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Biomedical subjects

H Krum

Publications and source records attributed to H Krum.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction.

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.

Animals↗
PubMed2000

Baseline predictors of tolerability to carvedilol in patients with chronic heart failure.

OBJECTIVE: To determine baseline predictors of tolerance to the alpha/beta blocker carvedilol in everyday clinical practice. DESIGN: Retrospective analysis of tolerance to carvedilol in patients with chronic heart failure. Tolerance was defined as currently on carvedilol or on it at the time of death or heart transplantation. To meet the criteria for tolerance, carvedilol had to be prescribed at a stable dose for >/= 3 months. SETTING: Everyday clinical practice, comprising both hospital specialist practice and private practice. Tolerance was assessed in all patients prescribed carvedilol for chronic heart failure in those practices. PATIENTS: 808 consecutive patients in both hospital specialist (611 patients) and private practice (197 patients). MAIN OUTCOME MEASURES: Baseline predictors of tolerance assessed by proportional hazards analysis. Both univariate and multivariate analyses were performed. RESULTS: Within the entire cohort of 808 patients, 95 had stopped carvedilol, 606 were currently receiving the drug, 50 had died, and 44 had received a heart transplant. Overall, 88% of patients tolerated carvedilol (87% in the hospital specialist group, 92% in the private practitioner group). Factors that indicated impaired tolerance by univariate analysis were increased age in years (hazard ratio 1.01, 95% confidence interval (CI) 1.0 to 1.3), low diastolic blood pressure (hazard ratio 1.04, 95% CI 1.02 to 1.08), and raised plasma urea concentration (hazard ratio 1.04, 95% CI 1.02 to 1.05). New York Heart Association (NYHA) class was also a marker of tolerance (proportion not tolerated: 3% class I; 9% class II; 13% class III, 22% class IV). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was also assessed in relation to traditional precautions or relative contraindications to beta blockade. Tolerance in these subgroups was: chronic obstructive airways disease/asthma 85% (89 patients), diabetes 86% (127 patients), peripheral vascular disease 84% (58 patients), concomitant amiodarone treatment 83% (230 patients), and heart rate < 70 beats/min 84% (184 patients). CONCLUSIONS: beta Blocker treatment was well tolerated in everyday clinical practice, including non-hospital-based private practice. There was no single predictor of poor tolerance on multivariate analysis, although there was a clear association with NYHA class as well as age, diastolic blood pressure, and plasma urea on univariate analysis. Carvedilol was tolerated well among selected patients with traditional contraindications to beta blockade in this situation.

Adolescent↗
PubMed1999

Reduced dietary fat intake increases parasympathetic activity in healthy premenopausal women.

1. Hypercholesterolaemia has been associated with decreased heart rate variability, a measure of cardiac parasympathetic activity. However, the effect of perturbation of the lipid profile on autonomic function has not been examined systematically. 2. The effects of short-term dietary lipid modification on autonomic function are studied in 25 normotensive, non-smoking, premenopausal women with normal bodyweight. Subjects consumed either a low (L, 25%) or high fat (H, 40%) diet for 2 weeks in an open, randomized, cross-over manner with a 2 week washout. 3. Baroreflex sensitivity was determined by gating beat-to-beat heart period (RR) interval and continuous non-invasive blood pressure recordings. Heart rate variability measures of cardiac parasympathetic nervous system activity were obtained in the time (standard deviation of RR intervals, root mean square of successive differences (rMSSD)) and frequency (high frequency power) domains. All assessments were made at the same timepoint in the menstrual cycle. 4. Both low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased significantly (P < 0.05) with increased dietary fat intake (H, 2.7 +/- 0.1 vs L, 2.2 +/- 0.1; H, 1.3 +/- 0.1 vs L, 1.1 +/- 0.1 mmol/L, respectively) as did mean arterial pressure (H, 78.1 +/- 1.5 vs L, 74.3 +/- 1.5 mmHg). Weight was unchanged by dietary lipid intake (H, 62.6 +/- 8.5 vs L, 62.3 +/- 8.3 kg, P = NS). 5. There was a significant increase in rMSSD (H, 29.6 +/- 3.4 vs L, 38.8 +/- 6.4 msec, P < 0.05) and natural logarithm of high frequency power following low fat diet (H, 4.4 +/- 0.2 vs L, 4.8 +/- 0.3 msec2, P = 0.01). Baroreflex sensitivity also increased following the low fat diet (H, 13.91 +/- 2.2 vs L, 16.9 +/- 3.2 msec/mmHg, P = 0.23). 6. Short-term dietary lipid modification can significantly increase cardiac parasympathetic nervous system activity in healthy premenopausal women. These changes in autonomic status appear to be independent of changes in bodyweight and may be of clinical relevance considering the prognostic implications of heart rate variability in cardiovascular disease.

