WHO meeting on community control of stroke and hypertension: Copenhagen, Geneva, 8-16 November 1972: pathophysiological aspects of mild hypertension

• WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTa WHO MEETING ON COMMUNITY CONTROL OF STROKE AND HYPERTENSION Copenhagen/Geneva, 8-16 November 1972 cvn/s/12.2a ENGLISH ONLY PATHOPHYSIOLOGICAL ASPECTS OF MILD HYPERTENSION by E. Varnauskas Department of Cardiology Sahlgren's Hospital, G~teborg, Sweden 1. Clinical definition The WHO criteria defining essential hypertension stage I (technical report No. 231, Geneva 1962) are generally used to define the patient groups in which pathophysiological aspects of mild hypertension are investigated. The arterial blood pressure of 140-150/90-100 as measured in the office or clinic is usually selected as a dividing line between normotension and hypertension. The dividing line between mild and successive stages of hypertension is defined as elevated but labile arterial pressure without evidence of organic changes in the cardiovascular system. It should be emphasized that this definition makes no claim of being precise with respect to the exact place of mild hypertension in the natural history.of essential hypertension. 2. Hemodynamics of mild hypertension 2.1 By definition the arterial pressure is on the average above the arbitrary chosen limit for normal pressure. The frequently quoted question of variability of blood pressure as a typical characteristic of mild hypertension is not settled. Studies employing automatic 24 hour recording of arterial pressure disclose that the fluctuations in pressure are very large both in patients with various stages of hypertension and in subjects with normal pressure. The "!ability" of blood pressure is thus not a specific finding in mild hypertension. 2.2 Systematical hemodynamic investigations of patients with essential hypertension have disclosed occurrence of increased cardiac output in relation to the values of selected normal controls. High cardiac output was more frequently found in the younger patient groups and in those with mild hypertension as compared with older patients and those with more severe hypertension respectively. Collected cardiac output data published by various investigators are, however, somewhat difficult to interpret because of the discrepancies in the simultaneously reported normal values. In some studies normal values were obtained from small series of predominantly young individuals. In other studies which have included larger series of normals no correlation was found between cardiac output and age. Again in some other studies such correlation was found to be statistically significant i.e. cardiac output decreases with increasing age. The issue of this document does not constitute formal publication. It should not be reviewed, abstracted or quoted without the agreement of the World Health Organization. Authors alone are responsible for views expreaaed in signed articles. Ce document ne constitue pas une publication. II ne dolt faire l'objet d'aucun compte rendu ou ,,sum, ni d'aucune citation sans l'autorisation de !'Organisation Mondlale de la Sant,. Les opinions exprlm,es dans lea articles slgn,a n'engagent que leura auteura. cvo/s/12.2a page 2 Cardiac output values from some selected studies are presented in figures. The available data suggest that cardiac output elevation in essential hypertension is not simply age dependent, that is to say, that high values are a~so found among the older subjects. Furthermore, increased cardiac output may be also present in patients with stage II hypertension and thus not only in stage I. A clear majority of stage II patients have, however, normal values. Subnormal cardiac output is generally encoun- tered in patients with marked changes in cardiovascular system (stage III hypertension). 2.3 The question whether the elevated fraction of cardiac output is evenly or unevenly distributed to all vascular beds cannot be definitely answered as yet. Studies of regional circulation in the upper and lower extremities indicate that muscle blood flow is increased. Investigations of blood flow in other regions if at all available offer no conclusive results. Some investigators have reported increased renal flow in patients with mild hypertension as compared with control values. Reliable measurements of coronary blood flow in mild hypertension are not available but it is quite probable that coronary blood flow is increased because of elevated systolic blood pressure and heart rate, factors directly determining myocardial oxygen consumption. Nevertheless it has been suggested that an increased cardiac output is preferentially distributed to muscle vessels while other circuits may become constricted implying that the blood flow to these circuits may be normal or decreased, 2.4 It has been shown that heart rate is higher in practically all stages of essential hypertension as compared with control values. Similarly to cardiac output findings larger heart rate differences were seen in younger patients and in those with mild hypertension. Contrary to this some other studies did not disclose any significant heart rate increase in essential hypertension. 