A testing time for heart disease.
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Apolipoproteins A↗
Biomedical subjects
H Ikram
Publications and source records attributed to H Ikram.
Hemodynamic effects of nitroprusside on valvular aortic stenosis.
The effects of acute reduction of left ventricular (LV) loading in valvular aortic stenosis (AS) were examined. Thirty-five consecutive patients with AS (peak-to-peak aortic valve gradient 66 +/- 26 mm Hg, aortic valve area 0.65 +/- 0.22 cm2) were given intravenous sodium nitroprusside (1 to 3 micrograms/kg/min) to reduce systolic aortic pressures by greater than 10 mm Hg (mean aortic pressure 99 +/- 15 to 80 +/- 15 mm Hg; p less than 0.001). Overall, nitroprusside infusion resulted in little change in cardiac index (2.72 +/- 0.61 to 2.67 +/- 0.58 liters/min/m2; p = not significant). Individual patients had a range of responses. Fourteen patients (group 1) had an increase in cardiac index (2.42 +/- 0.59 to 2.74 +/- 0.67 liters/min/m2; p less than 0.001), whereas 21 (group 2) had a decrease or no change (2.93 +/- 0.56 to 2.61 +/- 0.52 liters/min/m2; p less than 0.001). Comparison of these subgroups showed that a cardiac index increase with nitroprusside was significantly predicted by a higher LV end-diastolic pressure (26 +/- 12 vs 15 +/- 6 mm Hg), lower LV ejection fraction (44 +/- 18 vs 62 +/- 12%). smaller aortic valve area (0.52 +/- 0.12 vs 0.74 +/- 0.22 cm2) and lower cardiac index (2.42 +/- 0.59 vs 2.93 +/- 0.56 liters/min/m2) (all values groups 1 and 2, respectively). It is concluded that there is a disparate response to acute vasodilatation in AS. Potentially beneficial effects are seen in a subgroup of patients, especially those with increased filling pressures and impaired LV function.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Tissue plasminogen activator using a rapid-infusion low-dose regimen for unstable angina.
The clinical effect of a low-dose rapid-infusion intravenous regimen was assessed using human recombinant tissue-type plasminogen activator (rt-PA) in unstable angina. Fifty patients with unstable angina pectoris were randomly assigned to blinded treatment with either placebo (24 patients) or low-dose (20 mg bolus, 30 mg infusion over 1 hour) intravenous rt-PA (26 patients). Before randomization, all patients were treated with aspirin, twice-daily subcutaneous heparin, and maximally tolerated antianginal therapy. Of the 50 patients assigned, 26 received rt-PA and the outcome was successful in 15 (58%) (angina settled, no myocardial infarction or urgent intervention) compared with 9 (38%) successful outcomes in the 24 who received placebo (0.5 greater than p greater than 0.1). Angina remained refractory in 8 (31%) of the rt-PA group and in 13 (54%) of the placebo group (0.1 greater than p greater than 0.05). Urgent interventions were required in 6 patients (23%) who received rt-PA and in 11 patients (46%) who received placebo. Three patients in each group sustained a myocardial infarction within 72 hours of entering the trial and there were 3 deaths (1 in the active treatment group, 2 in placebo group) within 2 weeks of the trial (p = not significant). Administration of intravenous rt-PA was not associated with any complications. Low-dose rt-PA administration in patients with unstable angina was associated with a tendency to stabilization of anginal symptoms and a reduction in the need for urgent intervention. However, these trends did not achieve statistical significance.
Aged↗
Endothelin-induced changes in intracellular calcium concentration in rat vascular smooth muscle cells: effects of extracellular calcium and atrial natriuretic factor.
The purpose of this study was to examine whether different mechanisms might underlie the changes in intracellular calcium concentration ([Ca2+]i) stimulated by high and low concentrations of endothelin, and whether atrial natriuretic factor (ANF) has an inhibitory effect on endothelin-induced [Ca2+]i changes in cultured rat vascular smooth muscle cells (VSMCs). In calcium-replete buffer, cultured monolayers of rat VSMCs superfused with endothelin at a high concentration (10 nM) exhibited a marked transient rise in [Ca2+]i, followed by a sustained elevation, whereas a low concentration of endothelin (0.1 nM) induced a sustained monophasic elevation. When calcium-free buffer was used, 10 nM endothelin induced a transient rise in [Ca2+]i of lesser amplitude, whereas 0.1 nM endothelin did not produce a significant rise. Pretreatment of VSMCs with ANF and cosuperfusion with endothelin failed to inhibit either transient or sustained endothelin-induced changes in [Ca2+]i in calcium-replete buffer.
