Conference Highlights Three Key Issues in Antihypertensive Therapy

The Swedish League against Hypertension met on the 10th and 11 th of September to discuss three major concerns in antihypertensive therapy; cardiovascular hypertrophy, the pathogenesIs and prevention of renal damage and the quality of life during treatment of hypertension. The meeting, sponsored by Merck, Sharp and Dohme, was held in Stockholm and was attended by over 300 delegates

Cardiovascular Hypertrophy as a Complication of Hypertension The first session, chaired by Or L. Hansson from G6tenborg, focussed primarily on the pathogenesIs

of, and risks associated with, left ventricular hypertrophy (LVH) as a complication of hypertension.

Epidemiology and pathogenesis . .. Or O. Levy from Boston described findings from the Framingham Heart Study, which has investigated

cardiovascular function in over 5000 individuals for a period of more than 40 years. The overall incidence of L VH as detected by ECG was about 10-fold higher in hypertensive patients when compared to normotensive people, and patients with LVH are at increased risk for all cardiovascular events, including stroke and myocardial infarction. Additionally, LVH carries an increased risk for mortality: overall, 45% of cardiovascular disease deaths in the Framingham study were preceded by ECG-diagnosed LVH.

The use of echocardiography has allowed more sensitive detection of L VH and revealed a higher incidence of the condition within the general population than was previously known (16% of men and 19% of women). The prevalance of LVH increases with rising blood pressure, but a degree of LVH can be detected at what are usually considered 'normal' blood pressure values. LVH is also associated with obesity and there is a strong relationship between hypertrophy and ventricular arrhythmia.

In a review of the present knowledge about the pathogenesis of cardiovascular hypertrophy, Or B. oahlot from G6tenborg pointed out that this condition is a structural adaption by cardiac tissue in response to a sustained increase in load, and therefore work, and that some degree of change will already be present in the hypertensive patient who presents for treatment. Cardiac hypertrophy is not a late phenomenon; studies in renal-hypertensive rats showed an increase in left ventricular mass within 2 to 3 days of the onset of hypertension. Or oahlot explained that the development of cardiac hypertrophy cannot solely be explained by increased blood pressure and afterload and that permissive actions from circulating angiotensin II and the sympathetic nervous system may be involved. There is also evidence for a local renin-angiotensin system in heart tissue, and an as yet unidentified soluble factor which stimulates protein synthesis has been found in hypertrophied myocardium. In summary,or oahlof concluded that although the easiest and most immediate goal of treatment is to reduce blood pressure, a further aim should be the regression of structural cardiovascular changes .

. . . effects of antihypertensive therapies . .. This subject was reviewed by Or FH Messerli of New Orleans. The risk of cardiovascular morbidity

and mortality is increased by L VH because of reduced ventricular compliance, a predisposition to ventricular dysrhythmias and myocardial ischaemia and an eventual decrease in ventricular contractility. Despite effectiyely lowering blood pressure, not all antihypertensive treatments allow regression of LVH the thiazide diuretics and arteriolar dilators (e.g. minoxidil) in particular have no beneficial effects on LVH, while fj-blockers, ACE inhibitors, some calcium antagonists and anti adrenergic drugs do produce a decrease in left ventricular mass. It appears that a regression of LVH results in improved ventricular compliance and contractility, and a reduction in ventricular ectopic activity. Thus, it is likely that by selection of the most appropriate antihypertensive therapy it will be possible to actively reverse ventricular hypertrophy and thereby reduce the serious risks associated with this condition .

. . . and experimental models Finally, Or J.A. Levenson from Paris described the use of the forearm circulation as a model for

assessing the effects of antihypertensive drugs on arterial blood vessels. For a given decrease in blood pressure, different classes of drugs produce an increase (ACE inhibitors), decrease (vasodilators) or no change (a- and fj-antagonists) in large artery diameter and these diverse effects may produce varying actions in terms of the conduit, buffering and baroreflex functions of the major arteries. Since local blood flow is determined by a balance between the conduit function of large arteries and the resistive properties of arterioles, drugs which selectively dilate arterioles (e.g. urapidil) increase blood velocity and therefore blood flow, since arterial diameter is unchanged. In contrast, hydralazine increases velocity but does not change blood flow since it also decreases arterial diameter. ACE inhibitors and calcium antagonists dilate both arteries and arterioles and so produce large increases in blood flow. In addition to affecting blood supply to ischaemic tissues, changes in blood flow may also be Important in relation to arterial wall shear-stress phenomena, which are abnormal in hypertensive patients. The buffering capacity of large arteries depends upon compliance, and, in a double-blind comparison, 6 months of

10 INPHARMA· 10 October 1987 0156-2703/87/1010-0010/0$0100/0 <'1 ADIS Press

treatment with enalapril produced a chronic increase in the forearm artery compliance of hypertensive patients while propranolol had no effect despite similarly lowering blood pressure.

