Ischemic myocardial dysfunction assessed by temporal Fourier transform of regional myocardial wall thickening

A Fourier analysis including the first 20 harmonics was performed on sonomicrometric measurements of regional myocardial wall thickness in eight conscious dogs under control conditions and at four levels of ischemia produced by a hydraulic occluder on the left circumflex coronary artery. Systolic wall thickening was reduced from 26.47 +/- 6.20% (S.D.) (control) to 22.05 +/- 5.73% (mild stenosis), 17.00 +/- 5.86% (moderate stenosis), 11.46 +/- 3.56% (severe stenosis), and 3.69 +/- 2.57% (30-second occlusion), values significantly different from each other (p less than 0.01). The amplitude of the first harmonic decreased stepwise from 1.35 +/- 0.31 to 1.08 +/- 0.29 mm, 0.90 +/- 0.27 mm, 0.69 +/- 0.24 mm, and 0.43 +/- 0.12 mm, all significantly different from each other (p less than 0.05). These amplitude values correlated to percent systolic wall thickening (r = 0.894, p = 0.001). A phase shift of the first harmonic from 137 +/- 11 to 139 +/- 14 degrees, 150 +/- 15 degrees (p less than 0.05 vs control), 161 +/- 21 degrees (p less than 0.01 vs control), and 191 +/- 21 degrees (p less than 0.01 vs control and severe stenosis) correlated with the increase in time from end diastole to the point of maximum wall excursion (r = 0.662, p less than 0.001). These data indicate that the extent of ischemic regional myocardial hypokinesis can be adequately described by the amplitude of the first harmonic, and that the asynchrony of ventricular contraction and relaxation can be detected from the phase of the first harmonic.     

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.     

Comparison of two-dimensional echocardiographic wall motion and wall thickening abnormalities in relation to the myocardium at risk

Previous 2DE studies have suggested that left ventricular wall thickening determinants of regional left ventricular function may be more precise than left ventricular wall motion parameters in the assessment of myocardial ischemia and infarction. To study the relationship between regional wall motion and regional wall thickening abnormalities relative to myocardial ischemia, we performed 2DE in 27 dogs at baseline and following 1 hour of circumflex coronary occlusion. A 2DE circumferential map of regional wall motion and regional wall thickening was generated at 22.5-degree intervals over 360 degrees using a fixed centroid. With the use of three consecutive beats, 95% normal tolerance levels were derived for each individual left ventricular function map. The circumferential extent of left ventricular dysfunction was measured at the curve intercepts of the occluded and normal maps. The left ventricular ischemic area at risk for the corresponding 2DE slice was determined by technetium-99 autoradiography. Following coronary occlusion, left ventricular end-diastolic area increased (p less than 0.0005), left ventricular end-systolic area increased (p less than 0.0005), and left ventricular area ejection fraction decreased (50 +/- 2% to 30 +/- 2%, p less than 0.0005). The circumferential extent of regional wall motion overestimated the area at risk by 77% (226 +/- 11 degrees vs 128 +/- 7 degrees, p less than 0.0005), whereas the circumferential extent of regional wall thickening corresponded to the area at risk (147 +/- 9 degrees vs 128 +/- 7 degrees, p = NS). In addition, the circumferential extent of regional wall motion overestimated regional wall thickening by 54% (p less than 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of the interleukin-converting enzyme inhibitor HMR-3480 on myocardial stunning in pigs in vivo

BACKGROUND: The proinflammatory cytokine interleukin-1 beta is converted into its active form by interleukin-1 beta-converting enzyme (ICE). Circulating cytokines may promote myocardial dysfunction (stunning) after ischemia. OBJECTIVE: To investigate whether ICE inhibition by HMR-3840 improves myocardial stunning in vivo. METHODS: Anesthetized (isoflurane and fentanyl) pigs were used for measurement of left ventricular (LV) pressure, cardiac output and blood flow in the left anterior descending coronary artery (LAD) and left circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening and mean systolic thickening velocity in the anteroapical and posterobasal walls. The animals were subjected to 10 min of LAD occlusion followed by 4 h of reperfusion. The ICE inhibitor (flow-adjusted to achieve coronary plasma concentrations of 10 mug/mL) (ISCH, n=7) or the vehicle (CON, n=7) was infused via a side branch into the LAD during ischemia, or during ischemia and the first 60 min of reperfusion (REP, n=6). RESULTS: Occlusion of the LAD resulted in systolic outward movement (bulging) of the anteroapical wall during ischemia in all groups. Infusion of the ICE inhibitor had no effect on functional recovery when given during ischemia or when given during reperfusion (at the end of reperfusion in the anteroapical wall, values for systolic wall thickening were: CON 17.3+/-7.3%, ISCH 23.2+/-9.8% and REP 19.3+/-6.1%; and values for mean systolic thickening velocity were: CON 4.3+/-1.1 mm/s, ISCH 6.1+/-3.9 mm/s and REP 5.2+/-1.7 mm/s; all P values not significant for CON versus ISCH or REP). LAD blood flow was not affected by HMR-3840 (23.4+/-5.2 mL/min versus 24.3+/-8.1 mL/min; P not significant). Global myocardial function (LV pressure, maximum rate of LV pressure increase and cardiac output) was not different between controls and treatment groups during reperfusion. CONCLUSION: ICE inhibition by HMR-3480 had no effect on myocardial stunning in pigs in vivo.     

