Kim P. Gallagher

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.

Blood flow reductions in stenosed canine coronary arteries: vasospasm or platelet aggregation?

In 67 dogs with a 60-80% coronary stenosis produced by an external constricting plastic ring, blood flow measured with an electromagnetic flowmeter showed cyclical flow reductions of varying magnitude and duration, and then an abrupt return to control flow. In 45 dogs, heparin did not prevent these flow reductions, but ibuprofen (Motrin) or indomethacin abolished them. With incremental doses of each of these drugs, the cyclical flow reductions and the platelet function in vitro were diminished proportionately. In 10 more dogs, during low flow, pinching or poking the narrowed vessel suddenly restored normal flow. Topical application of papaverine and nitroglycerin proximal to the stenosis did not abolish the cyclic flow reduction, although a transient fall in systemic pressure indicated that they had been absorbed. Seven dogs had the constricting cylinder and flow probe chronically implanted for 4-6 weeks. A single oral dose of aspirin, 20 mg/kg, abolished their cyclic flow reductions for 2-4 days. In five dogs with 70% stenosis in the circumflex coronary artery, coronary arteriography was performed before coronary flow reduction and when coronary blood flow was low. This showed that there was a considerable additional reduction in the size of the mechanically constricted lumen during spontaneous flow reduction. In one dog, a nonopacified mass was dislodged from the area of constriction in 67 msec and this restored the lumen to its control diameter. Similar rapid clearing was filmed in two more dogs. In no case was vasospasm observed. These results suggest that obstruction from platelets aggregated in the narrowed lumen caused the cyclic flow reductions.

Dissociation between regional myocardial dysfunction and ECG changes during ischemia in the conscious dog.

The relations between regional ventricular function and regional and surface ECGs were studied in eight conscious dogs during complete and partial coronary obstructions. Wall thickness and local ECGs were measured using an implanted sonomicrometer, and 11 subcutaneous electrodes were implanted in a modified McFee vectorcardiographic array. Complete obstruction of the circumflex coronary artery (using a hydraulic occluder) produced regional hypokinesia after 15 seconds and regional dyskinesia at 1 minute. Significant ECG changes occurred first in the surface vectorcardiogram, ST segments changed at 30 seconds and mean epicardial and endocardial ECG ST segments increased after 1 minute. During mild partial coronary stenosis that produced stable reductions of systolic wall thickening (%δWT) of less than 25% of control, no ST-segment changes occurred in the surface vectorcardiogram during the 10-minute study period, although ST segments increased significantly in the endocardial and epicardial ECG. With moderate coronary stenoses that produced immediate 25-48% reductions of %δWT (average reduction 36 ± 4%), significant mean ST displacements occurred after 2 minutes in the endocardial ECG, after 3 minutes in the epicardial ECG and after 4 minutes in the surface vectorcardiogram. With coronary stenoses that produced more than 50% reduction of %A. WT (average reduction 69 ± 2%), mean endocardial ST-segment changes were noted after 2 minutes, and changes in both the mean epicardial ECG and the surface vectorcardiogram occurred after 3 minutes. Thus, during mild coronary stenosis, regional myocardial dysfunction can occur without surface ECG changes, while during moderate coronary stenosis, it occurs before endocardial ST-segment changes and precedes surface ECG alterations by several minutes. The surface ECG was slightly more sensitive than the local ECG during complete coronary occlusion and less sensitive during partial coronary obstruction. We conclude that regional contractile abnormalities provide a more sensitive indicator of ischemia than electrocardiographic ST-segment changes.

Effects of a calcium-entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs.

We examined the effects of diltiazem, a calcium-entry blocker, on exercise-induced myocardial ischemia in nine conscious dogs with chronic coronary stenoses. An ameroid constrictor, Doppler flow probe, and hydraulic occluder were placed around the left circumflex coronary artery, and left ventricular pressure was measured (Konigsberg micromanometer). Pairs of ultrasonic crystals were implanted for measuring left ventricular systolic wall thickening (% delta WTh) in control (left ventricular anterior wall) and ischemic (left ventricular posterior wall) regions, and regional myocardial blood flow was measured with the microsphere method. Eighteen days (average) after surgery mean coronary blood flow velocity had decreased and reactive hyperemic flow velocity after 10 sec of coronary occlusion was markedly reduced, but % delta WTh at rest remained normal, indicating collateral development. Control treadmill exercise was performed for 3.7 min (average), and 2 hr later administration of 0.3 mg/kg diltiazem was followed by an identical exercise bout. Control exercise increased % delta WTh in the normal region, while in the ischemic region % delta WTh decreased markedly and ischemia was evident (subendocardial flow, 0.29 +/- 0.12[SD] ml/min/g). After diltiazem hemodynamic and % delta WTh values at rest were not changed; during exercise the heart rate was significantly lower (204 +/- 24 vs 227 +/- 33 beats/min, p less than .01), but values for other hemodynamic measures were similar to those during the control run. % delta WTh in the control region was not changed during exercise after diltiazem, but compared with control exercise in the ischemic zone there was less dysfunction and subendocardial flow was greater. Recovery from exercise-induced dysfunction in the ischemic region occurred within 5 min, compared with over 30 min after control exercise. Thus, in a preparation of chronic coronary stenosis, the calcium-entry blocker improved the relationship between regional myocardial flow and function during exercise and led to more rapid recovery of regional myocardial dysfunction.

