Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs

BACKGROUND: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs. METHODS: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction. RESULTS: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05). CONCLUSIONS: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.     

Early changes in the time course of myocardial contraction after correcting aortic regurgitation

BACKGROUND: Correcting aortic regurgitation causes significant changes in left ventricular loading conditions, but few observations have been made intraoperatively of early effects on myocardial function. METHODS: We studied 18 patients (mean age, 59+/-12 years; 14 men) in whom aortic regurgitation was corrected with a stentless biologic valve. Overall left ventricular function was studied by thermodilution cardiac output, ventricular filling pressure, and systemic arterial pressure. Regional myocardial function was assessed from intraoperative transesophageal M-mode echocardiography and high fidelity ventricular pressure recordings before cardiopulmonary bypass, and 0.5, 1, 3, 6, 12, and 20 hours after operation. Time course of contraction, and magnitude of left ventricular systolic wall stress, dimensional shortening, myocardial power, and stroke work were measured. RESULTS: Global hemodynamics: there was an immediate decrease in left ventricular stroke volume (58+/-31 mL versus 80+/-30 mL, p = 0.004) and stroke work index (250+/-86 mJ/m versus 401+/-198 mJ/m, p = 0.005), but systemic arterial pressure (79+/-11 mm Hg versus 65+/-10 mm Hg, p = 0.002), increased at constant heart rate and end-diastolic pressure. Regional myocardial function and timing: peak systolic wall stress, dimensional shortening rate, and myocardial power production were all unchanged with operation. However, myocardial stroke work decreased (3.0+/-1.3 mJ/cm versus 4.8+/-2.4 mJ/cm, p = 0.009), attributable to shortening of the duration of systole (475+/-91 ms versus 543+/-67 ms, p<0.001). Diastolic time increased from 34%+/-18% to 71%+/-33% of systolic pulse duration (p<0.001). CONCLUSIONS: Correcting aortic regurgitation causes an early decrease in regional and global stroke work and increases diastolic time, although systolic wall stress does not decrease immediately. These beneficial effects are achieved by reducing the duration rather than altering the peak intensity (power) of myocardial contraction.     

Radio frequency heating of chronic ovine infarct leads to sustained infarct area and ventricular volume reduction

OBJECTIVE: Myocardial infarct expansion and subsequent left ventricular remodeling are associated with increased incidence of congestive failure and mortality. Collagen is known to denature and contract when heated above 65 degrees C. We therefore tested the hypothesis that radio frequency heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and left ventricular volume. METHODS: Thirteen male Dorset sheep underwent surgical coronary artery ligation. At least 14 weeks later, animals were randomized to either radio frequency infarct heating (95 degrees C) with application of a restraining patch or a sham operation. Before treatment, after treatment, and 10 weeks later, left ventricular volume was measured with transdiaphragmatic echocardiography and myocardial infarct area was measured with an array of sonomicrometry crystals. RESULTS: Radio frequency infarct heating causes an acute decrease of 34% (-215 +/- 82 mm(2); P =.0002) in infarct area at end-diastole that is maintained at 10 weeks (-144 +/- 79 mm(2); P =.0002). Radio frequency infarct heating causes a downward trend in end-diastolic left ventricular volume measured by echocardiography of 20% (-15.7 +/- 6.3 mL; P = no significant difference) and end-systolic left ventricular volume of 32% (-17.1 +/- 9.8 mL; P =.09), which are significantly decreased at 10 weeks (-13.6 +/- 22.3 mL; P =.007 and -15.3 +/- 21.9 mL; P =.008, respectively). Radio frequency infarct heating causes an acute improvement in systolic function (P <.001), a sustained increase in left ventricular ejection fraction (+0.11%; P =.06), and preserved stroke volume. CONCLUSION: Radio frequency heating of chronic left ventricular myocardial infarct causes a sustained reduction in infarct area and left ventricular volume. This technique may beneficially reverse infarct expansion and left ventricular remodeling after myocardial infarction.     

