Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action.

Angiotensin converting enzyme (ACE) inhibitors enhance contractile function of myocardium "stunned" by a brief episode of coronary artery occlusion, yet their mechanism(s) of action remain unresolved. In addition to possible hemodynamic effects, ACE inhibitors may stimulate the synthesis of cardioprotective prostaglandins. Furthermore, the beneficial effects of ACE inhibitors that contain a sulfhydryl group may be due in part to the ability of thiol compounds to act as nonspecific antioxidants or direct scavengers of cytotoxic oxygen-derived free radicals. To investigate this question we compared the effects of (1) the sulfhydryl-containing ACE inhibitor zofenopril, (2) the sulfhydryl-containing stereoisomer of captopril (SQ 14,534) with essentially no ACE inhibitor properties, (3) the nonsulfhydryl-containing ACE inhibitor enalaprilat, and (4) solvent alone, given at the time of reperfusion, on recovery of contractile function after 15 minutes of coronary occlusion in the anesthetized open-chest dog. Segment shortening in control animals remained depressed or "stunned" after reperfusion, recovering to only -5 +/- 12% of baseline preocclusion values at 3 hours after reperfusion. In contrast, all three treatment agents attenuated postischemic dysfunction: segment shortening was restored to 33 +/- 12%, 54 +/- 6%, and 83 +/- 5% of baseline values at 3 hours after reflow in dogs treated with SQ 14,534 (p less than 0.05), zofenopril (p less than 0.01), and enalaprilat (p less than 0.01), respectively (all vs control value). These improvements in segment shortening did not appear to be the result of altered oxygen supply or demand after reperfusion, inasmuch as no significant differences in systemic hemodynamic parameters or myocardial blood flow were observed among the groups. In the second phase of the study, we found that the improved contractile function associated with enalaprilat treatment could largely be reversed by infusion of the potent cyclooxygenase inhibitor indomethacin: segment shortening was reduced from 69 +/- 12% at 2 hours after treatment/reperfusion to 38 +/- 12% at 2 hours after indomethacin infusion (p less than 0.01 vs 2 hours after reperfusion). Infusion of indomethacin had no effect, however, on the improved contractile function associated with zofenopril treatment. We therefore conclude that sulfhydryl- versus nonsulfhydryl-containing agents enhance contractile function of stunned myocardium by different mechanisms of action: enalaprilat attenuates postischemic dysfunction at least in part by a prostaglandin-mediated mechanism, whereas the salutary effects of zofenopril and SQ 14,534 may be due in part to the antioxidant properties of the sulfhydryl moiety.     

Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion

BACKGROUND. There are several clinical situations in which large epicardial coronary arteries are deprived of blood flow, such as occurs when an obstructing thrombus or embolus lodges within a vessel or during coronary dissection. There is little information concerning the effect of flow deprivation on large epicardial coronary arteries. METHODS AND RESULTS. We studied a model in which a segment of a large epicardial coronary artery was deprived of blood flow using both proximal and distal clamps for 3 hours followed by reperfusion. On examination by light microscopy of cross sections of the arteries, 19 +/- 6 neutrophils were present in the intima of ischemic/reperfused vessels, whereas only a mean of 4 +/- 3 (SEM) were present in the intima of nonischemic vessels (p less than 0.02). On average, there were 17 +/- 9 neutrophils just under the elastic lamina in ischemic/reperfused vessels versus none in the nonischemic vessels (p less than 0.05); there were 16 +/- 10 neutrophils present within the media of ischemic/reperfused vessels, and none (p less than 0.05) in the nonischemic vessels. Electron microscopic analysis revealed that neutrophils in the ischemic/reperfused vessels were often "sandwiched" between the endothelial cells and the elastic lamina. Ultrastructural abnormalities within the myocardium also revealed damage to the microvasculature, including the presence of neutrophils within the vessels and erythrocyte stasis. To rule out the possibility that findings in the large epicardial arteries were due to toxic substances from static blood within the isolated arterial segment, a protocol was performed in which blood was removed from the isolated segment. Again, neutrophil infiltration into the vessel was observed. Resting mean epicardial coronary artery blood flow before coronary occlusion was 19 +/- 3 ml/min; mean coronary blood flow 2.5 hours after reperfusion was identical at 19 +/- 3 ml/min. Response to both endothelial-dependent vasodilation (acetylcholine) and endothelial-independent vasodilation (nitroglycerin) challenges was normal early after reperfusion but was depressed late after reperfusion, suggesting progressive vascular dysfunction and hence a form of vascular reperfusion injury in this model. CONCLUSIONS. When large epicardial coronary arteries are deprived of blood flow, followed by reperfusion in this model, neutrophils migrate into the vessel wall as well as into the microvasculature. These abnormalities are associated with reduced endothelial-dependent and endothelial-independent coronary vasodilator reserve.     

