Preconditioning and the human heart.

Brief episodes of ischemia prior to coronary occlusion protect the heart during sustained coronary ischemia and is known as ischemic preconditioning. During acute myocardial infarction it is associated with smaller infarction size, less cardiac arrhythmias, and better left ventricular function. Brief balloon inflation in the cardiac catheterization laboratory during coronary intervention enables the operator to have further prolonged balloon inflations with lesser degrees of ischemia. Brief ischemia prior to coronary bypass surgery results in smaller perioperative infarctions and lesser degrees of postoperative arrhythmias. Preconditioning mimetic drugs may have a promising future in simulating ischemic preconditioning.

Takayasu's arteritis: a report of three cases.

Takayasu's arteritis is a rare disease seen mainly in young Oriental women. We report three cases of Takayasu's arteritis seen in our clinic. All three involved white women, and the ages at diagnosis were 18, 24, and 46 years. The diagnosis was confirmed by arteriography. Prednisone therapy produced marked improvement in signs and symptoms. Takayasu's arteritis is an important diagnosis to consider in young women with postural dizziness and with absent or diminished pulses.

Flow-function dissociation following an acute dose of cocaine: effect of captopril on coronary flow.

BACKGROUND: Acute administration of cocaine leads to left ventricular dysfunction and a decrease in coronary blood flow. This experiment studied the relationship between function and flow over time in cocaine heart disease and examined the effects of captopril on this relationship. METHODS: Dogs anesthetized with pentobarbital (n = 13) were given a 3 mg/kg body weight intravenous bolus of cocaine followed by a 7 mg/kg infusion over 10 minutes. Animals were then randomly assigned to receive either captopril (0.5 mg/kg infused over 5 minutes, followed by 0.5 mg/kg/h) or an equivalent volume of saline beginning 15 minutes after cocaine administration. Coronary blood flow (radioactive microspheres and Doppler flow probes) and left ventricular function (two-dimensional echocardiogram and dP/dt) were monitored for 2 hours. RESULTS: Within 15 minutes, cocaine caused a drop in dP/dt by 39% to 42% and in coronary blood flow by 35%. Cocaine also caused an increase in left ventricular end-diastolic pressures in both groups. Cocaine resulted in prolongation of an index of end-diastolic isovolumic relaxation time (tau) from a baseline of 34 milliseconds to 56 milliseconds at 15 minutes after cocaine administration in the control group and from a baseline of 35 milliseconds to 49 milliseconds in the captopril group (P < 0.05). By 2 hours after therapy, the tau in the control group remained elevated, whereas in the captopril group it returned toward baseline. At 2 hours of observation, systolic function recovered while coronary flow remained depressed. There was no difference between the captopril and control groups in coronary blood flow or systolic cardiac function at any time during the study. CONCLUSIONS: Cocaine caused left ventricular systolic and diastolic dysfunction as well as reduced coronary blood flow. At 2 hours there is a dissociation of systolic function, which recovers, and of coronary blood flow, which does not. Captopril had no effect on coronary blood flow or systolic left ventricular function following cocaine administration.

Deleterious cardiac effects of captopril during acute myocardial ischaemia in the dog.

OBJECTIVE: The aim was to evaluate the effects of the angiotensin converting enzyme inhibitor captopril on acute myocardial ischaemia. METHODS: Seventeen anaesthetised open chest dogs were randomised to 3 minute angioplasty balloon occlusions of the left circumflex coronary artery before and after intravenous infusion of captopril (n = 8) or placebo (n = 9). RESULTS: There was apparent worsening of ischaemia during balloon inflation after captopril infusion, when compared with control inflation, as suggested by further ST segment elevation of 1.8 (SD 1.8) mm, p less than 0.03, and by further lowering of regional myocardial pH [-0.05(0.05), p = 0.06], and peak positive and peak negative dP/dt [-439(337)mm Hg.s-1, p less than 0.008; -470(316) mm Hg.s-1, p less than 0.004, respectively]. The increase in ischaemia occurred despite reduced double product after captopril administration. Regional myocardial blood flow in the ischaemic artery distribution was lower during post captopril balloon occlusion [-0.1(0.06) ml.min-1.g-1, p less than 0.005] than during control balloon inflation, while coronary vascular resistance increased by 161(172)% (range 45 to 497%, p less than 0.04). There were no significant differences in ST segments, pH, haemodynamic variables, or blood flow during balloon inflations before and after saline infusion. CONCLUSIONS: Despite lower myocardial metabolic demands, acute intravenous administration of captopril was associated with increased ischaemia during transient coronary artery occlusion.

