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Biomedical subjects

R Roberts

Publications and source records attributed to R Roberts.

At least 325 records · Page 18Linked to original sources
PubMed1989

Effective blocking of HIV-1 proteinase activity by characteristic inhibitors of aspartic proteinases.

Inhibitory constants (Ki) between 5 and 35 nM were derived (under different conditions of pH and ionic strength) for the interaction of HIV-1 proteinase with acetyl-pepstatin and H-261, two characteristic inhibitors of aspartic proteinases. Thus this enzyme, essential for replication of the AIDS virus, may be classified unequivocally as belonging to this proteinase family.

Aspartic Acid Endopeptidases↗
PubMed1989

Treatment of symptomatic peripheral atherosclerotic disease with a rotational atherectomy device.

Narrowings 70 to 90% in diameter in 3 iliac, 4 superficial femoral and 2 popliteal arteries were crossed and atherectomized successfully in 6 patients using the Squibb Rotablator under angiographic guidance during surgical bypass procedures on these arteries. The Rotablator consists of a 1.25 to 4.5 mm diameter oblong burr with tiny diamond blades mounted on a flexible shaft, which tracks over a spring-tip guidewire and rotates at speeds greater than 120,000 rpm. All stenoses were reduced to less than or equal to 50% of the normal luminal diameter. No significant complications occurred. Of the 6 patients having the atherectomy procedure, 5 were reevaluated by duplex Doppler measurements 1.5 to 5.5 (mean 3.5) months after atherectomy and found to be patient with only mild residual flow disturbance. Repeat follow-up by angiography after a mean of 5.2 months, however, showed only 3 (37%) of the atherectomized segments in 3 patients to still be patent. All were symptomatically improved. Of the effluent particles analyzed, 90% were less than 8 microns in size, while only 5% reached 250 microns. With improvements in technique, the largest particles were 150 to 180 microns, constituting only 1.4% of effluent debris. Samples of the effluent from 2 patients were injected in vivo into the left coronary system of 2 pigs. There were no acute hemodynamic or electrocardiographic complications or pathologic evidence of muscle necrosis or vascular thrombosis 18 to 48 hours later. These preliminary results with respect to feasibility and safety of the Rotablator are promising.

Adult↗
PubMed1989

The inverse relationship between baseline left ventricular ejection fraction and outcome of antiarrhythmic therapy: a dangerous imbalance in the risk-benefit ratio.

Each year, millions of prescriptions are written for antiarrhythmic drug suppression of ventricular arrhythmias. A large portion of these prescriptions are written for patients with asymptomatic, complex ventricular arrhythmias and organic heart disease, termed "potentially malignant" or "potentially lethal." Since arrhythmia suppression in this population is of unproven benefit, we performed the following study: A total of 246 patients (42% with significant left ventricular dysfunction) had complex ventricular arrhythmias, and were treated with one of eight antiarrhythmic drugs (Vaughan Williams classes IA, IB, IC, II, and III). The extent of arrhythmia suppression and the development of serious complications resulting from therapy after 2 weeks was of primary interest. A total of 82 of 246 (33%) maintained adequate (protocol definition) suppression of both ventricular premature beats (VPBs) as well as nonsustained ventricular tachycardia (VT) for 2 weeks, mostly in patients with left ventricular ejection fraction (LVEF) greater than or equal to 40% (p = 0.04 versus LVEF less than 40%). Life-threatening complications of antiarrhythmic therapy occurred most frequently in the 61 patients with an LVEF less than 30% compared to the 185 patients with LVEF greater than or equal to 30% (15% versus 2.1%, p = 0.0005). Suppression of VT was achieved nearly twice as commonly in patients with an LVEF greater than or equal to 30% than in those with an LVEF less than 30% (67% versus 36%; p = 0.0008). Life-threatening complications occurred seven times as frequently in patients presenting with nonsustained VT and an LVEF less than 30% (18% versus 2.3%; p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1989

Prolonged abnormalities of left ventricular diastolic wall thinning in the "stunned" myocardium in conscious dogs: time course and relation to systolic function.

