Dean Franklin

Regional Myocardial Function during Acute Coronary Artery Occlusion and Its Modification by Pharmacologic Agents in the Dog

Myocardial regional function during acute coronary artery occlusion was studied using ultrasonic dimension gauges in open-chest dogs. Three pairs of 2-mm ultrasonic crystals were implanted 1 cm apart near the endocardium in an ischemic segment, a control segment, and a segment at the margin of the ischemic zone. In the ischemic segment, coronary artery occlusion resulted in prompt dyskinesis which progressed to holosystolic expansion; length at enddiastole (diastolic length) increased by 11%, segment stroke work decreased by 91%, and the diastolic pressure-length relationship was displaced and steepened. In the marginal segment, active shortening and stroke work decreased by 37% and diastolic length increased by 4%. In the control segment, an initial increase in active shortening was observed, followed by compensatory operation of the Frank-Starling mechanism. Nitroglycerin administered during coronary artery occlusion decreased diastolic length and increased shortening in all three segments. An early beneficial effect of isoproterenol on all segments was later replaced by deterioration in marginal and ischemic segments. After propranolol administration, the decrease in shortening of the marginal segment was reduced to half of that observed during a control coronary artery occlusion, suggesting a protective effect of this drug. These results indicate the power of this approach, which provides continuous quantification of regional wall function in myocardial ischemia and during therapeutic interventions.

Adaptations of the left ventricle to chronic pressure overload.

Left ventricular (LV) function during the adaptation to chronic pressure overload produced by an ascending aortic constriction was analyzed in conscious dogs, instrumented with intraventricular micromanometers and pairs of ultrasonic crystals for measurement of LV wall thickness (WTh) and internal LV chamber diameter. During inflation of the cuff to produce LV pressures averaging 220 mg Hg, calculated peak wall stress (WSt) increased by 55% above control while percent shortening decreased by 24% and mean circumferential shortening velocity (VCF) decreased by 39% from control. By 9 days (mean) after aortic constriction, the cross-sectional area (CSA) of the LV wall increased by 10% and peak WSt fell to 37% above control. End-diastolic diameter (EDD) increased to 4% above control, while percent shortening and mean VCF remained reduced at -12% and -20% of control, respectively. During the phase of concentric hypertrophy (mean 2 1/2 weeks), CSA increased further to 15% above control and WSt fell to 22% above control, while EDD and percent shortening returned to control and mean VCF increased to -7% of control (not significant). At 24 hours after release of the cuff WSt, percent shortening, mean VCF, and peak velocity of LV pressure rise (peak dP/dt) were not significantly different from control. Rapid, partial regression of hypertrophy was observed in some dogs. Thus, the left ventricle responds to chronically elevated pressure by initial dilation with increased WSt followed by gradual wall thickening and consequent reduction of WSt to near normal. After successful adaptation to the pressure overload, hypertrophy per se did not produce intrinsic depression of the myocardial inotropic state.

Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog.

SUMMARY Pairs of ultrasonic dimension gauges and a micromanometer implanted in the subendocardium of the left ventricles of unanesthetized dogs were used to analyze serial changes in hemodynamic status and segmental function for up to 4 weeks after permanent circumflex coronary artery occlusion. Regional function was studied in control segments and in segments identified as marginal (hypokinetic) and ischemic. In three dogs, after transient regional dysfunction, no myocardial infarction developed, whereas in five dogs regional dysfunction at 3 hours after occlusion was followed by the development of persistent dysfunction and infarction. Left ventricular end-diastolic segment length (EDL) changes over time; EDL of the control segments increased progressively, but in marginal segments EDL was 12% below control and in the ischemic segments 30% below control by 4 weeks. Progressive increases in percent active shortening occurred in control segments, but holosystolic bulging was replaced by akinesia in ischemic segments, and persistent reduction in shortening was present in marginal segments at 4 weeks. Correlations were found between percent scar and reductions in percent shortening, EDL, and the ratio of change in diastolic length to change in diastolic pressure. These methods have detected hyperfunction in normal regions and variable segmental loss of contractile function, together with reduction of subendocardial dimensions and changes that may reflect decreased diastolic compliance in ischemic regions. We conclude that this model for the conscious animals may be useful for studying the influence of therapy on the extent of myocardial damage after experimental coronary occlusion.

