Fawaz Akhras

Genetic segregation analysis of familial mitral valve prolapse shows no linkage to fibrillar collagen genes.

Three pedigrees were identified in which mitral valve prolapse seemed to be inherited as a mendelian autosomal dominant trait. The segregation of the genes encoding the major fibrillar collagens present in valve tissue, collagens I and III, was analysed by use of restriction enzyme site variants as genetic markers. In one pedigree there was discordance between the segregation of the disease and markers for all three collagen genes. In another, there was discordance between the disease and markers for both collagen I loci. This is evidence against the disease being generally the result of mutations of the genes encoding the major fibrillar collagens.

Increased diastolic blood pressure response to exercise testing when coronary artery disease is suspected. An indication of severity.

One hundred and two consecutive patients with a history of chest pain or recent previous myocardial infarction underwent maximal treadmill stress testing and coronary angiography. The diastolic blood pressure response to exercise was evaluated independently of ST segment change and systolic blood pressure. In the presence of a normal systolic blood pressure response an increase in diastolic blood pressure of 15 mm Hg on at least two determinations during the same stage of exercise was considered abnormal. In 99 patients an accurate diastolic reading was possible. Of these, 61 had a normal diastolic blood pressure response; in 25 of these the ST segment was ischaemic and seven had three vessel coronary artery disease. Thirty eight patients had an abnormal diastolic blood pressure response and 27 of these had an ischaemic ST response. Of the 11 with a negative ST response for ischaemia one had left main stem disease, seven three vessel disease, and three two vessel disease. Patients with an abnormal diastolic response had greater ST depression with more angina at a reduced workload than those with a normal diastolic response. In patients with chest pain an abnormal increase in diastolic blood pressure on exercise reflects severe coronary artery disease. Although no false positives occurred in this study there was an appreciable number of false negatives (sensitivity 46%) in both patients with chest pain and those with infarction. An abnormal diastolic response therefore represents a useful additional diagnostic indicator of coronary artery disease when the ST segment response is normal or borderline. When the diastolic pressure becomes increased with or without ST changes the likelihood of severe coronary artery disease is increased.

The role of captopril as single therapy in hypertension and angina pectoris

Eighteen hypertensive patients with a resting diastolic blood pressure between 100 and 120 mmHg who also had angina and proven coronary arterial disease entered a dose titration study to evaluate the efficacy of captopril as a single therapy in hypertension and coexisting stable angina. Captopril was administered for 2 weeks at 25 or 50 mg three times daily and the patients evaluated subjectively and by maximal symptom limited treadmill exercise testing. In comparison to placebo captopril 25 mg and 50 mg dosage increased time to 1 mm ST depression from 188.2 +/- 24.4 sec on placebo to 337.6 +/- 29.5 and 364.2 +/- 36.2 sec respectively (P less than 0.01). The maximum ST segment depression was reduced from 2.5 +/- 0.25 mm on placebo to 1.4 +/- 0.22 mm on captopril 25 mg and 1.2 +/- 0.30 mm on captopril 50 mg (P less than 0.01). Exercise duration increased from 310.3 +/- 21.4 sec on placebo to 438.3 +/- 27.3 sec on captopril 25 mg and to 460.9 +/- 26.5 sec on captopril 50 mg (P less than 0.01). The resting systolic blood pressure decreased from 184.1 +/- 4.7 mmHg on placebo to 159 +/- 4.2 mmHg on captopril 25 mg and to 150.9 +/- 4.6 mmHg on captopril 50 mg (less than 0.01). Similarly, diastolic blood pressure decreased from 111.6 +/- 2.1 mmHg on placebo to 93.8 +/- 1.3 mmHg on captopril 25 mg and to 90.0 +/- 1.7 mmHg on captopril 50 mg (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Does atenolol improve physical and psychological function after coronary artery bypass surgery: A controlled study

