Emotional stressors trigger cardiovascular events.

AIMS: To describe the relation between emotional stress and cardiovascular events, and review the literature on the cardiovascular effects of emotional stress, in order to describe the relation, the underlying pathophysiology, and potential therapeutic implications. MATERIALS AND METHODS: Targeted PUBMED searches were conducted to supplement the authors' existing database on this topic. RESULTS: Cardiovascular events are a major cause of morbidity and mortality in the developed world. Cardiovascular events can be triggered by acute mental stress caused by events such as an earthquake, a televised high-drama soccer game, job strain or the death of a loved one. Acute mental stress increases sympathetic output, impairs endothelial function and creates a hypercoagulable state. These changes have the potential to rupture vulnerable plaque and precipitate intraluminal thrombosis, resulting in myocardial infarction or sudden death. CONCLUSION: Therapies targeting this pathway can potentially prevent acute mental stressors from initiating plaque rupture. Limited evidence suggests that appropriately timed administration of beta-blockers, statins and aspirin might reduce the incidence of triggered myocardial infarctions. Stress management and transcendental meditation warrant further study.

Evaluation of the effects of intramyocardial injection of DNA expressing vascular endothelial growth factor (VEGF) in a myocardial infarction model in the rat--angiogenesis and angioma formation.

OBJECTIVES: The effects of direct intramyocardial injection of the plasmid encoding vascular endothelial growth factor (phVEGF165) in the border zone of myocardial infarct tissue in rat hearts were investigated. BACKGROUND: Controversy exists concerning the ability of VEGF to induce angiogenesis and enhance coronary flow in the myocardium. METHODS: Sprague-Dawley rats received a ligation of the left coronary artery to induce myocardial infarction (MI). At 33.1 +/- 6.5 days, the rats were injected with phVEGF165 at one location and control plasmid at a second location (500 microg DNA, n = 24) or saline (n = 16). After 33.1 +/- 5.7 days, the hearts were excised for macroscopic and histologic analysis. Regional blood flow ratios were measured in 18 rats by radioactive microspheres. RESULTS: phVEGF165-treated sites showed macroscopic angioma-like structures at the injection site while control DNA and saline injection sites did not. By histology, 21/24 phVEGF165-treated hearts showed increased focal epicardial blood vessel density and angioma-like formation. Quantitative morphometric evaluation in 20 phVEGF165-treated hearts revealed 44.4 +/- 10.5 vascular structures per field in phVEGF165-treated hearts versus 21.4 +/- 4.7 in control DNA injection sites (p < 0.05). Regional myocardial blood flow ratios between the injection site and noninfarcted area did not demonstrate any difference between phVEGF,165-treated hearts (0.9 +/- 0.2) and saline-treated hearts (0.7 +/- 0.1). CONCLUSIONS: Injection of DNA for VEGF in the border zone of MI in rat hearts induced angiogenesis. Angioma formation at the injection sites did not appear to contribute to regional myocardial blood flow, which may be a limitation of gene therapy for this application.

Cardioprotection with ischemic preconditioning and MLA: role of adenosine-regulating enzymes?

Both ischemic preconditioning and pretreatment with the endotoxin derivative monophosphoryl lipid A (MLA) protect the heart against infarction, yet the cellular mechanisms responsible for the cardioprotection achieved with either intervention are unknown. Using pentobarbital-anesthetized dogs, we tested the hypothesis that increased activity of 5'-nucleotidase (5'-NT), the enzyme that catalyzes the formation of adenosine from AMP, may play a role. Twenty-two dogs underwent 1 h of coronary occlusion and 4 h of reperfusion: eight controls received no intervention, seven animals were preconditioned with four 5-min episodes of brief ischemia, and seven received MLA (35 micrograms/kg iv) 24 h previously. Collateral blood flow was measured by injection of radiolabeled microspheres, infarct size was delineated by tetrazolium staining, and myocardial 5'-NT activities were measured by quantifying the release of adenosine from AMP. Despite comparable values of collateral blood flow in all groups, infarct size was reduced in preconditioned and MLA-treated dogs vs. controls. In addition, 5'-NT activities were increased throughout the heart with preconditioning and MLA treatment. However, single and multivariate regression analyses revealed no correlation between infarct size and 5'-NT activities for either treatment group. In fact, in the preconditioned cohort, animals with the highest enzyme activities developed the largest infarcts. This dissociation between infarct size and 5'-NT suggests that increased activity of 5'-NT is not the mechanism by which preconditioning or MLA treatment protects the canine heart against infarction.

