Hypertension: from basic research to clinical practice

John M. Cruickshank, Cruickshank, John M.

Two major guide-line committees (JNC-8 and NICE UK) have dropped beta-blockers as first-line therapy in the treatment of hypertension. Also, recent meta-analyses (that do not take age into account) have concluded that beta-blockers are inappropriate first-line agents in the treatment of hypertension. This review seeks to shed some light on the "rights and wrongs" of such actions and conclusions. Because the pathophysiology of primary/essential hypertension differs in elderly and younger subjects, the latter being closely linked to obesity and increased sympathetic nerve activity, the author sought to clarify the efficacy of beta-blockers in the younger/middle-aged group in reducing the risk of death, and cardiovascular end-points. Four searches were undertaken, utilising PubMed up to 31st Dec 2015. One search was under the terms "hypertension AND obesity AND sympathetic nerve activity". A second was "hypertension AND plasma noradrenaline/norepinephrine AND survival". A third was "beta-blockers or adrenergic beta-antagonists AND hypertension AND age AND stroke or myocardial infarction or death". A fourth was "meta-analysis of beta-blockers AND hypertension AND age AND death, stroke, myocardial infarction" RESULTS: Diastolic (with or without systolic) hypertension, in contrast to isolated systolic hypertension, occurs primarily in younger subjects, and is linked to overweight/obesity and increased sympathetic nerve activity. In younger/middle-aged hypertensive subjects, high plasma norepinephrine levels are linked (independent of blood pressure) to an increased risk of future cardiovascular events and death. High resting heart rates (a surrogate for high sympathetic nerve activity) likewise predict premature all-cause death, coronary heart disease and cardiovascular events in younger hypertensive subjects. In this younger/middle-aged hypertensive group, antihypertensive agents that increase sympathetic nerve activity (diuretics, dihydropyridine calcium blockers, and angiotensin receptor blockers (ARBs)) do not decrease (and may increase) the risk of myocardial infarction, and are therefore inappropriate first-line agents in this age-group. By contrast, in younger/middle-aged hypertensive subjects (less than 60 years old), meta-analysis has shown that beta-blockers are significantly superior to randomised placebo, and at least as effective as randomised comparator agents, in reducing death/stroke/myocardial infarction. In this younger/middle-aged hypertensive group beta-blockers have been shown (vs randomised placebo or diuretics) to reduce the risk of myocardial infarction by 35-50 %, and stroke by 50-55 % (vs placebo), in non-smoker men. Atenolol was at least as effective as ACE-inhibition (captopril) in reducing all 7 cardiovascular endpoints (including stroke which was reduced by 50 %), vs less tight control of blood pressure, in obese hypertensive subjects with type-2 diabetes (UKPDS study); and after 20 years follow-up, atenolol was significantly (23 %) superior to the ACE-inhibitor in reducing the risk of all-cause death (beta-blockers have anti-cancer properties, which maybe relevant). Primary/essential hypertension in younger/middle-age is underpinned by high sympathetic nerve activity. In this age-group high resting heart rates and high plasma norepinephrine levels (independent of blood pressure) are linked to premature cardiovascular events and death. Thus, anti-hypertensive agents that increase sympathetic nerve activity ie diuretics, dihydropyridine calcium blockers, and ARBs, are inappropriate first-line choices in this younger age-group. Beta-blockers perform well vs randomised placebo and other antihypertensive agents regarding reduced risk of death/stroke/myocardial infarction in younger (<60 years) hypertensive subjects, and are a reasonable first-line choice of therapy (certainly in men). These facts should be reflected in the recommendations of guideline committees around the world.