A double-blind prospective randomized trial of atenolol (100 mg once daily) was carried out on 88 patients (78 men) awaiting coronary artery bypass graft surgery. Standardized ratings of both psychiatric morbidity and functional capacity were made before, 3 months (n = 82) and 12 months (n = 81) after surgery. One year after surgery men in the atenolol group had a significantly shorter treadmill exercise time than those on placebo (7.21 +/- 0.28 min vs 8.32 +/- 0.40 min; p less than 0.05), but the frequency of reported anginal attacks during the year was similar in both drug groups. Improvement in functional capacity (measured in exercise time) in the 71 men following surgery was related to both physical and psychological variables assessed before the operation. Men with more severe occlusive disease, lower neuroticism and higher extraversion scores pre-operatively showed greater percentage improvement in exercise time after surgery. Women had significantly levels of psychiatric morbidity and shorter treadmill exercise time than men both before and after surgery. Of the psychiatric and psychological variables, only ratings of Type A behaviour fell significantly in the atenolol group (170.9 +/- 5.3 vs 163.0 +/- 5.2; p less than 0.05). This change, which is probably not clinically important, occurred independently of any reduction in either overall psychiatric morbidity score or ratings of somatic symptoms mediated by beta-adrenergic receptors. The atenolol group reported more side-effects of both psychological and physical symptoms than the placebo group. We do not recommend the routine use of atenolol after bypass graft surgery. Our findings failed to support the suggestion that Type A characteristics may reflect an underlying sympathetic nervous system reactivity.

Oral labetalol in the management of stable angina pectoris in normotensive patients

The efficacy of labetalol, an alpha and beta receptor antagonist, was evaluated in 12 normotensive patients with stable angina pectoris in a single blind dose ranging study. After a two week period of placebo treatment, labetalol was given in doses of 100, 150, 200, and 300 mg twice daily, each for two weeks. Frequency of angina attacks decreased from 9.4 (SEM 2.3)/week in the control period to 7.3 (2.8), 5.2 (2.6), 3.8 (1.8), and 3.3 (1.9)/week in the four successive treatment periods. In the same periods the number of glyceryl trinitrate tablets consumed decreased from 7.0 (2.6)/week to 5.8 (3.3), 3.9 (2.9), 2.7 (1.8), and 2.6 (2.1)/week. Maximal symptom limited treadmill exercise tests were performed three and 12 hours after dosage at each dose. Exercise tolerance (expressed as seconds of the Bruce protocol) increased from 266 (44) with placebo to 306 (44), 369 (50), 396 (48), and 413 (51) in the four treatment periods. This improvement was accompanied by a significant blunting of the heart rate and blood pressure responses to exercise. Trough point exercise tolerance did not differ significantly from that at three hours after dosage. Thus labetalol is effective as an antianginal agent at doses of 150-300 mg twice daily and is well tolerated by the normotensive patient with angina.

An Interim Report on the Efficacy of Isosorbide-5-Mononitrate in a Sustained Release Formulation in Patients with Stable Angina

Eighteen patients of 70 years of age or less were evaluated in a prospective randomised double-blind crossover comparative study of isosorbide-5-mononitrate (IS-5MN) given as conventional tablets 20 mg twice daily or as 40 mg sustained release given once daily and nifedipine retard given 20 mg twice daily. They had a history of effort angina for a mean of 22 months with at least three attacks per week. All patients had positive results on treadmill stress tests prior to entry and angiographically proven coronary artery disease defined as 70% or more stenosis of at least one major vessel. Patients with recent myocardial infarction (within 3 months) were excluded from the study.

The appropriate dosage regime for the transition from intravenous lignocaine to oral tocainide after acute myocardial infarction

SummaryTo define the appropriate regime for the transition from intravenous lignocaine to oral tocainide after uncomplicated acute myocardial infarction, 43 patients received lignocaine to steady state. Each patient then received a tocainide dosage schedule. Plasma concentration of lignocaine and tocainide was measured frequently until the third peak plasma tocainide level. Tocainide 400 mg 8 hourly starting 4 h before cessation of lignocaine and tocainide 400 mg 4 hourly starting at the end of the infusion produced therapeutic plasma tocainide concentration (3.5–9 mg/l) only after the second dose. Tocainide 600 mg 12 hourly starting 6 h before cessation of lignocaine and tocainide 600 mg 6 hourly starting at the end of the infusion quickly achieved therapeutic plasma tocainide concentration which declined to give subtherapeutic first dose troughs of 2.42 mg/l (±0.28 SEM) and 2.79 mg/l (±0.27 SEM) respectively. Consistently therapeutic plasma tocainide concentrations were achieved by both of these regimes after the second dose. The short plasma halflife of lignocaine which for these regimes was 3.71 h (±0.25 SEM), resulted in subtherapeutic lignocaine concentrations before consistently therapeutic plasma tocainide concentrations had been achieved. On the basis of these results, the 600 mg 6 hourly tocainide dosage schedule was studied with cessation of lignocaine infusion either two or six h after the first tocainide dose. With the former regime only three of 5 patients had therapeutic lignocaine at the subtherapeutic tocainide trough. When lignocaine was discontinued on administration of the second tocainide dose however, therapeutic lignocaine concentration was maintained in all patients until tocainide was rising within the therapeutic range. The latter regime, which we would recommend, was not accompanied by increased side effects. Steady state tocainide was found to be present 12 h after the third tocainide dose allowing continued therapy with tocainide 600 mg 12 hourly.