2.5 Studies which have recorded increased heart rate values have also shown that stroke volume is normal in mild hypertension and that it decreases with decreasing cardiac output in older patients and in those with more severe disease. On the other hand those studies which disclose normal heart rate values showed an increased stroke volume in stage I hypertension while stroke volume was lower than normal in the successive stages of essential hypertension. Considering heart rate and stroke volume together it can be concluded that it is not entirely established whether observed high levels of cardiac output in mild hypertension are largely dependent on significant increase of heart rate or of stroke volume. The majority of the data favours however heart rate increase as the determinant variable of cardiac output increase. 2.6 The role of the intravascular blood volume in causing and/or maintaining an elevated arterial blood pressure in mild essential hypertension is not sufficiently clear despite all the measurements reported in the literature. This can possibly be due to the fact that none of the more extensive investigations included measurements of the total extracellular water space. The ratio between intravascular and interstitial fluid volumes might have more significance on changes in peripheral vascular resistance and arterial blood pressure than intravascular blood volume alone, 2.7 It is well established that (basal) oxygen consumption is higher in patients with mild hypertension than in normotensive subjects. So far there is no valid explanation for this significant observation. cvo/s/12.2e page 3 2.8 Arterio-venous oxygen difference is generally found to be lower than normal values due to higher oxygen content of th~ mixed venous blood. This suggests that oxygen extraction from the capillary blood by the tissue cells is less than normal in spite of increased total oxygen consumption. Consequently, the increase of cardiac output is in excess of metabolic demands of the tissues. Attempting to explain this "luxurious" perfusion of the tissues (predominantly muscle tissue) one could consider three mechanisms: (1) increased intravascular blood volume and thus increased venous return; (2) increased neurohumoral stimulus on the cardiovascular system which can be initiated from cortico-hypothalamic structures; (3) disorder of the subcellular mechanism for oxygen extraction in the muscle tissue. The relative importance of these three mechanisms is at the present time difficult to assess. 2.9 The above hemodynamic picture of mild hypertension, that is to say, variable blood pressure elevation, increased blood flow, elevated-normal heart rate, low arteriovenous oxygen difference and increased oxygen consumption corresponds to what is frequently defined as hyperkinetic circulation. Hyperkinetic circulation is known to occur in normal and various clinical conditions. Anxiety as encountered both in normal individuals and in cardiac patients is characterized by circulatory hyperkinesia due to the fact that physiological defence mechanisms are brought into play in this condition. Persons with neuro-circulatory asthenia have in general hyperkinetic circulatory features as in anxiety. Anaemia, hyperthyroidism, peripheral arterio-venous fistula also exhibit characteristics of hyperkinetic circula- tion. Furthermore, an important question arises whether hyperkinetic circulation is simply a quantitative extension of normal. la it possible to define a dividing line between normo- and hyperkinetic circulatory state? Hemodynamic studies of the effect of physical training both in normal men and in patients with coronary disease including those with elevated arterial pressure suggest that a circulatory state can be signifi- cantly altered by changes in physical fitness. Heart rate, cardiac output and arterial pressure may decrease while arteriovenous oxygen difference increases with increasing physical fitness. There is evidence favouring the hypothesis that these changes are brought about by subcellular adaptation in the trained muscle mass. It seems thus obvious that a definition of the dividing line between normal and hyperkinetic circulation (i.e. between hemodynamics of normotension and mild hypertension) calls for great caution and it probably always will be based on arbitrary and pragmatic criteria. 