Skeletal muscle extraaortic counterpulsation. A true arterial counterpulsation

Reduction of left ventricular work load during systole, a critical component of arterial counterpulsation, has not previously been documented for skeletal muscle-powered extraaortic counterpulsation. To assess its capacity for afterload reduction, a skeletal muscle extraaortic counterpulsator was connected to the thoracic aorta and counterpulsated. Canine hearts (n = 7) were instrumented with left ventricular Millar catheters (Millar Instruments, Inc., Houston, Tex.) for pressure measurements and with piezoelectric ultrasonic crystals for measurement of the left ventricular minor axis dimension and wall thickness. During systole, skeletal muscle extraaortic counterpulsation resulted in a significant change in all three determinants of left ventricular circumferential wall stress compared with control conditions (no counterpulsation). Pressure decreased (peak systole, 100 +/- 5 versus 75 +/- 6 mm Hg; p less than 0.05 by paired t test), minor axis dimension decreased (end systole, 46.4 +/- 1.1 versus 45.8 +/- 1.1 mm; p less than 0.05 by paired t test), and wall thickness increased (end systole, 10.4 +/- 0.7 versus 10.6 +/- 0.7 mm; p less than 0.05 by paired t test). Left ventricular wall stress/dimension work loops showed a shift downward and to the left, a shift consistent with afterload reduction. The mean systolic left ventricular wall stress was significantly reduced, from 67.3 +/- 10.6 to 47.7 +/- 8.1 10(3) dyne/cm2 (p less than 0.05 by paired t test). Skeletal muscle extraaortic counterpulsation increased the diastolic aortic pressure from 72 +/- 6 to 105 +/- 8 mm Hg (p less than 0.05 by paired t test). Our data, which documented the counterpulsator's direct effects on left ventricular functional mechanics, showed that skeletal muscle extraaortic counterpulsation is capable of both diastolic augmentation of arterial pressure and systolic unloading of the left ventricle. Skeletal muscle extraaortic counterpulsation has potential application for ventricular unloading in the treatment of chronic end-stage heart failure.     

Effects of chronic tachycardia-induced cardiomyopathy on the beta-adrenergic receptor system.

Chronic supraventricular (or ventricular) tachycardia causes a dilated cardiomyopathy. Effective treatment requires ablation of the tachycardia using antiarrhythmic agents, cryoablation, electroablation, or surgical interruption/excision. However, the underlying pathophysiologic mechanisms responsible for the development of supraventricular tachycardia-induced cardiomyopathy have not been fully identified. We hypothesized that chronic supraventricular tachycardia is associated with significant changes in the beta-adrenergic system that may have implications for the pathophysiology and treatment of supraventricular tachycardia-induced cardiomyopathy. Accordingly, we examined the relationship between left ventricular function, plasma norepinephrine level, beta-receptor number and affinity, and response to a beta-agonist (isoproterenol) infusion in eight control pigs and eight pigs subjected to supraventricular pacing-induced tachycardia (240 beats/min for 3 weeks). Left ventricular function was measured using simultaneous echocardiography and catheterization. Left ventricular end-diastolic dimension and pressure increased in pigs with supraventricular tachycardia (5.1 +/- 0.4 cm and 27 +/- 2 mm Hg) versus control pigs (3.8 +/- 0.3 cm and 8 +/- 2 mm Hg), p < 0.05. Left ventricular fractional shortening decreased in supraventricular tachycardia (10 +/- 1%) versus control pigs (34 +/- 1%), p < 0.05. In addition, in the pigs with supraventricular tachycardia the fractional shortening versus left ventricular end-systolic stress relationship fell below the control relationship. Plasma norepinephrine level (measured by high-performance liquid chromatography) increased in pigs with supraventricular tachycardia (3592 +/- 1606 pg/ml plasma) versus control pigs (323 +/- 74 pg/ml plasma), p < 0.05. beta-Receptor number and affinity (measured by [3H]dihydroalprenolol binding) did not change in supraventricular tachycardia (98.6 +/- 11.5 fmol/mg protein and 7.2 +/- 1.1 nmol) versus control pigs (99.1 +/- 9.4 fmol/mg protein and 6.8 +/- 0.5 nmol). The response to isoproterenol infusion (10 micrograms/kg) in supraventricular tachycardia was blunted: the absolute increase in left ventricular peak (+)dP/dt was reduced in supraventricular tachycardia (833 +/- 233 mm Hg/sec) versus control pigs (2180 +/- 139 mm Hg/sec), p < 0.05. Chronic supraventricular tachycardia caused a decreased contractile state, increased plasma norepinephrine level, and caused no change in beta-receptor number or affinity; however, the response to beta-agonist infusion was blunted. These results suggest that chronic supraventricular tachycardia is associated with uncoupling of the beta-receptor from subsequent intracellular components of the beta-adrenergic system. Therefore medical management of chronic supraventricular tachycardia-induced cardiomyopathy before and immediately after definitive ablation may require use of pharmacologic agents whose actions do not depend on an intact beta-adrenergic pathway.     