Myocardial reperfusion after reversible ischemia is known to be associated with prolonged abnormalities of systolic contractile function (myocardial "stunning"). However, no information is available regarding the recovery of diastolic function in the stunned myocardium in the conscious state. Accordingly, 10 conscious dogs instrumented with pulsed Doppler thickening probes underwent a 15 min occlusion of the left anterior descending coronary artery followed by 7 days of reperfusion. Regional systolic function was assessed as net systolic thickening fraction. Left ventricular regional diastolic properties were estimated from two variables: the mean rate to half end-diastolic thinning and the late diastolic thinning fraction. Both indexes of diastolic function remained severely impaired after restoration of flow. In general, the recovery of the mean rate to half end-diastolic thinning and of the late diastolic thinning fraction paralleled the recovery of systolic thickening, but the impairment of the mean rate to half end-diastolic thinning was more marked than that of the late diastolic thinning fraction. At 4 h of reperfusion, the values for the mean rate to half end-diastolic thinning and the late diastolic thinning fraction (expressed as percent of baseline) were 57 +/- 5% (p less than 0.001 versus baseline) and 79 +/- 7% (p less than 0.05), respectively, whereas systolic thickening fraction averaged 52 +/- 10% (p less than 0.001). At 24 h, the mean rate to half end-diastolic thinning and the late diastolic thinning fraction were no longer significantly different from baseline, whereas systolic thickening fraction remained decreased at 82 +/- 4% (p less than 0.001) and returned to control values by 48 h. This study demonstrates the presence of profound, prolonged abnormalities of regional diastolic wall thinning after a brief episode of ischemia in the conscious state and expands the concept of myocardial stunning from the traditional notion of impaired systolic performance to that of a global derangement in mechanical function that involves both systolic and diastolic properties.

Animals↗
PubMed1989

Thrombolytic therapy in acute myocardial infarction: Part II--rt-PA.

Thrombolysis with pharmacologic agents is a valuable modality for treatment of acute myocardial infarction. The results of several clinical studies indicate that early recanalization can be elicited with intravenous agents and that it is associated with substantial reductions of infarct size, improvement of ventricular function, and reduction in mortality. The recently introduced fibrin-selective agent, rt-PA, appears to represent a significant pharmacologic advance. Its use intravenously elicits high recanalization rates without marked derangements of the coagulation system, reflecting its relative fibrin selectivity. The efficacy of thrombolysis with any drug given by any route, unfortunately, is not 100 per cent. Bleeding remains an important risk. The optimal approach to management of residual stenosis after thrombolysis has not yet been delineated. Currently available information appears to justify the following conclusions: 1. Transmural myocardial infarction usually is caused by an acute obstructing coronary thrombus superimposed on a chronic atherosclerotic lesion. Myocardial necrosis following interruption of blood flow generally is complete within several hours. 2. The thrombus can be lysed and blood flow can be restored with intravenous agents that activate plasminogen. Intravenous rt-PA, a relatively fibrin-specific agent, elicits recanalization in 70 to 75 per cent of infarct-related arteries. 3. Recombinant t-PA evokes only modest depletion of fibrinogen (16 to 36 per cent reduction from baseline). 4. Early reperfusion preserves myocardium and ventricular function and reduces mortality. 5. The extent of benefit after pharmacologic reperfusion is correlated strongly with the brevity of myocardial ischemia prior to initiation of therapy. The greatest benefit is realized in patients treated within the first few hours of onset of acute myocardial infarction. 6. The incidence and optimal means of prevention of reocclusion and reinfarction following successful pharmacologic reperfusion are not yet entirely clear. Mechanical recanalization with PTCA in conjunction with thrombolysis is promising, but its routine immediate use on an emergency basis does not appear to be beneficial. Vigorous educational efforts are needed to heighten the awareness of prospective patients and all members of the health care team to the value of prompt diagnosis of incipient or evolving infarction so that prompt implementation of thrombolysis in appropriate candidates can be facilitated.

Heart↗
PubMed1989

Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog.

