Neville Bittar

Changes in tissue levels of carnitine and other metabolites during myocardial ischemia and anoxia

Abstract The induction of ischemia in the open chest dog, or anoxia in the perfused rat heart, causes dramatic changes in the tissue levels of free acyl carnitine and related metabolites. During the early phase of ischemia or anoxia the tissue levels of free carnitine decline, while acetyl carnitine rapidly increases. These changes are accompanied by elevation in long-chain acyl carnitine, long-chain acyl CoA, and lactate and by decreases in acetyl CoA, CoA, ATP, and creatine phosphate. As the degree of ischemia becomes more severe, carnitine appears to be lost from the myocardium. A scheme is presented which relates carnitine-linked mitochondrial metabolism to the activity of carnitine acyl transferase, ANT, carnitine/acyl carnitine translocase, creatine phosphokinase, and pyruvate dehydrogenase. It is suggested that the conversion of carnitine to acyl carnitine during the onset of ischemia may play an important role, by virtue of its effect on these enzymes, in the regulation of metabolism during the early or reversible phase of ischemia.

The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease☆

OBJECTIVES The effect of vardenafil, a potent and highly selective phosphodiesterase-5 (PDE5) inhibitor, on symptom-limited exercise time, time to first awareness of angina, and time to ischemic threshold (ST-segment depression > or =1 mm from baseline) during exercise tolerance testing (ETT) was examined in patients with stable coronary artery disease (CAD). BACKGROUND Erectile dysfunction (ED) is common among men with CAD. PDE5 inhibition is increasingly the preferred treatment option for ED. However, the effect of PDE5 inhibition on exercise-induced ischemia in CAD patients has received limited prospective evaluation. METHODS In this double-blind, crossover, single-dose multicenter study, 41 men with reproducible stable exertional angina due to ischemic CAD received vardenafil 10 mg or placebo, followed by ETT (5 to 10 metabolic equivalents [METS], Bruce protocol) 1 h postdose. Sublingual nitrate use was prohibited for > or =24 h pre- and postexercise study days. End points included symptom-limited treadmill exercise time, time to first awareness of angina, time to ischemic threshold, and safety. RESULTS Relative to placebo, vardenafil 10 mg did not alter exercise treadmill time (427 +/- 105 s vs. 433 +/- 109 s, p = 0.39), or time to first awareness of angina (292 +/- 110 s vs. 291 +/- 123 s, p = 0.59), but significantly prolonged time to ischemic threshold (334 +/- 108 s vs. 381 +/- 108, p = 0.0004). At peak exercise, vardenafil 10 mg did not alter blood pressure, heart rate, or rate-pressure product relative to placebo. The most common adverse events (facial flushing and headache) were of mild or moderate intensity, and short-lived. CONCLUSIONS Vardenafil 10 mg did not impair the ability of patients with stable CAD to exercise at levels equivalent or greater than that attained during sexual intercourse (average of 2.5 to 3.3 METS).

Protection of the ischemic dog myocardium with carnitine

Abstract In 25 open chest anestheslzed dogs, left anterior descending coronary arterial blood flow was measured with an electromagnetic flowmeter while aortic blood pressure and epicardlal electrocardiograms were recorded. Ischemia was produced in the left anterior descending arterial bed by decreasing mean flow to one third of control levels for a 5 minute period with a micrometer snare device. This produced an increase in S-T segment deviation greater than 4 mv in the ischemic bed. Control and ischemic left anterior descending arterial bed tissue samples were obtained by drill biopsy and were analyzed for adenosine triphosphate (ATP) and creatine phosphate levels and adenlne nucleotide translocase activity. The ATP levels decreased from 5.6 ± 1.2 to 3.6 ± 1.4 μmoles/g, and creatine phosphate decreased from 15.3 ± 4.6 to 5.8 ± 3.8 μmoles/liter. The adenine nucleotide translocase activity decreased from an average control value of 42,957 ± 9,480 to 29,100 ± 6,609 disintegrations per minute (dpm)/mg during the 5 minute period of ischemia. With the ischemia maintained, 100 mg/cc of L-carnitine was infused into the ischemic left anterior descending arterial bed at a rate of 1 cc/min for 5 minutes (17 dogs), and 80 mg/kg of D-L carnltine was given intravenously in 8 dogs. The epicardial S-T segment deviation decreased to approximately 2 mv after the carnltine infusion, with ischemia maintained. A third biopsy sample of the ischemic bed showed that the ATP level had increased to 5.2 ± 1.1 and the creatine phosphate to 10.8 ± 4.8 moles/g; the adenine nucleotide translocase activity had increased to 37,800 ± 7,210 dpm/mg. In 9 dogs ventricular fibrillation developed at this level of ischemia before infusion of carnitine, whereas only one dog had fibrillation at comparable levels of ischemia after infusion. These results support the hypothesis that infusion of carnitine may benefit the ischemic myocardium by maintaining tissue levels of free carnitine, reversing inhibition of adenine nucleotide translocase by long chain acyl coenzyme A esters and in this manner restoring mitochondrial function.

Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris☆

The efficacy and safety of extended-release isosorbide mononitrate tablets were evaluated in patients with stable effort angina. In a double-blind study, 313 patients with stable effort-induced angina were randomized to receive placebo or extended-release isosorbide mononitrate: 30, 60, 120 or 240 mg once daily in the morning. Serial exercise testing was performed using the standard Bruce treadmill protocol on days 1, 7, 14, 28 and 42 immediately before morning drug administration, and 4 and 12 hours after administration. After initial dosing, all groups that received extended-release isosorbide mononitrate had significant (p < 0.01) increases in mean total exercise time of approximately 30 to 50 seconds in relation to placebo 4 and 12 hours after administration. On day 42, mean changes from baseline in total exercise time of patients who received 120 or 240 mg of extended-release isosorbide mononitrate exceeded placebo by approximately 50 to 60 seconds 4 hours after dosing (p < 0.01), and by 30 to 35 seconds 12 hours after dosing (p < or = 0.05). No significant difference was detected between responses to extended-release isosorbide mononitrate and placebo 24 hours after administration (i.e., immediately before the next dose). Thus, there was neither significant activity nor demonstrable rebound of effort-induced angina (zero-hour effect) at the end of the dosing interval. Transient headache was the most prevalent adverse experience. Extended-release isosorbide mononitrate (120 and 240 mg administered orally once daily) significantly prolonged exercise time to development of moderate effort-induced angina 4 and 12 hours after dosing during long-term therapy, without development of nitrate tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics and management of acute stroke in patients with atrial fibrillation admitted to US university hospitals

The optimal evaluation and management of patients with atrial fibrillation who suffer an acute ischemic stroke remains controversial. Methods: Medical records of 171 consecutive patients with atrial fibrillation and acute stroke at six U.S. university hospitals were reviewed. Data collected included the use of antithrombotic therapy, brain and cardiac imaging, bleeding complications, stroke risk factors, and contraindications to anticoagulation. Results: Mean age was 75.4 years. Cardiovascular risk factors associated with increased stroke risk were present in 87%; 35% had at least one contraindication to anticoagulation. Half of the patients with stroke risk factors and no contraindications to anticoagulation were not receiving any antithrombotic therapy at the time of admission. Of the 22 patients who were treated with warfarin, and had INR values on admission, 16 had levels of <2.0; only six had INR values between 2.0 and 3.0. Transthoracic echocardiography was performed in 107 patients (63%); intracardiac thrombi were visualized in only 5%. Initial brain imaging revealed hemorrhagic transformation in nine. Heparin was used in 93 patients (54%), usually within 48 hours of stroke onset. Patients who received delayed heparin typically did not have repeat brain imaging prior to starting heparin. One patient had a delayed symptomatic cerebral hemorrhage. Of the survivors, 47% were discharged and treated with warfarin (or warfarin plus aspirin), 28% with ASA, 7% with other antithrombotic therapies, and 18% with no antithrombotic therapy. Conclusion: Antithrombotic therapy was underutilized and inadequately monitored in atrial fibrillation patients prior to stroke onset. After hospital admission, a wide range of diagnostic and management strategies, which often did not follow current recommendations, were employed.

Usefulness of nifedipine for myocardial ischemia and the nifedipine gastrointestinal therapeutic system

Although conventional treatment of angina pectoris with nifedipine capsules involves frequent daily dosing, a new vehicle for the once-daily delivery of this potent but insoluble calcium channel blocking agent has been developed. With the gastrointestinal therapeutic system (GITS) formulation, constant effective drug levels of nifedipine are delivered for a full 24-hour period. When nifedipine GITS 30, 60 or 90 mg was administered once daily to patients with stable angina pectoris taking beta blockers, clinical effectiveness was demonstrated both by an increase in time to angina and by exercise time compared with placebo. Improvement was noted to be more significant with the higher doses of nifedipine administered once daily. This study indicates that nifedipine GITS provides additional antianginal protection in patients with exercise-induced angina secondary to coronary artery disease who are receiving a fixed dose of beta blocker.

