Abnash C. Jain

ANTIOXIDANT BEHAVIOUR OF CAFFEINE : EFFICIENT SCAVENGING OF HYDROXYL RADICALS

Considerable controversy exists in the literature regarding the toxicity of coffee, including its possible carcinogenic and anticarcinogenic properties. This study reports on the reaction of 1,3,7-trimethylxanthine (caffeine) with the hydroxyl radical (.OH), as investigated by electron spin resonance (ESR) spin trapping. The .OH was generated by the Fenton reaction (Fe2+ + H2O2) as well as by the reaction of chromium(V) with H2O2. The results show that caffeine effectively scavenges .OH with a reaction rate constant of approximately 5.9 x 10(9) M-1 sec-1 that is comparable with those of other efficient .OH radical scavengers. ESR measurements provide evidence that a caffeine-derived oxygen-centred radical is formed in the reaction of caffeine with .OH and suggest a biochemical basis for the understanding of the reported anticarcinogenic properties of caffeine and related methylxanthine compounds.

A randomized, double-blinded, placebo-controlled, dose-ranging study measuring the effect of an adenosine agonist on infarct size reduction in patients undergoing primary percutaneous transluminal coronary angioplasty: the ADMIRE (AmP579 delivery for myocardial infarction REduction) study

BACKGROUND Evidence suggests that myocardial ischemic preconditioning and reperfusion injury may be mediated by adenosine A1 and A2 receptors. AMP579 is a mixed adenosine agonist with both A1 and A2 effects. In animal models of acute myocardial infarction (MI), AMP579 reduced infarct size at serum levels of 15 to 24 ng/mL. METHODS The AMP579 Delivery for Myocardial Infarction REduction study evaluated AMP579 in a double-blind, multicenter, placebo-controlled trial of 311 patients undergoing primary percutaneous transluminal coronary angioplasty (PTCA) after acute ST-segment elevation MI. Patients were randomly assigned to placebo or to 3 different doses of AMP579 continuously infused over 6 hours. The primary end point was final MI size measured by technetium Tc-99m sestamibi scanning at 120 to 216 hours after PTCA. Secondary end points included myocardial salvage and salvage index at the same time interval (in a subset of patients who underwent baseline technetium Tc-99m sestamibi scan), left ventricular ejection fraction and heart failure at 4 to 6 weeks, duration of hospitalization, and cardiac events at 4 weeks and 6 months. RESULTS Final infarct size did not differ among the placebo group and the active treatment groups for either anterior MI or nonanterior MI. In patients with anterior MI, median myocardial salvage was increasingly higher in the groups receiving ascending dosages of AMP579 plus PTCA. Serum levels approaching levels shown to reduce infarct size in animal models were achieved only in the 60-mcg/kg treatment group. CONCLUSION AMP579 was safe at the doses tested, but it did not reduce infarct size. There was a trend toward greater myocardial salvage in treated patients with anterior MI.

Early Repolarization on Scalar Electrocardiogram

Sixty thousand electrocardiograms were analyzed for 5 years. Six hundred (1%) revealed early repolarization (ER). Features of ER were compared with race-, age-, and sex-matched controls (93.5% were Caucasians, 77% were males, 78.3% were younger than 50 years, and only 3.5% were older than 70). Those with ER had elevated, concave, ST segments in all electrocardiograms (1—5 mv), which were located most commonly in precordial leads (73%), with reciprocal ST depression (50%) in aVR, and notch and slur on R wave (56%). Other results included sinus bradycardia in 22%, shorter and depressed PR interval in 38%, slightly asymmetrical T waves in 96.7%, and U waves in 50%. Sixty patients exercised normalized ST segment and shortened QT interval (83%). In another 60 patients, serial studies for 10 years showed disappearance of ER in 18%, and was seen intermittently in the rest of the patients. The authors conclude that in these patients with ER: 1) male preponderance was found; 2) incidence in Caucasians was as common as in blacks; 3) patients often were younger than 50 years; 4) sinus bradycardia was the most common arrhythmia; 5) the PR interval was short and depressed; 6) the T wave was slightly asymmetrical; 7) exercise normalized ST segment; 8) incidence and degree of ST elevation reduced as age advanced; 9) possible mechanisms of ER are vagotonia, sympathetic stimulation, early repolarization of sub-epicardium, and difference in monophasic action potential observed on the endocardium and epicardium.