Regional left ventricular wall thickening. Relation to regional uptake of 18fluorodeoxyglucose and 201Tl in patients with chronic coronary artery disease and left ventricular dysfunction.

BACKGROUND. In previous studies comparing regional 201Tl (201Tl) and 18fluorodeoxyglucose (FDG) activity in patients with chronic coronary artery disease and left ventricular dysfunction, we hypothesized that regions with mild-to-moderate reduction in FDG activity and regions with mild-to-moderate irreversible 201Tl defects after 3- to 4-hour redistribution represent viable myocardium. In the present study, regional FDG and 201Tl activities were compared with regional systolic wall thickening by gated magnetic resonance imaging (MRI) to confirm the presence of viable myocardium in these territories. METHODS AND RESULTS. Twenty-five patients with chronic stable coronary artery disease and left ventricular dysfunction (ejection fraction, 28 +/- 10) underwent exercise 201Tl tomographic imaging (SPECT), using a reinjection protocol, positron emission tomography (PET) with FDG and H2(15)O, and gated MRI. Matched SPECT, PET, and MRI tomograms were analyzed. From the PET data, 105 regions had matched reduction in FDG and blood flow, of which 69 regions had moderately reduced FDG uptake (50-79% uptake relative to a normal reference region) and 36 had severely reduced FDG uptake (less than 50% of normal activity). Regions with moderately reduced as compared with severely reduced FDG activity had greater end-diastolic wall thickness (9.4 +/- 2.6 versus 8.0 +/- 3.7 mm; p less than 0.05) and regional systolic wall thickening (1.7 +/- 2.7 versus -0.7 +/- 2.1 mm; p less than 0.01). From the SPECT data, 169 irreversible 201Tl defects after 3-4 hour redistribution were identified, of which 70 were mild (greater than 65 to less than 85% of maximal 201Tl activity), 52 were moderate (50-65% of maximal activity), and 47 were severe (less than 50% of maximal activity). Regional systolic wall thickening was greater in regions with normal 201Tl uptake (3.3 +/- 2.3 mm) as compared with all other regions. Regions showing only mild or moderate irreversible defects at redistribution, however, showed wall thickening (2.4 +/- 2.4 and 2.2 +/- 2.5 mm, respectively), which was similar to that observed in regions with reversible 201Tl defects (2.1 +/- 2.2 mm). Only regions with severe irreversible defects at redistribution showed absence of thickening (-0.1 +/- 2.9 mm, p less than 0.01 versus all other groups). After 201Tl reinjection, 12 of 47 (26%) regions with severe irreversible defects showed enhanced 201Tl uptake. The impairment in regional systolic wall thickening was not significantly different between 201Tl defects with and without enhanced 201Tl uptake after reinjection. FDG activity, however, was present in all 12 regions (100%) with enhanced 201Tl uptake after reinjection as compared with only five of 35 (14%) that were unchanged after reinjection (p less than 0.01). CONCLUSIONS. Therefore, preserved wall thickness and systolic wall thickening in regions with moderate reduction in blood flow and FDG activity, and in irreversible 201Tl defects that are only mild-to-moderate, provide additional evidence that such regions represent viable myocardium. Moreover, the finding of metabolic activity and 201Tl uptake in regions with reduced blood flow and absent wall thickening provides clinical evidence of hibernating myocardium in humans.     

