Barry D. Bertolet

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

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.

Pivotal Trial to Evaluate the Safety and Efficacy of the Orbital Atherectomy System in Treating De Novo, Severely Calcified Coronary Lesions (ORBIT II)

OBJECTIVES The ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) trial evaluated the safety and efficacy of the coronary Orbital Atherectomy System (OAS) to prepare de novo, severely calcified coronary lesions for stent placement. BACKGROUND Despite advances in interventional techniques, treatment of calcified coronary lesions remains a challenge. Stent placement in these lesions may result in stent underexpansion, malapposition, and procedural complications. METHODS ORBIT II is a prospective, multicenter, nonblinded clinical trial that enrolled 443 consecutive patients with severely calcified coronary lesions at 49 U.S. sites from May 25, 2010, to November 26, 2012. Investigators used the centrifugal action of the OAS diamond-coated crown to modify calcified lesions prior to stent placement. RESULTS The pre-procedure mean minimal lumen diameter of 0.5 mm increased to 2.9 mm after the procedure. The primary safety endpoint was 89.6% freedom from 30-day major adverse cardiac events compared with the performance goal of 83%. The primary efficacy endpoint (residual stenosis <50% post-stent without in-hospital major adverse cardiac events) was 88.9% compared with the performance goal of 82%. Stent delivery occurred successfully in 97.7% of cases with <50% stenosis in 98.6% of subjects. Low rates of in-hospital Q-wave myocardial infarction (0.7%), cardiac death (0.2%), and target vessel revascularization (0.7%) were reported. CONCLUSIONS The ORBIT II coronary OAS trial met both the primary safety and efficacy endpoints by significant margins. Preparation of severely calcified plaque with the OAS not only helped facilitate stent delivery, but improved both acute and 30-day clinical outcomes compared with the outcomes of historic control subjects in this difficult-to-treat patient population. (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions [ORBIT II]; NCT01092416).

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.

Theophylline for the treatment of atrioventricular block after myocardial infarction.