Device-based change in left ventricular shape: a new concept for the treatment of dilated cardiomyopathy

OBJECTIVE: We tested a unique new device, the Myosplint device (Myocor, Inc, Maple Grove, Minn), which is designed to change left ventricular shape, reduce left ventricular wall stress, and improve left ventricular systolic function. METHODS: Heart failure was induced in 15 dogs over 27 days by rapid pacing (230 beats/min). Seven animals underwent sham surgery, and 8 animals received 3 transventricular Myosplint devices each. Myosplint devices were tightened to create a symmetric bilobular left ventricular shape and were adjusted to produce a calculated 20% reduction in wall stress. Hemodynamic, 2-dimensional, and 3-dimensional echocardiographic studies were recorded at baseline, immediately after Myosplint placement (acute change), and at 1 month after both groups had a reduced rate (190 beats/min) of pacing designed to maintain heart failure. RESULTS: The Myosplint group had significant sustained improvements in left ventricular ejection fraction from baseline, to the acute change, to 1 month (19% +/- 5%; 36% +/- 8%; 39% +/- 13%) and reductions of left ventricular end-systolic volumes (73 +/- 9 mL; 34 +/- 5 mL; 42 +/- 12 mL) and end-systolic wall stress by 39% (341 +/- 68 10(3) dynes x cm(- 2) to 206 +/- 28 10(3) dynes x cm(-2)) acutely and 31% (372 +/- 83 10(3) dynes x cm(-2) to 250 +/- 40 10(3) dynes x cm(-2)) at 1 month. There were no significant changes in mitral regurgitation. CONCLUSION: Application of a Myosplint device to a dilated impaired left ventricle resulted in reduced wall stress and improved left ventricular systolic function that was sustained at 1 month. Device-based shape change is a promising new opportunity to treat patients with dilated cardiomyopathy.     

Simulated left ventricular aneurysm and aneurysm repair in swine

Patch reconstruction of left ventricular aneurysm may be superior to linear closure, but this hypothesis has not been tested experimentally. Accordingly, six anesthetized domestic pigs were instrumented to measure regional left ventricular wall thickening, stroke volume, systolic left ventricular pressure, and myocardial oxygen consumption. With total bypass and cardioplegia, a 6 by 8 cm Dacron patch was inserted into the anteroapical left ventricle. Simulations were as follows: left ventricular aneurysm, patch open; patch reconstruction, 50% patch plication; standard repair, ventriculotomy edges approximated. Global function, from stroke work (stroke volume x integral of left ventricular pressure)-left ventricular end-diastolic pressure curves, was depressed in all three simulations compared with control. A tendency for stroke work to be greater for standard repair than for left ventricular aneurysm and patch reconstruction at higher preloads was not statistically significant. Mechanical efficiency, from stroke work/myocardial oxygen consumption (joules per milliliter oxygen per beat), was 2.43 +/- 0.52 (mean +/- standard error of the mean) (control), 2.22 +/- 0.94 (standard repair), 1.27 +/- 0.39 (patch reconstruction), and 1.09 +/- 0.37 (left ventricular aneurysm) (no significant differences). Regional work was calculated as regional left ventricular wall thickening x integral of left ventricular pressure. The slope of the regional work-end-diastolic wall thickness relation decreased in the posterior wall 14.0 +/- 2.9 (control) versus 8.4 +/- 2.0 (left ventricular aneurysm), 6.9 +/- 1.4 (patch reconstruction), and 7.4 +/- 1.4 (standard repair) (p less than 0.05). In the anterior wall, contractility did not change significantly (7.4 +/- 1.2, control; 7.8 +/- 2.7, left ventricular aneurysm; 5.0 +/- 0.4, patch reconstruction; and 5.3 +/- 0.4, standard repair). Decreased end-diastolic wall thinning anteriorly suggested tethering. These results in the normal left ventricle suggest that patch ventriculoplasty is of no greater benefit than linear repair. Either repair may impede function of adjacent myocardium through restriction of regional diastolic lengthening.     

