran at speeds of 15-25 miles/hr behind a mobile recording unit for a distance averaging 1.5 miles, while continuous measurements of arterial blood pressure and blood flow were telemetered and recorded on magnetic tape. Severe exercise in normal dogs increased heart rate from 84 to 259/min, arterial pressure from 89 to 140 mm Hg, flow resistance in the mesenteric and renal beds by 59 and 52% respectively, and iliac blood flow 479% above control, while mesenteric and renal blood flows remained constant and iliac resistance decreased by 73%. In dogs with complete AV block, severe exercise at speeds of 10-18 miles/hr increased heart rate from 47 to 78/min, mean arterial pressure from 81 to 89 mm Hg, iliac flow 224%, resistance in the renal bed by 273%, and mesenteric bed by 222% while it decreased blood flow in mesenteric and renal beds by 61 and 65% respectively, and iliac resistance by 62%. A similar response occurred during exercise with pacing at 100/min, but when paced at 200/min a more normal exercise response reappeared. Thus, in normal dogs the peripheral vascular response to severe exercise involved increases in heart rate, arterial pressure and visceral resistance but visceral blood flow did not decrease. In dogs with heart block, where the ability to increase heart rate is severely compromised, compensatory reduction of mesenteric and renal blood flows occurred.

Effects of cardiac depression and of anesthesia on the myocardial action of a cardiac glycoside

The effects of ouabain (G-strophanthin) 20 mug/kg, on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (dD/dt), and dP/dt were studied in conscious dogs instrumented with ultrasonic diameter gauges and miniature pressure gauges. The effects of ouabain were compared on separate occasions in the same dogs after cardiac depression with propranolol, 3.0 mg/kg, and also after general anesthesia with Na pentobarbital, 30 mg/kg. Maximal pressor effects were observed in the first 10 min, but maximal effects on the contractile state occurred at 30 min after ouabain. At this time, in conscious dogs, ouabain had increased LV isolength systolic pressure by 5%, LV isolength velocity by only 9%, and LV (dP/dt)/P by 21%, while end systolic diameter (ESD) decreased slightly and end diastolic diameter (EDD) and heart rate (HR) were unchanged. After anesthesia, ouabain increased LV systolic pressure by 8%, velocity 32%, (dP/dt)/P by 47%, and ESD decreased by 1.2 mm while EDD rose slightly and HR fell by 26 beats/min. Returning HR to control with atrial pacing decreased EDD 0.9 mm below control. After cardiac depression with propranolol, ouabain caused responses similar to those observed in the anesthetized dogs. Thus, the cardiac glycoside was found to exert only minor inotropic effects on the nonfailing heart of conscious dogs but far more striking inotropic responses in the anesthetized state.

Effects of Cardiac Denervation on Development of Heart Failure and Catecholamine Desensitization

BACKGROUND Two signatures of heart failure are activation of the sympathetic nervous system and catecholamine desensitization. However, whether or not the elimination of cardiac nerves affects either the progression of heart failure or catecholamine desensitization is not clear. METHODS AND RESULTS We studied 8 dogs with selective ventricular denervation (VD) (surgical technique) and 10 intact dogs, chronically instrumented for measurement of left ventricular (LV) and arterial pressures, LV dP/dt, LV internal diameter, and wall thickness before and after heart failure was induced by rapid pacing (240 bpm) for 3 to 4 weeks. VD was confirmed by the absence of reflex effects induced by intracardiac veratrine and depletion of tissue norepinephrine and by supersensitive responses to norepinephrine. During the development of heart failure, LV end-systolic and end-diastolic stresses and heart rate increased, while myocardial contractility, as reflected by LV dP/dt and mean velocity of circumferential fiber shortening corrected for heart rate (Vcf(c)), decreased in both intact and VD dogs. However, the increases in LV end-diastolic stress and decreases in LV dP/dt as well as the relationship between LV systolic stress and Vcf(c) in heart failure were less (P<.05) in VD dogs. The responses of LV dP/dt and heart rate to both isoproterenol and norepinephrine in intact dogs were reduced in heart failure. The physiological desensitization to the inotropic effects of isoproterenol and norepinephrine was less in dogs with VD (P<.05), but chronotropic responses were similar because atrial innervation remained intact. Plasma norepinephrine levels were not different in VD dogs (592+/-79 pg/mL) compared with intact dogs (576+/-81 pg/mL) in heart failure. CONCLUSIONS Dogs with selective VD tolerated the development of heart failure better than intact dogs and demonstrated significantly less catecholamine desensitization. The latter indicates that intact ventricular innervation is required for physiological expression of catecholamine desensitization despite comparable elevation of plasma catecholamines during the development of heart failure.

Effects of Prostaglandin A1 on the Systemic and Coronary Circulations in the Conscious Dog

The effects of intravenous prostaglandin A1 (PGA1) on systemic and coronary hemodynamics were studied in 13 intact, conscious dogs after recovery from operation for implantation of Doppler ultrasonic flow probes on the ascending aorta and left circumflex coronary artery. Graded doses of PGA1 (0.01 to 1.0 μg/kg) caused arterial pressure and total systemic resistance to decrease progressively and heart rate and cardiac output to increase progressively. At the maximum dose administered (1.0 μg/kg), arterial pressure and systemic resistance decreased by averages of 30% and 51% below control, respectively, and heart rate and cardiac output rose 64% and 47%, respectively. After beta-receptor blockade with propranolol, PGA1 still caused a similar increase in cardiac output. In spite of arterial hypotension, PGA1 produced a progressive increase in coronary flow, with a peak increase of 74% above control with 1.0 μg/kg and a corresponding graded decrease in coronary resistance, with a decrease of 61% below control with 1.0 μg/kg. Marked increases occurred in systolic as well as diastolic coronary flow. The coronary vasodilation was not abolished by preventing the PGA1-induced tachycardia with electrical pacing, by beta-receptor blockade, or by combined blockade of beta receptors and cholinergic nerve fibers. While arterial Po2 remained constant, coronary sinus Po2 rose when coronary flow was increased by PGA1. Thus PGA1 is both a primary and secondary coronary vasodilator which increases cardiac output and decreases total systemic resistance.