Adolescent↗
PubMed1999

Sympathetic activation and the role of beta-blockers in chronic heart failure.

Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods as chronic catecholamine excess appears to contribute to disease progression and increased mortality in this condition. Therefore, blockade of sympathetic activation represents a logical, if somewhat counter-intuitive, approach to the management of the patient with systolic CHF. Pharmacological approaches to blockade of this system include inhibition of central sympathetic outflow (using central sympatholytics, e.g. rilmenidine, moxonidine), blockade of the catecholamine biosynthetic pathway (dopamine beta hydroxylase antagonists) and blockade of the cardiac effects of sympathetic activation (beta-adrenoceptor blocking agents). Beta-blockers have now been extensively studied in patients with symptomatic CHF of the New York Heart Association (NYHA) Class II and III severity. Provided beta-blocker therapy is carefully up-titrated from sub-therapeutic doses and given for at least three to four months, these agents have been associated with favourable long term haemodynamic, functional and mortality outcomes. Furthermore, beta-blockers delay disease progression in CHF by reversing the pathological myocardial remodelling process that accompanies the disease. Non-selective beta-adrenoceptor blocking drugs appear to be of particular benefit in CHF therapy. Myocardial beta2 receptors are down-regulated to a lesser extent than beta1 receptors in CHF, therefore blockade of the beta2 receptor sub-type may assume greater importance in inhibiting the deleterious effects of sympathetic activation on the myocardium in this disease. Newer agents that possess additional vasodilator properties (carvedilol, bucindolol, nebivolol) may be useful in overcoming the initial negative inotropy of the beta-blocking component of the drug, however, it is unlikely that vasodilation contributes greatly to long term clinical benefits. Drugs such as carvedilol are also anti-oxidant, anti-proliferative and have anti-endothelin actions; the clinical significance of these properties is yet to be determined. Unanswered questions remain regarding the use of beta-blockers in heart failure. Ongoing studies are further examining mechanisms underlying the clinical benefits of these agents as well as their therapeutic potential in NYHA Class IV patients, heart failure post-myocardial infarction and patients with asymptomatic left ventricular dysfunction.

Adrenergic beta-Antagonists↗
PubMed1999

Beta-blockers in heart failure. The 'new wave' of clinical trials.

There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of beta-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.

Adrenergic beta-Antagonists↗
PubMed1998

The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.

BACKGROUND: Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. METHODS: We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. RESULTS: As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). CONCLUSIONS: An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.

Adult↗
PubMed1998

Effect of endothelin-1 on exercise-induced vasodilation in normal subjects and in patients with heart failure.

Forearm blood flow (ml/min/100 ml) was determined with strain-gauge venous occlusion plethysmography at rest and in response to handgrip exercise in 7 patients with congestive heart failure and in 9 normal subjects before and after regional administration of endothelin-1 in the brachial artery. Administration of endothelin-1 significantly decreased forearm blood flow at rest and during exercise in normal subjects but did not change it at rest or during exercise in patients with congestive heart failure.

Adult↗
PubMed1998

Efficacy and safety of carvedilol in patients with chronic heart failure receiving concomitant amiodarone therapy. Australia/New Zealand Heart Failure Research Collaborative Group.

BACKGROUND: The beta-blocker/vasodilator carvedilol is found to have beneficial effects in patients with chronic heart failure. However, the safety and efficacy of this agent in the presence of concomitant amiodarone therapy has not been previously determined. METHODS AND RESULTS: We retrospectively analyzed the Australia/New Zealand Carvedilol Heart Failure Research Collaborative Group study of 415 patients with mild to moderate ischemic heart failure where amiodarone was administered as part of the treatment therapy (in 52 patients). After the open-label carvedilol run-in, patients received carvedilol (target dose 25 mg twice daily) or placebo for an average of 19 months. The main adverse events during this double-blind period were worsened heart failure, hypotension/dizziness, bradycardia/atrioventricular block, and aggravation of angina. By Chi square analysis, carvedilol and amiodarone together were not associated with a greater overall incidence of adverse effects than either drug alone. The beneficial effects of carvedilol on left ventricular ejection that were observed in the main trial were preserved in the presence of amiodarone. CONCLUSIONS: Carvedilol is a useful additional therapy for patients with chronic heart failure already receiving amiodarone. Carvedilol can be added to amiodarone in these patients without expectation of increased adverse effects or loss of clinical efficacy.

Adrenergic beta-Antagonists↗
PubMed1998

Drug administration in patients with diabetes mellitus. Safety considerations.

