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Biomedical subjects

H Ikram

Publications and source records attributed to H Ikram.

At least 37 records · Page 2Linked to original sources
PubMed1997

Hypothalamo-pituitary-adrenal axis response to coronary artery embolization: an ovine model of acute myocardial infarction.

Although previous studies have described the hypothalamo-pituitary-adrenal (HPA) response to the stress of acute myocardial infarction, it is not possible to study the hormone changes immediately after infarction in humans. Accordingly, we have examined the HPA response to microembolization of coronary arteries in 13 sheep compared with 5 sham control sheep. Plasma vasopressin (AVP; P < 0.001), ACTH (P = 0.005) and cortisol (P = 0.005) were all increased 2 h (first sample time) after embolization. Plasma ACTH and cortisol levels returned to baseline levels by 6 h but plasma AVP levels did not return to baseline levels until more than 12 h after embolization. Plasma corticotrophin-releasing hormone (CRH) showed no significant change in response to embolization. In a subset of six animals which were sampled more frequently, the peak responses for plasma AVP, ACTH and cortisol occurred at 40 min after embolization. The maximum responses in any individual sheep observed at this time point were 744 pmol/l for AVP, 144 pmol/l for ACTH and 492 nmol/l for cortisol. CRH levels tended to increase across the first hour but these changes were not statistically significant. In conclusion, the stress hormone responses to microembolization of the coronary arteries have been defined in an ovine model of myocardial infarction. This model is suitable for studying the effects of novel treatments to reduce the stress of myocardial infarction.

Adrenocorticotropic Hormone↗
PubMed1996

Nitric oxide inhibition in an ovine model of heart failure.

1. The role of nitric oxide (NO) in congestive heart failure was investigated by studying the acute haemodynamic, hormonal and renal effects of N(G)-monomethyl-L-arginine (L-NMMA(, a nitric oxide inhibitor, given as incremental bolus doses in six sheep before (normal) and after induction of heart failure (HF) by rapid left ventricular pacing (LVoff+). 2. 6-NMMA caused significant initial dose-dependent rises in left ventricular systolic pressure, mean arterial pressure (MAP), peripheral resistance (PR) and left atrial pressure and declines in cardiac output in both normal and HF states (maximum response in 2-6 min). These responses were all but abolished when L-arginine was given concurrently with L-NMMA. The dose-response curve for the L-NMMA-induced rise in MAP was shifted to the right following LVP (P < 0.05), which is consistent with previous observations of blunted NO synthase activity in HF. A subsequent decline in MAP and PR to below prebolus levels was observed 30-60 min after L-NMMA administration in the paced state. No significant hormonal or renal effects were observed. 3. In conclusion, the present study confirms the important haemodynamic role played by endogenous NO in the normal state and demonstrates a blunted pressor response to NO inhibition in this model of heart failure.

Animals↗
PubMed1996

Autonomic control of asystolic vasovagal syncope.

A 30 year old woman with a lifelong history of severe, recurrent, vasovagal syncope became asystolic for 30 seconds after 37 minutes of 60 degrees head-up tilt. During early tilt, sympathetic activity, heart rate, left ventricular contractility, and cardiac output increased. Mean blood pressure was initially maintained. Presyncope was associated with maximal contractility and bradycardia despite sustained sympathetic activity. Subsequently, asystole occurred associated with complete withdrawal of muscle nerve sympathetic activity. In asystolic vasovagal reactions, presyncope may be triggered by increased left ventricular contractility and is associated with increased levels of parasympathetic and sympathetic activity. Asystole and peripheral vasodilatation may be caused by sudden and complete withdrawal of the increased sympathetic activity.

Adult↗
PubMed1995

Losartan in heart failure. Hemodynamic effects and tolerability. Losartan Hemodynamic Study Group.