The effects of acute and chronic cocaine use on the heart.

It is clear that cocaine has cardiotoxic effects. Acute doses of cocaine suppress myocardial contractility, reduce coronary caliber and coronary blood flow, induce electrical abnormalities in the heart, and in conscious preparations increase heart rate and blood pressure. These effects will decrease myocardial oxygen supply and may increase demand (if heart rate and blood pressure rise). Thus, myocardial ischemia and/or infarction may occur, the latter leading to large areas of confluent necrosis. Increased platelet aggregability may contribute to ischemia and/or infarction. Young patients who present with acute myocardial infarction, especially without other risk factors, should be questioned regarding use of cocaine. As recently pointed out by Cregler, cocaine is a new and sometimes unrecognized risk factor for heart disease. Acute depression of LV function by cocaine may lead to the presence of a transient cardiomyopathic presentation. Chronic cocaine use can lead to the above problems as well as to acceleration of atherosclerosis. Direct toxic effects on the myocardium have been suggested, including scattered foci of myocyte necrosis (and in some but not all studies, contraction band necrosis), myocarditis, and foci of myocyte fibrosis. These abnormalities may lead to cases of cardiomyopathy. Left ventricular hypertrophy associated with chronic cocaine recently has been described. Arrhythmias and sudden death may be observed in acute or chronic use of cocaine. Miscellaneous cardiovascular abnormalities include ruptured aorta and endocarditis. Most of the cardiac toxicity with cocaine can be traced to two basic mechanisms: one is its ability to block sodium channels, leading to a local anesthetic or membrane-stabilizing effect; the second is its ability to block reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous system, resulting in increased sympathetic output and increased catecholamines. Other potential mechanisms of cocaine cardiotoxicity include a possible direct calcium effect leading to contraction of vessels and contraction bands in myocytes, hypersensitivity, and increased platelet aggregation (which may be related to increased catecholamine). The correct therapy for cocaine cardiotoxicity is not known. Calcium blockers, alpha-blockers, nitrates, and thrombolytic therapy show some promise for acute toxicity. Beta-Blockade is controversial and may worsen coronary blood flow. In patients who develop cardiomyopathy, the usual therapy for this entity is appropriate.     

Coronary cyclic flow variations "precondition" ischemic myocardium.