Efficacy of intermittent (eight hours off) transdermal nitrate therapy in stable angina

The efficacy of intermittent (16 h on/8 h off) transdermal nitrate therapy (0.4 mg/h) was assessed in 46 patients with chronic stable angina, all but one of whom were on concomitant beta-blocker and/or calcium antagonist therapy. The study was a randomised, double-blind placebo-controlled crossover with two consecutive 7-day treatment periods, conducted at two centres. Prior to entry into the study patients were screened for exercise test reproducibility and nitrate response. Patch efficacy was determined by maximal symptom limited treadmill stress testing (Bruce protocol) and subjective diary card data. Analysis of variance showed that active treatment significantly improved time to onset of angina (P < 0.001), time to 1 mm ST-segment depression (P < 0.001) and total exercise duration (P < 0.001) compared with placebo from 385.7, 310.8 and 458.1 s to 455.7, 385.2 and 497.1 s, respectively. Nitrate patch therapy significantly reduced diastolic and systolic blood pressures without significantly increasing resting heart rate. There was a marginal reduction in the incidence of angina attacks and sublingual nitroglycerine consumption during active treatment. We conclude that intermittent transdermal nitrate therapy significantly improves exercise tolerance in patients with chronic angina pectoris and that this improvement occurs in addition to conventional anti-anginal therapy.

Effect of Partial Agonist Activity on the Side Effects of β-Blockade in Patients with Chronic Stable Angina

SummarySome side effects of the β1-adrenoceptor blocker atenolol may result from depression of cardiac output at rest. They may, therefore, be reduced by the use of drugs with β1-partial agonist activity, such as epanolol. We compared once-daily atenolol 100mg and epanolol 200mg in 20 patients reporting side effects while taking atenolol for chronic stable angina. A double-dummy, double-blind, crossover design was used to assess side effects by use of visual analogue scales and interviews, and antianginal efficacy by treadmill exercise tests and diary cards. In a comparison with atenolol, no significant differences in exercise time (686 ± 11 seconds vs 685 ± 10 seconds), maximum ST depression (1.02± 0.09mm vs 1.07 ± 0.08mm), time to 1mm ST depression (8.4± 1.9 minutes vs 9.0 ± 2.0 minutes), or days without angina (median 100% in both) were shown. All visual analogue scores were higher with epanolol (subjective energy 58.3 ± 1.7 vs 54.3 ± 1.5, well-being 61.8 ± 1.8 vs 58.6 ± 1.5 and warmth of extremities 68.4 ± 3.6 vs 62.0 ± 3.1). Although these differences did not attain statistical significance, 11 patients expressed a preference for epanolol and only 6 for atenolol. We conclude that, in this study, epanolol is as effective as atenolol as an antianginal agent for chronic stable angina. It improved the side effect profile in some but not all patients.

Oral Beta and Alpha Blockade (Labetalol) in the Management of Stable Angina Pectoris in Normotensive Patients — A Preliminary Report

The efficacy of labetalol, an alpha and beta receptor antagonist, has been evaluated in nine normotensive patients with stable angina pectoris in a single blind dose ranging study. After a 2 week control placebo period labetalol was administered twice daily at dosages of 100, 150, 200 and 300 mg b.i.d. All patients had fewer anginal attacks and consumed fewer glyceryl trinitrate tablets than during the placebo period. Maximal symptom limited treadmill exercise tests performed 3 and 12 hours after dosage showed increased exercise time and decreased double products for all doses, but especially 200 and 300 mg b. i. d. Trough point exercise tolerance did not differ significantly from that at peak dosage. Thus, labetalol is an effective antianginal agent when given twice daily, especially at 200 mg and 300 mg b.i.d. dosage.