Adenosine is known to cause bradyarrhythmias, such as atrioventricular conduction delay [1]. Substantial evidence from laboratory animals [2] affirms that endogenous adenosine may play a mechanistic role in bradyarrhythmias associated with myocardial ischemia, hypoxia, or both. Similarly, case reports [3-9] suggest that endogenous adenosine may cause clinically significant arrhythmias in patients during acute myocardial infarction, the sick sinus syndrome, cardiac arrest, or cardiac transplant rejection. Adenosine mediates its cardiac actions through at least two cell-surface receptor subtypes, A1 and A12 [10]. The A1 receptor mediates both the negative chronotropic effects of adenosine on the sinoatrial node and the negative dromotropic effects of adenosine on the atrioventricular node. Activation of the A1 receptor also inhibits the positive inotropic, chronotropic, and dromotropic effects of catecholamines [10]. The A2 receptors that are present in endothelial and vascular smooth-muscle cells mediate vasodilatation [10]. In the presence of excess adenosine, these cardiac actions may become undesirable, causing bradyarrhythmias and hypotension and resulting in low cardiac output [11]. Methylxanthine derivatives, such as theophylline, antagonize the cardiac actions of adenosine in a competitive manner [12]. We previously showed that in the presence of clinically significant concentrations of adenosine in humans, theophylline reverses A1-mediated atrioventricular block more readily than it reverses A2-mediated coronary vasodilation [13]. In this report, we provide evidence to show that second- or third-degree atrioventricular block occurring as an early complication of acute inferior myocardial infarction is probably mediated by endogenous adenosine. This is shown by the fact that this atrioventricular block can be promptly converted to a normal sinus rhythm by using theophylline. Methods Patients admitted to the Gainesville Veterans Affairs Hospital with a diagnosis of acute inferior myocardial infarction were monitored for clinically significant and persistent atrioventricular conduction delay. When such a dysrhythmia was seen, the primary care physician was instructed to treat the patient with intravenous atropine according to the 1992 Emergency Cardiac Care/American Heart Association guidelines [14]. If this therapy failed to restore 1:1 atrioventricular nodal conduction and normal sinus rhythm, or if it was not used, 150 to 250 mg of theophylline were given as a slow intravenous injection at a rate of 100 mg/min. The patients heart rhythm was monitored for recurrent arrhythmias using 2-lead cardiac telemetry for at least 24 hours. No patient had a previous history of cardiac arrhythmias, and the electrocardiogram done for each patient at study entry showed a normal sinus rhythm. Patients were treated with oral aspirin (325 mg/d), intravenous heparin, and nitroglycerin. No patient had received -blockers or calcium antagonists before the onset of the bradyarrhythmia. Results During a 6-month period, 11 men who were hospitalized with acute inferior myocardial infarction developed persistent and clinically significant atrioventricular conduction delay within 4 hours of the onset of symptoms. Eight patients either failed to respond to the initial standard treatment with atropine or were directly treated, at the discretion of the primary physician, with theophylline. No bradyarrhythmia converted to a sinus rhythm before the administration of theophylline. Six of the 8 patients had received thrombolytic therapy before the onset of the atrioventricular conduction delay. Three patients developed hemodynamically significant third-degree atrioventricular block, and 5 developed high-grade second-degree atrioventricular block (Table 1). Table 1. Patient Characteristics and Infarction-Related Atrioventricular Nodal Blockade All patients developed clinically significant atrioventricular nodal conduction delays 30 to 240 minutes (mean SD, 69 72 minutes) after the onset of myocardial infarction symptoms. All had symptoms or signs of hypoperfusion (six had dizziness; one had fatigue; five had cool, clammy skin; three had changes in mental status; and the mean systolic blood pressure was 74 13 mm Hg). Two of the three patients who developed third-degree atrioventricular block and four of the five patients who developed second-degree atrioventricular block were initially treated unsuccessfully with atropine (1 mg given intravenously). Patients received theophylline (mean dose, 218 37 mg) as a slow intravenous injection. Figure 1 shows electrocardiographic recordings from a patient with third-degree atrioventricular block who converted to normal sinus rhythm after receiving 150 mg of theophylline and who remained in normal sinus rhythm with 1:1 atrioventricular conduction for 36 hours of observation. In all patients, 1:1 atrioventricular nodal conduction and normal sinus rhythm were restored within 1.8 0.7 minutes after the injection of theophylline. In association with the resumption of sinus rhythm and 1:1 atrioventricular conduction, the mean systolic blood pressure increased from 74 13 mm Hg to 112 6 mm Hg (n = 8), and all signs and symptoms of hypoperfusion subsided after administration of theophylline. No patient had worsening of anginal pain, and three patients reported a noticeable decrease in anginal pain. Figure 1. Electrocardiographic recordings from leads II and aVF. Top. Bottom. Discussion Our findings in this uncontrolled and observational but hypothesis-driven study show that theophylline, an adenosine-receptor antagonist, can convert ischemia-related atrioventricular nodal conduction disturbances to normal sinus rhythm. Because each of the eight patients converted to 1:1 atrioventricular nodal conduction with normal sinus rhythm within 3 minutes (1.8 0.7 minutes) of the administration of theophylline, it is unlikely that the dysrhythmias resolved spontaneously. The relevance of these findings is greatly enhanced by the fact that theophylline antagonizes the negative chronotropic and dromotropic effect of adenosine in humans [13]. Additionally, in the doses administered, the primary action of theophylline is adenosine antagonism and not sympathomimetic stimulation [15]. Atropine would not be expected to potentiate the effects of theophylline. These results indicate that, under conditions in which excessive depression of cardiac function (such as bradyarrhythmia) is secondary to an increased production of adenosine by the heart, A1 adenosine-receptor antagonists may prove to be useful. Patients with acute inferior myocardial infarctions are more likely than patients with anterior-wall myocardial infarctions to develop atrioventricular block because the blood supply to the atrioventricular node is usually supplied by the right coronary artery [16]. Patients with early atrioventricular block (occurring less than 24 hours into their hospital course) are less likely to respond to atropine, more likely to require temporary pacing, and more likely to have a morbid or mortal event than are similar patients who develop late atrioventricular block (occurring more than 24 hours into their hospital course) [17]. Because of the poor prognosis associated with early atrioventricular block and the ineffectiveness of the current therapy for it, the efficacy of alternative therapies, such as A1 1 adenosine-receptor antagonists, should be investigated. Our results are the first to suggest that theophylline can be used as primary or rescue therapy for early bradyarrhythmias associated with myocardial infarction. One of the limitations of our study is that the administration of theophylline was neither blinded nor directly compared with other standard therapy. Another is that the number of patients studied was relatively small. Nevertheless, our results provide strong circumstantial evidence to show that theophylline is useful in bradyarrhythmias related to myocardial infarction, and they provide the rationale for future evaluation of the role that endogenous adenosine plays in ischemia-related rhythm disturbances. In conclusion, adenosine produced by the ischemic myocardium may induce significant atrioventricular blockade. These arrhythmiaswhich may be resistant to conventional therapy, such as atropineappear to respond to the adenosine antagonist theophylline. In light of present and previous observations, theophylline can be considered as an alternative when standard front-line antiarrhythmic therapy has failed. By promptly converting dysrhythmia to normal sinus rhythm, theophylline may make invasive and risky procedures, such as temporary pacemaker placement, unnecessary. A1 adenosine-receptor antagonists more potent, specific, and selective than theophylline may prove to be valuable in the short- and long-term management of cardiac arrhythmias associated with excess endogenous adenosine production. @copy; 1995 American College of Physicians