Left ventricular function in uremia: echocardiographic assessment in patients on maintenance dialysis

Echocardiographic assessment of left ventricular function was performed in twenty-two unselected patients on stable, chronic maintenance dialysis. The statistically significant abnormalities were enlargement of the left ventricular cavity (end diastolic internal dimension or "diameter" 5.4 +/- 0.2 cm, normal 4.4 +/- 0.3 cm), thickening of the left ventricular wall (end diastolic thickness 1.1 +/- 0.05 cm, normal 0.9 +/- 0.03 cm) and a reduction in myocardial contraction (fractional shortening 28.2 +/- 2.0%, normal 35.7 +/- 0.9%). Myocardial impairment could not be attributed to the effects of hypertension or to ischemic heart disease. There was, however, a significant negative correlation between fractional shortening and total plasma catecholamines (r = 0.45, P less than 0.05) suggesting that excessive catecholamines may contribute to the decreased myocardial contraction seen in uremic patients.     

Effects of left ventricular venting and distention during heterogenous distribution of cardioplegic solution

The effects of left ventricular venting and distention on myocardial protection during heterogenous distribution of cardioplegic solution remain undefined. This study was undertaken to determine if left ventricular venting enhances and distention impairs myocardial cooling and recovery of global and regional left ventricular function. Twenty-one pigs were placed on cardiopulmonary bypass and subjected to 80 minutes of ischemic arrest with the mid-left anterior descending artery occluded. Hearts were protected with multidose potassium (25 mEq/L) crystalloid cardioplegic solution supplemented with topical (4 degrees C) and systemic (28 degrees C) hypothermia. During arrest, the left ventricle was vented in seven pigs, seven pigs were not vented, and seven others had systemic pump blood infused into the left ventricle to maintain an end-diastolic pressure of 15 mm Hg. Parameters measured included left ventricular temperature, stroke work index, compliance (end-diastolic pressure-end-diastolic volume curves) and wall motion scores (two-dimensional echocardiography). Distended hearts had the lowest mean left ventricular temperature beyond the left anterior descending arterial occlusion (10.1 degrees +/- 1.8 degrees C distended [p less than 0.025 from vented and nonvented groups] versus 14.2 degrees +/- 0.7 degrees C vented versus 15.5 degrees +/- 1.2 degrees C nonvented), the highest postischemic stroke work index (0.78 +/- 0.09 gm-m/kg distended versus 0.62 +/- 0.07 gm-m/kg vented versus 0.66 +/- 0.07 gm-m/kg nonvented at end-diastolic pressure = 10 mm Hg), and the best wall motion scores (0.7 +/- 0.04 distended [p less than 0.025 from vented and nonvented groups] versus 5.5 +/- 1.80 vented versus 4.8 +/- 1.20 nonvented). Postischemic end-diastolic pressure-end-diastolic volume curves were unchanged from preischemic values in each group. We conclude that during heterogenous cardioplegic arrest, left ventricular venting offers no additional myocardial protection and may negate the beneficial effects of moderate (end-diastolic pressure = 15 mm Hg) left ventricular distention.     

Transventricular non-transmural laser treatment of hypoperfused porcine myocardium acutely reduces left ventricular contractile function.

OBJECTIVE: Creation of non-transmural myocardial channels by lasers transmitted through endovascular fiberoptics is a novel therapeutic option in the management of patients with coronary artery disease. The acute effect of transventricular laser treatment (TvL) on coronary blood flow, myocardial metabolism and left ventricular function are not well established. METHODS: In five anesthetized pigs, flow in the proximal left anterior descending coronary artery (LAD) was reduced and maintained at 70% of baseline. A venous shunt had previously been established draining the hypoperfused region. At 30 min of ischemia, non-transmural myocardial channels were created through the endocardium using a Ho:YAG laser. We measured (a) left ventricular, central venous and arterial pressures, (b) ascending aortic, LAD and coronary venous blood flows, as well as (c) lactate concentration and blood gases in arterial and coronary venous blood, prior to ischemia (baseline), before and 30 min after TvL. Data (given as mean +/- SD) were analyzed with repeated measures ANOVA. RESULTS: Reduction of LAD blood flow resulted in reduced regional coronary venous blood flow and myocardial oxygen consumption, conversion of regional myocardial lactate uptake to release and adaptation of left ventricular contractility to a lower level. Following transventricular laser, the peak left ventricular systolic pressure declined from 86 +/- 12 to 77 +/- 11 mmHg (P < 0.05), its maximal first positive derivative (LV dP/dt) declined from 900 +/- 221 to 763 +/- 127 mmHg/s (P < 0.05) and the stroke volume decreased from 19.2 +/- 4.1 to 16.4 +/- 5.4 ml (P < 0.05). The changes in regional coronary venous flow, myocardial oxygen consumption and myocardial lactate release after TvL were not significant compared to before TvL. Significant intramural hematomas and tissue destruction were found around the channels at autopsy and by histologic examination. CONCLUSION: Transventricular laser treatment of hypoperfused myocardium decreased left ventricular contractility in the acute phase, possibly due to development of perichannel hematomas and disruption of the wall architecture. In addition, TvL did not alter the regional myocardial oxygen supply/demand balance. These results call for caution in the treatment of patients with coronary artery disease by transventricular Ho-YAG laser when there is significant impairment of the left ventricular contractile function.     

