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for 1.1% of male years of life lost and 1.4% of female years of life lost in the same year.3This high morbidity and unnecessary mortality occurred despite readily available and cost-effective treatment regimens. The aim of clinical guidelines is to promote good medical practice4by assisting practitioners to provide optimal and cost-effective care. Eccles et al.5in the former Northern Region of the UK, found that 25% of practices were not aware of the availability of guidelines for the management of asthma, diabetes and hypertension.5Studies have found that even when clinical guidelines are available they are not adopted. It is therefore imperative that a strategy promoting the acceptance and use of clinical guidelines by practitioners be developed.6By using asthma guidelines, the severity of asthma is more likely to be graded accurately and medicated appropriately. To encourage adherence to the prescribed regimen it is important for practitioners to ensure that patients understand the necessity for and the safety of inhaled steroids. The use of cough mixtures is neither recommended nor indicated in the management of asthma.
The finding in this study that 36.4% of patients did not
receive the recommended medication commensurate with the severity of their asthma is cause for concern. If this problem is not addressed, it is unlikely that there will be an improvement in the current unacceptably high morbidity and mortality associated with asthma in South Africa.
Sherwin Kathawaroo Graham Hukins Department of Family Medicine University of the Witwatersrand Johannesburg
1. Allergy Society of South Africa Working Group. Guideline for the management of chronic asthma in adults — 2000 update. S Afr Med J 2000; 90: Part 2, 540 - 541.
2. Mayo PH, Richman J, Harris HW. Results of a program to reduce admissions for adult asthma. Ann Intern Med 1999; 112: 864-871.
3. Bradshaw D, Schneider M, Dorrington R, Bourne DE, Laubsher R. South African cause-of-life death profile in transition — 1996 and future trends. S Afr Med J 2002; 92: 618-623.
4. Keffer JH. Guidelines and algorithms: perceptions of why and when they are successful and how to improve them. Clin Chem 2001; 47: 1563-1572.
5. Eccles MP, Souter J, Bateman DN, Campbell M, Smith JM. Influence on prescribing in non- fundholding general practices. Br J Gen Pract 1996; 46: 207-290.
6. Graham ID, Beardall S, Carter AO, Tetroe J, Davies B. The state of the science and art of practice guidelines development, dissemination and evaluation in Canada. J Eval Clin Pract 2003; 9: 195-202.
October 2004, Vol. 94, No. 10 SAMJ
A phosphodiesterase inhibitor promotes the premature development of adverse cardiac remodelling mediated by beta-adrenergic activation in hypertension
To the Editor:Cardiac dilatation is thought to contribute to pump dysfunction in heart failure. In hypertension, left ventricular hypertrophy (LVH) can progress from a concentric geometry to left ventricular (LV) dilatation. The mechanisms responsible for the transition from concentric LVH to cardiac dilatation in hypertension are uncertain. In human studies LVH is associated with an increased sympathetic activity to the myocardium, but not to other tissue beds.1Our group has therefore proposed that sympathetic over-activation in LVH could mediate the transition from concentric LVH to cardiac dilatation. Indeed, we have demonstrated that in
spontaneously hypertensive rats (SHRs) with concentric LVH, daily administration of low doses of a beta-adrenoreceptor (β-AR) agonist promotes the development of marked cardiac dilatation.2However, β-AR-induced effects can be mediated by cyclic adenosine monophosphate (cAMP)-dependent and independent pathways.3To explore the role of β-AR-cAMP pathways in mediating the transition from concentric LVH to LV dilatation, we evaluated the effect of a phosphodiesterase inhibitor (PDEI), used either alone or with a β-AR agonist, on LV geometry and function in SHRs with concentric LVH.
Methods
Fourteen-month-old SHRs and Wistar Kyoto (WKY) control rats were used for this study. SHRs either received no therapy, a β-AR agonist (isoproterenol, daily as previously described2), a PDEI (pentoxifylline, 50 mg/kg/day in the drinking water), or both the β-AR agonist and the PDEI for 3 months. To ensure that the β-AR agonist was effective, additional SHRs were either left untreated or received the β-AR agonist for 5.5 months.