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.

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.

Enhancement of coxsackievirus B4 virulence by indomethacin.

The safety of nonsteroidal anti-inflammatory agents in viral infections was assessed in a mouse model of coxsackievirus B4 neonatal myocarditis. Two-day-old mice were infected intraperitoneally with 10(4) TCID50 coxsackievirus B4 and then randomized to receive indomethacin or saline for 7 days. A number of them were killed on designated days. Mortality, viral titers, antibody, and interferon levels plus histopathologic changes in the heart were compared. Among treated animals, mortality was greater (22/45 vs 7/27; p = 0.07) and viral titers were higher on days 4 and 7 (p = 0.038 and 0.028, respectively). Interferon levels were lower on days 4 and 7 (p = 0.028 and 0.008, respectively), and histopathologic changes were more extensive on days 7 and 21 (p = 0.008 and 0.028, respectively). These findings show that indomethacin decreased interferon production, increased coxsackievirus4 titers, and enhanced the virulence of coxsackievirus B4. These results raise significant concerns about the safety of indiscriminate use of nonsteroidal anti-inflammatory agents during severe viral infections.

Beneficial effects of captopril in acute coxsackievirus B3 murine myocarditis.

To date, there is no universally accepted therapy for viral myocarditis. We investigated the effect of the angiotensin converting enzyme inhibitor captopril on both early and late phases of coxsackievirus murine myocarditis. Mice were infected with coxsackievirus B3 and were divided into two main protocols. Mice in the early treatment protocol (n = 30) were treated on day 1 after infection with either captopril or saline through day 6 of infection and euthanized on day 6 of infection. In the late treatment protocol, mice (n = 60) were treated starting on day 10 of infection through day 30 of infection with either captopril or saline. Mice were killed on days 20 and 30 of infection. In the early treatment protocol, heart weight was 67 +/- 14 mg in the captopril-treated group versus 98 +/- 17 mg in the control group (p less than 0.0001). The degree of inflammation, necrosis, and dystrophic calcification assessed with a semiquantitative histological score was significantly less in the captopril-treated group. The degree of pathological involvement determined by planimetry of histological sections was 8.1 +/- 7.2% for the captopril-treated group versus 22.5 +/- 10.0% for the saline-treated group (p less than 0.0001). In the late treatment protocol, captopril also caused a reduction in heart weight as compared with controls at day 20 (116 +/- 21 mg in captopril-treated group vs. 166 +/- 34 mg in controls, p less than 0.0001) and also at day 30 (136 +/- 23 mg in captopril-treated group vs. 185 +/- 48 mg in controls, p less than 0.004). On days 20 and 30 of infection, the degree of inflammation, necrosis, and dystrophic calcification was similar in both groups. We conclude that captopril is beneficial in acute coxsackievirus B3 murine myocarditis because it reduces heart weight and necrosis when administered early and reduces heart weight when administered in a delayed manner.

Adverse effects of cocaine on cardiovascular dynamics, myocardial blood flow, and coronary artery diameter in an experimental model.

