Relationship among mental stress-induced ischemia and ischemia during daily life and during exercise: the Psychophysiologic Investigations of Myocardial Ischemia (PIMI) study.

OBJECTIVES: The purposes of this database study were to determine: 1) the relationship between mental stress-induced ischemia and ischemia during daily life and during exercise; 2) whether patients who exhibited daily life ischemia experienced greater hemodynamic and catecholamine responses to mental or physical stress than patients who did not exhibit daily life ischemia, and 3) whether patients who experienced daily life ischemia could be identified on the basis of laboratory-induced ischemia using mental or exercise stress testing. BACKGROUND: The relationships between mental stress-induced ischemia in the laboratory and ischemia during daily life and during exercise are unclear. METHODS: One hundred ninety-six stable patients with documented coronary disease and a positive exercise test underwent mental stress testing and bicycle exercise testing. Radionuclide ventriculography and electrocardiographic (ECG) monitoring were performed during the mental stress and bicycle tests. Patients underwent 48 h of ambulatory ECG monitoring. Hemodynamic and catecholamine responses were obtained during mental stress and bicycle tests. RESULTS: Ischemia (reversible left ventricular dysfunction or ST segment depression > or = 1 mm) developed in 106 of 183 patients (58%) during the mental stress test. There were no significant differences in clinical characteristics of patients with, compared with those without, mental stress-induced ischemia. Patients with mental stress ischemia more often had daily life ischemia than patients without mental stress ischemia, but their exercise tests were similar. Patients with daily life ischemia had higher ejection fraction and cardiac output, and lower systemic vascular resistance during mental stress than patients without daily life ischemia. Blood pressure and catecholamine levels at rest and during the mental stress tests were not different in patients with, compared with those without, daily life ischemia. Patients with daily life ischemia had a higher ejection fraction at rest and at peak bicycle exercise compared with patients without daily life ischemia, but there were no other differences in peak hemodynamic or catecholamine responses to exercise. The presence of ST segment depression during routine daily activities was best predicted by ST segment depression during mental or bicycle exercise stress, although ST segment depression was rare during mental stress. CONCLUSIONS: Patients with daily life ischemia exhibit a heightened generalized response to mental stress. ST segment depression in response to mental or exercise stress is more predictive of ST segment depression during routine daily activities than other laboratory-based ischemic markers. Therapeutic management strategies might therefore focus on patients with these physiologic responses to stress and on whether lessening such responses reduces ischemia.

Calcium antagonists in the post-myocardial infarction setting.

At present, the use of calcium antagonists for the secondary prevention of cardiac events following an acute myocardial infarction (MI) is not recommended. This advice is based on several large mortality studies using short-acting calcium antagonists in the absence of coronary reperfusion therapy. Even in these studies, discrepancies between the different pharmacological classes of calcium antagonists were recognised. When separated from the dihydropyridine calcium antagonists, the rate-lowering calcium antagonists, verapamil and diltiazem, do appear to provide some benefit in reduction of recurrent MI. Three large trials using verapamil post-MI demonstrated a significant reduction in reinfarction with a favourable trend towards reducing death as well. Similarly, the effects of diltiazem post-MI have been evaluated in 3 large trials. In 2 earlier trials, diltiazem lessened cardiac events in patients with nonQ-wave infarctions and those without pulmonary congestion upon presentation. Overall, there was a significant benefit in lessening reinfarction with no effect on mortality. The recently completed Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis Post-Infarction (INTERCEPT) trial found that sustained-release diltiazem given after thrombolytic therapy for acute MI lessened cardiac events by 23% (a nonsignificant difference) without worsening congestive symptoms. Overall, there is adequate data to support the use of heart-rate-lowering calcium antagonists for secondary prevention post-MI provided the patient is intolerant of beta-blocker therapy. These trials are reviewed in detail, and suggestions for clinical practice are provided in this article.

Peripartum cardiomyopathy: a comprehensive review.