Intramyocardial injections and protection against myocardial ischemia. An attempt to examine the cardioprotective actions of adenosine.

BACKGROUND: Although adenosine has been proposed to be a cardioprotective agent, direct examination of such protection is confounded by its short half-life and hemodynamic effects. We attempted to avoid these problems by injecting adenosine directly into cardiac muscle. METHODS AND RESULTS: We gave four adenosine injections (each 0.15 mL, 5 mg.mL-1 saline) into the left ventricular wall of rat hearts before a 60-minute occlusion. Although infarcts were smaller in adenosine-treated hearts (29 +/- 6%) than in controls (52 +/- 5%; P < .05), injection of saline also reduced infarct size (29 +/- 7%). Infarcts in hearts subjected to needle insertion but no fluid injection differed neither from control nor from fluid-treated hearts (38 +/- 4%). Adenosine reduced ectopic beats and the incidence of ventricular tachycardia during occlusion. In contrast, saline injection prolonged the duration of arrhythmias. To examine the spatial relationship between protection and the injection site, we gave 18 saline injections (each 0.15 mL) into canine myocardium before a 60-minute occlusion. Infarcts were smaller in saline-treated hearts than in controls (P < .01). Because infarcts in four hearts occupied < 3% of the risk region, we concluded that fluid injection did not itself cause appreciable necrosis and speculated that muscle was protected in the vicinity of the injection site. Previous work indicated that muscle can be protected by stretch. We examined this hypothesis by adding gadolinium chloride (a stretch-activated channel blocker) to the saline (0.008 g.mL-1) injection in rat hearts. We again found small infarcts after saline injection (26 +/- 5%); however, gadolinium blocked protection (50 +/- 7%; P < .03). CONCLUSIONS: Although we were only partially successful in documenting adenosine-mediated cardioprotection, we found evidence for myocyte protection via a stretch-activated mechanism.

Oxygen radical scavenging agents as adjuvant therapy with tissue plasminogen activator in a canine model of coronary thrombolysis.

OBJECTIVES: Early thrombolysis can reduce infarct size and enhance the long term recovery of contractile function after acute myocardial infarction. These benefits of early reperfusion may be confounded, however, by platelet mediated reocclusion after initial lysis, and "reperfusion injury" mediated by oxygen derived free radicals. Superoxide dismutase (SOD)--as well as its action as a potent free radical scavenging agent--inhibits platelet aggregation in vitro. Thus our primary objectives were to determine whether SOD+catalase, given as adjuvant therapy with recombinant human tissue plasminogen activator, could inhibit platelet aggregation and thereby reduce the time to lysis and maintain arterial patency. Whether SOD+catalase enhanced myocardial salvage or improved acute recovery of contractile function in the setting of thrombosis/thrombolysis was also assessed. METHODS: Two anaesthetised open chest canine models were used: a model of thrombosis/thrombolysis and an in vivo model of platelet aggregation. In protocol I coronary thrombosis was induced by endothelial injury and injection of blood+thrombin+CaCl2. At three hours after occlusion, control animals received saline and tissue plasminogen activator and treated dogs received SOD+catalase and tissue plasminogen activator. Variables measured included coronary blood flow (for assessment of the time to lysis and incidence and duration of spontaneous reocclusion); regional myocardial blood flow; segment shortening; and infarct size. In protocol II dogs underwent endothelial injury and coronary stenosis, resulting in cyclic variations in coronary blood flow caused by formation and dislodgement of platelet thrombi. At 30 minutes after placement of the stenosis, dogs received either saline and tissue plasminogen activator or SOD+catalase and tissue plasminogen activator. Variables measured included the frequency of cyclic flow variations and the duration of occlusion per 30 minute time interval. RESULTS: SOD+catalase slightly reduced the time required to achieve reflow: time to lysis was 35(SEM 5) v 22(4) minutes for control v treated groups (p < 0.05). Protocol II showed that this accelerated time to lysis was due to acute inhibition of platelet aggregation by the scavenging agents. Despite continuous infusion however, SOD+catalase failed to maintain vessel patency in either limb of the study. In protocol I, reocclusion occurred in 90% of control dogs (with 49(8)% of the time after initial lysis spent reoccluded), v 83% in the treated group (36(12)% of the time reoccluded; NS v controls). Also, both groups remained dyskinetic after reflow: at one hour after initial lysis, segment shortening was -6(9)% v -6(20)% of baseline preocclusion values in the subset of control v treated dogs in which the left anterior descending coronary artery was patent at the time of measurement (NS). Finally, infarct size was similar in both groups, averaging 32(9)% v 38(9)% of the myocardium at risk in control v treated animals (NS). CONCLUSIONS: Although SOD+catalase acutely attenuated platelet aggregation and slightly accelerated lysis, these agents failed to limit platelet mediated rethrombosis. Furthermore, SOD+catalase did not enhance myocardial salvage and did not improve acute recovery of contractile function after thrombosis/thrombolysis. Thus SOD+catalase given as adjuvant therapy with tissue plasminogen activator did not have a substantial beneficial effect on either the efficacy of thrombolysis or on "reperfusion injury" in this canine model.