Diabetes mellitus is associated with alterations in a number of key metabolic pathways. Despite theoretical concerns, clinically significant alterations in the pharmacokinetic properties of commonly prescribed drugs are relatively uncommon. Indeed, dose adjustment is rarely required in the setting of well controlled diabetes mellitus. However, significant alterations in drug handling may occur in the context of poor metabolic control or in the presence of complications such as nephropathy. Metformin use may be complicated by lactic acidosis. Fortunately, this is a rare occurrence providing that the agent is not used in circumstances in which it is contraindicated. Indeed, the risk of death from metformin-related lactic acidosis is similar in magnitude to the risk of death related to hypoglycaemia in sulphonylurea-treated patients. The novel hypoglycaemic agent troglitazone may be associated with abnormalities in liver function in approximately 2% of patients. Discontinuation of treatment is followed by normalisation of liver enzyme levels. Current prescribing information recommends frequent monitoring of liver function tests and immediate cessation of therapy if abnormalities develop. In addition to disturbances in intermediary metabolism, diabetes mellitus may also lead to chronic microvascular and marcovascular complications. Thus, in addition to the use of drugs for the control of blood glucose, patients with diabetes mellitus are likely to be prescribed medication for associated conditions such as cardiovascular disease. Such medication includes the ACE inhibitors which are contraindicated in patients with bilateral renal artery stenosis. This complication may be theoretically more common in patients with diabetes mellitus because of accelerated atherosclerosis. However, in clinical practice this is an uncommon occurrence in the absence of clinical features that should alert the treating clinician that an individual patient might be at high risk. Although caution should also be used with beta-blocker therapy in patients with diabetes mellitus, current evidence suggests that, like ACE inhibitors, these drugs may be particularly useful in this patient group.

Acarbose↗
PubMed1998

New and emerging drug treatments for hypertension.

BACKGROUND: Existing antihypertensive therapies are effective in lowering blood pressure, however, they are associated with adverse effects that may contribute to medication non-compliance. Furthermore, morbidity and mortality benefits have not been established with commonly used agents such as ACE inhibitors and calcium channel blockers. OBJECTIVE: Newer antihypertensive therapies offer similar efficacy with fewer adverse effects and may be of benefit in a number of concomitant disease states. DISCUSSION: This article examines the promise of the newer therapies: angiotensin II antagonists, T-type calcium channel blockers, dual metalloprotease inhibitors and endothelin receptor antagonists.

Adrenergic beta-Antagonists↗
PubMed1998

Effect of endothelin-1 on endothelium-derived vascular responsiveness in man.

1. Endothelium-dependent vasodilatation via nitric oxide in response to muscarinic stimulation is decreased in chronic heart failure while basal release of nitric oxide may be increased. As production of the endothelium-derived vasoconstrictor endothelin-1 is increased in chronic heart failure, endothelin-1 may act in an autocrine manner to modulate these effects. 2. To test this, we determined whether prolonged endothelin infusion in normal subjects would reproduce the alterations in basal and stimulated nitric oxide release observed in patients with chronic heart failure. Basal nitric oxide production was determined by measurement of forearm blood flow using strain gauge venous occlusion plethysmography before and after brachial artery infusion of a nitric oxide synthase inhibitor (NG-monomethyl-L-arginine). Stimulated nitric oxide production was determined by brachial artery infusion of acetylcholine. As metabolic vasodilatation is thought to be mediated in part via nitric oxide and is decreased in chronic heart failure, forearm blood flow during peak reactive hyperaemia was also measured. Studies were then repeated during brachial artery infusion of endothelin-1 and a non-specific vasoconstrictor, noradrenaline. 3. Neither basal nor stimulated nitric oxide production was altered by endothelin-1 and noradrenaline infusion. However, absolute forearm blood flow responses to peak reactive hyperaemia were decreased during infusion of endothelin-1 in comparison to noradrenaline. These data suggest that increased endothelin-1 may not contribute greatly to altered basal and stimulated nitric oxide production in patients with chronic heart failure but may contribute to impaired metabolic vasodilatation, by mechanisms presumably unrelated to altered nitric oxide production.

Acetylcholine↗
PubMed1997

Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure.

To determine the effect of beta blockade on parasympathetic nervous system activity, we assessed RR variability during 24-hour Holter monitoring in 10 patients with congestive heart failure before and after 3 to 4 months of treatment with the beta blocker carvedilol. High-frequency power increased from 26 to 64 ms2, root-mean-square of successive differences in RR interval increased from 14.3 to 23.7 ms2, and percentage of absolute differences >50 ms between successive normal RR intervals increased from 0.8% to 4.7%, all p <0.01, indicating a substantial increase in parasympathetic modulation of RR intervals.

Adrenergic beta-Antagonists↗