Electron paramagnetic resonance (EPR) spectroscopy was used to investigate whether (i) the free radicals produced in the "stunned" myocardium (myocardium with postischemic contractile dysfunction) are derived from O2, (ii) inhibition of radical reactions improves function, and (iii) i.v. spin traps are effective. Open-chest dogs undergoing a 15-min coronary occlusion received an i.v. infusion of the spin trap, alpha-phenyl N-tert-butylnitrone (PBN) (50 mg/kg). In group I (n = 6), EPR signals characteristic of radical adducts of PBN appeared in the coronary venous blood during ischemia and increased dramatically after reperfusion. In group II (n = 6), which received PBN and i.v. superoxide dismutase (SOD; 16,000 units/kg) plus catalase (12,000 units/kg), myocardial production of PBN adducts was undetectable during ischemia (delta = -100%, P less than 0.01 vs. group I) and markedly inhibited after reperfusion (delta = -86%, P less than 0.001). This effect was seen at all levels of ischemic zone flow but was relatively greater in the low-flow range. In group III (n = 8), the same dosages of SOD and catalase without PBN markedly enhanced contractile recovery (measured as systolic wall thickening) after reperfusion [P less than 0.01 at 3 hr vs. controls (group IV, n = 7)]. Systemic plasma activity of SOD and catalase averaged 127 +/- 24 and 123 +/- 82 units/ml, respectively, 2 min after reperfusion. PBN produced no apparent adverse effects and actually improved postischemic contractile recovery in group I (P less than 0.05 at 3 hr vs. controls). This study shows that (i) SOD and catalase are highly effective in blocking free radical reactions in vivo, (ii) the radicals generated in the "stunned" myocardium are derived from univalent reduction of O2, and (iii) inhibition of radical reactions improves functional recovery. The results provide direct, in vivo evidence to support the hypothesis that reactive oxygen metabolites play a causal role in the myocardial "stunning" seen after brief ischemia.

Animals↗
PubMed1989

A review of postlysis strategy.

The postthrombolysis potential for rethrombosis, unstable angina, and reinfarction is considered, as is adjunctive pharmacologic treatment that may reduce the incidence of such complications.

Adrenergic beta-Antagonists↗
PubMed1989

Prevention of reinfarction subsequent to non-Q-wave infarction.

A multicenter, double-blind, randomized study was performed to evaluate the cardioprotective effects of diltiazem administered to patients with MB creatine kinase-confirmed acute non-Q-wave myocardial infarction. Nine centers enrolled a total of 576 patients, with 287 receiving diltiazem and 289 receiving placebo (90 mg every 6 h). Treatment was started 24-72 h after onset of clinical infarction and continued for up to 14 days. The primary endpoint was recurrent myocardial infarction, which was defined as an abnormal reelevation in plasma MB creatine kinase during the 14-day study period. MB creatine kinase samples were obtained every 12 h after randomization and were assayed by a central core laboratory using the glass bead adsorption method. Recurrent myocardial infarction was documented in 27 patients in the placebo group (9.3%) versus 15 patients in the diltiazem group (5.2%)--reflecting a reduction of 51.2% in the cumulative life-table reinfarction rate (p = 0.0297). The significance of this difference for treatment effect remained at a comparable alpha-level after individual adjustments (Cox model) for age, gender, previous infarction, obesity, site of qualifying infarction, Killip Class at entry, and concurrent use of beta-blocking agents. Diltiazem also reduced the incidence of refractory postinfarction angina necessitating study withdrawal, and angina associated with transient ST-T changes by 49.7% (p = 0.0345) and by 28% (p = 0.0057), respectively. Atrioventricular block, bradycardia, hypotension, and sinus pauses were more common in patients receiving diltiazem, but the drug was well tolerated overall despite the fact that 61% of diltiazem patients were also taking beta-blockers. These results indicate that high-dose diltiazem is well tolerated, safe, and effective in the prevention of early reinfarction and severe angina after non-Q-wave infarction.

Adult↗
PubMed1989

Favourable long term prognosis in patients with non-Q wave acute myocardial infarction not associated with specific electrocardiographic changes. Diltiazem Reinfarction Study Research Group.