A reappraisal of surgical intervention for acute myocardial infarction

Eighty-three patients underwent coronary artery bypass during acute evolving myocardial infarction 6.8 +/- 2.8 hours after the onset of symptoms. Linear discriminant analysis of preoperative variables identified predictors of mortality with an accuracy of 84%. Significant predictors in decreasing order of importance were cardiogenic shock, age over 65 years, left ventricular ejection fraction less than or equal to 0.30, cardiac index less than or equal to 2.0 L/min/m2, and absent collateral flow. Time to reperfusion did not influence outcome nor did the infarct-related artery. Hospital mortality was 15.6% (13/83). Among 51 low-risk patients under 65 years of age without cardiogenic shock, there were three deaths (5.9%). Follow-up angiography was performed in 21 patients. The graft patency rate was 94%. Left ventricular ejection fraction improved from 0.39 +/- 0.10 to 0.49 +/- 0.11 (p less than 0.05). Left ventricular end-systolic volume decreased from 53.2 +/- 19.3 ml/m2 to 41.4 +/- 16.8 ml/m2 (p less than 0.05), and end-diastolic volume remained unchanged: 86.2 +/- 21.2 ml/m2 before operation and 78.7 +/- 24.0 ml/m2 after operation (no significant difference). Regional ejection fraction of the infarct area, determined by the centerline method, increased 0.23 +/- 0.15. In contrast, among 215 patients treated by nonsurgical reperfusion (intracoronary thrombolysis or angioplasty, or both), mortality was 13.5%. In this group, reperfusion was successful in 144 patients (67%) and 89 underwent follow-up angiography. Persistent patency of the infarct artery was demonstrated in 73 (82%). Ejection fraction increased from 0.45 +/- 0.10 to 0.50 +/- 0.15 (p less than 0.05). We conclude that preoperative variables enable identification of patients with evolving acute myocardial infarction in whom coronary artery bypass is associated with low operative mortality and improved ventricular performance.     

Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling.

BACKGROUND: Tumor necrosis factor (TNF) causes myocardial extracellular matrix remodeling and fibrosis in myocardial infarction and chronic heart failure models. Pre-clinical and clinical trials of TNF inhibition in chronic heart failure have shown conflicting results. This study examined the effects of the administration of a TNF inhibitor immediately after myocardial infarction on the development of heart failure. METHODS: Lewis rats underwent coronary artery ligation and then received either intravenous etanercept (n = 14), a soluble dimerized TNF receptor that inhibits TNF, or saline as control (n = 13). Leukocyte infiltration into the infarct borderzone was evaluated 4 days post-ligation in 7 animals (etanercept = 4, control = 3). After 6 weeks, the following parameters were evaluated in the remaining animals: cardiac function with a pressure-volume conductance catheter, left ventricular (LV) geometry, and borderzone collagenase activity. RESULTS: Etanercept rats had significantly less borderzone leukocyte infiltration 4 days post-infarction than controls (10.7 +/- 0.5 vs 18.0, +/-2.0 cells/high power field; p < 0.05). At 6 weeks, TNF inhibition resulted in significantly reduced borderzone collagenase activity (110 +/- 30 vs 470 +/- 140 activity units; p < 0.05) and increased LV wall thickness (2.1 +/- 0.1 vs 1.8 +/- 0.1 mm, p < 0.05). Etanercept rats had better systolic function as measured by maximum LV pressure (84 +/- 3 mm Hg vs 68 +/- 5 mm Hg, p < 0.05) and the maximum change in left ventricular pressure over time (maximum dP/dt) (3,110 +/- 230 vs 2,260 +/- 190 mm Hg/sec, p < 0.05), and better diastolic function as measured by minimum dP/dt (-3,060 +/- 240 vs -1,860 +/- 230 mm Hg/sec; p < 0.05) and the relaxation time constant (14.6 +/- 0.6 vs 17.9 +/- 1.2 msec; p < 0.05). CONCLUSIONS: TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function.     