BACKGROUND: The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure. METHODS AND RESULTS: A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction < 40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure > or = 13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne.s-1.cm-5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and blood pressure (maximal fall in SVR against placebo, 318 dyne.s-1.cm-5 at 5 hours with 50 mg). In addition, pulmonary capillary wedge pressure fell with 2.5, 25, and 50 mg (largest reduction against placebo of 6.3 mm Hg at 6 hours with 50 mg), cardiac index rose with 25 and 50 mg, and heart rate was lower with all active treatment groups. Active treatment was well tolerated, and excess cough was not reported. CONCLUSIONS: This study showed that oral losartan administered to patients with symptomatic heart failure resulted in beneficial hemodynamic effects with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg.

Aged↗
PubMed1995

Neurohormonal changes after acute myocardial infarction. Relationships with haemodynamic indices and effects of ACE inhibition.

To determine the neurohormonal response to angiotensin-converting enzyme (ACE) inhibition after acute myocardial infarction, 36 patients presenting within 6 h of the onset of chest pain were studied in a single regional cardiology service. In this double-blind study, 13 patients were randomized to receive captopril, 12 patients received enalapril, and 11 patients received placebo, for 12 months. In patients receiving placebo, acute myocardial infarction was associated with activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, and stimulation of plasma brain natriuretic peptide and atrial natriuretic peptide levels. ACE inhibition did not significantly alter circulating levels of norepinephrine, brain natriuretic peptide or atrial natriuretic peptide. Compared with placebo, enalapril induced a steep decline in plasma ACE activity, and plasma angiotensin II levels were reduced by both ACE inhibitors. Using grouped data, circulating levels of brain natriuretic peptide at the zero sampling time were significantly higher than atrial natriuretic peptide values. Brain natriuretic peptide levels at 72 h were significantly correlated with the radionuclide left ventricular ejection fraction measured 5 days and 3 months after infarction. Similar associations were observed for atrial natriuretic peptide and norepinephrine. We confirm activation of the renin-angiotensin-aldosterone and sympathetic nervous systems after acute myocardial infarction. The atrial natriuretic peptide and brain natriuretic peptide and sympathetic nervous system responses to acute myocardial infarction were not significantly modified by ACE inhibition. Brain natriuretic peptide and atrial natriuretic peptide levels were significantly correlated with the left ventricular ejection fraction measured 5 days and again 3 months after myocardial infarction, and may prove a useful prognostic index.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Hemodynamic comparison of dopexamine and nitroprusside at high and low doses in patients with coronary artery disease and impaired left ventricular function.

Pure vasodilator drugs are currently the preferred agents for treatment of acute and chronic heart failure of all grades of severity. In contrast, the role of drugs that combine vasodilation with inotropic action remains highly controversial despite their several advantageous physiological actions and long therapeutic history in heart failure. We hypothesize that this uncertainty might be due first to subtle unfavorable hemodynamic effects not detectable by the relatively crude hemodynamic methods by which these agents are usually analyzed, particularly with regard to the quantification of afterload, and secondly to the narrow therapeutic range of these drugs, such that the dose administered is critical. We tested this hypothesis by comparing several refined hemodynamic measurements of dopexamine, an inotropic vasodilator, with a pure arteriovenous dilator (sodium nitroprusside, SNP) on left ventricular (LV) systolic and diastolic function, large arterial behavior, and coupling of the left ventricle to the arterial system at two dose levels in 35 patients with ischemic heart disease. The study protocol was a fixed order of 15-min infusions of saline, dopexamine 1 microg/kg/min, and dopexamine 3 + ++microg/kg/min, or saline, SNP 1 microg/kg/min, and SNP 3 microg/kg/min. Detailed hemodynamic observations were made at the end of each 15-min infusion period. Both drugs produced equivalent arterial vasodilation, as measured by the decrease in systemic vascular resistance index (SVRI), but dopexamine resulted in a significantly greater increase in cardiac index (CI). Myocardial contractility, assessed by several load-independent indexes, increased with dopexamine, as anticipated with an inotropic drug, but did not alter with SNP. Arterial compliance, a measure of the distensibility of large conduit arteries, was increased by SNP but not by dopexamine. Arterial wave reflection was increased by dopexamine, especially at high doses, but reduced by SNP. Increased arterial compliance and reduced wave reflection reduce LV afterload. SNP reduced preload, whereas dopexamine had no effect on this aspect of ventricular function. Vasodilator drugs and those which combine vasodilator and inotropy increase cardiac output (CO) and reduce SVR. Therapy with inotropic vasodilators has no effect on preload and does not reduce the dynamic components of ventricular afterload, although it does reduce its static components. These effects are dose dependent; there is less perturbation of afterload at lower doses. In contrast, vasodilator therapy reduces preload and both static and dynamic parts of afterload.