Smoking "crack" is currently popular; this results in rapidly peaking, high blood levels of cocaine. Our purpose was to investigate the effects of rapid cocaine administration. Hemodynamics, myocardial blood flow, and left ventricular cavity end-systolic and end-diastolic areas were measured in pentobarbital-anesthetized dogs before and 15 minutes after (1) a bolus intravenous injection of cocaine (n = 6), or (2) a 10-minute infusion of cocaine (n = 6), or (3) saline (n = 6) administration. In both treated groups cocaine caused a significant reduction in heart rate and left ventricular dP/dt compared with baseline measurements, and an increase in left ventricular end-diastolic pressure. Cocaine also caused dilation of the left ventricle and a fall in regional myocardial blood flow. In nine other dogs, proximal circumflex artery diameter, assessed by angiography, and regional myocardial blood flow were measured before and 3 to 5 minutes after cocaine (n = 7) or saline (n = 2). In treated animals, circumflex artery diameter was reduced 15 +/- 4% (range 2% to 29%, p less than 0.01 versus baseline) after cocaine. We conclude that in this model, rapid administration of cocaine depresses left ventricular function, causes left ventricular dilation, and is associated with coronary artery vasoconstriction and reduced myocardial blood flow.

The autoperfusion balloon angioplasty catheter limits myocardial ischemia and necrosis during prolonged balloon inflation.

A new balloon angioplasty catheter with multiple proximal and distal side holes has previously been shown to allow significant protection from ischemia during a 3 min balloon inflation in a coronary artery. Because of the potential benefits of very long periods of inflation, 21 anesthetized thoracotomized dogs were randomized to left circumflex coronary artery occlusion with either a standard or an autoperfusion balloon catheter for 90 min. Nine dogs sustained ventricular fibrillation before completing the study, eight after standard balloon inflation and one after autoperfusion balloon inflation (p = 0.04). ST segment elevation was 0.45 +/- 0.13 mV after 15 min of standard balloon inflation versus -0.03 +/- 0.03 mV after autoperfusion balloon inflation (p less than 0.001). Regional myocardial blood flow was 0.02 +/- 0.01 ml/min per g after 30 min of standard balloon inflation compared with 0.78 +/- 0.23 ml/min per g in the group subjected to autoperfusion balloon inflation (p = 0.01). The area of necrosis/area at risk in the standard catheter group was 40.4 +/- 19.3% versus 1.2 +/- 1.2% for the autoperfusion catheter group (p = 0.01). Thus, the autoperfusion catheter preserves blood flow and limits myocardial ischemia and necrosis despite 90 min of balloon inflation.

Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study.

Although there have been anecdotal reports of cardiac toxicity associated with fluorouracil (5-FU) therapy, this phenomenon has not been studied in a systematic fashion. We prospectively performed continuous ambulatory ECG monitoring on 25 patients undergoing 5-FU infusion for treatment of solid tumors in order to assess the incidence of ischemic ST changes. Patients were monitored for 23 +/- 4 hours before 5-FU infusion, and 98 +/- 9 hours during 5-FU infusion. Anginal episodes were rare: only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes (greater than or equal to 1 mm ST deviation) were common: six of 25 patients (24%) had ST changes before 5-FU infusion v 17 (68%) during 5-FU infusion (P less than .002). The incidence of ischemic episodes per patient per hour was 0.05 +/- 0.02 prior to 5-FU infusion v 0.13 +/- 0.03 during 5-FU infusion (P less than .001); the duration of ECG changes was 0.6 +/- 0.3 minutes per patient per hour before 5-FU v 1.9 +/- 0.5 minutes per patient per hour during 5-FU (P less than .01). ECG changes were more common among patients with known coronary artery disease. There were two cases of sudden death, both of which occurred at the end of the chemotherapy course. We conclude that 5-FU infusion is associated with a significant increase in silent ST segment deviation suggestive of ischemia, particularly among patients with coronary artery disease. The mechanism and clinical significance of these ECG changes remain to be determined.

Detection of experimental myocarditis by monoclonal antimyosin antibody, Fab fragment.