Ventricular failure and cellular remodeling with chronic supraventricular tachycardia

Chronic supraventricular tachycardia has been associated with ventricular dysfunction in human beings and in animals. The changes in ventricular size and shape and the myocyte remodeling that may occur with chronic supraventricular tachycardia are unknown. Left and right ventricular remodeling and myocyte changes were examined in 12 pigs after 3 weeks of atrial pacing (supraventricular tachycardia at 240 beats/min and in 10 control pigs (105 +/- 3 beats/min). Chronic supraventricular tachycardia resulted in decreased left ventricular and right ventricular ejection fractions compared with control values (left ventricle, 26% +/- 4% versus 60% +/- 1%; right ventricle, 19% +/- 3% versus 53% +/- 3%; p less than 0.05 for both), decreased wall thickness (left ventricle, 8.3 +/- 0.1 mm versus 10.5 +/- 0.2 mm; right ventricle, 2.8 +/- 0.3 mm versus 4.2 +/- 0.2 mm; p less than 0.05 for both), and increased end-diastolic volumes (left ventricle, 66 +/- 10 ml versus 54 +/- 4 ml; right ventricle, 78 +/- 8 ml versus 56 +/- 4 ml; p less than 0.05 for both). Myocardial water content was significantly higher with supraventricular tachycardia than in control pigs (left ventricle, 82% +/- 4% versus 76% +/- 4%; right ventricle, 83% +/- 4% versus 78% +/- 2%; p less than 0.05 for both). According to computer-aided stereological studies, the percent volume of myocytes in the subendocardial layer of the hearts that underwent supraventricular tachycardia was smaller than that of the control hearts (left ventricle, 62% +/- 2% versus 79% +/- 1%; right ventricle, 55% +/- 4% versus 77% +/- 1%; p less than 0.05 for both) and myocyte diameter was reduced (left ventricle, 16 +/- 1 microns versus 23 +/- 2 microns; right ventricle, 13 +/- 1 microns versus 22 +/- 2 microns; p less than 0.05 for both). Further, myocytes isolated from the left ventricles of the group with supraventricular tachycardia were significantly longer than were control myocytes (190 +/- 25 microns versus 145 +/- 30 microns, p less than 0.05 for both). In summary, chronic supraventricular tachycardia caused significant right and left ventricular failure, with a reduction in wall thickness and chamber dilatation. This was accompanied by a reduction in the percent volume of myocytes occupying the subendocardial layer, with reduced myocyte diameter and increased myocyte length and water content. These changes are likely to be important in understanding supraventricular tachycardia-induced ventricular dysfunction.     

Effects of direct mechanical ventricular assistance on regional myocardial function in an animal model of acute heart failure

Direct mechanical ventricular assistance (DMVA) improves hemodynamics in failing hearts without complications associated with a blood/device interface. Epicardial Doppler displacement transducers provide exact measurements of tissue displacement and regional myocardial function (RMF). An in vivo porcine model of acute heart failure was used to examine the effects of DMVA on RMF, which have not been reported before. In 8 anesthetized pigs cardiac output (CO), left ventricular pressure (LVP), aortic blood pressure (BP), systolic contractility (dp/dt max), and systolic wall thickening fraction (WT%) were measured. A multichamber pump system (IMPS) surrounding the left ventricle was implanted and the measurements were repeated. Then acute heart failure was induced by beta-blockade, resulting in a decline of all measured parameters to more than 30% compared to baseline values. In the further course of the experiment, repeated measurements were taken at several intervals with and without DMVA by the implanted device. The IMPS implantation caused no significant hemodynamic changes. Under conditions of acute heart failure DMVA improved LVP (46 +/- 7 to 81 +/- 9 mm Hg), dp/dt max (532 +/- 207 to 744 +/- 361 mm Hg/s), CO (1.5 +/- 0.1 to 1.9 +/- 0.5 L/min) and WT% (19 +/- 7% to 32 +/- 8%). Left ventricular myocardium not directly assisted by external pressure application showed improved regional myocardial function during DMVA. We conclude that DMVA is capable of improving hemodynamics due to extrinsic compression. It also enhances the remaining myocardial function of the failing heart, which might lead to myocardial recovery. These synergistic effects are considered responsible for the high efficiency shown by the IMPS in previous investigations.     

Repair of left ventricular aneurysm. Changes in ventricular mechanics, hemodynamics, and oxygen consumption.

