How far to lower blood pressure.
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Blood Pressure↗
Biomedical subjects
J M Cruickshank
Publications and source records attributed to J M Cruickshank.
Treatment of hypertension in older adults.
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Adrenergic beta-Antagonists↗
The J curve lives.
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Antihypertensive Agents↗
Remodeling and reparation of the cardiovascular system.
Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.
Animals↗
The role of coronary perfusion pressure.
Coronary flow is normally autoregulated so that within wide limits of changes in perfusion pressure (which approximate to diastolic BP) blood flow to the heart remains constant. Thus, as perfusion pressure falls, the coronary arterioles dilate to maintain flow; under basal conditions a five-fold increase in coronary flow can occur, i.e. a flow reserve of five. Coronary flow reserve is markedly impaired in the presence of severe coronary artery stenosis and/or LVH. In the presence of severe stenosis and LVH a fall in perfusion pressure (DBP), which would be normally well tolerated, results in a fall of coronary flow, ECG changes and ventricular dysfunction (fall in ejection fraction instead of the usual increase). The above mechanisms underlie the J-curve relationship between DBP and myocardial infarction (MI) in high risk hypertensives. In the absence of overt coronary artery disease (CAD) and LVH, the lower the DBP the better. However in the presence of CAD and LVH lowering the DBP (phase 5) to below the low-mid 80s results in an increased frequency of MI.
Blood Pressure↗
Beta-blockers: primary and secondary prevention.
Coronary heart disease is the most frequent cause of death in Western, industrialized countries. Coronary risk factors are prevalent in such countries and sometimes combine to constitute the so-called syndrome X--hypertension, central obesity, serum lipid and clotting disturbances, and insulin resistance. beta-Blockers, unlike calcium antagonists, have proved highly effective in secondary prevention of myocardial infarction. If present at the time of the myocardial infarction, beta-blockers (unlike calcium antagonists and diuretics) probably decrease mortality 1 month later. Early intervention (within 12 h) of chest pain with intravenous beta-blockers results in a 15% reduction in cardiovascular mortality at 1 week. Later intervention (3-28 days) with oral non-ISA beta-blockers results in a 30% reduction in mortality after 1 year; ISA-containing beta-blockers are probably less effective (less decrease in heart rate). Hydrophilicity/lipophilicity of beta-blockers is unimportant in terms of decreased mortality. Primary prevention of myocardial infarction, unlike stroke, in hypertensive patients has been disappointing, possibly due to treatment-induced biochemical/lipid changes or inappropriate lowering of diastolic blood pressure in high-risk subjects (J-curve effect). beta-Blockers should be first-line therapy for hypertensive patients up to the age of 65 years, particularly men (and nonsmokers) as Q-wave myocardial infarction is significantly decreased by beta-blockers and significantly increased by diuretics. However, in elderly hypertensive subjects, beta-blockers have not significantly decreased myocardial infarction (unlike stroke), whereas diuretics have. The effects of beta-blockers and diuretics on heart size (and thus coronary flow reserve) in the elderly may be important. Thus, beta-blockers should be second-line therapy for the elderly hypertensive individual but first-line if overt ischemia (e.g., angina or recent myocardial infarction) also is present. In patients with angina but normal blood pressure, beta-blockers tend to decrease and calcium antagonists increase cardiovascular events. Thus, beta-blockers are highly effective agents in the secondary prevention of myocardial infarction and are moderately effective in primary prevention of myocardial infarction in hypertensive patients (particularly men) under the age of 65 years.
Adrenergic beta-Antagonists↗
Clinical importance of coronary perfusion pressure in the hypertensive patient with left ventricular hypertrophy.