Effects of coronary artery reperfusion on regional myocardial blood flow and function in conscious baboons

The effects of coronary artery reperfusion initiated 1 hr and 3 hr after coronary artery occlusion were evaluated on measurements of overall and regional left ventricular function and on regional myocardial blood flow. These experiments were conducted in conscious baboons 2 to 3 weeks after recovery from instrumentation with a solid state left ventricular pressure gauge, aortic and left atrial catheters, a hydraulic occluder around the mid left anterior descending coronary artery, and pairs of ultrasonic transducers implanted in the endocardium of the left ventricular free wall or across the free wall to measure endocardial segment shortening and wall thickening, respectively. Coronary artery occlusion induced similar effects in both groups. At 1 hr after occlusion, the ischemic zone was characterized by severe and equal reductions in both endocardial (-97 +/- 1%) and epicardial (-95 +/- 4%) blood flows and complete loss of regional systolic function, which was replaced by paradoxical wall motion. Reperfusion initiated after 1 hr of ischemia was associated with a marked transient increase in endocardial (+386 +/- 51%) and epicardial (+544 +/- 79%) blood flows. During the subsequent 4 weeks, segment shortening and wall thickening tended to improve. However, at 4 weeks after reperfusion, segment shortening was still depressed by 45 +/- 12% and wall thickening by 58 +/- 14%. In contrast, reperfusion initiated after 3 hr of ischemia was not associated with a significant hyperemic response, and systolic segment shortening and wall thickening did not recover during the subsequent 4 week period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asynchronous left ventricular regional function and impaired global diastolic filling in patients with coronary artery disease: reversal after coronary angioplasty

Left ventricular diastolic filling is impaired in many patients with coronary artery disease and normal left ventricular systolic function, and is improved in many patients after coronary angioplasty (PTCA). To investigate the mechanisms for this improvement, we studied regional asynchrony by radionuclide angiography in 26 patients with single-vessel coronary artery disease before and after successful PTCA. Before PTCA, all patients had normal ejection fractions at rest and normal qualitative left ventricular regional wall motion, as determined by radionuclide and contrast angiography. Quantitative left ventricular regional function was assessed by dividing the left ventricular region of interest into 20 sectors. Phase analysis was performed on each sector's time-activity curve, and the average intersector phase difference was used as an index of left ventricular regional synchrony. Before PTCA, average intersector phase difference was increased compared with normal (6.0 +/- 2.2 vs 4.0 +/- 1.7 degrees, p less than .005), indicating asynchronous regional function. After PTCA, ejection fraction at rest was unchanged, but peak left ventricular filling rate at rest increased from 2.5 +/- 0.6 to 3.0 +/- 0.6 end-diastolic volume/sec (p less than .001) and was associated with a decrease in average intersector phase difference from 6.0 +/- 2.2 to 5.1 +/- 2.3 degrees (p less than .05). Average intersector phase difference decreased in 16 of 21 patients in whom peak filling rate increased after PTCA (p less than .005), compared with one of five patients in whom peak filling rate was unchanged or decreased. Hence, improved global left ventricular filling after PTCA was associated with more synchronous left ventricular regional behavior. To identify the cause of regional asynchrony before PTCA, we then generated time-activity curves from each of four left ventricular quadrants. These data indicated that the asynchrony was caused by regional variation in timing of diastolic rather than systolic events and that PTCA resulted in reduction in regional diastolic asynchrony. These data suggest that in many patients with coronary artery disease and normal left ventricular systolic function, impaired global diastolic filling may result from asynchronous left ventricular regional diastolic function, which is a reversible manifestation of myocardial ischemia or reduced coronary flow.     

Pressure-length loop area: its components analyzed during graded myocardial ischemia

The changes in total pressure-length loop area were compared with changes in effective shortening area, systolic lengthening area and postsystolic shortening area (defined with respect to end-diastolic and end-systolic lengths) of the pressure-length loop during myocardial ischemia in seven anesthetized dogs instrumented for measurement of left ventricular pressure and regional segmental wall motion (sonomicrometry) in the minor axis of the apical region of the left ventricle. Ischemia was induced by gradual tightening of a micrometer-controlled snare around the left anterior descending coronary artery, which supplied the apical myocardium. Data were obtained at normal flow, after critical constriction (loss of pulsatile coronary flow), mild ischemia (ischemia 1: onset of regional dysfunction, i.e., postsystolic shortening and mild hypokinesia) and moderate ischemia (ischemia 2: marked hypokinesia). At each stage, acute afterloading was performed by partially occluding the descending thoracic aorta. The pressure-length loops were analyzed in terms of four areas: total loop area, effective shortening area, postsystolic shortening area and systolic lengthening area. Total loop area decreased only when marked hypokinesia was present (176 +/- 18.3 mm Hg x mm at ischemia 2 versus 245.1 +/- 26.9 mm Hg x mm at ischemia 1, p less than 0.05). However, effective shortening area (98.2 +/- 0.8% of total loop area at baseline; 93.8 +/- 2.4% at critical constriction; 76.3 +/- 7.2% at ischemia 1; 51.9 +/- 12.2% at ischemia 2) and postsystolic shortening area (1.8 +/- 0.8% of total loop area at baseline; 5.2 +/- 1.9% at critical constriction; 14.3 +/- 3/4% at ischemia 1; 23.8 +/- 5.1% at ischemia 2) changed significantly with each progressive stage of ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation of dysfunction in the postischemic 'stunned' myocardium by dimethylthiourea