The objective of this article is to review the etiology, diagnosis, treatment, prognosis, and natural history of peripartum cardiomyopathy. The English language medical literature was accessed though MEDLINE from 1966 to the present; additional sources were obtained by cross-referencing. Because of the limited number of studies and patients, metaanalysis could not be performed; however, the existing data regarding the etiology, diagnosis, treatment, and prognosis of peripartum cardiomyopathy are presented. Approximately 1000 U.S. women will have peripartum cardiomyopathy this year, and for many it will be fatal. The etiology of this disease remains uncertain, but current evidence suggests myocarditis of viral, autoimmune, or idiopathic origin. The utility of immunosuppressive therapy remains ambiguous; however, other advances in medical therapy for dilated cardiomyopathy and cardiac transplantation have significantly improved quality of life and survival for patients. As the initial patient contact, obstetricians and family practitioners must recognize this malady early and rapidly institute the proper medical therapy directed toward the congestive state.

Myocardial infarction related atrial fibrillation: role of endogenous adenosine.

Exogenous administration of adenosine induces atrial fibrillation in up to 7.0% of patients. Animal studies affirm endogenous adenosine released in response to tissue hypoxia may play a mechanistic role in arrhythmias associated with myocardial ischaemia or hypoxia. Therefore, atrial fibrillation occurring early after the acute phase of myocardial infarction involving atrial tissue may be secondary to an excessive accumulation of adenosine that leads to a shortening of atrial refractory period. Early in the course of acute inferior myocardial infarction, two patients (males aged 45 and 68) suffered new onset sustained atrial fibrillation that was abrupt in onset and complicated their clinical management. They were administered 250 mg theophylline as a slow intravenous injection at a rate of 100 mg/min or until conversion to normal sinus rhythm occurred. Both patients converted to normal sinus rhythm within five minutes of the administration of theophylline. In up to 52 hours of continuous ECG monitoring after the theophylline administration the atrial fibrillation did not recur. Neither patient experienced any adverse outcome from theophylline administration. These observations are the first reported in humans or laboratory animals to suggest that atrial fibrillation, presumably due to elevated interstitial atrial concentration of adenosine caused by myocardial ischaemia, can be terminated with an adenosine receptor antagonist. However, the hypothesis that excessive accumulation of endogenous adenosine in atrial tissue may induce atrial fibrillation is well substantiated by other investigators. Thus, A1 adenosine receptor antagonists may prove to be valuable in the management of ischaemia related atrial fibrillation.

Differential antagonism of cardiac actions of adenosine by theophylline.

OBJECTIVE: To determine the relative sensitivity of cardiac A1- and A2-adenosine receptor-mediated effects to antagonism by theophylline in man. METHODS: Baseline measurements of the A-H interval (A1-adenosine receptor-mediated effect) and coronary blood flow (A2-adenosine receptor-mediated effect) were made in 10 patients with angiographically normal coronary arteries. Adenosine was then administered as a continuous intravenous infusion followed by a rapid intravenous bolus, and measurements repeated. Theophylline (5 mg/kg i.v.) was then administered, and the adenosine infusion repeated. To corroborate the results found in man, the cardiac A1- and A2-adenosine receptor-mediated effects were measured in guinea pig isolated hearts exposed to increasing concentrations of adenosine, in the absence and presence of theophylline (60 microM). RESULTS: Compared to baseline, adenosine infusion and bolus caused significant prolongation of the A-H interval (109 +/- 41 vs. 116 +/- 44 vs. 168 +/- 57 ms, respectively), and increase in coronary blood flow (46 +/- 37 vs. 86 +/- 71 vs. 172 +/- 98 ml/min, respectively). Theophylline abolished the prolongation of the A-H interval during adenosine infusion and bolus (99 +/- 36 and 107 +/- 44 ms, respectively), yet had minimal effect on the increase in coronary blood flow (63 +/- 51 and 136 +/- 121 ml/min, respectively). In guinea pig isolated hearts, theophylline was shown to significantly antagonize the A2-adenosine receptor-mediated effects only when the concentrations of adenosine were < or = 1.0 microM. CONCLUSIONS: In man, theophylline completely antagonizes the A1-adenosine receptor-mediated prolongation of the A-H interval, but has minimal effect on the A2-receptor-mediated coronary vasodilation, particularly when adenosine concentrations exceed 1.0 microM.

