Effects of Propranolol on Regional Myocardial Function, Electrograms, and Blood Flow in Conscious Dogs with Myocardial Ischemia

The effects of coronary occlusion and of subsequent propranolol administration were examined in 18 conscious dogs. Overall left ventricular (LV) function was assessed by measurements of LV pressure and dP/dt, and regional myocardial function was assessed by measurements of segment length (SL), velocity of SL shortening and regional myocardial “work”, i.e., pressure-length loops in normal, moderately, and severely ischemic zones. Regional intra-myocardial electrograms were measured from the same sites along with regional myocardial blood flow as determined by the radioactive microsphere technique. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones with graded flow reduction and graded elevation of the ST segment. Propranolol depressed overall LV function, function in the normal zone (work fell by 17±4%), and in the majority of moderately ischemic segments (work fell by 7±3%). In severely ischemic segments the extent of paradoxical motion and post-systolic shortening was reduced by propranolol. After propranolol regional myocardial blood flow fell in the normal zone (11±2%) and rose in the moderately (15±4%) and severely (63±10%) ischemic zones. Thus, in the conscious dog with regional myocardial ischemia, propranolol induces a redistribution of myocardial blood flow, with flow falling in normal zones and rising in moderately and severely ischemic zones. The improvement in perfusion of ischemic tissue was associated with slight but significant depression of shortening, velocity, and work in the moderately ischemic zones and of paradoxical bulging and post-systolic shortening in the severely ischemic zone.     

Effects of isoproterenol on regional myocardial function, electrogram, and blood flow in conscious dogs with myocardial ischemia.

The effects of coronary occlusion and of subsequent isoproterenol infusion were examined in conscious dogs. Left ventricular (LV) function was assessed by measurements of LV diameter, pressure, velocity and dP/dt/P, and regional myocardial function was assessed by measurements of segment length (SL) and velocity of SL shortening in normal, border, and ischemic zones. Regional myocardial function was measured from the same sites, along with intramyocardial electrograms and regional myocardial blood flow as determined by radioactive microspheres. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones with graded flow reductions and graded increases in ST segment elevation. Isoproterenol improved overall LV function, and function in the normal zone. Isoproterenol also improved function in 19 of 21 border-zone segments and in all moderately ischemic segments, while elevating further the ST segments. These changes were accompanied by increases in myocardial blood flow. In contrast, in severely ischemic segments, isoproterenol resulted in a deterioration of function, in that paradoxical motion occurred in segments previously akinetic during systole, while paradoxical motion was intensified in those segments in which it was already present. These changes were accompanied by further ST segment elevation but not by concurrent increases in blood flow. In addition, in 2 of 21 border zone segments, myocardial blood flow fell and these segments responded to isoproterenol with complete loss of function; paradoxical motion developed. Thus, in the conscious dog, a strong inotropic agent can improve function, even in the ischemic myocardium, as long as the required additional blood flow can be provided wither through primary or collateral channels.     

Nicotinic acid, free fatty acids and myocardial function during coronary occlusion and reperfusion in the dog

The effect of nicotinic acid on regional myocardial blood flow, percentage of segment shortening and myocardial uptake of free-fatty acids during a 15-min occlusion of the left anterior descending coronary artery and 3-hr reperfusion period was compared to a saline-treated control group. Nicotinic acid (2.4 mumol/kg/min i.v.) was infused 30 min before and throughout the occlusion period. Heart rate, arterial blood pressure and left ventricular systolic and end diastolic pressures were not different during occlusion and reperfusion in the nicotinic acid or saline-treated groups. However, left ventricular dP/dt, an index of global myocardial function and percentage of segment shortening in the ischemic region were greater during occlusion and reperfusion after nicotinic acid. Even though myocardial blood flow was unaltered in the normal or ischemic region during nicotinic acid infusion, subendocardial blood flow during reperfusion was enhanced significantly when compared to the control group. Nicotinic acid also decreased free-fatty acid uptake by the heart during occlusion which returned gradually to the pretreatment control during 3 hr of reperfusion. Thus, the improvement in percentage of segment shortening, dP/dt and subendocardial blood flow during reperfusion may be related to the ability of nicotinic acid to reduce free-fatty acid uptake by the heart during coronary occlusion.     