The mechanism for the prolonged contractile dysfunction observed in myocardium reperfused after reversible regional ischemia ("stunned" myocardium) is unclear. Recent studies suggest that myocardial stunning may be mediated by oxygen-derived free radicals, but the precise molecular species involved remain unknown. Thus we explored the role of the highly cytotoxic hydroxyl radical in regional postischemic dysfunction by using dimethylthiourea (DMTU), an effective and highly permeable hydroxyl radical scavenger. Open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery followed by 4 hr of reperfusion received either DMTU (0.5 g/kg iv over 45 min starting 30 min before occlusion, n = 14) or saline (n = 15). Control and treated dogs were comparable with respect to variables that may affect postischemic dysfunction, including heart rate, aortic pressure, left atrial pressure, arterial blood gases and hemoglobin concentration, size of the occluded bed (determined by postmortem perfusion), and collateral blood flow (determined by radioactive microspheres). Regional myocardial function was assessed by measuring wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesis during ischemia. After reperfusion, however, wall thickening (expressed as percent of baseline) was considerably greater in treated as compared with control dogs: 53 +/- 9% (mean +/- SEM) vs 9 +/- 14% (p less than .03) at 1 hr, 55 +/- 9% vs 23 +/- 13% (p less than .05) at 2 hr, 60 +/- 9% vs 28 +/- 14% (p less than .05) at 3 hr, and 67 +/- 5% vs 36 +/- 13% (p less than .05) at 4 hr. Thus DMTU produced a significant and sustained improvement in recovery of contractile function. In concentrations greater than the plasma levels attained in vivo, DMTU did not scavenge either hydrogen peroxide or superoxide anion in vitro. These results suggest that the myocardial dysfunction occurring after a brief episode of regional ischemia is mediated in part by the hydroxyl radical.     

Ventricular performance and biochemical alteration of regional ischemic myocardium after reperfusion in the pig

Reperfusion of acutely ischemic myocardium may cause profound alterations in left ventricular wall performance and metabolism. This study evaluates regional left ventricular wall thickness, analyzes metabolic and biochemical alterations, and examines tissue hemorrhage during 15, 30, and 120 minutes of myocardial ischemia, each followed by 120 minutes of reperfusion. Reperfusion after 15 minutes of ischemia showed nearly normal ventricular wall thickening and motion, intact metabolic and biochemical function, and no tissue hemorrhage. However, reperfusion after 30 and 120 minutes of ischemia was associated with ventricular wall thickening and failure to resume systolic and diastolic wall motion. Furthermore, adverse metabolic and biochemical alterations and reperfusion zone hemorrhaging increased proportionally with the duration of ischemia. These findings suggest critical myocardial damage occurring between 15 and 30 minutes of ischemia in an animal model without preexisting coronary collateral circulation. The observed metabolic and biochemical changes are consistent with irreversible cell membrane defects, allowing calcium ion accumulation and thus adversely affecting diastolic relaxation and systolic thickening.     

Segmental systolic responses to brief ischemia and reperfusion in the hypertrophied canine left ventricle.

OBJECTIVES AND BACKGROUND. Left ventricular hypertrophy is associated with increased mortality, increased myocardial infarct size and an increased incidence of sudden death. Although reperfusion after ischemia has been shown to result in decreased infarct size and recovery of systolic thickening, it is unknown how left ventricular hypertrophy might influence recovery of regional systolic thickening after ischemia and reperfusion. We hypothesized that left ventricular hypertrophy might attenuate or abolish the functional response to reperfusion. METHODS. Three groups of chronically instrumented, conscious dogs (dogs with left ventricular hypertrophy and hypertension; dogs with left ventricular hypertrophy and reduced blood pressure and a control group without hypertrophy and with normal blood pressure) underwent 15 min of ischemia and 24 h of reperfusion. Segmental systolic thickening was measured by sonomicrometers and myocardial segments were grouped by percent of control segmental systolic thickening retained at 15 min of ischemia (class 1 greater than or equal to 67%, class 2 from 0% to 66%, class 3 less than 0% control systolic thickening). The recovery of each class of segment was measured serially during reperfusion. Hemodynamic variables and regional myocardial blood flow were also measured. RESULTS. There were no differences among groups in recovery of segmental systolic thickening for class 1 segments. Systolic thickening in class 2 (hypokinetic) segments was significantly depressed (p less than 0.05 compared with control value) in the group with left ventricular hypertrophy and reduced blood pressure (but not in the group with hypertrophy and hypertension) during early reperfusion; systolic thickening in class 3 (dyskinetic) segments showed a similar trend in the group with hypertrophy and reduced pressure. CONCLUSIONS. Although left ventricular hypertrophy with hypertension did not attenuate the contractile response to reperfusion, hypertrophy with reduced blood pressure was associated with significantly greater depression of segmental systolic thickening early during reperfusion.     