Electrocardiograms obtained serially from 544 patients with non-Q wave infarction in the Diltiazem Reinfarction Study were analysed to compare the short term (less than or equal to 14 days) and long term (one year) follow up of 105 patients (19%) whose admission electrocardiogram showed no localisable repolarisation abnormalities (group 1) with the outcome in 439 patients (81%) who had ST-T wave abnormalities (group 2) localised to two or more contiguous leads within an anterior, inferior, or lateral lead group. There were no major between group differences in baseline clinical variables, concomitant medications, or treatment allocation (diltiazem v placebo). Group 2 patients, in the first year, had a higher incidence of early recurrent ischaemia (angina greater than or equal to 24 hours after myocardial infarction associated with ischaemic repolarisation changes), reinfarction, and readmission for chest pain than group 1 patients, despite comparable creatine kinase and creatine kinase MB activities in both groups. About 20% of patients with acute non-Q wave myocardial infarction did not have definable ST-T wave abnormalities. These patients had a similar clinical and enzymatic profile as patients with non-Q wave infarction with definable ST-T wave abnormalities and they were more likely to have a favourable short term and long term outcome.

Creatine Kinase↗
PubMed1989

Influence of neutrophil depletion on myocardial function and flow after reversible ischemia.

We explored the role of polymorphonuclear leukocytes (PMN) in the genesis of contractile dysfunction (myocardial "stunning") and of vascular abnormalities after reversible ischemia. Open-chest dogs underwent a 15-min coronary occlusion and 4 h of reperfusion (REP); treated animals (n = 16) received intravenous goat antiserum against canine PMN, whereas controls received nonimmune goat serum (n = 10) or saline (n = 15). In treated dogs, the average blood PMN levels were 10% of those in saline controls. During ischemia, collateral flow tended to be higher, and paradoxical systolic wall thinning tended to be less in neutropenic dogs, but despite this, recovery of wall thickening after REP was not enhanced in these animals. Similarly, arrhythmias during ischemia or REP did not differ among the three groups. Four hours after REP, both resting and minimal coronary resistance (the latter assessed by adenosine infusion) were higher in the stunned compared with the nonischemic myocardium; these vascular derangements, however, were similar in all three groups. Thus profound neutropenia failed to attenuate mechanical dysfunction, to reduce arrhythmias, and to prevent vascular abnormalities after a 15-min coronary occlusion. Although previous studies have suggested that neutrophils mediate cell death during prolonged ischemia, the present findings suggest that PMN do not contribute importantly to the damage associated with brief, reversible ischemia. The duration of flow reduction may be a critical factor determining whether PMN exacerbate ischemic injury.

Adenosine↗
PubMed1989

Nonuniform transmural recovery of contractile function in stunned myocardium.

With the use of an epicardial Doppler probe, systolic wall thickening was selectively measured in the inner, mid, and outer layers of the left ventricular (LV) wall in 16 conscious dogs undergoing a 15-min left anterior descending artery (LAD) occlusion followed by 7 days of reperfusion (REP). Under control conditions, percent thickening fraction (ThF) was significantly greater (P less than 0.01) in the inner layer [36.0 +/- 2.3% (mean +/- SE)] than in the mid (28.6 +/- 2.1%) or outer (21.3 +/- 2.2%) layers. During LAD occlusion, 11 dogs exhibited transmural dyskinesis (group 1), whereas 5 had transmural hypokinesis (group 2). In group 1, all layers exhibited comparable degrees of paradoxical systolic thinning during LAD occlusion. After REP, however, recovery was delayed in the inner compared with the mid and outer layers. At 2 h, ThF averaged 34.2 +/- 11.9% of base line in the endocardium vs. 61.7 +/- 16.2% in the midmyocardium and 51.0 +/- 12.3% in the epicardium (F = 4.29, P less than 0.002); similar differences were noted at 3 and 4 h. In the mid and outer layers, ThF returned to base-line values by 24 h, whereas in the inner layer it was still significantly depressed (P less than 0.05) at 24 h (77.3 +/- 5.1% of base line) and recovered by 48 h. The inner-to-outer ThF ratio was decreased (P less than 0.01) for 24 h after REP, indicating maldistribution of thickening in the "stunned" myocardium. In group 2, all layers exhibited hypokinesis during LAD occlusion. Again, recovery of function after REP was delayed in the endocardium compared with the other layers. This study demonstrates that after both severe ischemia resulting in dyskinesis and mild ischemia resulting in hypokinesis, REP is associated with slower recovery of function in the inner than in the outer layers. Thus myocardial "stunning" is a nonuniform phenomenon with maximal severity in the subendocardium.