Coronary Disease↗
PubMed1994

Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the "PRACTICAL" study).

Left ventricular (LV) function and survival can be improved with captopril when initiated later than 24 hours after acute myocardial infarction. Animal studies suggest additional benefits may be obtained with earlier initiation of angiotensin-converting enzyme (ACE) inhibitors. The effects on LV function of captopril and enalapril initiated within 24 hours of myocardial infarction were studied. Two hundred twenty-five patients with acute myocardial infarction were enrolled within 24 hours of the onset of chest pain. They were randomized to receive either captopril 25 mg three times daily, enalapril 5 mg three times daily, or placebo. LV ejection fraction (EF) and volumes were measured by radionuclide ventriculography at baseline during treatment and at 3 months after a 3-day withdrawal from therapy. The ACE inhibitor group had a significant increase in EF (45 +/- 1 to 47 +/- 1%; p = 0.005) and significantly attenuated LV dilatation compared with results in the placebo group (175 +/- 6 to 189 +/- 7 ml in the placebo group vs 168 +/- 4 to 172 +/- 4 ml in the ACE inhibitor group; p = 0.051 for LV end-diastolic volume; and 99 +/- 6 to 108 +/- 7 ml in the placebo group vs 94 +/- 3 to 94 +/- 4 ml; p = 0.026 for LV end-systolic volume). The beneficial effects of ACE inhibitor therapy on LV function were observed irrespective of the degree of initial LV dysfunction and were comparable in both the captopril and enalapril groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

The pharmacokinetics of quinapril and quinaprilat in patients with congestive heart failure.

The pharmacokinetics of quinapril and its active metabolite quinaprilat were studied in 12 patients with congestive heart failure (CHF) after multiple oral doses of 10 mg quinapril twice daily. Six patients had an ejection fraction of < 35% and six had an ejection fraction between 35%-50%. Increases in the apparent elimination half-life and in AUC(0, 12h) values of quinaprilat were associated with smaller ejection fractions, decreased creatinine clearance, and increased patient age. Comparison with data from age-matched controls having comparable renal function suggests that creatinine clearance is the major determinant of quinaprilat clearance. CHF per se appears to have minimal effect. Dosing of quinapril in patients with CHF should be based on their renal function.

Administration, Oral↗
PubMed1994

Plasma corticotrophin releasing hormone, vasopressin, ACTH and cortisol responses to acute myocardial infarction.