The purpose of this study was to determine whether monoclonal antimyosin Fab (antigen binding fragment) was capable of labeling hearts with experimental coxsackievirus myocarditis, and to determine whether Fab could be used for detecting myocardial damage in either early or chronic phases of the disease. Sixty-five, 3-week-old cesarean-derived 1 (CD 1) mice were divided into two groups: group I (noninfected animals) and group II (infected with coxsackievirus B3). Mice from each group were killed on days 7, 17, 30, or 90 of infection. Forty-eight hours before killing, mice were injected with monoclonal I125 antimyosin, Fab (25 microCi/injection) and radioactivity was counted in the heart. Selected heart sections were also examined by autoradiography. Heart radioactivity, count/m/mg (m +/- SEM) on days 7, 17, 30, and 90 of infection was 10.8 +/- 1.7, 21.3 +/- 1.1, 11.2 +/- 3.4, and 12.4 +/- 1.5 for group I, versus 36.7 +/- 8.0 (p less than 0.01), 50.0 +/- 4.5 (p less than 0.001), 33.4 +/- 16.1 (p = NS), and 40.6 +/- 8.5 (p less than 0.01) for group II, respectively. Autoradiography revealed focal uptake within areas of necrotic myocardium. We conclude that I125 Fab may be useful in detecting myocardial damage in the experimental model of murine myocarditis up to day 90 of infection.

Amelioration of ischemia during angioplasty of the left anterior descending coronary artery with an autoperfusion catheter.

A new autoperfusion balloon angioplasty catheter with sideholes proximal and distal to the balloon--facilitating distal blood flow during inflation--was compared with standard angioplasty catheters in a prospective, randomized study with blinded data analysis. Hemodynamic and electrocardiographic markers of ischemia after 1 minute of standard or autoperfusion catheter inflations were compared with ischemia after control inflation with standard balloons. In the patient group randomized to standard balloon inflation only, ST-segment elevation after control inflation with a standard balloon catheter was 0.37 +/- 0.04 mV; ST-segment elevation after final balloon inflation with a standard catheter was unchanged at 0.35 +/- 0.04 mV (difference not significant). In the group randomized to the autoperfusion catheter, control inflation with a standard catheter resulted in 0.48 +/- 0.1 mV ST elevation; final inflation with the autoperfusion catheter demonstrated 0.16 +/- 0.09 mV ST elevation (p less than 0.005). Autoperfusion catheter inflation was continued for 2 minutes without change in electrocardiographic findings: ST segments remained at 0.08 +/- 0.03 mV, unchanged from 0.07 +/- 0.03 mV before angioplasty (difference not significant). Thus, while coronary angioplasty performed with standard catheters resulted in marked ST-segment elevation, in patients undergoing angioplasty with the autoperfusion catheter, ischemia was generally not seen, despite sustained balloon inflation for 2 minutes.

Effect of metoprolol in acute coxsackievirus B3 murine myocarditis.

Recent studies suggest that beta-adrenergic blocking agents show promise in the management of cardiomyopathies; however, their role in acute myocarditis is unknown. One hundred 3 week old mice were infected with coxsackievirus B3 and were given either metoprolol (n = 50) or normal saline solution (n = 50) intraperitoneally for 10 days. Twenty mice from each group were observed for mortality for 30 days. Of the remaining 60 mice, 10 from each group were killed on day 3, 6 or 10 and examined for heart viral titers and pathologic changes. Mortality rate in the metoprolol group was 60% compared with 0% in the saline group (p less than 0.005). Viral titers on day 10 of infection were 10(2.6 +/- 0.2) median tissue culture infective dose for the metoprolol group versus 10(2.1 +/- 0.1) for the saline group (p less than 0.05). Whereas pathologic changes at days 3, 6 and 10 of infection were similar in both groups, on day 30 of infection, inflammation, necrosis and mineralization scores (mean +/- SEM) were 1.1 +/- 0.3, 2.1 +/- 0.4, 2.2 +/- 0.5 for the metoprolol group versus 0.3 +/- 0.1, 0.4 +/- 0.3, 0.4 +/- 0.3 for the saline group, respectively (p less than 0.01). Six noninfected mice received metoprolol intraperitoneally for 10 days; there was no mortality during 30 days of observation. In conclusion, metoprolol administration exerts deleterious effects in acute coxsackievirus B3 murine myocarditis.