Animals↗
PubMed1989

ST segment shifts are poor predictors of subsequent Q wave evolution in acute myocardial infarction. A natural history study of early non-Q wave infarction.

Acute ST segment elevation is regarded generally as the sine qua non of evolving Q wave myocardial infarction (MI) because such electrocardiographic (ECG) injury is believed to be a marker of transmural ischemia and a forerunner of transmural necrosis. Alternatively, ST segment depression with or without T wave inversion is viewed as the dominant ECG feature of non-Q wave MI. However, this hypothesis has not been assessed prospectively in an acute MI population. We analyzed 2,304 serial ECGs at study entry (admission), day 2, day 3, and predischarge (mean, 10.2 +/- 2 days) from 576 patients with creatine kinase MB confirmed acute non-Q wave MI to determine what percentage of patients with early ST segment elevation culminated in subsequent Q wave development. Of this group, 187 patients (32%) exhibited 1 mm or greater ST segment elevation in two or more contiguous entry ECG leads. Of those patients whose non-Q wave MI could be localized on the basis of diagnostic admission ST segment shifts, the prevalence of early ST segment elevation was 43% (187 of 439). The sum total mean (+/- SD) peak ST segment elevation by lead group (anterior, inferior, lateral) was 4.0 +/- 2.4, 4.5 +/- 2.4, and 2.5 +/- 0.6 mm, respectively. Despite this, only 20% of patients with ST segment elevation (37 of 187) developed Q waves. Of 252 patients who exhibited early ST segment depression or T wave inversion or both, 39 (15%) evolved subsequent Q waves. Thus, while the prevalence of early ST segment elevation in acute evolving non-Q wave MI was higher than previously reported, 80% of patients with and 85% of patients without ST segment elevation and absent Q waves on the admission ECG did not develop subsequent Q waves during a 2-week period of observation (p = NS). In addition, when patients with ST segment elevation were compared with patients with ST segment depression or T wave inversions or both, there were no between-group differences in log peak creatine kinase (404 vs. 383 IU), reinfarction (6% vs. 8%), postinfarction angina (50% vs. 42%), or early recurrent ischemia (49% vs. 45%), defined as postinfarction angina with transient ECG changes. Thus, in patients who present with initial acute non-Q wave MI, ST segment shifts on admission are unreliable predictors of subsequent Q wave evolution and do not discriminate significant differences in postinfarction outcome. In particular, ST segment elevation during the early hours of evolving infarction is not an invariable harbinger of subsequent Q wave development.

Creatine Kinase↗
PubMed1989

Risk stratification of patients with non-Q wave myocardial infarction. The critical role of ST segment depression. The Diltiazem Reinfarction Study Research Group.

One-year follow-up data on 515 patients who survived hospitalization with MB-creatine kinase-confirmed, acute non-Q wave myocardial infarction were analyzed for factors related to mortality (n = 57) and late reinfarction (n = 64). Twelve of 24 analyzed variables were significantly associated with mortality. Those factors, which were independently predictive of mortality by Cox regression analysis, were persistent ST depression (p = 0.0009), a history of congestive heart failure (CHF) (p = 0.0069), older age (p = 0.0128), and ST elevation at hospital discharge (p = 0.0173). In-hospital reinfarction achieved borderline significance (p = 0.0512). Mortality during the follow-up period was 5.5% in patients with no ST depression, 10.1% in those with ST depression at baseline or discharge, and 22.2% in patients with ST depression at baseline and discharge (i.e., "persistent" ST depression). The age-adjusted risk of mortality for patients with persistent ST depression, discharge-ST elevation, and CHF was 13.99 times as high as was the risk for patients with no ST depression, no discharge-ST elevation, and no CHF. Of the 483 patients with complete electrocardiographic data at both baseline and discharge, 203 (42%) could be stratified into a high risk population with a risk ratio for 1-year mortality more than sevenfold that of patients with no risk factors. Although persistent ST depression was significantly associated with several measures of structural left ventricular damage, the independent significance of ST depression persisted even after adjusting for these factors. The independent predictors of late reinfarction (persistent ST depression, p = 0.0058; Killip class II or III, p = 0.0106; and left ventricular hypertrophy, p = 0.0470) permitted a similar risk stratification. We conclude that 1) easily identified clinical and electrocardiographic factors permit stratification of patients with non-Q wave infarction into high-risk subsets who may benefit from aggressive therapy; 2) ST depression is a highly significant and independent predictor of poor prognosis; and 3) the powerful predictive value of persistent ST depression suggests that non-Q wave myocardial infarction patients with this depression should be viewed as potentially high-risk patients who may be candidates for additional noninvasive testing or early coronary angiography.