In patients with severe left ventricular hypertrophy (LVH), but no significant coronary artery disease (CAD), acute lowering of diastolic blood pressure (DBP) to less than 85 mm Hg is reported to result in a 26% fall in coronary blood flow and an increase in myocardial oxygen demand; S-T segment and T-wave changes in the ECG are observed when DBP is acutely lowered to the 70s in these patients. In the presence of good resting left ventricular function, acute lowering of DBP to the 60s in well-controlled hypertensives on a beta-blocker, with either CAD or LVH, results in a mean increase of about 20% in ventricular ejection fraction. By contrast, patients with a combination of CAD and LVH experience a mean 6% fall in ejection fraction implying poor left ventricular functional reserve. In low risk populations, which exclude patients with severe ischaemia, diabetics and smokers, the lower the DBP the fewer the number of myocardial infarctions. However, in heterogeneous hypertensive populations which include high risk patients, such as ischaemics and diabetics (e.g. the MRFIT population), there is a strong U- or J-curve relationship between DBP and CAD deaths. Meta-analysis of high quality studies involving heterogeneous populations has shown that the U- or J-point is at 84 mm Hg and probably relates to high risk patients with ischaemia and/or LVH. Recent data from the Framingham group indicate that the patients most at risk are those with a combination of CAD and LVH: these patients showed a marked U-shaped curve with the U- or J-point at about 85-89 mm Hg DBP.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reversibility of left ventricular hypertrophy.
Left ventricular hypertrophy (LVH) is a powerful independent risk factor for coronary artery disease. This overview of 104 studies examines the ability of various types of antihypertensive therapies to reverse LVH as assessed by echocardiography. Combination therapy, angiotensin converting enzyme (ACE) inhibitors, and methyldopa were the most effective in reversing LV mass; vasodilators such as minoxidil and hydralazine had no effect on LVH. These differences were independent of the degree of fall in blood pressure and duration of therapy. beta-blockers were as effective as ACE inhibitors in decreasing LV wall thickness. Possible reasons for drug differences in reversing LVH are discussed. Preliminary evidence suggests that reversing LVH by antihypertensive drug therapy is associated with a reduction in cardiovascular complications.
Antihypertensive Agents↗
The case for beta-blockers as first-line antihypertensive therapy.
REASON FOR TREATMENT: In patients with asymptomatic high blood pressure, antihypertensive treatment is initiated for only one reason, to prevent the hypertensive sequelae of myocardial infarction, stroke and heart failure. MORBIDITY, MORTALITY AND SURROGATE ENDPOINTS: Only diuretics and beta-blockers have been shown to benefit hypertensive patients in terms of the hard endpoints morbidity and mortality. beta-Blockers and diuretics are cheaper than newer drugs and thus represent good value for money. It is not acceptable to use drug effects on plasma lipids or insulin resistance as measures of the effects on coronary heart disease, since dihydropyridine calcium antagonists improve these parameters while significantly increasing coronary heart disease events in the acute and chronic ischaemic situation. PATIENT PROFILING: Diuretics. Diuretics appear particularly suited to elderly hypertensives, especially those with isolated systolic hypertension, but they may increase cardiac events in younger and middle-aged diabetic and non-diabetic hypertensives. Angiotensin converting enzyme (ACE) inhibitors. ACE inhibitors are undoubtedly valuable in the presence of left ventricular dysfunction, and possibly in the diabetic in maintaining good renal function. beta-Blockers. beta-Blockers are particularly well suited to younger and middle-aged hypertensives at all blood pressure levels, especially white males; where ischaemia and/or stress is a factor, beta-blockers can significantly reduce the incidence of myocardial infarction and strokes. beta-Blockers benefit elderly hypertensives by preventing strokes and may prevent coronary heart disease if prescribed with a diuretic.
Adrenergic alpha-Antagonists↗
Antihypertensive drugs and cardioprotection.
Cardioprotection is a broad term; this short review deals with six aspects: 1. Secondary prevention of myocardial infarction (MI) has been shown for beta-blockers in both early and late intervention studies. Dihydropyridine calcium antagonists are associated with an excess incidence of coronary events, whereas non-dihydropyridines prevent reinfarction provided left ventricular (LV) function is adequate; dihydropyridines tend to increase heart rate and stimulate the sympathetic and renin-angiotensin systems. 2. Primary prevention of MI has been shown for beta-blockers in younger/middle-aged hypertensives but not in the elderly. Diuretics, by contrast, possibly increase the risk of coronary events in younger/middle-aged hypertensives but significantly reduce coronary events in older hypertensives. These results might be explained by the larger, noncompliant left ventricle of the elderly hypertensive, which, in the absence of overt ischemia, responds poorly to beta-blockade (further enlargement with increased wall stress and impaired coronary reserve), while diuretics have the opposite effect. Primary prevention of coronary events in patients with chronic angina is likely to occur with beta-blockers, while studies with calcium antagonists have shown a significant excess of coronary events. 3. Ischemic events occurring during the "vulnerable" period between 7 and 10 AM (when sympathetic activity is maximal) are significantly reduced by beta-blockers but not by calcium antagonists. 4. Stress-induced myocardial necrosis in humans is markedly reduced by beta-blockers. 5. Coronary risk factors, such as elevated blood lipids, hyperglycemia, and insulin resistance, are possibly adversely affected by diuretics and beta-blockers, with the former also increasing heart rate, plasma renin activity, and plasma catecholamine levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Do we need more beta-blockers?