Quantitative assessment of regional left ventricular function by densitometric analysis of digital-subtraction ventriculograms: correlation with myocardial systolic shortening in dogs

Conventional wall motion analysis of contrast ventriculograms assesses only that part of the wall that is tangential to the x-ray beam. To assess regional left ventricular function in three dimensions, a new computerized method based on densitometric analysis of digital subtraction left ventriculograms was developed and validated in nine open-chest dogs instrumented with a circumflex coronary artery occluder and sonomicrometers in the anterior and posterior walls. Each dog underwent digital subtraction ventriculography at baseline and at five levels (I to V) of dysfunction of the inferior wall induced by progressive stenoses of the circumflex coronary artery. The ventriculogram was divided into six segments around the end-diastolic center of gravity. Time-volume curves were obtained by densitometry in the normal anterior and ischemic inferior segments containing the sonomicrometers. From these curves, regional ejection fraction (R-EF), regional peak ejection rate (R-PER), and regional phase (R-PH) and amplitude (R-AMP) of the first Fourier harmonic were derived. From baseline to level V of dysfunction, myocardial systolic shortening determined by sonomicrometry decreased by 124 +/- 34% of control (mean +/- SD; p less than .001) in the ischemic wall, while it increased by 12 +/- 19% (NS) in the normal wall. At the same time, R-EF, R-PER, and R-AMP decreased in the ischemic segment by 65 +/- 12%, 46 +/- 30%, and 45 +/- 15% of control, respectively (all p less than .01), while they remained unchanged or increased in the normal segment. R-PH was delayed by 14 +/- 5% (p less than .01) in the ischemic segment, but remained unchanged in the normal segment, reflecting the asynchrony of regional left ventricular contraction during ischemia. Densitometric indexes of regional function correlated well with sonomicrometric systolic shortening both in normal and ischemic segments, with r values of .84 for R-EF, .80 for R-AMP, .64 for R-PER, and .55 for R-PH (all p less than .0001). Thus, densitometric analysis of digital subtraction left ventriculograms allows three-dimensional assessment of the extent, velocity, and synchrony of regional left ventricular contraction. Densitometric indexes of regional contraction correlate well with direct measurements of myocardial systolic shortening and are useful in quantitating regional left ventricular dysfunction.     

Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischemia

Reperfusion after reversible regional ischemia has been shown to result in delayed recovery of myocardial function, but the mechanism responsible for this phenomenon remains unknown. We explored the potential role of oxygen-free radicals as mediators of postischemic dysfunction in open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 hr of reperfusion. Treated animals (n = 19) received an infusion of the oxygen free-radical scavengers superoxide dismutase (SOD; 15,000 U/kg) and catalase (CAT; 55,000 U/kg) for 1 hr starting 15 min before LAD occlusion, while control animals (n = 20) received an equal volume of saline. SOD and CAT produced no discernible effect on heart rate, aortic pressure, or left atrial pressure. Collateral flow to the ischemic zone (radioactive microspheres) was 0.07 +/- 0.01 ml/min/g in both groups. The size of the occluded bed as determined by postmortem perfusion was 26.1 +/- 1.2% of the left ventricle in the control group and 26.5 +/- 0.9% in the treated group. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed-Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs, both at 1 hr (43.8 +/- 14.3 vs 12.8 +/- 11.6) and 2 hr of reperfusion (74.2 +/- 8.4 vs 31.6 +/- 9.8, p less than .005). This improved recovery of function obtained with SOD and CAT suggests that oxygen-free radicals play an important role in the genesis of myocardial dysfunction after a brief episode of regional ischemia.     

