Chronic Heart Failure(University of Dundee, UK)

Unit Code

01473

Department/Institution Offering Unit

Department of Clinical Pharmacology
University of Dundee
Ninewells Hospital and Medical School
Dundee DD1 9SY
UK

Unit Points

Research Points: 100

Coursework Points: 0

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Contacts

Unit Coordinator/s:

Professor Chim Choy Lang MD FRCP FACC
Professor of Cardiology
Division of Medicine and Therapeutics
Ninewells Hospital and Medical School
Dundee DD1 9SY
UK

email: c.c.lang@dundee.ac.uk

Alternative Contact:

Dr AnnaMaria Choy
Senior Lecturer in Cardiology
Division of Medicine and Therapeutics
Ninewells Hospital and Medical School
Dundee DD1 9SY
UK

email: a.choy@dundee.ac.uk

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Overall Objectives

• Increase the student's knowledge and understanding of biomedical science
• Develop the process and practice of research in biomedical science
• Develop individual investigative skills, critical thought and the ability to evaluate information and to analyse experimental data
• Develop the ability to present research results both orally and in the written form
• Develop a habit of safe laboratory practices

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Content

Coursework: N/A

Research: Aldosterone plays a pathologic role in CHF in many ways. By promoting the retention of sodium and water and the excretion of potassium and magnesium, aldosterone contributes to the edematous state and to electrolyte derangements. In CHF, angiotensin II is also increased contributing to sodium reabsorption. Ultimately in the decompensated patient, aldosterone and angiotensin II together overcome the beneficial effects of the NP system. Though ACE inhibitors are a well-established mainstay of CHF therapy, they fail to suppress the aldosterone production completely. In the key RALES trial it was shown that the addition of a relatively low dose of spironolactone to standard therapy (ACE inhibition, loop diuretic and digoxin) in NYHA class III or IV patients resulted in a substantial reduction in all cause mortality, cardiac health and hospitalizations compared with placebo. HF symptoms and NYHA functional class improved and serious hyperkalemia was rarely reported (1) . The mechanisms leading to improved survival by a low daily dose of spironolactone (25 mg/day) remain unclear. Extra-renal effect of anti-aldosterone therapy on myocardial fibrosis, sympathetic stimulation and neurohormonal dysregulation have been suggested as well as actions on renal electrolyte and volume regulation. A substudy of RALES showed that patients receiving spironolactone who had improved survival also had lowering of type III procollagen marker providing further evidence for aldosterone's promotion of collagen synthesis (2).
In an experimental model of CHF, Bauersachs and colleagues (3) demonstrated that the addition of a low-dose spironolactone to an ACE inhibitor induced a striking natriuresis and diuresis whereas neither compound alone modulated renal electrolyte regulation. The likely explanation for this finding is that such a therapeutic modulation of sodium reabsorption in both the proximal (through ACE inhibition) and distal (through mineralocorticoid antagonism) tubule leads to additive effects on renal sodium and volume excretion. Indeed, in patients with liver cirrhosis, a combination of spironolactone and captopril produced a pronounced increase of a previously blunted diuresis (4). However, the increased natriuresis might also be explained by an interaction of ACE inhibitors and spironolactone at the cellular and molecular level with ACE inhibitors potentially sensitizing the renal tubule to the natriuretic actions of spironolactone. Indeed, ACE inhibitors have been shown to modulate the binding characteristics of the vasopressin receptor in the collecting tubule (5). The potential beneficial interaction between spironolactone and ACE inhibition appears not to be limted to the kidneys and may extend to the vasculature. Farquharson and Struthers have previously demonstrated that spironolactone improved endothelial vasodilator dysfunction in patients with CHF (6). Evidence for a potential positive interaction between spironolactone and ACE inhibition comes from a more recent study in a rat experimental model of CHF which showed that spironolactone asses to ACE inhibition completely restored the attenuated endothelium-dependent relaxation whereas spironolactone alone did not modulate it and ACE inhibition alone only slightly improved the endothelium dependent vasodilator response (7). In recent years, attention has focused on eplerenone, a selective aldosterone antagonist which is reported to have a lower incidence of adverse effects when compared to spironolactone. The recently published results of the EPHESUS group reported that addition of eplerenone to optimal treatment, which includes ACE inhibitors, resulted in significant reductions in overall mortality and the rate of death from cardiovascular causes or hospitalizations among patients whose acute myocardial infarction was complicated by left ventricular dysfunction and heart failure. There was also a reduction in cardiovascular mortality and the rate of death from any cause among patients assigned to eplerenone (8). Clinical studies have shown that eplerenone is a useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or angiotensin receptor blockers (9). There are recent reports that eplerenone, like spironolactone, may also interact positively with ACE inhibition on improving endothelial dysfunction (10). Clearly further studies are needed to investigate this potentially important interaction. Hence, the objective of our study proposal is to examine the effect of low-dose spironolactone and enalapril alone and in combination on urinary sodium excretion in healthy volunteers given a sodium load and to the antinatriuretic effect of nordrenaline.