Animals↗
Comparison of the effect of renin inhibition and angiotensin-converting enzyme inhibition in ovine heart failure.
The acute hemodynamic and hormonal effects of incremental doses of a specific ovine renin inhibitor (RI: EMD 52 297) and captopril were compared in an ovine model of heart failure. Both RI and captopril inhibited the renin-angiotensin II (ANG II) system, although the decrease in plasma aldosterone (ALDO) was significant only during captopril infusion. Both agents exhibited strong vasodilator properties with similar decreases in mean arterial pressure (MAP, maximum decrease: RI = -20.5 +/- 2.2 mm Hg, p less than 0.001; captopril = -19.8 +/- 1.7 mm Hg, p less than 0.001) and left atrial pressure (LAP, maximum, decrease: RI = -6.8 +/- 1.5 mm Hg, p less than 0.01; captopril = -6.9 +/- 0.4 mm Hg, p less than 0.01) along with a slight increase in cardiac output (CO, maximum increase: RI = 0.54 +/- 0.11 L/min; captopril = 0.79 +/- 0.26 L/min). The slope of the response between MAP and LAP was similar in all animals, indicating that the agents have a similar effect on cardiac preload and afterload. The similar hemodynamic actions of RI and captopril in this model of congestive heart failure suggest that beneficial effects are due to inhibition of ANG II. Thus, orally active renin inhibitors may offer a useful therapeutic alternative when side effects preclude use of angiotensin-converting enzyme (ACE) inhibitors.
Aldosterone↗
Acute hemodynamic, hormonal, and renal effects of neutral endopeptidase inhibition in ovine heart failure.
The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.
Analysis of Variance↗
Angiotensin II receptor antagonism in ovine heart failure: acute hemodynamic, hormonal, and renal effects.
The hemodynamic, hormonal, and renal effects of angiotensin II-type 1 receptor antagonism (AT1A) have not been documented previously in heart failure (HF) or compared with angiotensin-converting-enzyme inhibition (ACEI). Accordingly, we investigated the acute (2-h) response to losartan (1 and 10 mg/kg iv) or vehicle (N saline) followed by captopril (12.5 mg) on separate days in an ovine model of HF induced by 7 days of rapid ventricular pacing. Losartan induced a significant rise in plasma renin activity (PRA) and plasma angiotensin II levels (P less than 0.01 and P less than 0.001, respectively), in association with a fall in the plasma aldosterone-to-PRA ratio (P less than 0.001) and plasma atrial natriuretic peptide (P less than 0.05). Mean arterial and left atrial pressure both fell significantly after losartan (P less than 0.001), whereas the rise in cardiac output was not sustained. The response to captopril was similar except for plasma angiotensin II, which declined (P less than 0.001). Glomerular filtration and urine sodium excretion were maintained despite a fall in renal perfusion pressure. In conclusion, the vasodilatation and renal effects of AT1A were similar to ACEI. Thus AT1A may be a useful therapeutic alternative to ACEI in HF.
Angiotensin Receptor Antagonists↗
Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.
The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1, p < 0.001; group 2, p < 0.01; overall treatment effect for combined data, p < 0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p < 0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p = 0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p < 0.001 and p < 0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, -70 +/- 21 mmol; p < 0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Angiotensin converting enzyme inhibitors versus digoxin for the treatment of congestive heart failure.
Angiotensin converting enzyme (ACE) inhibition and digoxin may be used in the management of heart failure. Digoxin increases myocardial contractility in vitro, and has a modest but durable beneficial effect in congestive heart failure due to impaired left ventricular systolic function. ACE inhibitors have clear beneficial effects in all grades of heart failure and, in addition, modify the natural history and reduce mortality. Comparative studies in mild to moderate heart failure reveal a tendency towards greater benefits and tolerability of ACE inhibitors over digoxin. ACE inhibition is indicated, in conjunction with diuretic therapy, for all grades of heart failure. Digoxin is best reserved for patients with atrial fibrillation and a rapid ventricular response, and for those whose heart failure is not controlled with an ACE inhibitor plus a diuretic. In patients with heart failure following myocardial infarction, digoxin is of modest benefit. Digoxin should be administered slowly and carefully to avoid acute vasoconstriction and toxicity. Provisional data suggest ACE inhibitors are also beneficial in these patients. However, the results of clinical trials presently in progress are required to clarify their role following myocardial infarction.
Angiotensin-Converting Enzyme Inhibitors↗
Acute inhibition of endopeptidase 24.11 in essential hypertension: SCH 34826 enhances atrial natriuretic peptide and natriuresis without lowering blood pressure.