Contrasting effects of verapamil and nifedipine on pH of ischemic myocardium in the dog

It remains unknown whether the actions of verapamil to depress and nifedipine to enhance contractile function of ischemic myocardium influence the degree of myocardial ischemic injury. Thus, we measured intramyocardial pH using fiberoptic pH probes in 43 anesthetized open-chest dogs pretreated for 30 min with verapamil, or nifedipine in doses that decreased aortic pressure 10 to 15 mm Hg before ligation of the left anterior descending coronary artery for 15 min. Drugs were continued during the 15-min ischemic period until the animals were euthanized without reperfusion: verapamil, 10-20 micrograms/kg/min and nifedipine, 2 to 4 micrograms/kg/min i.v. Verapamil-treated dogs showed higher pH of ischemic subendocardium after 15 min ischemia (6.75 +/- 0.07) than did the nifedipine (6.48 +/- 0.04) or placebo (6.43 +/- 0.05) groups, even if the animals were paced (6.71 +/- 0.11) to prevent the negative chronotropic effect of verapamil (P less than 0.01). Neither verapamil nor nifedipine changed collateral myocardial blood flow from 0.10 +/- 0.02 in the subendocardium and 0.17 +/- 0.03 ml/min/g in the subepicardium. Left ventricular function estimated by left ventricular dp/dt was depressed 15% by verapamil and enhanced 26% by nifedipine. Thus, verapamil, but not nifedipine, relieves acidosis of ischemic myocardium after acute coronary occlusion in doses that sustain a 10 to 15 mm Hg decrease in aortic pressure. Nifedipine, in doses that produced the same 10 to 15 mm Hg decrease in mean aortic pressure, did not increase intramyocardial pH, as it enhanced contractile function, estimated by left ventricular dp/dt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal Global Left Ventricular Relaxation Occurs Early During the Development of Pharmacologically Induced Ischemia

In animal and human models, left ventricular (LV) diastolic function has been observed to be highly sensitive to myocardial ischemia. The response of LV diastolic parameters to pharmacologically induced ischemia, however, has not been characterized and might be important in the interpretation of dobutamine stress echocardiography. Eight mongrel dogs, in which were inserted a high-fidelity micromanometer LV catheter, coronary sinus sampling catheter, and ultrasonic coronary artery flow probe, underwent intravenous dobutamine infusion at escalating doses both before (control protocol) and after (ischemia protocol) creation of left anterior descending coronary artery stenosis with a hydraulic cuff occluder adjusted to maintain resting coronary artery flow but attenuate reactive hyperemia. At each dobutamine dose, epicardial short-axis 2-dimensional echocardiographic images and hemodynamic measurements were obtained. LV diastolic function was examined by calculation of peak (–)dP/dt and the time constant of isovolumic relaxation (τ). The dobutamine infusion protocol was terminated on the earliest recognition of an anterior wall motion abnormality. Peak (+)dP/dt normalized for developed isovolumetric pressure was calculated as a relatively load-independent index of global LV contractile function. Dobutamine infusion with and without ischemia resulted in comparable changes in heart rate and (+)dP/dt/IP, with no change in LV end-diastolic or -systolic pressure. The magnitude of peak (-)dP/dt increased less during the ischemia (1231 ± 109 to 1791 ± 200 mm Hg/sec) versus the control (1390 ± 154 to 2432 ± 320 mm Hg/sec) protocol (P < .05). Similarly, the observed decrease in τ was less during the ischemia (53 ± 3 to 38 ± 4 msec) than the control (51 ± 5 to 23 ± 3 msec) protocol, corresponding to a slower rate of relaxation (P < .05). In addition, the smaller decrease in τ was observed at the dobutamine dose before the dose at which an echocardiographic wall motion abnormality was first recognized. Dobutamine-induced ischemia is associated with abnormal LV diastolic function. In addition, these abnormalities seem to occur early in the development of ischemia. These observations extend to pharmacologically induced ischemia prior findings from other models of ischemia, suggesting the high sensitivity of LV diastolic function to the development of myocardial ischemia. (J Am Soc Echocardiogr 1999;12:113-20.)     