Effect of intensive lifestyle changes on endothelial function and on inflammatory markers of atherosclerosis.

Intensive lifestyle changes have been shown to regress atherosclerosis, improve cardiovascular risk profiles, and decrease angina pectoris and cardiac events. We evaluated the influence of the Multisite Cardiac Lifestyle Intervention Program, an ongoing health insurance-covered lifestyle intervention conducted at our site, on endothelial function and inflammatory markers of atherosclerosis in this pilot study. Twenty-seven participants with coronary artery disease (CAD) and/or risk factors for CAD (nonsmokers, 14 men; mean age 56 years) were enrolled in the experimental group and asked to make changes in diet (10% calories from fat, plant based), engage in moderate exercise (3 hours/week), and practice stress management (1 hour/day). Twenty historically (age, gender, CAD, and CAD risk factors) matched participants were enrolled in the control group with usual standard of care. At baseline endothelium-dependent brachial artery flow-mediated dilatation (FMD) was performed in the 2 groups. Serum markers of inflammation, endothelial dysfunction, and angiogenesis were performed only in the experimental group. After 12 weeks, FMD had improved in the experimental group from a baseline of 4.23 + or - 0.13 to 4.65 + or - 0.15 mm, whereas in the control group it decreased from 4.62 + or - 0.16 to 4.48 + or - 0.17 mm. Changes were significantly different in favor of the experimental group (p <0.0001). Also, significant decreases occurred in C-reactive protein (from 2.07 + or - 0.57 to 1.6 + or - 0.43 mg/L, p = 0.03) and interleukin-6 (from 2.52 + or - 0.62 to 1.23 + or - 0.3 pg/ml, p = 0.02) after 12 weeks. Significant improvement in FMD, C-reactive protein, and interleukin-6 with intensive lifestyle changes in the experimental group suggests > or = 1 potential mechanism underlying the clinical benefits seen in previous trials.

Cardiac Arrhythmias Following Intravenous Nicotine: Experimental Study in Dogs

Background: Nicotine, the active agent in tobacco, is released into the circulation during cigarette smoking. It elevates plasma catecholamines, heart rate, and arterial blood pressure; produces coronary spasm; and increases myocardial work and oxygen demand with con comitant reduction in oxygen supply. This may generate cardiac arrhythmias that might con tribute to an increased incidence of sudden death due to smoking. It is hypothesized that acute administration of nicotine will induce cardiac arrhythmias, and this experimental study was planned with an aim to assess arrhythmogenic activity as a result of acute administration of nicotine. Methods: Nicotine was administered in different doses intravenously in 16 anesthesized dogs, and 52 experiments were carried out at weekly intervals. In each experiment, continu ous electrocardiograph rhythm strip records were obtained for 30 minutes before and follow ing anesthesia and after nicotine administration. They were scrutinized by two experienced electrocardiographers at intervals of 1, 2, 3, 4, 5, 10, 15, and 30 minutes. Results: Data revealed nonsignificant arrhythmias with doses of 2.5, 5.0, and 10.0 mg/kg of intravenous nicotine. The dose of 50 μg/kg induced supraventricular arrhythmias, atrioven tricular junctional arrhythmias, and ventricular arrhythmias. Supraventricular bradycardia in 30 (83%; P < .000 1), supraventricular arrhythmia in 30 (83%; P < .0001), sinus arrest in 18 (50%; P < .003). atrial ectopics in 24 (67%; P < .0004), and atrial tachycardia in 9 experi ments (25%; P < .021). These results were statistically significant. In 18 experiments, sinus arrest was observed to be missing P waves and QRS complexes for a period corresponding to 4:1-10:1 SA block, lasting 2-6 seconds, within 3 seconds of injection. Occurrence of wan dering pacemaker was observed in 6 experiments, atrial flutter in 2, and atrial fibrillation in 2, but these incidents were not significant. Atrioventricular junctional arrhythmias consisted of escape beats in 9 subjects (25%; P < .02), premature contractions in 12 (33%; P < .005), first-degree heart block in 9 (25%; P < .02), second degree heart block in 9 (25%; P < .02) and atrioventricular dissociation in 9 (25%; P < .02). All arrhythmias in this category were significant. Ventricular arrhythmias consisted of ventricular premature contractions that were unifocal in 32 subjects (89%; P < .0001), multifocal in 30 (83%; P < .0001), bigeminy in 28 (78%; P < .0003), trigeminy in 18 (50%; P < .003), interpolated in 15 (42%; P < .004), and salvos in 18 (50%; P < .003). Sustained ventricular tachycardias (> 30 beats) in 12 experi ments (33%; P < .005) proved significant. The dose of 100 μg/kg induced fatal ventricular flutter and ventricular fibrillation. The dog expired and experiments with that dose were not repeated. Conclusion: Data reveal dose-dependent arrhythmogenecity of nicotine in dogs. Smaller doses of nicotine did not produce significant arrhythmias. Higher doses, bioequivalent to smoking two standard cigarettes, may generate cardiac arrhythmias of simple to severe nature. Further work in human beings may confirm whether nicotine in cigarette smoke will generate similar cardiac arrhythmias especially in patients with autonomic imbalance and/or compromised and ischemic myocardium.