Detection of left ventricular ischemia during atrial pacing: simultaneous assessment by echocardiography and invasive hemodynamic measurements

The ability of cross-sectional echocardiography to detect myocardial ischemia induced by atrial pacing was assessed during cardiac catheterization in 11 patients with coronary arterial disease. Angina pectoris was precipitated in all patients with increase in left ventricular end-diastolic pressure after pacing by 5 +/- 6 (mean +/- standard deviation) mm Hg (P less than 0.01). Regional left ventricular dysfunction occurred during pacing in all patients as determined by quantitative echocardiographic assessment of wall motion. Simultaneously, systolic reduction in parasternal short-axis area decreased (from 42 +/- 13 to 28 +/- 9%, P less than 0.01) with concomitant decrease in ejection fraction as determined in the apical four-chamber view (from 49 +/- 5 to 40 +/- 8%, P less than 0.01). In conclusion, echocardiography may detect pacing-induced myocardial ischemia through detection of regional and global left ventricular dysfunction. Inadequate regional perfusion may be indicated by echocardiography even in patients without apparent evidence of ischemia as determined by invasive hemodynamic measurements.     

Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine

Determination of the effect of inotropic stimulation on regionally ischemic and hypokinetic myocardium is complicated when intravenous administration of the inotropic agent also causes stimulation of nonischemic adjacent and distant regions, thereby altering global ventricular hemodynamics. To obviate such events, 16 anesthetized swine were studied during regional inotropic stimulation by infusion of dobutamine hydrochloride (2.5 +/- 1 microgram/min) into the cannulated left anterior descending coronary artery. Coronary inflow was controlled by a pump in an extracorporeal circuit. Two groups of swine with different degrees of ischemia were studied. In the first group of animals (n = 8), reduction in coronary inflow to produce a fall in coronary artery pressure (CAP) from 114 +/- 7 mm Hg to 62 +/- 2 mm Hg caused a decrease in percent systolic wall thickening (%WTh) from 34.6 +/- 8.1% to 25.4 +/- 5.8% (p less than 0.005). In the second group of animals (n = 8), CAP was decreased to 46 +/- 5 mm Hg (control: 115 +/- 8 mm Hg) and % WTh decreased from 34.1 +/- 16.4% to 10.4 +/- 6.9% (p less than 0.001). Subendocardial blood flow was reduced from 1.41 +/- 0.38 ml/min/g to 0.65 +/- 0.13 ml/min/g (group 1, p less than 0.001) and from 1.08 +/- 0.22 ml/min/g to 0.24 +/- 0.08 ml/min/g (group 2, p less than 0.001). Regional infusion of dobutamine caused asynchronous ventricular contraction with early systolic augmentation in wall thickening followed by late systolic thinning. Therefore, during hypoperfusion regional myocardial function assessed by %WTh remained unchanged (26.2 +/- 5.8%, p = NS) in group 1 and decreased significantly to 1.6 +/- 5.1% (p less than 0.041) in group 2. Subendocardial blood flow decreased to 0.44 +/- 0.15 ml/min/g in group 1 (p less than 0.005) and to 0.15 +/- 0.07 ml/min/g in group 2 (p less than 0.012). To account for the augmented early systolic thickening that occurred during asynchronous contraction, a myocardial work index was developed in which the sum of the instantaneous left ventricular pressure-wall thickness product was calculated for estimation of regional myocardial work. Increases in this work index were apparent with the addition of dobutamine at both levels of hypoperfusion. This significant enhancement in regional myocardial function in group 2 caused a significant increase of 16% (p less than 0.009) in overall left ventricular power during ejection. Thus, regional inotropic stimulation with dobutamine caused enhancement of maximum work of the ischemic myocardium in the steady state despite a further decrease in subendocardial blood flow.     

Early identification with ultrasonic integrated backscatter of viable but stunned myocardium in dogs