LV cavity size was assessed using three techniques. First, two-dimensional directed M-mode echocardiography was performed using a Sonos model 2500 Hewlett Packard echocardiograph with a 7.5 MHz transducer.4Second, LV end diastolic (LVED) dimensions were assessed using piezoelectric ultrasonic transducers placed across the short axis of the heart at controlled LVED pressures (LVEDP) in open-chest,
ventilated rats.2Third, LV diastolic pressure-volume relations were constructed in isolated, perfused heart preparations and the volume intercept at a diastolic pressure of 0 mmHg (LV V0) was determined.2,4To assess further the impact of the β-AR agonist and the PDEI on cardiac remodelling, myocardial collagen content was determined using hydroxyproline ((HPRO) determinations.2,4
October 2004, Vol. 94, No. 10 SAMJ
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Results
LV cavity dimensions were similar between WKY rats (data not shown) and untreated SHRs (Table I). Although the β-AR agonist was able to induce significant cardiac dilatation after 5.5 months of administration to SHRs (data not shown), 3 months of administration of the β-AR agonist to SHRs failed to induce LV dilatation (Table I). Further, although administration of the PDEI alone failed to modify LV parameters (data not shown), co-administration of the β-AR agonist and the PDEI to SHRs produced marked increases in LV cavity dimensions and myocardial collagen concentrations (Table I).
Discussion
The main findings of this study are that a PDEI potentiates β-AR agonist-mediated LV dilatation in SHRs with concentric LVH. As PDEIs and β-AR agonists share a common cellular pathway, namely the β-AR-cAMP pathway, these data suggest that cAMP is an important mediator of the transition from concentric LVH to LV dilatation. The clinical implication of these findings is that pharmacological agents that increase the activity of this pathway could promote further dilatation in LVH in heart failure.
These findings were presented at the 13th Biennial Congress of the South African Hypertension Society, Johannesburg, 7 - 9 March 2003.
D Badenhorst C Anamourlis M Gibbs M Maseko O Osadchii A J Woodiwiss G R Norton
Cardiovascular Pathophysiology and Genomics Research Unit Schools of Physiology and Medicine
University of the Witwatersrand Johannesburg
1. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relations between cardiac sympathetic activity and hypertensive left ventricular hypertrophy.
Circulation 2003; 108: 560-565.
2. Badenhorst D, Veliotes D, Maseko M, et al. Beta-adrenergic activation initiates chamber dilatation in concentric hypertrophy. Hypertension 2003; 41: 499-504.
3. Ma YC, Huang XY. Novel signaling pathway through the beta-adrenergic receptor. Trends in Cardiovascular Medicine 2002; 12: 46-49.
4. Norton GR, Woodiwiss AJ, Gaasch WH, et al. Heart failure in pressure overload hypertrophy:
the relative roles of ventricular remodeling and myocardial dysfunction. J Am Coll Cardiol 2002; 39: 664-667.
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Table I. Effect of chronic administration of the phosphodiesterase inhibitor (PDEI), pentoxifylline, on left ventricular (LV)
dimensions and myocardial collagen characteristics in spontaneously hypertensive rats (SHRs) (mean ± SEM)
SHR groups
β-AR agonist +
Treatment Placebo β-AR agonist PDEI
Sample size (N) 8 7 9
LVEDD (cm) 0.67 ± 0.02 0.65 ± 0.03 0.75 ± 0.03*
LVEDr†(cm) 0.25 ± 0.04 0.31 ± 0.04 0.37 ± 0.03*
LV V0 (ml) 0.20 ± 0.01 0.22 ± 0.01 0.27 ± 0.01*
HPRO‡ 5.6 ± 0.6 6.4 ± 0.9 8.5 ± 0.8*
*p < 0.05 versus placebo treated.
†At an LVED pressure of 2 mmHg.
‡In µg/mg dry LV.
β-AR = beta-adrenoreceptor; PDEI = phosphodiesterase inhibitor; LVEDD = left ventricular end diastolic diameter; LVEDr = left ventricular end diastolic radius;
LV V0= volume intercept at a left ventricular diastolic pressure of 0 mmHg; HPRO = hydroxyproline.