Anteroapical left ventricular aneurysms were produced in 23 sheep by coronary arterial ligation. Plication of the aneurysm does not change stroke volume or cardiac output and does not significantly change left ventricular oxygen consumption from the preoperative value of 5.1 +/- 2.6 ml/100 gm per minute. Plication, however, does increase left ventricular end-systolic elastance from 3.2 +/- 0.9 to 4.4 +/- 1.5 mm Hg/mm (p = 0.005). In nine of these sheep the midsagittal plane of the left ventricle was imaged by means of an array of sonomicrometry crystals before and after plication of the aneurysm. Regional wall stresses at end-systole and end-diastole and changes in diastolic function were calculated for anterior and posterior ventricular walls in the border zone adjacent to the aneurysm and in more basilar myocardium remote from the infarct. Plication significantly reduced end-systolic wall stresses and systolic stress integrals in the posterior border zone and remote myocardium, but it did not significantly change anterior wall systolic stresses or stress integrals. Plication also decreased diastolic stretching of border zone myocardium. Plication of anteroapical left ventricular aneurysm produced a shorter, more spherical ventricle and removed the dyskinetic segments but altered deformation (strain) in both circumferential and longitudinal directions. The changes in ventricular wall geometry and deformation provide an explanation for the increased ventricular end-systolic elastance and unchanged stroke volume observed after aneurysm plication.     

Pretreatment with angiotensin-converting enzyme inhibitors attenuates ischemia-reperfusion injury

BACKGROUND: The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that ischemic events are decreased in patients receiving angiotensin-converting enzyme (ACE) inhibitors. This study sought to determine whether pretreatment with ACE inhibitors would attentuate ischemic injury during surgical revascularization of ischemic myocardium. METHODS: In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest, and 180 minutes of reperfusion. Ten pigs received quinapril (20 mg p.o. q.d.) for 7 days prior to surgery; 10 others received no-ACE inhibitors. RESULTS: Quinapril-treated animals required less cardioversions for ventricular arrhythmias (1.58 +/- 0.40 vs 2.77 +/- 0.22; p < 0.05), had higher wall motion scores assessed by two-dimensional echocardiography (4 = normal to -1 = dyskinesia; 2.11 +/- 0.10 vs 1.50 +/- 0.07; p < 0.05), more complete coronary artery endothelial relaxation to bradykinin (45% +/- 3% vs 7% +/- 4%; p < 0.005), and lower infarct size (24.0% +/- 3.0% vs 40.0% +/- 1.7%; p < 0.0001). CONCLUSIONS: ACE inhibition prior to coronary revascularization enhances myocardial protection by decreasing ventricular irritability, improving regional wall motion, lowering infarct size, and preserving endothelial function.     

Controlled reperfusion of the regionally ischemic myocardium with leukocyte-depleted blood reduces stunning, the no-reflow phenomenon, and infarct size.

Open-chest sheep underwent 90 minutes' occlusion of the diagonal branch of the left anterior descending coronary artery, followed by vented cardiopulmonary bypass. After 30 minutes of cardioplegic arrest, simulating distal anastomoses, the occlusion on the coronary artery branch was released. Controlled reperfusion (40 to 50 mm Hg, 135 to 150 ml/min) for the first 20 minutes was delivered at the aortic root with either unmodified whole blood (control, n = 7) or blood passed through leukocyte filters (filters, n = 7). Serial measurements were made during 3 additional hours reperfusion off cardiopulmonary bypass. During ischemia, the major determinants of infarct size, which include area at risk, collateral myocardial blood flow, and rate-pressure product were not significantly different between groups. Overall, during reperfusion, mean left ventricular stroke work index in the filter group was greater than in the control group (28.7 +/- 5.8 versus 12.6 +/- 6.4 x 10(3) erg/gm, p less than 0.05), as was mean rate of rise of left ventricular pressure (1900 +/- 260 versus 1348 +/- 279 mm Hg/sec, p less than 0.05). Myocardial blood flow to the area at risk at 3 1/2 hours of reperfusion in the filter group was also significantly better than in the control group (0.57 +/- 0.15 versus 0.27 +/- 0.05 ml/min/gm, p less than 0.05), as was necrotic area as a percentage of area at risk (40% +/- 6% versus 70% +/- 5%, p less than 0.05). These results demonstrate amelioration of myocardial stunning and the no-reflow phenomenon, as well as decreased infarct size. We conclude that controlled reperfusion with leukocyte-depleted blood is superior to whole-blood reperfusion for the surgical treatment of acute regional ischemia.     

Modified Glenn connection for acutely ischemic right ventricular failure reverses secondary left ventricular dysfunction.