THE PSYCHOPHYSIOLOGICAL INVESTIGATIONS OF MYOCARDIAL ISCHEMIA (PIMI) STUDY: OBJECTIVE, METHODS, AND VARIABILITY OF MEASURES

Objective This study evaluated physiological, neuroendocrine, and psychological status and functioning of patients with coronary artery disease in order to clarify their role in the expression of symptoms during myocardial ischemia (MI), and to establish repeatability of responses to mental stress. Design and methods of the study are presented. Methods One hundred ninety-six coronary artery disease patients were examined during physical and mental stress tests in four hospitals. Eligibility criteria included narrowing of at least 50% in the diameter of at least one major coronary artery or verified history of myocardial infarction, and evidence of ischemia on an exercise treadmill test. Psychological, biochemical, and autonomic function data were obtained before, during, and after exposure to mental and exercise stressors during 2 or 3 half-days of testing. Ventricular function was assessed by radionuclide ventriculography, and daily ischemia by ambulatory electrocardiography. Sixty patients returned for a short-term mental stress repeatability study. Twenty-nine individuals presumed to be free of coronary disease were also examined to establish reference values for cardiac responses to mental stress. Results Study participants were 41 to 80 years of age; 83 (42%) had a history of MI, 6 (3%) of congestive heart failure, and 163 (83%) of chest pain; 170 (87%) were men; and 90 (46%) had ischemia accompanied by angina during exercise treadmill testing. Ischemia during ambulatory monitoring was found in 35 of 90 (39%) patients with and 48 of 106 (45%) patients without angina during exercise-provoked ischemia. Intraobserver variability of ejection fraction changes during bicycle exercise and two mental stress tests (Speech and Stroop) was good (kappa = 1.0, .90, and .76, respectively; percent agreement = 100, 97.5, and 93.8%, respectively). Variability of assessed wall motion abnormalities during bicycle exercise was better (kappa, agreement = 85%) than during Speech or Stroop kappa and .57, percent agreement = 70% and 82.5%, respectively). Conclusions Study design, quality control data, and baseline characteristics of patients enrolled for a clinical study of symptomatic and asymptomatic myocardial ischemia are described. Lower repeatability of reading wall motion abnormalities during mental stress than during exercise may be due to smaller effects on wall motion and lack of an indicator for peak mental stress.

Unrecognized left ventricular dysfunction in an apparently healthy alcohol abuse population

To examine effects of chronic alcohol abuse on left ventricular function, 162 otherwise relatively healthy alcohol abusers, having been admitted to a rehabilitation program, underwent cardiac evaluation including chest X-ray, electrocardiogram, and radionuclide angiography after 2 weeks abstinence. Twenty-nine of the 162 alcoholic subjects (18%) with left ventricular dysfunction were identified. Twenty-two had regional wall motion abnormalities, suggesting a localized process, of whom 12 also had depressed ejection fractions. Seven others had a depressed ejection fraction alone with a more global myopathic process. Only 4 of these 29 patients had any history suggesting prior heart disease. Two of the 29 had Q-waves greater than or equal to 0.4 s and 8 had an abnormal cardiothoracic ratio on chest X-ray. Chronic alcohol abusers appear to be at relatively high risk for left ventricular dysfunction; most of which is unrecognized. Routine screening methods failed to identify 85% of our subjects who later were recognized by radionuclide angiography. Since historical and electrocardiographic abnormalities are often absent in this population, detection of left ventricular dysfunction by other methods such as radionuclide angiography must be used.