BACKGROUND. Repeated brief episodes of myocardial ischemia performed by mechanical clamping of a coronary artery "precondition" the heart and reduce infarct size after a subsequent sustained ischemia. It is not known, however, whether spontaneous episodes of transient ischemia caused by formation of platelet thrombi, which may occur in unstable angina, have a similar cardioprotective effect. METHODS AND RESULTS. Therefore, our objective was to determine whether brief spontaneous thrombotic episodes of ischemia/reperfusion could limit infarct size and preserve contractile function following 60 minutes (protocol 1) or 90 minutes (protocol 2) of sustained ischemia and 4-4.5 hours of reperfusion in the canine model. Before the sustained coronary occlusion, dogs underwent a 30-minute "treatment" period consisting of: no intervention (control group), four repeated episodes of 3-minute mechanical occlusion plus 5-minute reperfusion (preconditioned group), or coronary artery stenosis and endothelial injury, resulting in a mean of four spontaneous episodes of cyclic flow variations (CFV group) caused by formation and dislodgment of platelet thrombi. In protocol 1 (60-minute sustained ischemia plus 4.5-hour reperfusion), infarct size was significantly smaller in both the preconditioned and CFV groups compared with controls (3.5 +/- 1.4%,* 3.4 +/- 2.1%,* and 9.9 +/- 2.7% of the myocardium at risk, respectively; *p less than 0.05 versus control). In contrast, neither preconditioning nor CFV preserved contractile function: Segment shortening during sustained occlusion was equally depressed at -15% to -20% of baseline values among the three groups and equally stunned at +12% to +18% of baseline during the 4.5 hours of reflow. In protocol 2 (90-minute sustained ischemia plus 4-hour reperfusion), only CFV continued to exert a cardioprotective effect: Infarct size averaged 15.0 +/- 4.1%, 7.4 +/- 2.5%,* and 16.5 +/- 4.4% of the region at risk in the preconditioned, CFV, and control groups, respectively (*p less than 0.05 versus control). Contractile function, however, was similar among all three groups both during 90 minutes of sustained occlusion and throughout 4 hours of reperfusion. CONCLUSIONS. We therefore conclude that repeated coronary thrombus formation preconditions the ischemic myocardium: In fact, in contrast to mechanical preconditioning, cardioprotection provided by CFV persisted following 90 minutes of sustained coronary occlusion. However, preconditioning by thrombotic or mechanical occlusion neither preserved myocardial contractile function during sustained coronary occlusion nor prevented stunning after reperfusion. These data raise the possibility that clinical episodes of unstable angina prior to acute myocardial infarction may precondition the ischemic myocardium.     

Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light

Summary Collagen plays a major role in the structural organization of the heart and therefore direct visualization of collagen fibers is a crucial component of cardiac analysis. Although linearly polarized light has proven an effective tool for the examination of myocardial collagen in histologic sections, the use of circularly polarized light may offer advantages and additional possibilities. We examined the potential enhancement of collagen analysis using circularly polarized light in two ways. We first measured the brightness, and hence indirectly assessed the birefringence, of collagen fibers in scars examined at different times after myocardial infarction. Secondly, we measured collagen content in myocardial tissue and compared results obtained from brightfield analysis of trichrome stained sections with those obtained from circularly polarized light analysis of picrosirius red stained sections. We observed a progressive increase in the maximum brightness of collagen fibers in the scar with time, and a time-dependent shift in the relative distribution of collagen fiber brightness from lower to higher levels. We found consistently lower values of collagen content in trichrome stained versus picrosirius red stained tissue, and concluded that trichrome staining underestimated collagen content. The information provided by these studies could not be obtained by brightfield analysis and could be only partially obtained from linearly polarized light analysis. Thus, analysis using circularly polarized light has the ability to enhance histologic assessment of tissue and can provide additional insights into the composition and structure of myocardial collagen.Presented in part at the 64th Scientific Sessions of the American Heart Association in Anaheim, California, November 1991     

Effects of nisoldipine, a new calcium antagonist, on myocardial infarct size and cardiac dynamics following acute myocardial infarction

While some calcium antagonists are effective in reducing myocardial infarct size, this beneficial effect may be accompanied by negative inotropic effects. In the following study, a new dihydropyridine calcium antagonist, nisoldipine, was assessed for its effect on infarct size, hemodynamics, and regional function as assessed by percent systolic wall thickening of the left ventricle (SWT) by 2D echocardiography. Open-chest, anesthetized dogs were subjected to 6 h of coronary artery occlusion. After 10 min of coronary artery occlusion, the ischemic area at risk of infarction (AR; % of left ventricle) was determined by left atrial injection of 99mTc-labeled albumin microspheres with subsequent postmortem autoradiography. After 6 h, the hearts were excised, and the area of necrosis (AN) determined by incubation of left ventricular slices in triphenyltetrazolium chloride stain. Treated dogs received 0.005 mg/kg nisoldipine by intravenous infusion at 1.91 ml/min (lasting approximately 8.7 min) during three dosing periods: 15 min, 2 h, and 4 h postocclusion. The AR of eight controls (25.7 +/- 1.8%) was not significantly different from that of 11 treated dogs (25.1 +/- 1.9%). However, the AN/AR X 100 of treated dogs was significantly less than that of controls (62.8 +/- 9.3 vs. 91.6 +/- 7.0%; p less than 0.05). Mean arterial pressure fell in treated dogs by 15.7% (p less than 0.01) at 15 min and by 5.7% (p less than 0.05) at 4 h but not at 2 h postocclusion. Heart rate was not affected by nisoldipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estradiol, Administered Acutely, Protects Ischemic Myocardium in Both Female and Male Rabbits