STIMULATION OF MYOCARDIUM DURING REPERFUSION INJURY BY A NEW INOTROPE-VASODILATOR AGENT, MCI-154

The systemic and coronary hemodynamic actions of a newly synthesized inotropic agent structurally related to milrinone and amrinone, MCI-154 (0.5-4.0 micrograms/kg/min IV), were studied in 2 groups of conscious, chronically instrumented dogs with normal or depressed postischemic, reperfused myocardium after a 15-min coronary artery occlusion. In an additional group of control experiments, the time course of recovery of postischemic, reperfused myocardium was studied to verify the constancy of regional segment shortening in the previously ischemic zone during the time corresponding to drug infusion. Similar inotropic actions of MCI-154 were observed in both normal and postischemic, reperfused hearts, indicating significant contractile reserve to be present in 'stunned' myocardium. Global contractility as measured by peak positive dP/dt was significantly increased in both groups. In postischemic, reperfused myocardium 90 min after initiation of reflow, regional segment function remained depressed at 44% of control but improved to 93% of control after administration of MCI-154. In addition, MCI-154 produced significant dose-related decreases in mean arterial pressure, left ventricular end-diastolic pressure, end-diastolic segment length, and diastolic coronary vascular resistance. The data demonstrate that in addition to producing beneficial hemodynamic changes, MCI-154, a new non-sympathomimetic inotropic agent, markedly enhances regional contractility of postischemic, reperfused myocardium.     

Intravenous infusion of bone marrow mesenchymal stem cells improves myocardial function in a rat model of myocardial ischemia

OBJECTIVE: We investigated the effects of three different sites for delivery of bone marrow mesenchymal stem cells (MSCs) in a rat model of myocardial ischemia. DESIGN: Prospective, randomized, controlled study. SETTING: University affiliated research institute. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: A thoracotomy was performed under general anesthesia. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery. One month later, animals were randomized to receive 5 x 10(6) MSCs labeled with PKH26 in phosphate buffer solution or phosphate buffer solution alone as a placebo by injection into right femoral vein, directly into the left ventricular (LV) cavity, or into the ischemic zone in the anterior ventricular free wall. MEASUREMENTS AND MAIN RESULTS: Echocardiographically measured myocardial function, including ejection fraction and fractional shortening, was quantitated 2 wks and 4 wks after administering MSCs or phosphate buffer solution. Hemodynamics, including cardiac index, LV dP/dt40, LV negative dP/dt, and LV diastolic pressure were measured 4 wks after administering MSCs or phosphate buffer solution. MSCs were counted in 5-microm sections obtained with cryostat from each harvested heart. Significant improvements in ejection fraction, fractional shortening, cardiac index, LV dP/dt40, LV negative dP/dt, and LV diastolic pressure followed injection of MSCs, regardless of the site of injection. However, the number of MSCs counted in the heart sections was significantly greater after direct myocardial injection. CONCLUSIONS: Independently of the site of injection and regardless of the different concentration of bone marrow mesenchymal stem cells identified in the myocardium, myocardial function was comparably improved in all groups of animals treated with MSCs.     

Effects of morphine on coronary and left ventricular dynamics in conscious dogs.