The acute renal, endocrine, and hemodynamic effects of the orally active endopeptidase inhibitor SCH 34826 (400 mg every 6 hours for five doses) were investigated in a group of 6 male patients [with established mild to moderate essential hypertension and left ventricular (LV) hypertrophy] in a balanced random-order double-blind, placebo-controlled cross-over study. Plasma atrial natriuretic factor (ANF) concentrations increased (p < 0.05) to fourfold control values after the first dose of inhibitor, but later postdose increments of ANF were less pronounced. Plasma cyclic GMP also increased significantly (p < 0.05). These effects were associated with a transient modest but significant (p < 0.05) increase in sodium excretion (50 mmol sodium in excess of placebo values) that was complete in 24 h. Mean 24-h urinary excretions of cyclic GMP and immunoreactive ANF were also significantly increased by 55 and 86%, respectively. Other urine indexes (including other electrolytes, volume, creatinine, aldosterone, and cortisol) and renal hemodynamics [including glomerular filtration rate (GFR) and effective renal plasma flow (RPF)] were unchanged. Renin-angiotensin-aldosterone system (RAAS) activity was not significantly altered. Plasma epinephrine increased after the initial three doses of SCH 34826. Systolic blood pressure (SBP) and heart rate (HR) were not altered by SCH 34826. Diastolic BP (DBP) increased slightly (p = 0.044). Acute inhibition of endopeptidase 24.11 by SCH 34826 in essential hypertension caused significant increments in plasma ANF and cyclic GMP together with modest natriuresis. No antihypertensive effect was observed in the first 30 h of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial Natriuretic Factor↗
EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide.
Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.
Adult↗
Prolonged inhibition of endopeptidase 24.11 in normal man: renal, endocrine and haemodynamic effects.
The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies. Group 2 (but not group 1) exhibited a significant transient natriuresis (P less than 0.01) and a consequent sustained negative cumulative sodium balance (70 +/- 21 mmol) which was established within 48 h and remained for the duration of dosing with UK 79300. Urine and plasma cyclic guanosine monophosphate (cGMP) levels rose significantly above placebo values (P less than 0.01 and P less than 0.001, respectively) in both groups and the effect was sustained throughout the dosing period. Plasma atrial natriuretic factor (ANF) was slightly enhanced by UK 79300 in group 1 (P less than 0.05) but not significantly increased in group 2. Despite a significant increase in heart rate in both groups (P less than 0.001) and of natriuresis in group 2, there was minimal evidence of renin-aldosterone activation in either group. Trends towards lower systolic pressures, observed in both groups, did not attain statistical significance. These findings suggest chronic treatment with UK 79300 induces an increase in tissue ANF levels, with sustained enhancement of plasma and urine concentrations of ANF second messenger (cGMP) and increased heart rate.
Aldosterone↗
Fourier coefficient description of left ventricular shape.
A method of quantifying the shape of the left ventricle of the heart as seen in 2D echocardiograms was developed. It is based on describing the shape in terms of the coefficients a fifth-order trigonometric Fourier series. Such a series has eleven Fourier coefficients which is too large a number for clinical application so pairs of coefficients are combined to give six coefficients (alpha 0, alpha 1, ... , alpha 5). A trial was conducted to test the ability of the coefficient description to classify subjects as having normal right ventricles or ventricles with an apical abnormality. The tests showed that one of the coefficients (alpha 2) was higher for the subjects with an apical abnormality and that this difference increased with exercise. This is as was expected. However, it was found to be difficult to get a reliable estimate of alpha 2 from a single scan of a patient and that it is therefore probably necessary to average data from several scans to obtain a reliable alpha 2 value for a single patient.
Coronary Angiography↗
ANP infusion in the treatment of heart failure and comparison with ACE inhibition.
The therapeutic potential of atrial natriuretic peptide (ANP) was assessed in an ovine model of heart failure induced by rapid left ventricular (LV) pacing and compared with the effects of angiotensin converting enzyme (ACE) inhibition. Hemodynamic, hormonal, and metabolic measurements were studied during three 5-day periods of LV pacing. No treatment (control) or a continuous ANP infusion (25 ng/kg/min) was given in random order during the first two periods, while ACE inhibitor was always given during the third period. Baseline measurements immediately prior to the start of each pacing phase showed no significant variation. Significant neurohumoral activation and hemodynamic responses were observed in each pacing phase. During ANP infusion, plasma ANP levels were 3-5-fold higher than those observed in the control or ACE inhibition treatment phases. Compared with control, a natriuresis was observed on the first day, whereas glomerular filtration rate (GFR) tended to be maintained during ANP infusion. The rise in left atrial pressure and plasma aldosterone tended to be blunted. When the two treatment phases were compared, the rise in left atrial pressure during LV pacing was less with ACE inhibition, whereas there was a similar reduction in sodium retention after the initial natriuresis with ANP. By contrast, GFR tended to be maintained better during ANP infusion compared to ACE inhibition. These results suggest that ANP, or a similar "enhancing" analogue, may be useful in the treatment of heart failure, especially if administered early in the development of the disorder.