Assessment of Systolic and Diastolic Left Ventricular and Left Atrial Function Using Vector Velocity Imaging in Takotsubo Cardiomyopathy

Five adult patients with Takotsubo cardiomyopathy (TC) diagnosed by usual criteria were studied with velocity vector imaging (VVI) on admission and at follow‐up, when their LV function had improved, as assessed by 2D TTE wall‐motion score (WMS) index. Averaged peak segmental longitudinal strain (S) in systole, and velocity (V) and strain rate (SR) in both systole and diastole were measured from apical 4‐ (A4C) and 2‐chamber views (A2C) in all patients. The data obtained by VVI were analyzed separately for involved and uninvolved segments, which were independently assessed by WMS. In the involved segments, systolic S, V, SR, and diastolic SR improved (P‐value < 0.05) on follow‐up. Diastolic V showed a trend toward improvement but did not reach statistical significance. In the uninvolved segments, none of the parameters improved significantly either during systole or diastole. In three of these five patients, left atrial (LA) walls were also studied by placing region of interest (ROI) points in the middle of each wall. Peak segmental LA systolic and diastolic V and SR as well as systolic S were obtained for both involved and uninvolved LA walls which were assessed independently using WMS similar to LV. In the involved LA walls, none of the atrial systolic and diastolic parameters changed significantly but all parameters with the exception of systolic V showed a tendency toward improvement during follow‐up. Among the uninvolved LA walls, none changed significantly but atrial systolic SR and, diastolic V and SR tended to increase during follow‐up. Our retrospective study using VVI demonstrates that TC patients also have LV systolic and diastolic longitudinal dysfunction, not just systolic radial dysfunction as assessed by traditional 2D TTE indices. Longitudinal LA dysfunction may also be present.

Combined effects of alcohol and nicotine on cardiovascular performance in a canine model.

Alcohol and tobacco consumption are correlated. Smokers consume more alcohol than do nonsmokers, and alcohol consumers smoke more than do teetotalers. The independent effects of alcohol and nicotine on the cardiovascular system are well documented, but combined effects of short-term administration are unknown. This experimental work was designed to study the effects due to short-term administration of alcohol and nicotine on cardiovascular system. In phase I, 30 experiments were performed to study the dose-response curve of both the drugs. In phases II and III, 15 dogs were subjected to 30 experiments. In phase II, ethanol, 400 mg/kg, was given i.v., followed by nicotine 50 microg/kg, i.v., and in phase III, sequence of drug administration was reversed to study the effects on hemodynamics and coronary artery blood flow. The dose-response curve established the i.v. dose of ethanol, 400 mg/kg, and nicotine, 50 microg/kg. Ethanol administration caused a nonsignificant increase in heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVS), and left ventricular mechanical work (LVMW), and a decrease in maximal rate of increase of LV pressure per second (dP/dt), stroke volume (SV), and systemic vascular resistance (SVR). Left ventricular end-diastolic pressure (LVEDP), pulmonary artery mean pressure (PAM), right atrial pressure (RAP), pulmonary vascular resistance (PVR), myocardial oxygen consumption (MVO2), and average peak velocity of coronary blood flow (APV) had mild significant increases as compared with controls. Nicotine significantly increased heart rate, mean arterial pressures, LVEDP, and pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Nicotine increased dP/dt (2,062-3,188; p < 0.006) and decreased APV (9 to 8; p < 0.03). Combined ethanol followed by nicotine had synergistic increase in HR, SD, MAP, LVS, LVEDP, pulmonary pressures, CO, SV, dP/dt (2,184 > 5,206; p < 0.005), MVO2, and LVMW. However, the excitatory effects of nicotine were attenuated when ethanol was administered after nicotine (dP/dt, reduced from 2,058 to 1,653; p < 0.04, and APV increased from 10 to 12; p < 0.02). We conclude that ethanol increased APV but had nonsignificant effects on the hemodynamics, whereas nicotine reduced the APV and had significant excitatory responses. In combination (i.v.), ethanol + nicotine produced significant synergistic excitatory effects. On the other hand, the nicotine + ethanol combination increased APV and caused attenuation of the excitatory effects of nicotine in dogs.