It has been shown that canine and human hearts exhibit a cardiac cycle-dependent variation of integrated backscatter (cyclic variation) that reflects intrinsic regional contractile performance. To determine whether ultrasound tissue characterization can identify viable though stunned myocardium before recovery of regional wall thickening, transient ischemic injury was produced in eight open chest dogs for 15 min followed by reperfusion for 2 h. Cyclic variation and wall thickening were measured before ischemia, at 15 min after the onset of ischemia and at selected intervals after the onset of reperfusion from multiple sites within the ischemic zone with a novel combined two-dimensional and M-mode acquisition system. Cyclic variation and wall thickening were computed from digitized M-mode integrated backscatter images with an algorithm developed and validated for this purpose. Magnitude and "delay" of cyclic variation and wall thickening were compared. Delay represents the degree of synchrony of regional cyclic variation or wall thickening with global ventricular mechanical systole. Baseline cyclic variation and wall thickening magnitudes were 3.8 +/- 0.2 dB and 37 +/- 1.4%, respectively. With ischemia, cyclic variation and wall thickening decreased to 1.7 +/- 0.2 dB and 17 +/- 2%, respectively (p less than 0.05, compared with baseline). Cyclic variation recovered to baseline levels within 20 min after reperfusion (3.3 +/- 0.4 dB, p = NS). Wall thickening remained depressed for 2 h after the onset of reperfusion (23 +/- 2%, p less than 0.05 compared with baseline). Delay of cyclic variation in a unitless ratio expressed as delay (in milliseconds) divided by the QT interval (in milliseconds) increased from 0.87 +/- 0.03 at baseline to 1.10 +/- 0.12 with ischemia, a change consistent with mild asynchrony, and returned to baseline (0.95 +/- 0.07, p = NS compared with baseline) within 20 min after reperfusion. Delay of wall thickening was 0.88 +/- 0.02 at baseline, increased to 1.23 +/- 0.09 with ischemia and remained significantly increased 2 h after reperfusion (1.07 +/- 0.05, p less than 0.05 compared with baseline). Recovery time constants for cyclic variation and wall thickening with reperfusion reflected earlier restoration of cyclic variation (8.1 min) than of wall thickening (420.5 min). Thus, cyclic variation recovers before wall thickening with reperfusion. Its analysis appears to provide a useful index of the presence of viable and potentially salvageable tissue in regions of stunned myocardium that is independent of wall thickening.     

A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats

OBJECTIVE: Opioids have a cardioprotective effect during ischemia. Previously, we showed in an ex-vivo model of myocardial ischemia and reperfusion that 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2, a highly potent and long-acting opioid peptide analgesic with fewer side effects than morphine, provides improved cardioprotection compared with morphine. The purpose of this study was to confirm, in an in-vivo model, the cardioprotective effect of 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2. METHODS: Rats (n=6/group) were randomized to 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 therapy (intravenous 10 nmol bolus 30 min before ligation and 10 nmol/h continuous infusion), morphine (100 nmol bolus and 100 nmol/h infusion), or placebo, and underwent left anterior descending (LAD) ligation for 10 min followed by reperfusion for 30 min. Continuous transesophageal echocardiogram and electrocardiogram were monitored. Fractional shortening and systolic wall thickening of the ischemic area were calculated. Time to recovery of left ventricular function was the duration of time needed for fractional shortening to recover to 90% of baseline following reperfusion. Duration of reperfusion arrhythmia was the time to the cessation of salvo (at least three consecutive premature ventricular contractions (PVCs)) following reperfusion. RESULTS: Time to recovery of left ventricular function was significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (4.4+/-2.2 min) and morphine groups (6.0+/-2.5 min) than in the controls (10.5+/-2.2 min; p<0.01). The 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 group showed significantly higher fractional shortening and systolic wall thickening of the ischemic area than the control group. Duration of reperfusion arrhythmia was also significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (2.8+/-1.7 min) and morphine groups (5.8+/-3.9 min) than in the controls (11.8+/-2.0 min; p<0.05). CONCLUSION: 2',6'-Dimethyltyrosine-D-Arg-Phe-Lys-NH2 provides a cardioprotective effect against myocardial ischemia and reperfusion in vivo.     

Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.