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Adrenergic beta-Antagonists↗
Reversibility of left ventricular hypertrophy by differing types of antihypertensive therapy.
Left ventricular hypertrophy (LVH), as assessed by ECG or echocardiography, is a powerful independent coronary risk factor. The present overview of 104 studies sets out to compare the ability of various forms of antihypertensive therapy to reverse LVH as assessed by echocardiography. Most observations involved four classes of treatment--combination therapy, ACE inhibitors, beta-blockers and calcium antagonists (mainly dihydropyridines). The former two therapies were significantly more effective than the latter two in reversing LV mass, independently of length of time on treatment and degree of fall in blood pressure. Possible reasons for these differences are discussed. The clinical significance of these results is unclear although preliminary data indicate that regressing LVH is associated with fewer cardiovascular events.
Antihypertensive Agents↗
Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study.
OBJECTIVE: To examine the hypothesis that a J curve relation between blood pressure and death from coronary heart disease is confined to high risk subjects with myocardial infarction. DESIGN: Cohort longitudinal epidemiological study with biennial examinations since 1950. SETTING: Framingham, Massachusetts, USA. SUBJECTS: 5209 subjects in the Framingham study cohort followed up by a person examination approach. MAIN OUTCOME MEASURES: Coronary heart disease deaths and non-cardiovascular disease deaths in men and women with or without myocardial infarction relative to blood pressure. RESULTS: Among subjects without myocardial infarction non-cardiovascular disease deaths were twice to three times as common as coronary heart disease deaths. Furthermore, there was no significant relation between non-cardiovascular disease death and diastolic or systolic blood pressure. Also coronary heart disease deaths were linearly related to diastolic and systolic blood pressures. Among high risk patients (that is, people with myocardial infarction but free of congestive heart failure) death from coronary heart disease was more common than non-cardiovascular disease death. There was a significant U shaped relation between coronary heart disease death and diastolic blood pressure. Although there was an apparent U shaped relation between coronary heart disease death and systolic blood pressure, it did not attain statistical significance when controlling for age and change in systolic blood pressure from the pre-myocardial infarction level. None of the above conclusions changed when adjustments were made for risk factors such as serum cholesterol concentration, antihypertensive treatment, and left ventricular function. The U shaped relation between diastolic blood pressure and high risk subjects existed for both those given antihypertensive treatment and those not. CONCLUSIONS: These data suggest that an age and sex independent U curve relation exists for diastolic blood pressure and coronary heart disease deaths in patients with myocardial infarction but not for low risk subjects without myocardial infarction. The relation seems to be independent of left ventricular function and antihypertensive treatment.
Adult↗
Identification of patients at risk from ischaemic complications.
Several risk factors for cardiovascular disease are discussed, including blood pressure, left ventricular hypertrophy, stress and smoking. Beta-blockers have a modest effect in reversing increased left ventricular mass, compared with angiotensin converting enzyme (ACE) inhibitors, although beta-blockers are as effective as ACE inhibitors in reducing posterior wall and interventricular septal thickness. Coronary events and many risk factors show a circadian rhythm. Beta-blockers can reduce the mid-morning (0700-1000 h) risk of ischaemic events and myocardial infarction. Catecholamine levels peak at 0700-1000 h, and catecholamine-induced myocardial necrosis can be significantly reduced by beta-blockade. Beta-blockers appear to be more effective than calcium antagonists in modifying the mid-morning vulnerable period and reducing the duration of ischaemia. However, the problems of using surrogate endpoints are discussed. In young to middle-aged hypertensives, beta-blockers are more effective in primary prevention of myocardial events than diuretics, though this is not the case for the elderly. Beta-blockers are also more effective than calcium antagonists in reducing morbidity and mortality after a myocardial infarction (i.e. secondary prevention). Patients with hypertension associated with ischaemic heart disease are most likely to get maximal benefit from treatment with beta-blockers.