OBJECTIVES: We assessed the magnitude and duration of the response of hypothalamic-pituitary-adrenal hormones to the stress of myocardial infarction, in the presence and absence of angiotensin converting enzyme inhibitors. In particular, we wished to analyse the interrelationships between peripheral plasma levels of corticotrophin releasing hormone (CRH), vasopressin (AVP) and adrenocorticotrophin (ACTH), and also between ACTH and cortisol, during a prolonged medical stress. DESIGN: All hormones were measured within 6 hours of the onset of an acute myocardial infarction. Patients were randomly allocated to three different study groups according to a double blind procedure. PATIENTS: Group 1 (10 patients) received placebo treatment, Group 2 (13 patients) received a maintenance dose of captopril 25 mg three times daily, Group 3 (11 patients) received enalapril 5 mg three times daily. MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, and cortisol by ELISA. Reference ranges for all hormones were obtained from 40 or more volunteers from the electoral roll. RESULTS: At the start of the study, mean +/- SEM plasma AVP (27.9 +/- 4.6 pmol/l) was significantly (P < 0.001) raised above the mean for the reference range (1.82 +/- 0.09 pmol/l), and 12 patients had values > 50 pmol/l. Mean plasma cortisol (960 +/- 89.6 nmol/l) was also raised above the reference range mean (554 +/- 28 nmol/l, P < 0.001), as was mean plasma CRH (4.97 +/- 0.5 pmol/l, reference mean 1.52 +/- 0.09 pmol/l, P < 0.001). By contrast, mean ACTH (3.88 +/- 0.66 pmol/l) was significantly less than the reference mean (10.7 +/- 0.7 pmol/l, P < 0.001). During the 72-hour observation period there was a highly significant fall (P < 0.001) in plasma CRH, AVP and cortisol. By contrast, plasma ACTH rose, and the change with time of ACTH was significantly different from the fall in plasma CRH, AVP or cortisol (P < 0.001 for each comparison). No significant differences in plasma CRH, AVP, ACTH or cortisol responses to placebo, captopril or enalapril were observed. CONCLUSIONS: Within 6 hours of a myocardial infarction, mean plasma CRH, AVP and cortisol values were very significantly raised above mean control values, while ACTH was very significantly reduced. During the 3 days following an acute myocardial infarction, plasma CRH, AVP and cortisol fell substantially, and this pattern was not influenced by angiotensin converting enzyme inhibitors. By contrast, plasma ACTH showed a significant increase with time. This suggests that the usual relationships between CRH, AVP and ACTH, and between ACTH and cortisol are disturbed in patients admitted to hospital with myocardial infarction. Maximum levels of AVP observed in 12 patients exceeded 50 pmol/l, which may be sufficiently high to interfere with tissue perfusion. It is postulated that V1 AVP receptor antagonists may have a therapeutic application in limiting infarct size.

Adrenocorticotropic Hormone↗
PubMed1994

Angiotensin converting enzyme inhibition in chronic stable angina: effects on myocardial ischaemia and comparison with nifedipine.

OBJECTIVES: To determine the anti-ischaemic effects of a new angiotensin converting enzyme inhibitor, benazepril, compared with nifedipine, alone and in combination, in chronic stable angina caused by coronary artery disease. DESIGN: Placebo controlled, double blind, latin square design. SETTING: Regional cardiology service for a mixed urban and rural population. SUBJECTS: 40 patients with stable exertional angina producing at least 1 mm ST segment depression on exercise test with the Bruce protocol. 34 patients completed all four phases of the trial. INTERVENTIONS: Each patient was treated with placebo, benazepril (10 mg twice daily), nifedipine retard (20 mg twice daily), and a combination of benazepril and nifedipine in the same doses, in random order for periods of two weeks. MAIN OUTCOME MEASURES AND RESULTS: Total duration of exercise was not increased by any treatment. Exercise time to the development of 1 mm ST segment depression was not significantly changed with benazepril alone or in combination with nifedipine but was increased with nifedipine from 4.18 (1.8) min to 4.99 (1.6) min (95% confidence interval (95% CI) 0.28 to 1.34; p < 0.05). There was a significant relation between increase in duration of exercise and resting renin concentration (r = 0.498; p < 0.01). Myocardial ischaemia during daily activity, as assessed by ambulatory electrocardiographic monitoring, was reduced by benazepril and by the benazepril and nifedipine combination. This was significant for total ischaemic burden (451(628) min v 231(408) min; 95% CI -398 to -41 min; p < 0.05) and maximal depth of ST segment depression (-2.47(1.2) mm v -2.16 mm; 95% CI 0.04 to 0.57; p < 0.05) for the combination and for maximal ST segment depth for benazepril monotherapy (-2.47 (1.2) mm v -1.96(1.2) mm; 95% CI 0.18 to 0.91; p < 0.05). Benazepril significantly altered the circadian rhythm of cardiac ischaemia, abolishing the peak ischaemic periods at 0700 to 1200 and 1700 to 2300 (p < 0.05). CONCLUSIONS: Benazepril, an angiotensin converting enzyme inhibitor, had a modest anti-ischaemic effect in effort angina, but this effect was not as pronounced as with nifedipine. The anti-ischaemic action was more noticeable in asymptomatic ischaemia during daily activity, whereas nifedipine had little effect on this aspect of myocardial ischaemia. The combination of benazepril and nifedipine reduced ischaemia of daily activity.