End-systolic dimension-wall thickness relations during myocardial ischemia in conscious dogs: A new approach for defining regional function

Overall and regional left ventricular (LV) function was studied during progressive coronary stenosis in conscious dogs by determining the relations at end-systole between LV pressure, chamber dimensions, and regional LV wall thickness. An index of regional wall stress was also analyzed. Using ultrasonic dimension gauges, measurements were made of LV wall thickness in control and ischemic regions, and the external long- and short-axis LV diameters were determined; an implanted micromanometer measured LV pressure. Internal LV diameters were obtained from the external diameters by subtraction of wall thickness, and the index of regional wall stress employed a thick-walled ellipsoidal model. During regional ischemia, the LV long axis at end-systole did not change, whereas the short-axis diameter progressively increased (from 24 +/- 7 mm [standard deviation] to 30 +/- 9 mm, p less than 0.001, indicating a more spherical LV shape during ischemia). The end-systolic pressure did not change, and therefore the end-systolic pressure-diameter relation shifted progressively, suggesting a global decrease in LV contactility. The end-systolic points relating LV wall thickness in the ischemic region to the end-systolic LV pressure revealed the regional nature of the abnormality, showing a progressive displacement to the left, whereas there was no significant displacement of this relation in the control region. The application of this index over a range of loading conditions during partial vena caval occlusion was illustrated. Thus, the regional end-systolic wall thickness-pressure relation provides a new index for defining the regional contractile state of the LV myocardium which is potentially load-independent and offers the possibility for echocardiographic application.

Effects of changes in ventricular size on regional and surface QRS amplitudes in the conscious dog.

SUMMARYEight conscious dogs instrumented with wall thickness sonomicrometers and 11 subcutaneous electrodes in a modified McFee vectorcardiographic array were studied during changes in ventricular volume. Simultaneous measurements were made of QRS amplitudes of the endocardial and epicardial ECG, QRS spatial vector magnitudes (SVM), end-diastolic wall thickness (EDT), end-systolic wall thickness (EST) and the amount of systolic thickening (δWT). Ventricular size was decreased by atropine and infulsion of 0.02 μg/kg/min of isoproterenol to increase the mean heart rate from 81 ± 5 beats/min (mean ± SEM) to 174 10 beats/min (p < 0.001), and was reflected by an increased mean EDT (9.06 ± 0.64 mm to 9.94 ± 0.61 mm, p < 0.005). The endocardial QRS amplitude increased in each dog (mean increase 21.55 ± 1.36 mV to 25.13 ± 1.35 mV, p < 0.001), whereas the SVM decreased from 7.69 ± 0.75 mV to 6.18 ± 0.48 mV (p < 0.02). Ventricular size was then increased by rapid saline infusion and was reflected by a decrease of EDT from 9.65 ± 0.66 mm to 9.09 ± 0.66 mm (p < 0.001), while heart rate remained unchanged. Endocardial amplitude decreased in each dog (average decrease 3.59 ± 0.25 mV, p < 0.001), while the SVM increased in each dog (average increase 0.81 ± 0.18 mV, p < 0.005). The mean epicardial amplitudes did not change significantly during either increases or decreases in ventricular volume. In each dog, there was a linear relation between EDT and endocardial amplitudes (r values > 0.88) and an inverse linear relation between EDT and SVM (r values > −0.80). The relations between EST or AWT and regional and QRS surface amplitudes were nonlinear. We conclude that in the conscious dog changes in endocardial QRS amplitudes and SVM respond in an opposite manner to changes in ventricular volume. In this experimental model, alterations in endocardial QRS amplitudes were related directly to changes in diastolic wall thickness; changes in body surface QRS amplitudes were inversely related to wall thickness, a finding that may relate in part to alterations in the distance of the heart from the chest wall.