BACKGROUND: The benefits of chronic administration of estrogen to postmenopausal women are well documented; however, the acute effects of exogenous estradiol on myocardium after coronary artery occlusion and reperfusion in male and female animal models are unknown. We tested the influence of acute pretreatment with estradiol on the development of myocardial necrosis in two protocols, studying intact anesthetized female and male rabbits. METHODS AND RESULTS: 17beta-estradiol (1 mg) was given 15 minutes before coronary artery occlusion in the treated groups (n = 10 females, 10 males); control rabbits (n = 11 females, 10 males) received water. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Myocardial blood flow was similar between groups at 10 minutes after treatment and during coronary artery occlusion and reperfusion. Thus estradiol did not increase blood flow. Heart rate and systemic pressure were also similar between groups. Estradiol levels during coronary artery occlusion were 1-8 pg/mL in untreated female and male rabbits and 66 +/- 28 (male) and 352 +/- 273 (female) in treated rabbits. Although the size of the ischemic risk zones was similar in both groups in both protocols, estradiol-treated rabbits of both sexes developed significantly less necrosis. Infarct size as a percent of the risk region was 10 +/- 1% in female estradiol-treated rabbits compared with 23 +/- 5% in controls (P <.03) and 16 +/- 4% in estradiol-treated male rabbits compared with 31 +/- 5% in control males (P =.03). Although male rabbits had larger infarcts than female rabbits, sex was not a significant covariate for infarct size. CONCLUSIONS: Estradiol exerts a protective effect on ischemic myocardium that is not associated with an increase in myocardial blood flow or alteration in hemodynamics. This study shows that acute administration of estrogen before coronary artery occlusion reduces infarct size in both male and female rabbits.     

Air pollution and cardiovascular injury epidemiology, toxicology, and mechanisms

Recent epidemiologic studies show that increased levels of air pollutants are positively associated with cardiovascular morbidity and mortality. Inhalation of air pollutants affects heart rate, heart rate variability, blood pressure, vascular tone, blood coagulability, and the progression of atherosclerosis. Several categories within the general population (i.e., people with pre-existing cardiovascular disease and diabetic and elderly individuals) are considered to be more susceptible to air pollution-mediated cardiovascular effects. Major mechanisms of inhalation-mediated cardiovascular toxicity include activation of pro-inflammatory pathways and generation of reactive oxygen species. Although most studies focus on the influence of systemic effects, recent studies indicate that ultrafine particles may be translocated into the circulation and directly transported to the vasculature and heart where they can induce cardiac arrhythmias and decrease cardiac contractility and coronary flow.     

Analysis of healing after myocardial infarction using polarized light microscopy.

To better understand the healing process after permanent coronary artery occlusion in a canine model, the authors used polarized light microscopy. At 6 weeks after occlusion the scar collagen was mainly type I. Some regions of the scar contained a fiber lattice which appeared to be type III collagen. Collagen orientation was measured using a universal stage; subepicardial collagen was obliquely aligned (-14.0 +/- 3.5 degrees), midmyocardial collagen circumferentially aligned (1.4 +/- 0.4 degrees) and subendocardial collagen obliquely aligned (12.7 +/- 2.1 degrees). The molecular organization of scar collagen increased from 1 to 6 weeks after occlusion. Muscle cell disarray, similar to that in hypertrophic cardiomyopathy, was seen in the viable muscle adjacent to the scar. Such abnormal organization extended as far as 1 cm from the edge of the scar. The ability of polarized light microscopy to assess these different parameters from histologic sections demonstrates that it is a useful adjunct to other methods commonly used to study myocardial healing.