BACKGROUND: Right heart failure after cardiopulmonary bypass can result in severe hemodynamic compromise with high mortality, but the underlying mechanisms remain poorly understood. After ischemia-induced right ventricular failure, alterations in the interventricular septal position decrease left ventricular compliance and limit filling but may also distort left ventricular geometry and compromise contractility and relaxation. This study investigated the effect of acute isolated right ventricular ischemia on biventricular performance and interaction and the response of subsequent right ventricular unloading by use of a modified Glenn shunt. METHODS: In 8 pigs isolated right ventricular ischemic failure was induced by means of selective coronary ligation. A modified Glenn circuit was then established by a superior vena cava-pulmonary artery connection. Ventricular performance was determined by conductance catheter-derived right ventricular pressure-volume loops and left ventricular pressure-segment length loops. Hemodynamic data at baseline, after right ventricular ischemia, and after institution of the Glenn circuit were obtained during inflow occlusion, and the load-independent contractile indices were derived. RESULTS: Right ventricular free-wall ischemia resulted in acute right ventricular dilation (118 +/- 81 mL vs 169 +/- 70 mL, P =.0008) and impairment of left ventricular contractility indicated by the reduced end-systolic pressure-volume relation slope (50.0 +/- 19 mm Hg/mm vs 18.9 +/- 8 mm Hg/mm, P =.002) and preload recruitable stroke work index slope (69.6 +/- 26 erg x cm(-3) x 10(3) vs 39.7 +/- 13 erg x cm(-3) x 10(3), P =.003). In addition, left ventricular relaxation (tau) was significantly prolonged (33.3 +/- 10 ms vs 53.0 +/- 16 ms, P =.012). Right ventricular unloading with the Glenn shunt reduced right ventricular dilation and significantly improved left ventricular contraction, end-systolic pressure-volume relation slope (18.9 +/- 8 mm Hg/mm vs 35.8 +/- 18 mm Hg/mm, P =.002), preload recruitable stroke work index slope (39.7 +/- 26 erg x cm(-3) x 10(3) vs 63.0 +/- 22 erg x cm(-3) x 10(3), P =.003), and diastolic performance (tau 53.0 +/- 16 ms vs 43.5 +/- 13 ms, P =.001). CONCLUSIONS: Right ventricular ischemia-induced dilation resulted in acute impairment of left ventricular contractility and relaxation. A modified Glenn shunt attenuated the left ventricular dysfunction by limiting right ventricular dilation and restoring left ventricular cavity geometry.     

Therapeutic angiogenesis with intramyocardial administration of basic fibroblast growth factor

BACKGROUND: Basic fibroblast growth factor (bFGF) induces endothelial cell and smooth muscle cell proliferation and stimulates angiogenesis. This study was designed to evaluate the effects of intramyocardial administration of bFGF on myocardial blood flow, angiogenesis, and ventricular function in a canine acute infarction model. METHODS: Myocardial infarction was induced in 12 dogs by ligation of the left anterior descending coronary artery. Within 5 minutes after coronary occlusion, 100 microg of human recombinant bFGF in 1 mL of saline was injected into the infarct and border zone in 6 dogs, whereas saline alone was used in 6 control dogs. Myocardial blood flow was determined with colored microspheres before and immediately after coronary ligation and again 3, 7, 14, and 28 days after treatment and it was expressed as percent of normal. Angiogenesis was evaluated by immunohistochemical studies 28 days later. Cardiac function was evaluated by repeated echocardiographic measurement. RESULTS: Treatment with bFGF significantly increased the endocardial blood flow in the border zone (7 days after infarction, 75%+/-7% and 41% +/-7% in the bFGF and control groups, respectively, p<0.01) as well as epicardial blood flow in the infarcted zone. Treatment with bFGF significantly increased the capillary density (39.7+/-2.3 and 22.7+/-1.1 vessels per visual field in the bFGF and control groups, respectively, p<0.01) as well as arteriolar density in the border zone. Treatment with bFGF significantly reduced the change in ratio of thickness of the infarcted wall to the normal wall (44%+/-6% and 26% +/-5% in the bFGF and control groups, respectively, p<0.05). It improved the left ventricular ejection fraction (7 days after infarction, 0.54+/-0.02 and 0.37+/-0.03 in the bFGF and control groups, respectively, p<0.01). CONCLUSIONS: Intramyocardial administration of bFGF increased the regional myocardial blood flow, reduced thinning of the infarcted region, and improved ventricular function in acute myocardial infarction. Intramyocardial administration of bFGF may be a new therapeutic approach for patients with acute myocardial infarction.