Dynamic changes in left ventricular wall thickness and their use in analyzing cardiac function in the conscious dog

The thickness of the left ventricular free wall and internal chamber diameter were continuously measured by pairs of ultrasonic crystals together with left ventricular pressure in normal conscious dogs. During the resting state, wall thickness decreased abruptly with the onset of atrial contraction from 10.5 mm to an average end-diastolic valueof9.8 mm. In contrast to most previous studies, there was no change in wall thickness during isovolumic systole, and with ejection the wall thickened by 31.3 percent of end-diastolic wall thickness. Atrial pacing, phenylephrine, isoproterenol and propranolol produced significant changes in chamber size with reciprocal changes in wall thickness. In addition, changes in the extent and velocity of left ventricular chamber shortening in the minor equator were associated with comparable reciprocal changes in the extent and velocity of free wall thickening (correlation coefficients 0.97 to 0.99). During acute coronary occlusion, progressive reductions in the extent and velocity of regional wall shortening with partial ischemia were associated with comparable changes in systolic wall thickening characteristics (r = 0.96 and 0.95), and holosystolic elongation in fully ischemic areas was associated with holosystolic wall thinning. During chronic pressure overload, despite wall thickening, the relation between chamber shortening and wall thickening were retained and direct computation of dynamic wall stress variations was possible. These measurements allowed precise definition of the dynamics of the left ventricular wall during normal and abnormal cardiac states. The demonstration that in the absence of regional dysfunction analysis of wall thickness in a single region of ventricular free wall can be used to describe myocardial and overall left ventricular function, as well as regional function in the presence of ischemia, constitutes a new approach to the assessment of cardiac function that has potential for echocardiographic applications.

Left Ventricular Dimensions Recorded by Sonocardiometry

A new technic for continuously recording the dimensions of internal organs in intact unanesthetized animals has been developed as a modification of sonar technics. A sound is emitted by a small barium titanate crystal mounted on one side of the left ventricle, and the time required for the sound waves to pass through the chamber to another crystal on the opposite side is monitored 1,000 to 2,500 times/sec. Such crystals have continued to function reliably for more than 3 months after installation in the animal. Changes in left ventricular diameter have been recorded during spontaneous cardiac responses to various conditions including physical exertion on a treadmill.

Coronary arterial reperfusion. III. Early and late effects on regional myocardial function and dimensions in conscious dogs

Regional myocardial function was studied in five conscious chronically instrumented dogs for 4 weeks after coronary reperfusion following a 2 hour period of occlusion of the left circumflex coronary artery. A cuff and flowmeter were placed around the left circumflex coronary artery, and a micromanometer and three pairs of ultrasonic crystals were implanted 1 cm apart subendocardially in control, marginal and ischemic segments of the left ventricle. Control normal segments showed progressive increases in end-diastolic length and extent of active shortening. Ischemic segments tended to show slight improvement early after reperfusion, but in succeeding weeks, despite some improvement in shortening, they showed progressive decreases in end-diastolic length compatible with subendocardial tissue loss. In marginally ischemic segments, shortening initially remained depressed after reperfusion, but showed late recovery so that shortening and end-diastolic length were not different from control values by 4 weeks. These results contrasted with findings in five similarly studied dogs subjected to permanent coronary occlusion; in that group the data suggested greater tissue loss and less recovery of function in marginal and ischemic segments. The late return of segmental function and reduced loss of subendocardial tissue several weeks after coronary reperfusion suggest that substantial time periods may be required to assess the ultimate effect of therapeutic interventions. The findings further indicate that in this experimental model the usual time constraints for occurrence of irreversible tissue damage do not apply to all of the myocardium within the ischemic zone.