Prevalence of pseudoischemic ST-segment changes during ambulatory electrocardiographic monitoring

Abstract Ambulatory electrocardiographic monitoring (AEM) is frequently used to record ST-segment changes suggesting transient myocardial ischemia in patients with coronary artery disease. 1 AEM has also been used to assess the efficacy of antiischemic therapy. 2–6 The value of AEM for ischemia monitoring is dependent on the ST-segment changes detected being reliable markers for transient myocardial ischemia. Frequently, before AEM and exercise treadmill tests, technicians perform provocative maneuvers (i.e., position change, hyperventilation and Valsalva maneuver) to elicit ST-segment or T-wave changes that may interfere with electrocardiographic determinations of transient myocardial ischemia. Despite this practice, there are few studies examining the incidence of these electrocardiographic artifacts. One such study found that in subjects without cardiac disease, ST-segment depression or T-wave changes suggesting ischemia seldom occurred. 7 The aim of this study was to determine the prevalence of these pseudoischemic ST-segment or T-wave changes in cardiac patients referred for AEM.

Biomedical and Psychosocial Predictors of Anginal Frequency in Patients Following Angioplasty with and Without Coronary Stenting

This study examined the contribution of biomedical and psychological variables in the report of anginal frequency at 6-week, 6- and 12-month follow-up in patients who received angioplasty with and without stent. Patients (N = 70) completed a battery of standardized questionnaries, including measures of depression, anxiety, and anger. Principal components analysis computed a single factor of negative emotion for use as a predictor in regression analyses. For the 6-week model, only baseline anginal frequency predicted anginal freqency. Negative emotion joined baseline anginal frequency in the prediction model for 6-month anginal frequency, and collectively accounted for 23% of the variance. For the 12-month model, baseline anginal frequency, female sex, and negative emotions remained in the model, accounting for 46% of the variance in anginal frequency. These results highlight the importance of biomedical and psychosocial variables in predicting anginal frequency with psychological variables sustaining predictive value over the course of recovery.

The State of the Absorb Bioresorbable Scaffold: Consensus From an Expert Panel

Significant progress has been made in the percutaneous coronary intervention technique from the days of balloon angioplasty to modern-day metallic drug-eluting stents (DES). Although metallic stents solve a temporary problem of acute recoil following balloon angioplasty, they leave behind a permanent problem implicated in very late events (in addition to neoatherosclerosis). BRS were developed as a potential solution to this permanent problem, but the promise of these devices has been tempered by clinical trials showing increased risk of safety outcomes, both early and late. This is not too dissimilar to the challenges seen with first-generation DES in which refinement of deployment technique, prolongation of dual antiplatelet therapy, and technical iteration mitigated excess risk of very late stent thrombosis, making DES the treatment of choice for coronary artery disease. This white paper discusses the factors potentially implicated in the excess risks, including the scaffold consideration and deployment technique, and outlines patient and lesion selection, implantation technique, and dual antiplatelet therapy considerations to potentially mitigate this excess risk with the first-generation thick strut Absorb scaffold (Abbott Vascular, Abbott Park, Illinois). It remains to be seen whether these considerations together with technical iterations will ultimately close the gap between scaffolds and metal stents for short-term events while at the same time preserving options for future revascularization once the scaffold bioresorbs.

Absence of adenosine-induced chest pain after total cardiac afferent denervation

tic regurgitation, but no effect on mitral valve function. The presence of both submitral and subaortic aneurysm has been reported in the same patient.‘t2 In a description of a transatrial approach to these aneurysms in 9 patients, Antunes recommended a posterior incision, because in all of his patients, the neck was located in the posterior annulus. Failure to appreciate an anterior position, as in 2 of the present patients, may result in an inability to adequately expose and ligate the neck of the aneurysm. Hemodynamic impairment is related to valvular regurgitation, systolic expansion of the aneurysm,’ or in very few cases, mitral inllow obstruction by the aneurysm! The present study is the lirst to document preoperatively rupture of the aneurysm into the left atrium as another mechanism of volume overload. Accurate demonstration of the neck of the aneurysm is crucial, because surgical success is determined by complete closure of the neck. Optimal demonstration of anatomic relations of the aneurysm was best achieved in the present patients by the horizontal-plane basal 4chamber and longitudinal views of the mitral valve by scanning it through its entire mediolateral width. In using these views, the location of the neck, and the direction and extent of the body of the aneurysm could easily be determined. Furthermore, with the addition of color flow Doppler, the mechanism of mitral regurgitation, and the contribution of the aneurysm to the degree of volume overload were accurately defined. Therefore, we conclude that: (1) TEE is a useful imaging modality in patients with congenital submittal aneurysms; (2) contrary to previous reports, these aneurysms may originate from the anterior mitral annulus, necessitating a different surgical approach; and (3) rupture into the left atrium may not be uncommon.