Effects of A1 adenosine receptor agonism using N6-cyclohexyl-2'-O-methyladenosine in patients with left ventricular dysfunction.

BACKGROUND: The role of adenosine as a neuromodulator in heart failure was studied with the use of a selective adenosine A1 receptor agonist, N6-cyclohexyl-2'-O-methyladenosine (SDZ-WAG 994). METHODS AND RESULTS: Fifty patients with heart failure symptoms and moderate left ventricular systolic dysfunction had a balloon flotation catheter inserted. Patients received placebo or a single oral dose of either 1, 2, or 5 mg SDZ-WAG 994. After baseline measurements were obtained, hemodynamic and electrophysiological recordings were repeated at 30-minute intervals for the next 4 hours, then every 6 hours for the next 24 hours. Blood samples for norepinephrine, epinephrine, aldosterone, atrial natriuretic peptide, and plasma renin activity were drawn at baseline and 2 hours after drug administration. A adenosine receptor agonism produced no important effects on systemic, right atrial, pulmonary artery, or pulmonary capillary wedge pressures; cardiac index; respiratory rate; or heart rate. The PR interval (a reflection of A1 receptor-mediated activity) increased significantly in a stepwise fashion. At the 5-mg dose of SDZ-WAG 994, significant increases in atrial natriuretic peptide (216 +/- 137 to 407 +/- 146 pg/mL) and norepinephrine (477 +/- 243 to 618 +/- 237 pg/mL) levels were noted. CONCLUSIONS: A1 adenosine receptor agonism with SDZ-WAG 994 resulted in no significant hemodynamic changes at rest in this subset of patients with left ventricular dysfunction. An increase in the PR interval and atrial natriuretic peptide level, consistent with adenosine A1 receptor-mediated activity, was observed. In addition, an increase in the norepinephrine level was observed, suggesting a role for adenosine as a peripheral nervous system neuromodulator.

Bradycardia after heart transplantation: reversal with theophylline.

OBJECTIVES: We attempted to demonstrate that theophylline, an adenosine receptor antagonist, can reverse bradyarrhythmias after orthotopic heart transplantation. BACKGROUND: Sinus node dysfunction, primarily sinus bradycardia, frequently occurs after orthotopic heart transplantation and may lead to permanent pacemaker implantation. Endogenous adenosine has been implicated as a cause of such posttransplantation bradyarrhythmia. METHODS: Twenty-nine transplant recipients (group 1) were given theophylline after bradyarrhythmias developed after transplantation. Data in these patients were compared with those in a control group of 18 patients without bradyarrhythmias (group 2) who were not given theophylline. RESULTS: The mean heart rate in group 1 increased from 62 +/- 7 to 89 +/- 10 beats/min after administration of theophylline (p < 0.0001); the mean heart rate in group 2 was 88 +/- 12 beats/min. Patients in group 1 required more days of temporary atrial pacing (3.5 +/- 1 vs. 1.5 +/- 3, p < 0.04) before the administration of theophylline than did patients in group 2. The length of hospital stay after transplantation did not differ significantly between groups 1 and 2 (17 +/- 7.5 vs. 20 +/- 16 days, p = NS). Age, gender, underlying disease, preoperative use of amiodarone, graft ischemia time or the incidence of moderate to severe rejection were not different between patient groups. CONCLUSIONS: The use of theophylline for posttransplantation bradyarrhythmias increased heart rate and facilitated the withdrawal of chronotropic support. We conclude that theophylline offers effective and specific therapy for heart transplant patients with early bradyarrhythmias, reducing the need for implantation of a permanent pacemaker.

Lysis of intravascular thrombus prior to coronary stenting using the dispatch infusion catheter.