Usefulness of left atrial abnormality for predicting left ventricular hypertrophy in the presence of left bundle branch block

The objective of this study was to identify left atrial (LA) abnormality on the electrocardiogram and other related variables as predictors of left ventricular (LV) hypertrophy in the presence of left bundle branch block (LBBB). In the presence of complete LBBB, the diagnosis of electrocardiographic abnormalities is problematic and that of LV hypertrophy remains difficult. The usual electrocardiographic criteria applied for the diagnosis of LV hypertrophy may not be reliable in the presence of LBBB. Therefore, noninvasive criteria will help physicians diagnose LV hypertrophy with electrocardiography. LA abnormality on the electrocardiogram was assessed by 2 independent observers as predictor of LV hypertrophy in the presence of LBBB in 120 patients, and data were compared with those of 100 patients without LA abnormality. LV mass was calculated from echocardiographic data. Besides LA abnormality, the other variables studied for prediction of LV hypertrophy were gender, age, body surface area, body mass index, frontal axis, and QrS duration. Of the 6 criteria analyzed, the P terminal force was found to be the most common and consistent criterion to detect LA abnormality. LV hypertrophy was confirmed by echocardiographic determination of LV mass in both groups. Observers reliably differentiated between the hypertrophied and normal-sized left ventricle in the presence of LBBB by correlating LA abnormality with LV mass determined by echocardiography. Observer 1 detected LA abnormality in 89% and observer 2 in 84% of patients. False-positive results were present in 11% and 16%. The observers recognition of LA abnormality in the present study was 91%. The 2 observers showed a sensitivity of 81% and 79% and a specificity of 91% and 88%, respectively, when diagnosis of LV hypertrophy was determined. LV mass increased significantly and was diagnostic of LV hypertrophy in 92% of patients with LA abnormality. In the remaining 11 patients (8%), the LA abnormality was of marginal abnormal magnitude. Each 0.01-mV/s increase in LA abnormality gave an increase of 30 g of LV mass. LV mass was increased in 86% of patients when corrected by body surface area. LV hypertrophy in the presence of LBBB on electrocardiography was found in only 13 patients (10%) when the 6 frequently used conventional criteria for diagnosis of LV hypertrophy by electrocardiography were used. Regression analysis revealed LA abnormality to be a strong independent predictor of increased LV mass. Multivariate analysis also revealed age, body mass index, body surface area, frontal axis, and QrS duration to be significant predictors of LV mass. This noninvasive study correlates LA abnormality by electrocardiogram and LV hypertrophy with echocardiography to conclude that LA abnormality was significantly diagnostic of LV hypertrophy in the presence of LBBB. Age, body mass index, body surface area, frontal axis, and QrS duration were also significant predictors of LV mass.

Etiologies of Left Bundle Branch Block and Correlations With Hemodynamic and Angiographic Findings