The Pathogenesis and Prevention of Renal Damage The role of intra glomerular pressure ...

To introduce this session, Professor M Aure/l of Gotenborg reviewed recent findings on the importance of intraglomerular pressure in renal damage. Systemic hypertension, once the major cause of end-stage renal failure, was traditionally thought to involve chronic excessive constriction of renal blood vessels with subsequent ischaemia and nephron damage. However, successful antihypertensive treatment does not always prevent renal damage. Professor Aurell explained that recent evidence correlates glomerular injury with intraglomerular pressure and that the damage in hypertension may in fact be due to inadequate dilation of efferent blood vessels, allowing the increased blood pressure to be transmitted to the delicate glomerular capillaries. In animal models of hypertension, direct measurement has shown elevated intraglomerular pressure. This could be reduced by treatment with enalaprll and there was also evidence that glomerular damage was reduced. In man, untreated hypertension produces a decrease in renal blood flow, but filtration rate is maintained, indicating increased intraglomerular pressure and constriction of the afferent vessels. Since these vessels are mostly controlled by angiotensin II, this may explain why ACE inhibitors are the only antihypertensive drugs that reduce intraglomerular pressure. · .. prognostic indicators ...

Proteinuria in patients on long term antihypertensive therapy may be evidence of renal damage. Dr a. Samuelsson, also from Gotenborg, stated that clinically apparent proteinuria has been found in between 4 and 18% of hypertensive patients, while microalbuminuria has an observed prevalence of 17 to 18%. Prospective epidemiological studies in both treated and untreated hypertensive patients have shown that proteinuria is an independent risk factor for cardiovascular morbidity and mortality. Treatment of hypertension with the standard triple-therapy has been found to reduce proteinuria providing the condition is mild, and preliminary studies using ACE inhibitors in combination with a thiazide diuretic have also demonstrated that proteinuria can be reduced. Dr Samuelsson concluded by saying that the ACE inhibitors may prove to be the most effective drugs in this respect, but whether a reduction of proteinuria is of real clinical benefit to the patient is not yet known.

· .• withdrawal of treatment ... Dr S. Ljungman described a study in patients who, after 7 years of treatment (mostly with

metoprolol), had their antihypertensive therapy withdrawn until a state of hypertension had returned. At the end of the treatment period, significant decreases were observed in renal blood and plasma flow and glomerular filtration rate. These decreases were greater than those seen in a control group of normotensive men and so were not simply due to ageing. Hypertension returned between 1 and 4 weeks after withdrawal of therapy and while the above renal parameters remained significantly reduced, renal vascular resistance increased to above pretreatment levels. Therefore treatment with metoprolol seemed to have little effect on renal function variables, but Dr Ljungman speculated that more aggressive treatment or other drugs may prevent the renal deterioration that occurs in hypertension.

· .. renal failure in diabetics ... Up to 50% of insulin-dependent diabetics develop signs of renal damage associated with

hypertension and Professor B. Schersf(m from Dalby discussed the use of antihypertensive therapies in diabetic patients. Metoprolol in combination with hydralazine and/or frusemide slows the reduction of glomerular filtration rate in these patients, and similar results have been seen with captopriL However, the use of p-blockers is not recommended in diabetics since they may have undesirable metabolic effects and may also mask the signs of hypoglycaemia. Animal studies have shown that enalapril reduces renal damage in rats with streptozocin-induced diabetes, while verapamil does not.

The current concensus of thought is that ACE inhibitors, calcium antagonists and prazosin are preferable to p-blockers and thiazide diuretics as first-line therapy for hypertensive diabetics

· .. and benefits of long term enalapril therapy

Dr JH Bauer of Columbia presented data from patients with essential hypertension who were treated for up to 3 years with enalapril with or without additional hydrochlorothiazide Arterial blood pressure was well controlled over this period and renal function tests revealed a 17% increase in renal plasma flow with glomerular filtration rate, filtration fraction and urinary protein excretion remaining unchanged. In a sub group of patients who had moderately impaired renal function on entry into the study, both glomerular filtration rate and renal plasma flow substantially increased with enalapril treatment.

Enalapril also proved beneficial for a small group of patients who had renal parenchymal disease. Treatment for up to 6 months produced a 22% increase in renal plasma flow with a subsequent reduction in filtration fraction, a 45% reduction in urinary protein excretion, and glomerular filtration rate was maintained. Dr Bauer remarked that these promising results may be drug- rather than class-specific, and similar effects may not be seen with ACE inhibitors other than enalapriL (continued next week) ADIS Editors

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