The presence of angiographic evidence of thrombus is generally thought to be a contraindication to coronary stent placement. This report describes four patients in whom angiographic thrombus was lysed using the Dispatch infusion catheter prior to coronary stenting. Urokinase was infused via the Dispatch catheter with resolution of angiographic evidence of thrombus in all cases. No complications were encountered using this technique, and all patients had excellent angiographic results after stenting. We conclude that lysis of intracoronary thrombus using the Dispatch infusion catheter is feasible and appears safe in this small study. Further trials are needed to determine if this technique reduces the acute stent thrombosis rate compared to other techniques for stent deployment in the presence of angiographic evidence of thrombus.

Selective attenuation by N-0861 (N6-endonorboran-2-yl-9-methyladenine) of cardiac A1 adenosine receptor-mediated effects in humans.

BACKGROUND: To determine the adenosine receptor subtype selectivity of the novel antagonist N-0861, the A1 and A2 receptor-mediated cardiac effects of adenosine were investigated in 13 patients during continuous intravenous infusion and boluses of adenosine before and after intravenous infusion of N-0861. METHODS AND RESULTS: Measurements of the the atria-to-His (A-H) interval, chest pain severity, and coronary blood flow velocity were made before and after low-dose (69 microg x kg(-1) x min(-1)) intravenous infusion and bolus (2.5 mg) adenosine. Two doses of N-0861 were infused intravenously, and the adenosine protocol was repeated. N-0861 0.25 mg/kg abolished the negative dromotropic effect (A-H interval prolongation) and chest discomfort experienced during infusion of adenosine and attenuated discomfort observed during the boluses of adenosine; however, the increase in coronary blood flow velocity was not significantly affected. CONCLUSIONS: These actions of N-0861 support the concept that the negative dromotropic effect and anginalike pain caused by adenosine are A1 adenosine receptor-mediated, whereas the increase in coronary blood flow velocity is due to activation of A2 adenosine receptors. N-0861 appears to be an effective and selective A1 adenosine receptor antagonist in humans.

Theophylline for the treatment of atrioventricular block after myocardial infarction.

OBJECTIVE: To show that second- or third-degree atrioventricular block occurring as an early complication of acute inferior myocardial infarction is mediated by adenosine. SETTING: Cardiac care unit. DESIGN: Uncontrolled, observational, hypothesis-driven study. PATIENTS: Patients who developed clinically significant atrioventricular nodal blockade within 4 hours of admission for acute inferior myocardial infarction. INTERVENTION: Theophylline, 100 mg/min intravenously to a maximum of 250 mg. MEASUREMENTS: Continuous multilead electrocardiographic monitoring before and after administration of theophylline. RESULTS: During a 6-month period, eight men who had had acute inferior myocardial infarction developed clinically significant atrioventricular block. Three had third-degree block, and five had high-grade second-degree block. In all patients, 1:1 atrioventricular nodal conduction was restored and normal sinus rhythm reappeared within 3 minutes of the administration of theophylline. All patients remained free of arrhythmia for at least 24 hours. CONCLUSIONS: Adenosine produced by the ischemic myocardium may induce atrioventricular nodal block. In our patients, atrioventricular nodal block was resistant to conventional therapy such as atropine, but it responded to the adenosine antagonist theophylline.

Asymptomatic Cardiac Ischemia Pilot (ACIP) study: outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. The ACIP Investigators.