2.10 The discovery that total peripheral vascular resistance defined as arterial blood pressure/cardiac output is generally within normal limits in patients with mild hypertension gives rise to many hypothetical explanations of the causes of blood pressure elevation in essential hypertension. The established concept that hypertension is always due to increased peripheral vascular resistance has been questioned. Nevertheless it was also apparent that the control of peripheral vascular resistance must be impaired: the vascular bed cannot adjust itself to an increased cardiac output. The increased cardiac output has to be impelled by elevated perfusion pressure. cvo/s/12.2e page 4 2.11 Regional resistance to flow. Forearm and hand blood flow measurements together with simultaneous blood pressure recordi~g in the brachial artery have convincingly demonstrated that the resistance to flow is increased in mild hypertension both in the basal state and at maximal dilatation of the vascular bed. The basal tone, defined as basal resistance divided by the resistance at maximal dilatation was found to be the same in hypertensive as in normotensive subjects. This indicates that significantly increased amounts of direct acting circulating constrictor agents, or other factors causing vascular smooth muscle excitation, cannot be present during the prevailing experimental conditions. The concept of an increased smooth muscle tone, as caused e.g. by circulating pressor substances has been widely accepted as the main hemodynamic factor behind the increased blood pressure in essential hypertension, although no-one has definitely proved the existence of such an increased tone. The smooth muscle sensitivity in the resistance vessels, as expressed by the threshold to a graded intra-arterial noradrenaline infusion was found to be equal in normotensive and hypertensive subjects. 'lbus, the sensitivity of the vascular smooth muscle to noradrenaline is not increased in patients with essential hypertension. The reactivity of the resistance vessels as defined by the slope of the dose- response curve during graded intra-arterial noradrenaline infusion was found to be increased in hypertensive subjects. The increased slope of the dose-response curve is easily explained by a decrease of vascular lumen. The cause of this lumen decrease can of course be structural or functional. When taken together, the hemodynamic alterations in the vascular bed of the hand indicate the presence of a wall thickening in the resistance vessels of such a nature that it encroaches upon the lumen even at maximal dilatation. The wall/lumen ratio is increased. This does, of course, not exclude the possibility of an increased vasomotor fibre activity being superimposed on the structurally based increase of flow resistance. An intermittently increased vasomotor fibre activity during daily life is a normal physiological phenomenon which undoubtedly influences the resistance to flow and arterial pressure. Vasomotor fibre activity must be inhibited when experimental studies are performed to investigate the nature of an increased peripheral vascular resistance, as it has been done in some of the above-mentioned studies. 2.12 However, the explanation of the increased arterial pressure in mild essential hypertension on the basis of such structural vessel wall changes requires an assumption that other vascular beds are structurally changed in the same degree as the hand vessels. The validity of such assumption has as yet not been properly tested. Evidence favouring generalized distribution of structural vessel changes is provided by the results of graded exercise studies in patients with mild hYpertension. These studies have shown that peripheral vascular resistance does not decrease to the same low level in patients with mild hypertension as in normotensive subjects. Submaximal or near maximal exercise levels cannot produce the same degree of vasodila- tation in patients with mild hypertension as in normotensive subjects. Studies on cerebral vascular flow also suggest that patients with essential hyper- tension cannot dilate their vessels to the same degree as normotensives when exposed to co2 inhalation. 3. In conclusion, even if it is highly possible that an early stage of essential hyper- tension (i.e. mild hypertension) is generally characterized by increased "labile" arterial pressure, elevated cardiac output and possibly heart rate, decreased arterio-venous oxygen difference and increased oxygen consumption (hyperkinetic circulation) it cannot be I I • cvn/s/12.2e page 5 excluded that this disease may also start with a comparatively normokinetic circulation. There is no sharp dividing line between "normokinetism" and "hyperkinetism" of the circulation just as there is no such line between normal and elevated arterial pressure. So far the most rewarding studies with respect to the definition of early hypertension have been those concerned with regional blood flow studies and those which have investigated cardiovascular response to high levels of exercise. Regional blood flow studies have permitted relatively precise measurements of the resistanc~ to flow which have shown that this resistance is elevated even at maximal dilatation of vascular bed probably due to structural vessel wall changes. Exercise studies have demonstrated that total peripheral vascular resistance, even if normal at rest, does not decrease to the same levels during exercise in patients with mild hypertension as in subjects with stable low blood pressure; this suggests that the lumen of the resistance vessels cannot increase in a great number of vascular circuits .