We studied the effects of i.v. 2 mg/kg morphine sulfate (MS) on coronary blood flow and resistance, left ventricular (LV) diameter and pressure (P), rate of change of pressure (dP/dt), and dP/dt/P in conscious dogs. An initial transient reduction in coronary vascular resistance, associated with increases in heart rate, dP/dt, dP/dt/P, and reductions in LV end-diastolic and end-systolic size were observed. This was followed by a prolonged increase in mean coronary vascular resistance, lasting from 5 to 30 min, while heart rate, arterial pressure, and LV end-diastolic diameter returned to control levels and dP/dt/P remained slightly but significantly above control. At 10 min, late diastolic coronary flow had fallen from 44 plus or minus 3 ml/min to a minimum level of 25 plus or minus 3 ml/min, while late diastolic coronary resistance had risen from 1.68 plus or minus 0.10 to 3.04 plus or minus 0.28 mm Hg/ml/min. Morphine also induced substantial coronary vasoconstriction when heart rate was held constant. Neither the MS-induced coronary vasoconstriction nor the positive inotropic response was abolished by bilateral adrenalectomy. The positive inotropic response of MS was reversed after beta blockade, but not the coronary vasoconstriction. Alpha receptor blockade abolished the late coronary vasoconstriction effects of morphine, and only dilatation occurred. In anesthetized dogs MS failed to produce late coronary vasoconstriction. Coronary after a respiratory-depressant dose of morphine, 10 mg/kg i.v. Smaller doses of MS, 0.25 mg/kg every 15 min, produced significant coronary vasoconstriction after a total dose of 0.75 mg/kg in the conscious dogs. The effects of morphine may differ in the normal dog and man and may vary depending upon the presence or absence of coronary artery disease. However, in the normal conscious dog, MS elicits a mild beta adrenergic increase in contractility and an important coronary vasoconstrictor effect, which is mediated through alpha adrenergic receptors.     

Effect of pericardium on regional myocardial systolic function in acute ischemia.

To know whether or not the pericardium affects regional myocardial systolic function in acute ischemia, we measured ischemic and non-ischemic segment lengths of the left ventricle using ultrasonic crystals in 10 open-chest dogs with the pericardium preserved. When the left ventricular pressure and segment lengths were stable after left circumflex coronary occlusion, we opened the pericardium widely. After coronary occlusion, end-diastolic length (EDL) in ischemic and non-ischemic segments increased, and the ischemic segment showed paradoxical systolic expansion while the non-ischemic segment increased its active shortening. After pericardiectomy, heart rate, left ventricular systolic pressure, and peak positive and negative dP/dt did not change. EDL in ischemic and non-ischemic segments further increased from 12.02 +/- 0.18 to 12.50 +/- 0.16 mm (mean +/- S.E., p less than 0.01) and from 11.12 +/- 0.20 to 11.45 +/- 0.18 mm (p less than 0.05), respectively, despite the concomitant fall in left ventricular end-diastolic pressure (LVEDP) from 12.4 +/- 0.6 to 10.6 +/- 0.8 mmHg (p less than 0.01). End-systolic length in ischemic and non-ischemic segments also increased from 12.37 +/- 0.25 to 12.70 +/- 0.20 mm (p less than 0.05) and from 8.50 +/- 0.13 to 8.74 +/- 0.13 mm (p less than 0.01), respectively, although the left ventricular end-systolic pressure did not change. Maximum expanded systolic length of the ischemic segment also increased from 12.99 +/- 0.20 to 13.42 +/- 0.16 mm (p less than 0.01). These results indicate that, in acute ischemia, the pericardium inhibits paradoxical systolic expansion of the ischemic region and increase in end-systolic length of non-ischemic segment. Thus, it is concluded that the pericardium modifies the regional myocardial systolic function in acute ischemia, perhaps through the mechanical restraint of the pericardium.     

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

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

Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy.