OBJECTIVES: This report discusses the outcome at 1 year in patients in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study. BACKGROUND: Comparative efficacy of medical therapy versus revascularization in treatment of asymptomatic ischemia is unknown. The ACIP study assessed the ability of three treatment strategies to suppress ambulatory electrocardiographic (ECG) ischemia to determine whether a large-scale trial studying the impact of these strategies on clinical outcomes was feasible. METHODS: Five hundred fifty-eight patients with coronary anatomy amenable to revascularization, at least one episode of asymptomatic ischemia on the 48-h ambulatory ECG and ischemia on treadmill exercise testing were randomized to one of three treatment strategies: 1) medication to suppress angina (angina-guided strategy, n = 183); 2) medication to suppress both angina and ambulatory ECG ischemia (ischemia-guided strategy, n = 183); or 3) revascularization strategy (angioplasty or bypass surgery, n = 192). Medication was titrated atenolol-nifedipine or diltiazem-isosorbide dinitrate. RESULTS: The revascularization group received less medication and had less ischemia on serial ambulatory ECG recordings and exercise testing than those assigned to the medical strategies. The ischemia-guided group received more medication but had suppression of ischemia similar to the angina-guided group. At 1 year, the mortality rate was 4.4% in the angina-guided group (8 of 183), 1.6% in the ischemia-guided group (3 of 183) and 0% in the revascularization group (overall, p = 0.004; angina-guided vs. revascularization, p = 0.003; other pairwise comparisons, p = NS). Frequency of myocardial infarction, unstable angina, stroke and congestive heart failure was not significantly different among the three strategies. The revascularization group had significantly fewer hospital admissions and nonprotocol revascularizations at 1 year. The incidence of death, myocardial infarction, nonprotocol revascularization or hospital admissions at 1 year was 32% with the angina-guided medical strategy, 31% with the ischemia-guided medical strategy and 18% with the revascularization strategy (p = 0.003). CONCLUSIONS: After 1 year, revascularization was superior to both angina-guided and ischemia-guided medical strategies in suppressing asymptomatic ischemia and was associated with better outcome. These findings require confirmation by a larger scale trial.

Effect of precordial electrocardiographic electrode placement on ST-segment measurement during exercise.

Research protocols often utilize serial exercise testing to examine the efficacy of anti-ischemic therapies. These tests, however, are prone to multiple sources of bias. This investigation sought to determine the influence of varying precordial electrocardiographic (ECG) electrode placement on the detection of exercise-induced ST-segment shifts. Fifteen coronary artery disease patients with abnormal exercise tests were studied. Based on the previous exercise test, the precordial electrode position exhibiting the greatest ST-segment shift was selected as the reference electrode. Four additional electrodes were placed around this reference electrode and exercise testing was performed. ECG strips were recorded every minute. The time-to-onset and -offset of ischemic-type ST-segment depression was recorded. ST-segment depression was recorded during exercise from the reference electrode in 12 of 15 patients. Ischemic-type ST-depression was also recorded in each of these 12 patients with the surrounding electrodes; however, the time-to-onset detected by all four surrounding electrodes concurred in only 5 of 12 (42%) patients. The time-to-offset of the ST-segment depression concurred in 9 of 12 (75%) patients. Serial ECGs recorded from similar but not exactly the same precordial ECG electrode position should yield similar results for the detection of ischemia, but time-to-onset or -offset of ischemia may differ by 60 s or more. Small changes in the time-to-onset and -offset of ischemia should not be considered reliable indicators of anti-ischemia efficacy.

Daily life cardiac ischaemia. Should it be treated?

Daily life cardiac ischaemia is defined as reversible myocardial cellular hypoxia that occurs during activities of daily living, without artificial provocation. Most of these daily life ischaemic episodes are not associated with symptoms. However, it is not practical to distinguish silent versus symptomatic daily life ischaemia as both are associated with haemodynamic abnormalities and future adverse outcomes. Daily life cardiac ischaemia is best detected using ambulatory electrocardiogram (ECG) monitoring; however, there are other diagnostic tools (e.g. exercise treadmill) that can be used. Once detected, the optimal therapy for daily life myocardial ischaemia has yet to be identified. However, it does appear that usual antianginal medications including nitrates, beta-blockers, calcium antagonists and antiplatelet drugs are effective in reducing the incidence and severity of daily life myocardial ischaemia. Medical therapy and revascularisation should be utilised to obliterate all episodes of daily life cardiac ischaemia to prevent future cardiac events. Moreover, the efficacy of the chosen therapeutic regimen for each patient should be documented with follow-up objective testing. The diagnosis and management of daily life myocardial ischaemia is continually evolving. Future research as well as economic considerations will shape future management strategies.