References:
1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. (RALES) Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341: 709-17
2. Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001;345: 1689-97
3. Bauersachs J, Fraccarollo D, Ertl G, Gretz N, Wehling M, Christ M. Striking increase of natriuresis by low dose spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES. Circulation 2000;102: 2325-8
4. Jolobe OM. Efficacy of low dose captopril in addition to furosemide and spironolactone in patients with decompensated liver disease during blunted diuresis. J Hepatol 1993; 19: 321-322
5. Nishida N, Ogawa T, Yamauchi T et al. Treatment of cilazapril, an angiotensin converting enzyme inhibitor, changes the affinity of arginine receptor in the kidney of the spontaneously hypertensive rat. Res Commun Chem Pathol 1994; 84: 143-152
6. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, imp[roves endothelial vasodilator dysfunction and suppresses vascular angiotensin I/ angiotensin II conversion in patients with chronic heart failure. Circulation 2000; 101: 594-597
7. Bauersachs J, Heck M, Fraccarollo D et al. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction. J Am Coll Cardiol 2002;39: 351-8
8. EPHESUS Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348(14): 1309-1321
9. Krum H, Nolly H, Workman D et al.Efficacy of eplerenone added to rennin angiotensin bloackade in hypertensive patients. Hypertension 2000; 40: 117-123
10. Schafer A, Fraccarollo D, Hildemann SK , Tas P, Ertl G, Bauersachs J. Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: Effect on endothelial dysfunction. Cardiovascular Research 2003 (in press).

Sample Research Topics:

1. The Effects of Spironolactone and Enalapril Alone and in Combination on Sodium Load in Healthy Subjects.
   
   Twelve healthy male subjects will be studied. The absence of significant medical problems will be verified by history and physical examination. All subjects will give informed consent for this study which will be approved by the local ethics committee.
   The study will be a double blind randomized crossover comparison of 2 weeks treatment with spironolactone 25 mg per day or enalapril 20 mg b.i.d alone or in combination, with a 2 week washout between treatments. Five days before the end of each treatment limb, subjects will add 14 Slow Sodium tablets (Ciba Laboratories, Horsham , UK ) a day to their daily sodium intake to achieve a daily sodium intake of 150 mmol. On the 14th day of each treatment period, subjects will arrive at the research study room having fasted overnight. A cannula will be inserted into an antecubital vein under local anaesthesia. An initial water load of 5 ml/kg will given followed by 2 ml/kg hourly throughout the study. After 2 h of sitting, each subject then received a 300 mmol sodium chloride load of a 60-min infusion of 2 liters of 0.9% sodium chloride as previously described (11). Subjects will remain seated throughout the study, except for blood pressure measurements or for micturition. After the intravenous sodium loading subjects will then be observed for an additional 4 h. Urine will be collected every 30 min throughout the study from 2 h before until 5 h after the sodium load. Measurements were made of urinary volume and electrolytes. Blood samples were taken before and at 90, 150, and 270 min after the start of the sodium load for measurement of hematocrit and hormones.
2. The Effects of Spironolactone and Enalapril Alone and in Combination on the AntiNatriuretic Effect of Noradrenaline in Healthy Subjects.
   
   Twelve healthy male subjects will be studied. The absence of significant medical problems will be verified by history and physical examination. All subjects will give informed consent for this study which will be approved by the local ethics committee.
   The study will be a double blind randomized crossover comparison of 2 weeks treatment with spironolactone 25 mg per day or enalapril 20 mg b.i.d alone or in combination, with a 2 week washout between treatments. Five days before the end of each treatment limb, subjects will add 14 Slow Sodium tablets (Ciba Laboratories, Horsham , UK) a day to their daily sodium intake to achieve a daily sodium intake of 150 mmol. On the 14th day of each treatment period, subjects will arrive at the research study room having fasted overnight. A cannula will be inserted into an antecubital vein under local anaesthesia. An initial water load of 5 ml/kg will given followed by 2 ml/kg hourly throughout the study. After 2 h of sitting, each subject then received a 30 min intravenous infusion of noradrenaline 0.075 mg/kg/min as previously described (12). Subjects will remain seated throughout the study, except for blood pressure measurements or for micturition. After the intravenous noradrenaline subjects will then be observed for an additional 1 h. Urine will be collected every 30 min throughout the study from 2 h before until 1 h after the noradrenaline. Measurements were made of urinary volume and electrolytes. Blood samples were taken before and 30 and 60 min after the start of the noradrenaline infusion for measurement of hematocrit and hormones.
   
   References
   11. Singer DR , Markandu ND , Buckley MG, Miller MA, Sagnella GA , MacGregor GA Contrasting endocrine responses to acute oral compared with intravenous sodium loading in normal humans. Am J Physiol. 1998 Jan;274(1 Pt 2):F111-9
   12. Lang CC, Rahman AR, Balfour DJK, Struthers AD. The renal effects of circulating noradrenaline in overhydrated and euhydrated man . Clinical Science 1993; 85: 487-494

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Assessment Breakdown

Research Component: 100 points
Research Report (up to 10,000 words): 75%
Oral presentation: 10%
Supervisor Evaluation: 15%

Coursework Component: 0 points
N/A

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Student Numbers

Number of places available:
1