The effects of exercise on regional myocardial blood flow and function were examined in the presence and absence of beta-adrenergic receptor blockade in 10 adult conscious dogs with severe left ventricular (LV) hypertrophy induced by aortic banding in puppies, which increased the LV weight/body weight ratio by 87%. Exercise at the most intense level studied increased LV systolic (+87 +/- 8 mm Hg) and end-diastolic (+28 +/- 5 mm Hg) pressures, systolic (+85 +/- 12 g/cm2) and diastolic (+49 +/- 11 g/cm2) wall stresses, and subepicardial wall thickening (+0.18 +/- 0.05 mm) but reduced subendocardial wall thickening (-0.45 +/- 0.12 mm) and full wall thickening (-0.42 +/- 0.13 mm). This was associated with a fall in the subendocardial/subepicardial (endo/epi) blood flow ratio to 0.87 +/- 0.06 from 1.24 +/- 0.08. Subendocardial dysfunction persisted during recovery, at a time when transmural blood flow distribution returned to baseline, suggesting myocardial stunning. At the least intense level of exercise studied, the endo/epi blood flow ratio did not fall (1.27 +/- 0.14), but increases in heart rate (+73 +/- 8 beats per minute) and LV systolic (+35 +/- 8 g/cm2) and diastolic (+27 +/- 3 g/cm2) wall stresses were observed, and subendocardial wall thickening fell significantly (-0.21 +/- 0.08 mm, p less than 0.05). With anticipation of exercise, subendocardial wall thickening was not changed. However, subendocardial dysfunction was even evident after 10 beats, i.e., the first 3 seconds of exercise, at a time when LV pressures and stresses had not increased. After beta-adrenergic receptor blockade with propranolol, the most intense level of exercise was associated with lesser increases in systolic and diastolic LV wall stresses, heart rate, and LV dP/dt, and the endo/epi blood flow ratio was no longer reduced below unity (1.17 +/- 0.09). In addition, there were no decreases in subendocardial or full wall thickening, and myocardial stunning was no longer observed. Thus, the subendocardial hypoperfusion and depression in subendocardial wall thickening observed during exercise in dogs with LV hypertrophy was prevented by pretreatment with beta-adrenergic receptor blockade. Furthermore, the subendocardial dysfunction occurred rapidly, before alterations in LV systolic or diastolic wall stress or an alteration in the endo/epi blood flow ratio.(ABSTRACT TRUNCATED AT 400 WORDS)     

Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine

There is now evidence that under resting conditions coronary vasodilator reserve exists even in the presence of myocardial ischemia. Therefore, we tested the hypothesis that a vasodilator reserve may exist during exercise so that during exercise-induced ischemia a reduction in coronary constrictor tone can be produced that attenuates the decreases in regional myocardial blood flow and function distal to a severe coronary stenosis without changing the determinants of myocardial oxygen demand. Nine dogs were instrumented with an ameroid constrictor on the left circumflex coronary artery and were studied 2 to 3 weeks later. During a control treadmill run, heart rate increased from 119 +/- 20 to 225 +/- 20 beats/min and peak left ventricular pressure increased from 144 +/- 17 to 163 +/- 28 mm Hg. Poststenotic subendocardial blood flow (measured by a microsphere technique) fell from 1.19 +/- 0.36 to 0.51 +/- 0.30 ml/min X g and systolic wall thickening (by sonomicrometry) decreased from 24.3 +/- 5.8% to 6.0 +/- 6.1%. During an identical run after nifedipine (10 micrograms/kg iv), systemic hemodynamics were not significantly altered. However, subendocardial blood flow was increased to 0.85 +/- 0.51 ml/min X g (p less than .05) and systolic wall thickening to 11.4 +/- 7.8% (p less than .01). We conclude that in this study the amelioration of exercise-induced myocardial ischemia was due to the recruitment by nifedipine of coronary vasodilator reserve.     

Prolonged abnormalities of left ventricular diastolic wall thinning in the "stunned" myocardium in conscious dogs: time course and relation to systolic function

Myocardial reperfusion after reversible ischemia is known to be associated with prolonged abnormalities of systolic contractile function (myocardial "stunning"). However, no information is available regarding the recovery of diastolic function in the stunned myocardium in the conscious state. Accordingly, 10 conscious dogs instrumented with pulsed Doppler thickening probes underwent a 15 min occlusion of the left anterior descending coronary artery followed by 7 days of reperfusion. Regional systolic function was assessed as net systolic thickening fraction. Left ventricular regional diastolic properties were estimated from two variables: the mean rate to half end-diastolic thinning and the late diastolic thinning fraction. Both indexes of diastolic function remained severely impaired after restoration of flow. In general, the recovery of the mean rate to half end-diastolic thinning and of the late diastolic thinning fraction paralleled the recovery of systolic thickening, but the impairment of the mean rate to half end-diastolic thinning was more marked than that of the late diastolic thinning fraction. At 4 h of reperfusion, the values for the mean rate to half end-diastolic thinning and the late diastolic thinning fraction (expressed as percent of baseline) were 57 +/- 5% (p less than 0.001 versus baseline) and 79 +/- 7% (p less than 0.05), respectively, whereas systolic thickening fraction averaged 52 +/- 10% (p less than 0.001). At 24 h, the mean rate to half end-diastolic thinning and the late diastolic thinning fraction were no longer significantly different from baseline, whereas systolic thickening fraction remained decreased at 82 +/- 4% (p less than 0.001) and returned to control values by 48 h. This study demonstrates the presence of profound, prolonged abnormalities of regional diastolic wall thinning after a brief episode of ischemia in the conscious state and expands the concept of myocardial stunning from the traditional notion of impaired systolic performance to that of a global derangement in mechanical function that involves both systolic and diastolic properties.