Previous reports have shown that increases in heart rate may result in enhanced left ventricular (LV) systolic and diastolic performance. To assess whether this phenomenon occurs in the presence of depressed LV function, the effects of pacing on LV pressure and volume were compared in seven patients with dilated cardiomyopathy (LV ejection fraction 0.19 +/- 0.11) and six patients with no or minimal coronary artery disease (LV ejection fraction 0.69 +/- 0.11). Patients with normal LV function demonstrated significant increases in LV peak-positive dP/dt, LV end-systolic pressure-volume ratio, LV peak filling rate, and a progressive leftward and downward shift of their pressure-volume diagrams, compatible with increased contractility and distensibility in response to pacing tachycardia. There was no change in LV peak-negative dP/dt or tau. Patients with dilated cardiomyopathy, in contrast, demonstrated no increase in either LV peak-positive dP/dt or the end-systolic pressure-volume ratio, and absence of a progressive leftward shift of their pressure-volume diagrams. Moreover, cardiomyopathy patients demonstrated no increase in LV peak-negative dP/dt or LV peak filling rate and a blunted downward shift of the diastolic limb of their pressure-volume diagrams. Tau, as determined from a derivative method, became abbreviated although never reaching control values. We conclude that patients with dilated cardiomyopathy may demonstrate little or no significant enhancement in systolic and diastolic function during atrial pacing tachycardia, suggesting a depression of both inotropic and lusitropic reserve.     

关于缺血心肌组织多普勒频谱识别的探讨

【目的】确认缺血心肌组织多普勒 (DTI)频谱各速度波及缺血前后的变化。【方法】开胸犬 13条 ,于冠脉左旋支的分支结扎前、后记录乳头肌水平左室后壁短轴方向的DTI运动频谱 ,结合同步记录的心电图、心内压力曲线 (P ,dP/dt)及心音图辨认DTI频谱的各速度波 ,比较冠脉结扎前、后DTI频谱的变化 ;观察19例心肌梗死患者 ,记录左室壁及二尖瓣环DTI频谱和组织速度图 (TVI) ,结合心电图辨认各速度波。【结果】正常开胸犬左室后壁短轴方向运动速度波 ,等容收缩期以正向为主 (IVC1) ,急性缺血时出现明显的反向运动波 (IVC2 )并可延至射血期 ,冠脉结扎前、后IVC1和IVC2 峰值均发生显著变化 [(16 .6 0± 4 .11)cm/s对(4 .6 0± 5 .38)cm/s和 (5 .97± 6 .2 5 )cm/s对 (19.5 7± 3.5 8)cm/s,P <0 .0 1];冠脉结扎后射血期S波峰值显著降低 [(11.30± 1.5 8)cm/s对 (7.16± 1.80 )cm/s ,P <0 .0 1],舒张早期E波反向或双向变化 [(10 .86±3.32 )cm/s对 (- 10 .72± 6 .36 )cm/s,P <0 .0 1],左房收缩期A波峰值速度降低 [(11.0 8± 3.35 )cm/s对 (6 .71± 4 .81)cm/s ,P <0 .0 5 ]。临床观察心肌梗死患者亦发现类似犬急性缺血心肌DTI频谱的变化。【结论】在心肌严重缺血或梗死的情况下 ,DTI频谱等容收缩期出现反向 ,S波峰值     

冠脉血流显像评价慢性冠脉闭塞后心肌内侧支循环状态的实验研究

目的：应用冠脉血流显像技术检测前降支慢性闭塞后其供血区心肌内冠脉血流信号的变化，探讨该技术在评价心肌内侧支循环方面的价值。方法：24只实验小型猪，在前降支(LAD)近端放置ameroid收缩环建立慢性心肌缺血模型。放环6周后做选择性左冠状动脉造影；分别在基础状态及模型形成后应用冠脉血流显像技术观察左室前壁和室间隔心肌内冠脉血流信号的分布，同时记录其血流频谱并测定峰值血流速度(Vmax)；比较心肌内冠脉血流在模型形成前后的变化并与冠脉造影结果相对照，分析侧支循环的形成。结果：14只动物成功建立模型，根据左室前壁和前间隔内有无血流信号，将动物分为A、B两组：A组6只，前降支供血区心肌内未见明显血流信号显示，冠脉造影亦未见心外膜侧支形成；B组8只，前壁和室间隔内可见不同形式的血流信号，冠脉造影有4条见心外膜侧支形成。结论：冠脉血流显像技术能直观显示冠脉闭塞后其供血区心肌内侧支循环的建立，是冠脉造影的重要补充。     