Decreased systolic wall thickening in myocardium adjacent to ischemic zones in conscious swine during brief coronary artery occlusion

The purpose of this study was to examine wall thickening in normally perfused myocardium adjacent to acutely ischemic zones. Regional wall thickening (%WT), internal minor axis diameter, and hemodynamics were monitored in nine conscious swine during temporary occlusion of the left circumflex coronary artery (LCCA). Animals were chronically instrumented with ultrasonic dimension gauges for measuring left ventricular (LV) wall thickness and minor axis, catheters in the left atrium and aorta, and a pneumatic occluder around the proximal LCCA. During a 2-minute occlusion of the LCCA, radiolabeled tracer microspheres (10 micron) were injected into the left atrium to determine regional myocardial blood flow (RMBF). Within the ischemic zone, reduction of %WT was related linearly (Y = 24.9 X -4.1, p less than 0.001) to reduced RMBF and endocardial/epicardial blood flow ratio was reduced from 1.30 +/- 0.12 (mean +/- SE) to 0.87 +/- 0.11 (p less than 0.01). In zones adjacent to the ischemic zones RMBF was unchanged by LCCA occlusion. RMBF and %WT were poorly correlated (r = 0.38) and endocardial/epicardial blood flow ratio was unchanged from preocclusion values. Therefore, myocardium adjacent to ischemic zones may have reduced thickening despite no apparent blood flow changes. We conclude that such dysfunction may be due to either mechanical tethering effects or a reduction of global LV function due to the presence of an acutely ischemic zone.

Reduction of exercise-induced ischemic regional myocardial dysfunction by verapamil in conscious dogs.

The effects of verapamil on exercise-induced changes in left ventricular (LV) function were examined in nine conscious dogs in which an Ameroid constrictor and Doppler flow probe were placed around the left circumflex coronary artery. Ultrasonic crystals were implanted for measuring LV systolic wall thickness (SWTh) in control and ischemic regions, and a micromanometer measured high fidelity LV pressure. At 23 days (average) postoperatively, coronary collaterals had developed and complete cessation of coronary flow was confirmed by the flowmeter. Control treadmill exercise was then performed for 3.8 minutes at speed 12.1 km/hr and grade 5.3% (average). Two hours after oral administration of verapamil (120 to 160 mg), the same exercise bout was repeated. During the control runs, significant increases occurred in heart rate (101 to 243 bpm), LV end-diastolic pressure (13.3 to 27.5 mm Hg), peak LV pressure (129.8 to 165.7 mm Hg) and its first derivative (3140 to 6275 mm Hg/sec) with an increase of SWTh in control regions, while percent SWTh in ischemic regions decreased markedly (19.6% to 5.9%, p < 0.001); wall thickening velocity also decreased (0.90 to 0.44 SWTh/sec). During the runs after verapamil, the exercise heart rate was significantly lower than in the control run (221 ± 30 bpm), but other hemodynamic measures were similar. SWTh in control regions was unchanged, but exercise-induced dysfunction in the ischemic zone was substantially less (SWTh during exercise 11.5%, p < 0.01 compared to control runs) and wall thickening velocity did not fall. Thus verapamil can reduce regional LV dysfunction produced by exercise in collateral dependent zones, indicating a beneficial effect of this agent on stress-induced ischemia.

Cyclical coronary flow reductions in conscious dogs equipped with ameroid constrictors to produce severe coronary narrowing

SummaryIn conscious dogs equipped with ameroid constrictors to produce gradual coronary occlusion, coronary flow velocity was monitored prior to complete occlusion when coronary constriction was severe (resting flow velocity reduced by 10–50% from control recordings made 7–10 days after ameroid implantation). In six of the ten dogs, we observed spontaneous cyclical variations in coronary flow velocity, characterized by gradual reduction in flow followed by very abrupt restoration of flow. The cyclic coronary flow reductions were observed between 20 and 31 days after ameroid implantation. These changes in flow bear striking similarity to those observed by previous investigators using anesthetized, open-chest canine preparations, in which the role of platelets was clearly demonstrated. Consequently, we hypothesize that spontaneous platelet aggregation and de-aggregation within the severely narrowed coronary lumen (enclosed by the ameroid constrictors) could account for our observations.

Comparison of postpacing and exercise-induced myocardial dysfunction during collateral development in conscious dogs.

In 10 conscious dogs, a model was developed for studying regional contractile responses in a coronary collateral-dependent bed. Regional myocardial function was compared after terminating a maximum paced rate of 240 beats/min maintained for 3 minutes (postpacing period) with that during telemetrymonitored exercise at comparable heart rates (average 252 i 34 beats/min, duration 2.4 minutes) at different times during collateral development. Ultrasonic dimension gauges were used to measure control and ischemic segment (CS and IS) lengths and ischemic zone regional wall thickness (IW). An ameroid constrictor and a Doppler flow probe were placed around the left circumflex coronary artery, and pacing electrodes were sutured to the right ventricle. An average of 23 days postoperatively, coronary obstruction was complete. Studies at that time showed that percent shortening (%AL) of IS and percent wall thickening (%AW) of IW decreased after pacing to 57% and 35% of control, respectively, and during exercise to 37% and 32% of control. One week later (average 30 days postoperatively), significant depression of regional function no longer occurred postpacing. However, exercise at a comparable heart rate still provoked regional dysfunction in the collateral-dependent zone: Both IS%AL and IW%AW decreased to 51% of control. Regional function at rest did not differ during these studies. Thus, the effectiveness of the postpacing response for detecting limited collateral reserve was eliminated by further collateral development, but regional myocardial dysfunction during exercise stress served to detect ischemia despite increased collateral circulation.