Adult↗
PubMed1994

Blockade of the renin-angiotensin system.

HISTORICAL OVERVIEW: Milestones in understanding the renin-angiotensin system (RAS) until the development of angiotensin II antagonists are described briefly. Sites at which the RAS might be blocked are outlined. PEPTIDE ANALOGUE ANTAGONISTS OF ANGIOTENSIN II RECEPTORS: Saralasin-like compounds were used in numerous experimental and clinical situations and clarified the role of the RAS. Some of these situations are described (e.g. hypertension and cardiac failure) particularly in regard to the control of arterial pressure and aldosterone secretion by the RAS. Saralasin and its analogues allowed visualization, for the first time, of complete angiotensin II/effector (especially blood pressure) dose-response curves. ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: The clinical usefulness of ACE inhibitors in hypertension, cardiac failure, diabetes mellitus and after acute myocardial infarction is emphasized. In particular, ACE inhibitors have actions beyond blockade of angiotensin II formation, necessitating cautious interpretation of data from their use. RENIN INHIBITORS: Experience with renin inhibitors in documenting and confirming the role of the RAS is outlined. NON-PEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS: Characteristics of losartan-like compounds are discussed in brief, and the results of their limited use in clinical medicine are outlined. CONCLUSION: Blocking agents have led to great advances in knowledge of the RAS and its physiological and pathophysiological functions. ACE inhibitors are used regularly in a number of clinical disorders and, in theory, have therapeutic potential beyond alternative antihypertensive drugs in the prevention of cardiovascular complications in essential hypertension. The place of renin inhibitors and angiotensin II receptor antagonists in clinical practice, however, remains to be determined.

Angiotensin Receptor Antagonists↗
PubMed1993

Radiofrequency ablation of anomalous cardiac pathways: initial experience.

AIM: To describe the initial experience of radiofrequency ablation of anomalous cardiac pathways in patients with supraventricular tachycardias. METHODS: A total of 10 patients with refractory supraventricular tachycardias mediated by anomalous cardiac pathways underwent electrophysiological assessment and attempted pathway ablation. RESULTS: Seven patients with left free wall atrioventricular pathways (two concealed) and two patients with dual atrioventricular nodal pathways had successful pathway ablations and have had no recurrence of arrhythmia. One patient with a concealed posteroseptal atrioventricular pathway was not able to be ablated. All patients tolerated the initial procedure well, but one developed pericarditis later. CONCLUSION: Radiofrequency ablation promises to be an important new technique for the management of patients with anomalous cardiac pathways and supraventricular tachycardias. Our initial experience has been favourable and comparable to other reported series with a high success rate and infrequent complications.

Adult↗
PubMed1993

Therapeutic controversies with use of beta-adrenoceptor blockade in heart failure.

In response to early reports indicating a beneficial adrenoceptor effect of beta blockade, 2 small trials were conducted to investigate the hemodynamic effects of acute and chronic beta-adrenoceptor blockade in patients with congestive cardiomyopathy. Acute beta-blocker therapy with intravenous acebutolol, 25 mg, resulted in a significant decline in cardiac performance, whereas chronic therapy with acebutolol, 200 mg twice daily, resulted in no beneficial effects on exercise tolerance, as reported by the original Swedish investigators. Further, beta-adrenoceptor blockade has been associated with a number of clinical problems: beta blockers tend to interfere with the compensatory mechanisms that support circulation during early or mild heart failure and therefore have little value as routine therapy at that stage of the disorder. Although excessive beta-adrenoceptor blockade may worsen ventricular function by decreasing myocardial contractility, beta blockers appear to have a useful role in patients with moderate heart failure accompanied by tachycardia. Carefully titrated doses of beta blockers in conjunction with afterload-reducing agents may also provide a benefit in patients with rapid heart rates and grossly elevated levels of circulating catecholamines.

Acebutolol↗