Effects of Carnitine in Ischemic and Fatty Acid Supplemented Swine Hearts

FREE FATTY ACIDS (FFA) IN EXCESS FFA: albumin molar ratios have been determined to additionally compromise mechanical performance in ischemic hearts. Carnitine, an intracellular carrier of FFA and an agent which is lost to the heart during ischemia, has been postulated to in part restore function with its replacement. To test whether its benefits are also operative in a setting of excess FFA, these studies were performed. In the main protocol, four groups of perfused swine hearts (n = 45) were compared during 50 min of control flow (179.7 ml/min) and 40 min of global ischemia (106.1 ml/min). Initial base-line serum FFA:albumin molar ratios and carnitine levels in all groups were 1.3:1 and 8.5 nmol/ml, respectively. In two of these groups FFA:albumin ratios were increased to 5.9:1 with constant infusions of Intralipid. In two alternate groups (one with and one without extra FFA supplements) dl-carnitine was supplied, sufficient to increase serum levels nearly 200-fold. Ischemia per se in 14 hearts significantly decreased several parameters of global and regional mechanical function including left ventricular (LV) and mean aortic pressures, LV isovolumetric pressure development (max dp/dt), LV epicardial motion, and LV work, together with concomitant decreases in myocardial oxygen consumption. Elevated FFA in 12 hearts rendered similarly ischemic further decreased mechanical function (LV pressure: -20.8%, P < 0.05; mean aortic pressure -26.9%, P < 0.05; LV max dp/dt: -39%, P < 0.05; regional LV shortening: -51.1%, P < 0.05; and LV work: -50.3%, P < 0.05) as compared with nonsupplemented hearts. dl-Carnitine treatments in nine hearts, not supplemented with extra FFA were without apparent effect in improving overall hemodynamic performance. However, dl-carnitine in 10 high FFA-ischemic hearts effected several improvements as compared with the untreated group: LV pressure was increased 25.6%, P < 0.025; mean aortic pressure: +43.5%, P < 0.05; LV max dp/dt: +41.5%, P < 0.05; regional LV shortening: +241.3%, P < 0.001; and LV work: +76.2%, P < 0.05 at comparable levels of myocardial oxygen consumption. In a separate protocol, the effects of stereospecificity were also studied by comparing l- with dl-carnitine in globally perfused, palmitate-supplemented hearts (five hearts in each treatment group). At similar conditions of flow and serum FFA, changes in mechanical function were comparable, except for a tendency to perform greater LV work at reduced flows in the l-carnitine-treated hearts. Thus, it was demonstrated that carnitine in ischemic hearts is capable of preserving mechanical function under conditions of excess FFA, presumably by modifying the toxic effects of FFA intermediates. The major therapeutic actions appeared to derive from the l-isomer of carnitine.     

Evaluation of cardiac function by tissue Doppler echocardiography: hemodynamic determinants and clinical application

A total of 32 patients without regional wall motion abnormality of the left ventricle underwent sequential tissue Doppler echocardiography and cardiac catheterization. Peak velocities of systolic (Sa), early diastolic (Ea), and late diastolic (Aa) motion of the mitral annulus were measured. Normal references for Sa, Ea and Aa were obtained from 138 volunteers. Indices of left ventricular (LV) systolic and diastolic function were evaluated using high-fidelity LV pressure and volume signals. By multivariate analysis, Sa, Ea and As were significantly and independently related to the maximum of the first derivative of pressure over time (dP/dt(max)), LV relaxation time constant (tau), and LV ejection fraction (EF), respectively. Using the fifth percentiles of the age-stratified normal references as cut-offs, low Sa, low Ea and low Aa identified declined dP/dt(max), prolonged tau and reduced EF, respectively, with good sensitivities and specificities. In conclusion, mitral annulus velocities by tissue Doppler echocardiography can be used to identify patients with declined dP/dt(max), prolonged tau and reduced EF.     

Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone

Recent studies suggest that oxygen free radicals may mediate postischemic myocardial dysfunction ("stunning"), but all the evidence for this hypothesis is indirect. Thus, we used electron paramagnetic resonance (EPR) spectroscopy and the spin trap, alpha-phenyl N-tert-butyl nitrone (PBN), to directly investigate whether free radicals are produced after a 15-min coronary artery occlusion and subsequent reperfusion in 30 open-chest dogs. After intracoronary infusion of PBN, EPR signals characteristic of oxygen- and carbon-centered radical adducts were detected in the venous blood draining from the ischemic/reperfused vascular bed. The myocardial release of PBN adducts began during coronary occlusion but increased dramatically in the first few minutes after reperfusion. After this initial burst, the production of radicals abated but did not cease, persisting up to 3 h after reflow. The EPR spectra (aH beta = 2.67-2.79 G, aN = 14.75-15.00 G) were consistent with the trapping by PBN of secondary oxygen- and carbon-centered radicals, such as alkoxy and alkyl radicals, which could be formed by reactions of primary oxygen radicals with membrane lipids. There was a linear, direct relationship between the magnitude of PBN adduct production and the degree of ischemic flow reduction. Recovery of contractile function (measured as systolic wall thickening) after reperfusion was greater (P less than 0.05) in dogs given PBN than in controls. This study demonstrates that reversible regional myocardial ischemia in the intact animal is associated with prolonged free radical generation, and that the intensity of such generation is related to the severity of ischemia. The results provide direct evidence to support the hypothesis that reactive oxygen metabolites contribute to the persistent contractile dysfunction (myocardial stunning) observed after brief ischemia in vivo.     

Direct and reflex effects of nitroglycerin on coronary and left ventricular dynamics in conscious dogs

The effects of intravenous and sublingual glyceryl trinitrate (nitroglycerin), 40 mug/kg, were studied on coronary blood flow and resistance, left ventricular (LV) pressures (P) and diameters (D), rate of change of pressure (dP/dt), (dP/dt)/P, and on the velocity (V) of myocardial fiber shortening in conscious dogs. Nitroglycerin i.v. caused substantial coronary vasodilatation prior to any changes in systemic hemodynamics. Mean coronary flow increased by a maximum of 47 ml/min and coronary sinus P(o2) rose from 16 to 26 mm Hg while pressure and diameter began to fall, and heart rate began to rise. After the maximal fall in mean arterial pressure (-26 mm Hg), a secondary peak in coronary flow occurred which was associated with increases in heart rate (100 beats/min), (dP/dt)/P (22%), and isolength V (12%). Beta blockade prevented the reflex increases in contractility but only a part of the reflex tachycardia; the remainder was prevented by cholinergic blockade. Maintaining heart rate constant minimized the decreases in LV D and increases in contractility. When the reflex inotropic and chronotropic effects were prevented by a combination of atrial pacing and beta blockade the early coronary vasodilatation was unaltered, but the later coronary vasodilatation was minimized.Thus i.v. nitroglycerin in the conscious dog exerts a potent direct coronary vasodilating action and also a secondary coronary vasodilation caused by reflex increases in contractility and heart rate. The decreases in diameter are largely the result of tachycardia. Sublingual nitroglycerin produced directionally similar, but quantitatively lesser effects on coronary flow and resistance, LV D, LV P, and contractility.     

Beneficial effect of MCI-154, a cardiotonic agent, on ischemic contractile failure and myocardial acidosis of dog hearts: comparison with dobutamine, milrinone and pimobendan.