Adrenergic beta-Antagonists↗
Atenolol and ischaemic heart disease: an overview.
Data generated to date on the use of beta-blockers, especially atenolol, in ischaemic heart disease are reviewed and compared with the results available with the calcium antagonists. Atenolol appears to be effective as an anti-ischaemic agent in patients with obstructive coronary artery disease when reduction in myocardial oxygen supply (ischaemia not preceded by an increase in heart rate and due presumably to functional coronary stenosis) or increase in demand are the likely causes. Based on current concepts and available data, there is convincing evidence to support the use of atenolol across the spectrum of ischaemic heart disease. In contrast, results with the calcium antagonists have been disappointing and variable. Atenolol, to date, is the only beta-blocker which has been demonstrated to have a life-saving benefit in acute intervention (within 12 hours of onset) in myocardial infarction. This cardioprotective aspect of the drug is likely to be applicable to other areas of ischaemic heart disease, including silent ischaemia.
Atenolol↗
What does the future hold for ACE inhibitors?
The most common cause of death in hypertensive patients is myocardial infarction (MI), being three times more common than stroke. Lowering raised BP results in 40% fewer strokes, but only 14% fewer MIs. This may be because other coronary risk factors that often accompany hypertension (e.g. obesity, lipid and thrombotic disturbances, insulin insensitivity, increased plasma renin activity and increased sympathetic activity) are either unaffected or exacerbated by some of the traditional antihypertensive agents. Some of these risk factors show a diurnal rhythm peaking at 07.00-10.00 hours, thus this time constitutes a 'vulnerable period' for sudden death or death from MI. beta-blockers and diuretics have been effective in preventing stroke, but diuretics (at least potassium-losing diuretics) might actually increase the incidence of sudden death and MI in young to middle-aged hypertensive subjects (though elderly patients may benefit). Quality of life can be impaired by some beta-blockers, and diuretics can cause metabolic upset and male impotence. Thus, antihypertensive agents that are not only effective and well tolerated but are beneficial to the broader coronary risk profile are desirable. ACE inhibitors should prove particularly useful in terms of: good quality of life; non-exacerbation or improvement of coronary risk factors; treating patients with impaired left ventricular function; reversing left ventricular hypertrophy and vascular wall hypertrophy, thus improving coronary flow reserve; atheroma regression; renal protection, particularly in diabetes; and prevention or regression of LV dilatation (remodelling) following MI.
Angiotensin-Converting Enzyme Inhibitors↗
The stress response in subarachnoid haemorrhage and head injury.
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Adult↗
Beta-blockers and central nervous system side effects.
Beta-adrenergic blocking drugs are a widely used, well tolerated and effective treatment for a variety of cardiovascular and noncardiovascular disorders. Over the years, beta-blockers have been associated with an incidence, albeit low, of CNS side effects. The question of interest, however, is whether the incidence is the same for all members of the class or whether other properties, such as hydrophilicity, have a bearing on the incidence of this type of side effect? This article addresses this question. In pharmacokinetic terms the lipophilic beta-blockers have been shown, both in animals and man, to readily cross the blood-brain barrier in contrast to hydrophilic beta-blockers. This is thought to have possible clinical relevance with respect to the relative incidence of CNS side-effects. To clarify the situation every published clinical paper, in which the beta-blockers propranolol (highly lipophilic, nonselective, no intrinsic sympathomimetic activity (ISA)), pindolol (moderately lipophilic, nonselective, moderate ISA), metoprolol (moderately lipophilic, beta 1-selective, no ISA) and atenolol (hydrophilic beta 1-selective, no ISA) were compared, was assessed for information pertaining to CNS side effects. This comprehensive review of the literature has shown, with few exceptions, that the incidence of CNS side effects such as sleep disturbances, dreaming, nightmares and hallucinations following clinically accepted doses of the four beta-blockers under scrutiny is generally low and that effects on short-term memory are minimal or absent. However, within this group of four drugs the incidence of these side effects is lowest with hydrophilic atenolol and generally highest with pindolol and propranolol. Metoprolol occupies an intermediate position. This order is in agreement with the pharmacokinetic observation that the more hydrophilic the molecule, the less is found in the brain tissue of both animals and man, although in the case of pindolol other factors may be important. The clinical relevance of studies involving psychometric testing is not clear.
Adrenergic beta-Antagonists↗