Angiotensin-Converting Enzyme Inhibitors↗
Renal effects of ACE inhibition in ovine heart failure: a comparison of intermittent and continuous ACE inhibition.
Results of uncontrolled studies suggest that the duration of action of an ACE inhibitor may be an important determinant of renal impairment when using these agents to treat patients with heart failure. To determine whether there is experimental evidence for this hypothesis, we compared the effects of intermittent (captopril, 25 mg i.v. bolus twice daily) and continuous (captopril. 25 mg bolus, then 50 mg/day by constant infusion) ACE inhibition in an ovine model where heart failure was induced by rapid left ventricular pacing (LVP). Six sheep underwent three 4-day periods of LVP with intermittent, continuous, or no treatment (control) given in random order from the onset of LVP. Despite evidence that intermittent captopril administration allowed significant recovery of serum ACE activity (4.6 +/- 1.2 vs. 1.1 +/- 0.5 pmol/L before and after captopril bolus on day 4, p less than 0.001) and restitution of arterial pressure between successive boluses (48 +/- 7 vs. 41 +/- 4 mm Hg, p less than 0.01), there was no difference in the renal effects of intermittent and continuous ACE inhibition (creatinine clearance was 44 +/- 14 and 47 +/- 8 ml/min on day 4 of the intermittent and continuous phase, respectively). Nevertheless, there was a significant correlation between the decline in arterial pressure and fall in creatinine clearance induced by ACE inhibition (r = 0.65, p less than 0.05), with evidence that drug accumulation may potentiate hypotension and renal impairment should arterial pressure be reduced below the threshold for renal autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Hypertension in valvar aortic stenosis.
The indirect arterial blood pressure in 50 cases of catheter-proven aortic stenosis without significant incompetence was examined. Defining the upper limit of normal blood pressure as 140/90mmHg, 14 percent had borderline, 18 percent had mild and 8 percent had severe hypertension. There was a significant positive correlation of systolic and diastolic blood pressure with age; ie pressures rose with age. The rate of increase was virtually identical with that of the normal population except for those over 70. Hypertension interferes with reliable clinical and haemodynamic quantitation of the valve lesion. The two lesions summate to increase the systolic burden on left ventricle.
Adolescent↗
A pharmacokinetic comparison of two sustained-release oral procainamide preparations.
1 The pharmacokinetics of two different sustained-release oral procainamide preparations were studied in ten hospital patients with normal blood ureas and no clinical evidence of heart failure. Each patient received either one or other preparation at 12 hourly intervals for four doses. Frequent blood sampling enabled close monitoring of blood levels. 2 Results showed that both preparations were essentially similar in their pharmacokinetics. Both effectively double the half-life of conventional oral procainamide to 6.5 h and are suitable as prophylactic preparations. One patient developed toxic levels, thought to be related to her metabolic status of being a very slow acetylator. To avoid toxicity pre-therapy assessment of a patient's cardiac and renal function and acetylator status is advised.
Adult↗
Haemodynamic effects of acute beta-adrenergic receptor blockade in congestive cardiomyopathy.
Acebutolol ('Sectral'), a cardioselective beta-blocking drug, was administered intravenously in a dose of 25 mg to 10 patients with congestive cardiomyopathy. All of them were in a stable condition on antifailure regimens. The drug resulted in a statistically significant decline in left ventricular contractility as judged by peak left ventricular dP/dT and the contractility index. The mean aortic blood pressure also fell. There was a significant increase in end-diastolic and end-systolic left ventricular volumes. Mean values for heart rate, ejection fraction, left ventricular stroke work index, and cardiac output also fell, but the results were not statistically significant. Left ventricular distensibility as judged by the slope of the diastolic pressure-volume relation also improved significantly. A reduction in myocardial energy requirements, improved compliance, and lowering of arterial pressure would be haemodynamically advantageous. However, further cardiac dilatation and reduction contractility--the basic defects in congestive cardiomyopathy--could lead to further deterioration.
Acebutolol↗