Comparison of Effects of Nisoldipine-Extended Release and Amlodipine in Patients With Systemic Hypertension and Chronic Stable Angina Pectoris

The efficacy and safety of nisoldipine-extended release (ER) and amlodipine were compared in a 6-week multicenter, randomized, double-blind, double-dummy, parallel group, titration-to-effect trial in patients with stage 1 to 2 systemic hypertension (90 to 109 mm Hg diastolic blood pressure [BP]) and chronic stable angina pectoris. After a 3-week placebo run-in period, patients (n = 120) were randomly assigned to active treatment with either nisoldipine-ER (20 to 40 mg) or amlodipine (5 to 10 mg) once daily, titrated as necessary after 2 weeks to achieve diastolic BP <90 mm Hg. After 6 weeks, the mean reduction in systolic/diastolic BP from baseline was 15/13 mm Hg with nisoldipine-ER and 13/11 mm Hg with amlodipine (p = NS/p = NS). Both drugs resulted in similar BP responder rates (diastolic BP <90 mm Hg in 87% of patients who received nisoldipine-ER and 78% of patients on amlodipine, p = NS) and anti-ischemic responder rates (increasing exercise time >20% in 20% and 27%, respectively [p = NS], and increasing exercise time >60 seconds in 32% and 29% of patients, respectively [p = NS]. Also, after 6 weeks of active therapy, there was a similar mean increase in total exercise duration (23 seconds in the nisoldipine-ER group and 21 seconds in the amlodipine group, p = NS). Neither drug increased heart rate and both decreased frequency of anginal episodes. Adverse events were infrequent, and typically were vasodilator-related effects (including headache and peripheral edema) that occurred with somewhat higher incidence in the nisoldipine-ER group. Thus, nisoldipine-ER and amlodipine provided comparable antihypertensive and anti-ischemic efficacy, and both were generally well tolerated.

Pharmacologic profile of survivors of acute myocardial infarction at United States academic hospitals

Optimal drug therapy for patients with acute myocardial infarction (AMI) is well described in the medical literature. However, data on the actual pharmacologic management of patients surviving AMI at academic hospitals is unavailable. The purpose of this study was to document treatment profiles in 500 patients surviving AMI at 12 academic hospitals in the United States. These profiles were compared with established guidelines and were evaluated for trends. Overall, thrombolytics (streptokinase > or = tissue-type plasminogen activator) were administered in 29% of the patients, with a greater proportion of patients receiving beta-blockers than calcium channel antagonists in the initial 72 hours (61% vs 40%; p < 0.005) and at discharge (51% vs 35%; p < 0.005). Further, women were less likely than men to receive thrombolytic therapy (odds ratio [OR] = 0.61; confidence interval [CI], 0.54 to 0.69) or beta-blocker therapy within the first 72 hours (OR = 0.61; CI, 0.55 to 0.67) or at hospital discharge (OR = 0.53; CI, 0.48 to 0.58). Overall, improvements could still be made in the number of patients who receive thrombolytic and acute and chronic beta-blocker therapies after AMI, particularly in women. Changes in treatment profiles may be a reflection of the publication of large clinical trials.

Exogenous superoxide dismutase and catalase promote recovery of function in isolated rat heart after regional ischemia and may be transported from capillaries into myocytes

SummaryThe effects of infusing superoxide dismutase (SOD) and catalase (CAT) into the coronary circulation were investigated in isolated, working rat hearts prior to and during a 15 minute episode of regional ischemia followed by 30 minutes reperfusion. Aortic output, left ventricular pressure and dP/dT were recorded. Compared to untreated hearts, SOD and CAT significantly improved function during reperfusion, but had no effect during the pre-ischemic or the ischemic period. To investigate possible transport of SOD and CAT into rat myocytes, cryotome sections of isolated, Langendorff perfused rat hearts were exposed to rabbit antibody prepared against the exogenous SOD and CAT. Bound antibody was detected by the indirect-fluorescent antibody test. The interior of myocytes from rat hearts exposed to SOD and CAT bound antibodies prepared against these enzymes, whereas myocytes from rat hearts not exposed to exogenous SOD and CAT only bound the CAT antibodies. This indicates the anti-SOD we prepared is specific for exogenous SOD, and also suggests exogenous SOD can gain access to the cytoplasm of myocytes from the coronary circulation.

Angiotensin-converting enzyme inhibitor use in survivors of acute myocardial infarction

Abstract The present study found that a significant percentage of patients with myocardial infarction, who according to the results of large-scale clinical trials should benefit from ACE inhibitor therapy, did not receive such treatment at discharge.