E and Rothberger1 introduced the concept of bundle branch block (BBB) 60 years ago in Vienna. The causes of left BBB are varied. Clinical2 and pathologic3 studies suggest systemic hypertension and coronary artery disease (CAD) as the most common causes.2–7 Cardiomyopathy, valvular heart disease, and several other less common causes have been described.7 It has also been known that some patients with left BBB have apparently normal hearts except for conduction system abnormalities.4 However, the true incidence of various etiologic groups needs further corroboration by a larger study.7 Therefore, this communication provides additional data in a large number of patients regarding the various etiologies of left BBB and correlates electrocardiographic and clinical observations with left ventricular (LV) functions and coronary angiocardiographic data. • • • A review of 25,522 patients who underwent cardiac catheterization during 8 years (1995 to 2002) revealed 550 patients aged 18 to 87 years (mean 56 14), of which 226 were women (41%) who had electrocardiographic criteria of left BBB (Figure 1). The criteria set by the Criteria Committee of the New York Heart Association8 used to interpret left BBB are: (1) QRS interval 120 ms; (2) slurred/notched wide and predominant R waves in leads I, aVL, V5, and V6; (3) slurred/notched and broad S waves in V1 and V2 with absent or small R waves; (4) midconduction delay defined as notching or a plateau in the mid-QRS wave; (5) ventricular activation time 50 ms at the onset of the QRS interval; (6) M-shaped QRS variants with occasionally wide R waves in V5 and V6; (7) no initial Q wave over the left precordium; and (8) absence of preexcitation. History, physical examination, 12-lead electrocardiograms, chest x-rays, pertinent laboratory findings, blood sugar, risk factors for CAD, electrolytes, complete blood counts, stress tests, and echocardiograms were evaluated. Hemodynamic studies in all 550 patients included left heart catheterization, selective cineangiography of coronary arteries, and left ventriculography. LV end-diastolic pressure was measured with fluid-filled catheters, and ejection fraction was calculated by the area-method technique. Techniques for coronary angiography were in accordance with those of Sones and Shirey9 or Judkins.10 LV cineangiograms were obtained in a 40° right oblique position and were followed by selective coronary angiograms recorded in multiple projections.9,10 Each x-ray film was reviewed by 2 observers, with particular attention to the details of calibers of coronary arteries, the degree of narrowing, the smallest opacified arteries, the extent of collaterals, and possible artifacts. The total pattern of contractility of the left ventricle, abnormal localized myocardial contraction,11 LV ejection fraction, and end-diastolic pressure were evaluated during left ventriculography. Coronary artery obstruction was measured at the maximal luminal diameter narrowing observed on the cine film. A lesion in the coronary artery was considered to be of significance if there was 50% narrowing of the internal diameter. The number of coronary arteries (left main, left anterior descending, right coronary, and circumflex) involved with significant disease was noted. Narrowing of coronary arteries was graded on the basis of the following score system previously defined12: grade 0, 25%; grade 1 , 25% to 50%; grade 2 , 50% to 75%; grade 3 , 75% to 95%; and grade 4 , 100% occlusion. In Table 1,grades 2 to 3 represent subtotal occlusion and grade 4 total occlusion. The main left coronary lesions were considered separately. Uncommon and rarer causes of left BBB included in this report had a well-proved diagnosis. The pattern of LV contraction was determined by reviewing the superimposition of end-diastolic and end-systolic silhouettes and using terminology as defined by Herman et al.11 LV contractility was classified as normal, hypokinetic, dyskinetic, or akinetic. Electrocardiographic data, width of the QRS, and largest width and mean axis of the QRS in the frontal plane were analyzed in detail. These data were correlated with clinical, roentgenologic, hemodynamic, and coronary cineangiographic findings in these patients and were independently reviewed by both the investigators. Statistical analyses were performed using analysis of variance and Student’s t test. Mean values are expressed as mean SD. Univariate, bivariate, and multivariate analyses were performed using Statistica software (version 6.0; Tulsa, Oklahoma). A p value 0.05 was considered significant. Subjects included in the study belonged to 6 etiologic groups (Figure 2): group 1 (12%) with normal hearts (Table 2); group 2 (49%) had a history of CAD (26% myocardial infarction and 23% angina pectoris; Figure 3); group 3 (8%) had systemic hypertension (Table 1); group 4 (9%) had valvular and congenital heart disease; group 5 (8.5%) had cardiomyopathy; and group 6 (18 patients, 3.5%) had uncommon and From the Department of Medicine, Section of Cardiology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia. Dr. Mehta’s address is: Section of Cardiology, West Virginia University, 2203 Robert C. Byrd Health Sciences Center South, PO Box 9157, Morgantown, West Virginia 26506-9157. E-mail: mmehta@hsc.wvu.edu. Manuscript received December 27, 2002; revised manuscript received and accepted February 24, 2003.

Left Ventricular Function After Cigarette Smoking by Chronic Smokers: Comparison of Normal Subjects and Patients With Coronary Artery Disease

Twenty normal subjects and 25 patients with coronary artery disease underwent systolic time interval analysis before and after rapidly smoking two cigarettes. A slight increase in heart rate and arterial pressure was seen in both groups. In patients with coronary artery disease, preejection period/left ventricular ejection time ratio increased; in normal subjects it decreased. Left ventricular performance is diminished after cigarette smoking among subjects who have preexisting significant coronary artery disease.