The effects of MCI-154, a cardiotonic agent with Ca++ sensitizing actions, on the ischemic contractile failure and myocardial acidosis were studied in the dog heart, in which the left anterior descending coronary artery (LAD) was partially occluded for 90 min, and compared with those of dobutamine, milrinone, pimobendan and isosorbide dinitrate (ISDN). Partial occlusion of LAD decreased segment shortening (measured by sonomicrometry) and myocardial pH (assessed by a micro glass pH electrode) in the ischemic myocardium. MCI-154, when administered i.v. 30 min after ischemia, improved the segment shortening in the ischemic zone, whereas dobutamine, milrinone and pimobendan failed to improve it when the drugs increased peak positive left ventricular dP/dt. Among the cardiotonic agents tested only MCI-154 attenuated myocardial acidosis during ischemia. The degree of the attenuation of acidosis by MCI-154 was equivalent with that by ISDN. However, the improvement of the ischemic zone segment shortening by MCI-154 was more pronounced than that by ISDN. These results suggest that in addition to the attenuation of myocardial acidosis the positive inotropic action of MCI-154, presumably increasing the responses of myofilaments to Ca++, may be possibly responsible for the improvement of regional contractile function in the ischemic myocardium. Thus, MCI-154 may be useful in the management of ischemic heart failure.     

Adenoviral gene transfer of sphingosine kinase 1 protects heart against ischemia/reperfusion-induced injury and attenuates its postischemic failure

Sphingosine kinase 1 (SPK1) has been identified as a central mediator of ischemia preconditioning and plays a protective role in ischemia/reperfusion (I/R)-induced cardiomyocyte death. In the present study, we investigated the protective effect of adenovirus-mediated SPK1 gene (Ad-SPK1) transfer on I/R-induced cardiac injury, and evaluated its therapeutic action on postinfarction heart failure. Cardiac SPK1 activity was increased about 5-fold by injection of Ad-SPK1, compared with injection of adenovirus carrying the green fluorescent protein gene (Ad-GFP). A more potent performance and a lower incidence of arrhythmia were observed in Ad-SPK1-injected hearts during the reperfusion period, compared with Ad-GFP-injected hearts. An enzymatic activity assay showed that creatine kinase release was also less in Ad-SPK1-injected hearts. To investigate the therapeutic action of the SPK1 gene on postischemic heart failure, the left anterior descending branch of the coronary artery in Wistar rats was ligated after direct intramyocardial injection of Ad-SPK1 or Ad-GFP as a control. Ad-SPK1 injection significantly preserved cardiac systolic and diastolic function, as evidenced by left ventricular (LV) systolic pressure, LV end-diastolic pressure, and peak velocity of contraction (dP/dt). The LV morphometric parameters of Ad-SPK1-treated animals were also preserved. In addition, SPK1 gene delivery significantly enhanced angiogenesis and reduced fibrosis. These results demonstrate that adenovirus-mediated SPK1 gene transfer could efficiently prevent I/R-induced myocardial injury and attenuate postischemic heart failure. Thus, SPK1 gene delivery would be a novel strategy for the treatment of coronary heart disease.     

Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70.

Brief ischemic periods lead to myocardial dysfunction without myocardial infarction. It has been shown that expression of inducible HSP70 in hearts of transgenic mice leads to decreased infarct size, but it remains unclear if HSP70 can also protect against myocardial dysfunction after brief ischemia. To investigate this question, we developed a mouse model in which regional myocardial function can be measured before and after a temporary ischemic event in vivo. In addition, myocardial function was determined after brief episodes of global ischemia in an isolated Langendorff heart. HSP70-positive mice and transgene negative littermates underwent 8 min of regional myocardial ischemia created by occlusion of the left descending coronary artery, followed by 60 min of reperfusion. This procedure did not result in a myocardial infarction. Regional epicardial strain was used as a sensitive indicator for changes in myocardial function after cardiac ischemia. Maximum principal strain was significantly greater in HSP70-positive mice with 88+/-6% of preischemic values vs. 58+/-6% in transgene-negative mice (P < 0.05). Similarly, in isolated Langendorff perfused hearts of HSP70-positive and transgene-negative littermates exposed to 10 min of global ischemia and 90 min of reperfusion, HSP70 transgenic hearts showed a better-preserved ventricular peak systolic pressure. Thus, we conclude that expression of HSP70 protects against postischemic myocardial dysfunction as shown by better preserved myocardial function.