Effects of amlodipine on myocardial infarction, infarct expansion, and ventricular geometry in the rat.

Infarct expansion remains an important sequela of myocardial infarction. Both angiotensin converting enzyme inhibitors and intravenous nitrates reduce early infarct expansion in humans. This is believed to be caused by the reduction in left ventricular systolic wall stress that results from the arteriolar vasodilatation they produce. Patients are frequently already receiving calcium channel blockers at the time of infarction or these drugs are sometimes administered in the perimyocardial infarction period. The calcium blockers of the dihydropyridine class might be expected to modify infarct expansion. However, their effect on this process has not been studied. We therefore evaluated the effect of early treatment with the calcium blocker amlodipine, a potent arteriolar vasodilator with minimal negative inotropic properties, on chronic myocardial infarction in the rat. Permanent left coronary occlusion was created after pretreatment with amlodipine, 0.25 mg/kg (low dose) or 1.0 mg/kg (high dose), or placebo, intravenously twice a day, and continued for 7 days after infarction. Hearts (n = 50) were perfusion fixed 21 days after infarction and analyzed for infarct extent, scar thickness, left ventricular shape and size, and expansion index. Both doses decreased mean blood pressure (119 +/- 3 to 99 +/- 5 mm Hg low dose, p = 0.004; 110 +/- 5 to 84 +/- 4 mm Hg high dose, p = 0.0003), with reflex tachycardia only after the high dose (heart rate 395 +/- 9 to 434 +/- 11, p = 0.001). Infarct extent was equal in the three groups (39 +/- 2%, 41 +/- 2%, and 41 +/- 3% of left ventricular circumference for control, low, and high doses, respectively). The three groups did not differ significantly with regard to left ventricular cavity cross-sectional area (80 +/- 4, 77 +/- 3, and 87 +/- 3 mm2, control, low, and high doses, respectively; p = 0.07 high dose vs control), mean scar thickness (0.74 +/- 0.06, 0.73 +/- 0.05, and 0.65 +/- 0.06 mm, control, low, and high doses, respectively; p = NS), and expansion index (1.52 +/- 0.10, 1.58 +/- 0.12, and 1.95 +/- 0.19, control, low, and high doses, respectively; p = 0.08 high dose vs control). In the subgroup with larger infarcts (infarct extent greater than 0.39 of left ventricle), the expansion index was higher in the high-dose group (2.37 +/- 0.23 vs 1.64 +/- 0.17 control; p = 0.04). In this model, treatment with amlodipine does not limit infarct extent or reduce early infarct expansion and left ventricular dilatation, even when initiated before infarction.(ABSTRACT TRUNCATED AT 400 WORDS)

Nifedipine protects the heart from the acute deleterious effects of cocaine if administered before but not after cocaine.

BACKGROUND: We tested the hypothesis that nifedipine, a calcium channel blocker, could ameliorate the toxic effects of cocaine on the myocardium. METHODS AND RESULTS: In an initial protocol, anesthetized dogs were pretreated with nifedipine or saline and then administered cocaine (10 mg/kg, i.v. bolus). Coronary blood flow, heart rate, mean arterial pressure, and the first derivation of left ventricular pressure (dP/dt) were measured at baseline, 2 minutes, and 15 minutes after cocaine administration. Nifedipine pretreatment prevented the early cocaine-induced decrease in coronary blood flow and improved left ventricular dP/dt compared with untreated control animals. After cocaine, ejection fraction fell in the saline group to 37 +/- 3% but increased in the nifedipine group to 59 +/- 4% (p less than 0.05). In a second protocol, vehicle or intravenous nifedipine was administered after an infusion of cocaine (10 mg/kg). In contrast to pretreatment, there was no significant improvement in left ventricular function or coronary blood flow in nifedipine-treated versus control animals. Data from the study also suggested that cocaine acts directly on the myocardium. Within seconds of cocaine bolus administration, coronary blood flow in control animals increased to a peak level 59 +/- 14% higher than before cocaine and left ventricular dP/dt decreased by 23 +/- 5%, providing evidence that cocaine causes direct depression of myocardial function independent of a decrease in myocardial blood flow. CONCLUSIONS: We conclude that nifedipine administered as a pretreatment protects against the depression of myocardial function and decrease in coronary blood flow caused by acute cocaine administration. However, when nifedipine is given after cocaine, no improvement is seen. Cocaine has a direct negative inotropic effect on the heart that is independent of a decrease in coronary blood flow.

Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis.

The effect of captopril on coxsackievirus B3 murine myocarditis was investigated. Thirty-two, 3-week-old mice were infected with coxsackievirus B3 on day 0 of the study, then randomized into a placebo group or a captopril group starting on day 3 of infection. On day 9 of infection, the mice were put to death. Hearts were weighed and processed for light microscopic examination. Heart weight was 125 +/- 19 mg in the control group versus 102 +/- 14 mg in the captopril group (p less than 0.0003). Amount of necrosis as a percentage of left ventricular section was 3.5% (2.0% to 7.5%) in the placebo group versus 2.0% (0.0% to 5.0%) in the captopril group (p less than 0.01). The amount of dystrophic calcification was 5.0% (0.0% to 27.5%) in the placebo group versus 1.3% (0.0% to 20.0%) in the captopril group (p less than 0.01). The extent of the histopathologic involvement by planimetry was 10.2% in the placebo group versus 5.4% in the captopril group (p = 0.052). We conclude that captopril is beneficial in decreasing left ventricular mass and the amount of myocardial necrosis and calcification in the short term in the murine myocarditis model.

Progress in cardioprotection: the role of calcium antagonists.

Calcium antagonists are now widely used for the treatment of clinical hypertension and angina pectoris. They are efficacious for the treatment of vasospastic, fixed atherosclerotic and mixed angina; they reduce the incidence of silent ischemia; and they have been shown to reduce postmyocardial infarct angina. Experimental data suggest that they may have certain cardioprotective properties in cases of acute myocardial ischemia and infarction, stunned myocardium, diastolic dysfunction, left ventricular hypertrophy and atherosclerosis. Moreover, they have been shown to improve exercise performance, as well as the diastolic abnormalities in patients with hypertrophic cardiomyopathy. In animals, they may delay or reduce the extent of myocardial necrosis after coronary occlusion or coronary occlusion followed by reperfusion, and in low doses that do not alter the hemodynamic profile, they have been shown to enhance the return of ventricular function in animals with stunned myocardium. However, the early first-generation calcium antagonists (nifedipine, verapamil, diltiazem) have not been shown to reduce myocardial infarct size or to enhance survival in patients with acute myocardial infarction. There now are clinical studies that suggest that, unlike beta blockers or nitrates, nifedipine may slow the development of atherosclerotic progression in humans over a 2-year period, and it seems likely that in the 1990s there will be further expansion of the use of calcium antagonists for not only angina and hypertension but also for aspects of cardioprotection. That calcium antagonists may delay, prevent or possibly regress atherosclerotic lesions is an exciting possibility.

Acodazole hydrochloride: phase I trial, pharmacokinetics, and evaluation of cardiotoxicity in dogs.

Acodazole (NSC 305884) was examined in a Phase I trial evaluating a 1-h infusion repeated every 21 days in 37 patients with advanced carcinomas. Cardiac toxicity was dose-limiting at 1370 mg/m2, manifested as multiple premature ventricular contractions, QTc interval prolongation, and decreasing heart rate. Other toxicities included mild to moderate nausea and vomiting and local reaction near the i.v. injection site requiring the use of central venous catheters. Antineoplastic activity was not observed. Acodazole levels assayed by high-performance liquid chromatography disclosed a peak plasma level of 19 +/- 4 (SEM) micrograms/ml for 1370 mg/m2. Acodazole plasma levels decreased in a triphasic manner over a 100-fold range. The volume of distribution at steady state was 238 +/- 18 liter/m2 suggesting extensive tissue binding. The total body clearance was 13.6 +/- 0.9 liter/h/m2; the percentage of urinary excretion was 29 +/- 2% for 48 h. To evaluate cardiac toxicity, acodazole was administered to five dogs at 2262 mg/m2 (1-h infusion) which provided plasma concentrations similar to those achieved at 1370 mg/m2 in humans. Consistent findings in dogs were drug-related prolongation of QTc intervals, and reduction in heart rate, left ventricular dP/dt, and mean blood pressures. Clinical development of acodazole requires studies to further elucidate and alleviate this cardiac toxicity.