Diltiazem↗
PubMed1989

Thrombolysis and its sequelae. Calcium antagonists as potential adjunctive therapy.

Randomized, placebo-controlled trials have documented that both streptokinase and rt-PA given early are associated with limitation of infarct size, improved ventricular function, and reduced mortality. Other concerns, however, documented experimentally include myocardial hemorrhage, the "no-reflow" phenomenon, myocardial "stunning," reperfusion-induced injury, and clinically, rethrombosis that occurs at a rate of 20% and reinfarction at 8-10%. Thus, even with the ideal thrombolytic agent, adjunctive therapy to prevent rethrombosis will remain a requisite to obtaining long-term benefit. Calcium blockers in association with reperfusion have been shown experimentally to be protective, resulting in limitation of infarct size and improved ventricular function. There is no data on the role of calcium blockers in conjunction with thrombolysis in patients. Results are available from two randomized trials with the calcium blocker, diltiazem, in patients with non-Q wave infarction. In the short-term trial involving 576 patients with non-Q wave infarction, the incidence of early reinfarction was reduced by 50%, and in the long-term study (non-Q wave infarction, n = 634), reinfarction and death were reduced by 40% after 1 year and by 34% after 4.5 years. Non-Q wave infarction is believed to undergo early spontaneous reperfusion based on the following: small infarct size, contracture necrosis at postmortem, early peaking of plasma CK, coronary patency on angiography, residual ischemia, and a high incidence of reinfarction. Thus, thrombolysis occurring spontaneously or induced therapeutically is associated with a high incidence of reinfarction. The implications of these clinical studies together with the experimental data suggests that the hypothesis of a calcium blocker being important adjunctive therapy following thrombolysis is worthy of clinical evaluation.

Animals↗
PubMed1989

Review of calcium antagonist trials in acute myocardial infarction.

Nine randomized trials in patients with acute myocardial infarction have been performed to assess the effect of nifedipine on infarct size, reinfarction and/or survival. In none of the trials was there any benefit and in some there was a deleterious effect. In the most recent trial, SPRINT II, the study was stopped prematurely-because of deleterious side effects in the diltiazem-treated group. Thus, nifedipine is not recommended in patients with acute myocardial infarction or postmyocardial infarction for prevention of reinfarction or death, and further trials are not necessary. In a single study involving 1,436 patients, verapamil showed no statistical benefit on reinfarction or survival, but due to a high drop-out rate, the result appears less than definitive. A second trial has been completed but results are not yet available. In a randomized, double-blind short-term (2 weeks) trial consisting of 576 patients with non-Q-wave infarction, diltiazem caused a 50% reduction in the incidence of reinfarction and refractory angina. In a long-term trial (12-52 mos.) consisting of 2,466 patients with Q- and non-Q-infarction, there was no benefit overall, but in the patients without failure (80%) there was a 28% reduction in cardiac events. In the patients with non-Q-infarction (634), there was a 40% reduction in cardiac events, and at the end of 4-5 years there was still a reduction of 34% in the diltiazem group. In patients admitted to the study with failure, the mortality was increased in patients with Q- or non-Q-infarction. Thus, diltiazem is recommended for routine prophylaxis in patients with non-Q-infarction without cardiac failure.

Calcium Channel Blockers↗