Effects of Carotid Sinus Nerve Stimulation on Blood-Flow Distribution in Conscious Dogs at Rest and during Exercise

The effects of stimulating the carotid sinus nerves on the distribution of cardiac output and peripheral vasoactivity was studied in intact, unanesthetized dogs instrumented with ultrasonic or electromagnetic flow probes on the ascending aorta, mesenteric, renal, and iliac arteries, and miniature pressure gauges in the aorta. A radiofrequency pacemaker was used to stimulate the nerves in dogs at rest, during treadmill exercise, and after autonomic blockade. Thirty-second periods of stimulation in the resting dog resulted in an average decrease in aortic pressure of 28%, cardiac output remained unchanged, total peripheral resistance fell 29%, mesenteric flow 12%, mesenteric vascular resistance 18%, renal flow 8%, and renal vascular resistance 22%. In the iliac bed flow increased by 90% while resistance declined by 62%. Heart rate decreased initially by 13%, and returned to control during stimulation. The bradycardia was determined to be predominantly due to vagal stimulation. During treadmill exercise carotid sinus nerve stimulation resulted in similar decreases in arterial pressure, mesenteric and renal resistance, and a further decrease in iliac resistance from exercise control values. Thus, electrical stimulation of the carotid sinus nerves in the conscious dog produced a differential pattern of peripheral vasodilatation, the most profound dilatation being observed in the hind-limb circulation. This release of sympathetic tone also occurred during stimulation in exercising animals when the muscular bed was already dilated on a metabolic basis.

Effects of diltiazem, a calcium antagonist, on regional myocardial function and mitochondria after brief coronary occlusion

Abstract The purpose of the study was to assess the effect of the calcium antagonist diltiazem on mechanical and mitochondrial function of ischemic myocardium of the dog. Persistent depression of developed tension following brief coronary occlusion was measured in anesthetized and thoracotomized dogs. The extent of persistent depression of developed tension during reperfusion depended on the duration of occlusion and also on the pressure-rate index during occlusion. Diltiazem prevented the marked drop in developed tension of the ischemic segment of the myocardium following 5 min or 10 min of coronary occlusion. The inactive optical isomer of diltiazem had no effect on developed tension before or after coronary occlusion. Depression of the state 3 rate of respiration of mitochondria observed following 10 min of occlusion of coronary artery was almost completely reversed by pretreatment with diltiazem. Diltiazem may reduce the damage of ischemic myocardium during occlusion by hemodynamic action of the drug, and possibly by preventing damage to mitochondria.

Effects of a Digitalis Glycoside on Coronary and Systemic Dynamics in Conscious Dogs

The effects of ouabain (G-strophanthin), 20 μg/kg were compared in 12 conscious dogs with Doppler flow transducers on the ascending aorta and left circumflex coronary artery and pressure gauges in the aorta, and in 9 of these dogs after general anesthesia with Na pentobarbital. In conscious dogs ouabain caused an initial bradycardia, but heart rate returned almost to control at 15 to 30 minutes, while arterial pressure rose and remained elevated. Cardiac output and coronary blood flow decreased initially, returned to control by 5 minutes and then remained constant. Systemic, mean, and late diastolic coronary resistances were elevated within 1 minute and remained elevated for 30 minutes. After anesthesia, ouabain caused similar increases in arterial pressure and slightly greater increases in systemic resistance, but the bradycardia and reduction of cardiac output were more profound and sustained. In the anesthetized state, coronary resistance rose when heart rate was allowed to slow after ouabain but was not elevated when heart rate was returned to control. Thus, in the conscious state, ouabain caused a distinct elevation in coronary and systemic resistances with no change in cardiac output, while in the anesthetized state ouabain reduced cardiac output and when heart rate was controlled, did not alter coronary resistance.

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.