The effect of digitalis on experimental myocardial infarct size and hemodynamics.

Early studies suggested that digitalis exacerbated ischemia (ST segment data); however, there are no studies assessing the effect of this agent on anatomic infarct size with the use of a risk zone technique. Therefore, the aim of this study was to assess quantitatively whether digitalis extends necrosis in a model of coronary artery occlusion. Anesthetized dogs were subjected to 6-hour occlusion and, 30 minutes after occlusion, were randomized to digoxin (250 micrograms bolus/5 min intravenously, n = 9) or saline (n = 9) groups. At 6 hours, in vivo area at risk was determined by monastral blue dye injection and area of necrosis was assessed by tetrazolium staining. Heart rate and blood pressure were not different between groups before treatment or at 6 hours after occlusion. Left ventricular dP/dt was similar in both groups before occlusion (2350 +/- 293 mm Hg/sec digoxin vs 1839 +/- 122 mm Hg/sec saline, p = NS), but after 6 hours of coronary occlusion, had increased in the digoxin group to 2583 +/- 340 mm Hg/sec while it decreased in the saline group to 1517 +/- 128 mm Hg/sec (p less than 0.05 between groups at 6 hours), suggesting that digoxin increased contractility. Area at risk was 17.7 +/- 1.3% of the left ventricle in the digoxin group and 20.9 +/- 2.0% of the left ventricle in the saline group (p = NS). Area of necrosis, expressed as a percentage of area at risk, was 90.0 +/- 3.5% in the digoxin group vs 88.6 +/- 2.1% in the saline group (p = NS). Therefore, during acute myocardial infarction, digitalis confers a moderate increase in contractility without extending necrotic damage.

Scar thinning due to ibuprofen administration after experimental myocardial infarction.

Although much attention has been directed toward interventions which reduce myocardial infarct size, the effect of such agents on the healing phase of myocardial infarction is not well understood. The present study examines the effect of the nonsteroidal anti-inflammatory agent ibuprofen, previously demonstrated to be able to reduce infarct size, and of aspirin on the healing of experimentally produced myocardial infarcts. Thirty-nine anesthetized, open-chest dogs were subjected to proximal left anterior descending coronary artery occlusions for 6 weeks. Four groups of dogs were studied: (1) a control (untreated) group: (2) ibuprofen, 12.5 mg/kg intravenously 15 minutes and 6, 12, 18, and 24 hours after occlusion (high dose); (3) ibuprofen, 12.5 mg/kg intravenously 15 minutes and 3 hours after occlusion (low dose); (4) aspirin, 30 mg/kg intravenously 15 minutes and 3 hours after occlusion. The average thickness of the transmural scar and of the noninfarcted left ventricular wall was determined from multiple measurements of formalin-fixed left ventricular slices. The ratio of transmural scar to noninfarcted wall thickness was determined. In control animals the ratio was 0.87 with only 1 of 15 animals having a ratio less than 0.60. High-dose ibuprofen-treated animals had an average ratio of 0.59 (difference not significant [NS] compared with control values), with 6 of 9 animals having a ratio less than 0.60 (p less than 0.02 compared with control values). Low-dose ibuprofen-treated animals had an average ratio of 0.66 (p less than 0.05 compared with control values), with 4 of 8 animals having a ratio less than 0.60 (p = NS compared with control values). In the aspirin-treated animals, the ratio was 0.88 (p = NS compared with control values), with 0 of 7 animals having a ratio less than 0.60 (p = NS compared with control values). Although 1 of 22 animals had ratios less than 0.60 in the control and aspirin groups, 10 of 17 had ratios less than 0.60 in the ibuprofen-treated groups (p less than 0.001). Scars in treated animals did not differ from those in control animals histologically or by analysis of hydroxyproline content per unit weight. Thus, ibuprofen, a nonsteroidal anti-inflammatory agent which reduces infarct size, is shown to increase the incidence of scar thinning after myocardial infarction.