Haemodynamics in hypertension

6 Haemodynamics in hypertension H A N S E SCHOBEL* MD Assistant Professor of Medicine

R O L A N D E. S C H M I E D E R MD Associate Professor of Medicine

Department of Internal Medicine, Universi~ of Erlangen-Niirnberg, Erlangen, Germany

The haemodynamic changes that occur during the development of established essential hypertension can be detected only by longitudinal studies. Several long-term studies thus indicate that the circulation in essential hypertension shifts from a 'high-output, normal resistance' state in young age toward a 'low-output, high-resistance' state in old age. However, this pattern is not a uniform one, and essential hypertension may also start by an increase in peripheral resistance without a prior phase of an elevated cardiac output. The reasons for these different haemodynamic patterns are not yet understood. Sympathetic overactivity may, at least in part, be responsible for the haemodynamic changes seen in the starting phase of essential hypertension. The haemodynamic characteristics in the different developmental stages of essential hypertension may vary considerably and are also influenced by ageing. Therefore, the proper use of anti-hypertensive drug treatment should be directed individually according to the underlying haemodynamic disturbances.

Key words: essential hypertension; developmental stages; cardiac output; peripheral resistance; regional circulations; sympathetic nervous system.

The major haemodynamic determinants of arterial blood pressure are cardiac output and total peripheral resistance. Thus hypertension is due to an unphysiological increase in either one or even both factors. A number of extensive studies in the past three decades have shown that the haemodynamic pattern of hypertension may differ considerably. Besides the severity of the hypertensive disease, age greatly influences the haemodynamic situation in hypertension (Freis, 1960; Frohlich et al, 1969;

* Correspondence: Hans E Schobel, Med. Klinik IV, Universitfit Erlangen-Ntimberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.

BailliOre's Clinical Anaesthesiology-Vol. 11, No. 4, December 1997 ISBN 0-7020-2360-4 0950-3501/97/040623 + 15 $12.00/00

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Folkow, 1982; Conway, 1984; Lund-Johansen and Omvik, 1990). It is therefore important first briefly to discuss the effects of age on haemodynamics. HAEMODYNAMIC CHANGES THAT OCCUR WITH AGEING IN NORMAL SUBJECTS It is well established that resting blood pressure increases with age, the increase being greatest for systolic blood pressure. The diastolic blood pressure also increases up to the age of 50-60, but plateaus or even declines during the later years (Landahl et al, 1986; Schoenberger, 1986). With regard to cardiac output, however, the data are less clear. Earlier studies found that cardiac output at rest decreases with age (Brandfonbrener et al, 1955; Amery et al, 1978), and therefore, since blood pressure increases, it follows that calculated total peripheral resistance increases. In contrast, however, the Baltimore Longitudinal Study on Aging (Rodeheffer et al, 1984; Fleg, 1986) did not detect a reduction in resting cardiac output as measured by gated radionuclide angiography in healthy people of older age. The reduction in heart rate that was observed with ageing was compensated by an increase in stroke volume, thus leaving cardiac output unchanged. Several invasive studies have shown that, with ageing, cardiac output decreases during exercise (Amery et al, 1978) owing to a decrease in stroke volume and a limitation in heart rate response. Again, the Baltimore Longitudinal Study showed strikingly different results in the effects of ageing on exercise haemodynamics (Rodeheffer et al, 1984). Although exercise heart rate decreased with age, stroke volume increased, thereby maintaining cardiac output. There is general agreement that blood pressure and total peripheral resistance increase with age at rest as well as during exercise (Levy et al, 1967; Amery et al, 1978). Furthermore, the haemodynamic changes that occur with older age are regarded as the result of a combination of loss of elasticity in the aorta, reduction in compliance of the left ventricle, decrease in baroreflex sensitivity and decrease in beta-adrenergic responsiveness (Conway et al, 1971; McGarry et al, 1983; Smulyan et al, 1983; Iskandrian and Hakki, 1986). HAEMODYNAMIC CHARACTERISTICS IN THE DIFFERENT DEVELOPMENTAL STAGES OF HUMAN ESSENTIAL HYPERTENSION

Borderline and mild hypertension (the starting phase of essential hypertension) It is obviously very difficult to find subjects who are definitely in the initial phase of essential hypertension. Most earlier studies performed invasive measurements in young adults (18-40 years old) with borderline (some readings above and some readings below 140/90 mmHg) or mild (diastolic

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blood pressure between 90 and 105 mmHg) hypertension and compared them with age-matched normotensive controls. Thus numerous studies have shown that the characteristic haemodynamic findings in these patients, believed to represent an early phase in the development of established essential hypertension, are a high cardiac output and a high heart rate, together with normal values for total peripheral resistance (Bello et al, 1967; Julius et al, 1971). More recent invasive studies have confirmed these findings of a so-called 'hyperkinetic' form of hypertension in borderline and mild hypertensives (Jern, 1982; Fujita and Noda, 1983; Sato, 1983). A survey of typical studies is given in Table 1. Messerli et al (1981) examined the relationship between age and haemodynamics in borderline hypertensive subjects. Whereas young (under 30-year-old) subjects showed the 'typical' hyperdynamic findings of borderline hypertension (an increase in cardiac output and normal total peripheral resistance), older patients (over 40 years) were characterized by an elevated total peripheral resistance and a normal cardiac output, suggesting a shift of the haemodynamic profile from high cardiac output hypertension in the young, to a high arteriolar resistance hypertension in the older patient.

Table 1. Mean values for mean arterial pressure (MAP), cardiac index (CI), total peripheral resistance index (TPRI), heart rate (HR) and stroke index (S1) in young subjects (aged 20-40 years) with borderline or mild essential hypertension in the supine position at rest.* References

N

MAP (mmHg)

CI TPRI HR SI (l/min/mz) (dyn/sec/cm-Tm2) (min -t) (ml/stroke/m"~)

Frohlich et al (1969) Safar et al (1970) Julius et al (1971) Fujita and Noda (1983)

9 23 77 56

106 105 100 107

3.53 4.09 3.79 3.68

(93) (86) (83) (88)

(3.05) (3.15) (3.31) (3.46)

2400 2100 2220 2380

(2400) (2220) (2090) (2098)

77 80 76 69

(68) (72) (67) (63)

46 51 50 54

(45) (44) (50) (55)

* Mean values for control groups are in parentheses. Adapted from Lund-Johansen and Omvik (1990).

More recent approaches to the study of pre-hypertension or very early hypertension have focused on the investigation of 'hypertensive' children and adolescents, and offspring from hypertensive parents. The Muscatine study compared blood pressure data (by the cuff method) and cardiac index values (by echocardiography) in 264 children and adolescents (aged 9-18 years) (Schieken et al, 1981). According to their blood pressure values, the subjects were stratified in three categories: low, middle and high (low about 100/50 mmHg, high about 112/55 mmHg). The authors found that those with the highest blood pressure had a slightly higher heart rate and cardiac index than those with the lowest blood pressure and suggested that the children with the highest cardiac index values represented a 'hyperkinetic' phase of essential hypertension. Confirming these data, a similar study in children and adolescents (aged 8-19 years) from Baltimore found slightly higher cardiac index values in

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subjects with mild hypertension (141/94 mmHg) compared with controls (l14/68mmHg) (Zahka et al, 1981). In both studies, the differences between 'hypertensives' and controls were less than those found in the invasive studies in 20- to 30-year-old men. However, despite these relatively minor changes in haemodynamics in this very young age group, left ventricular mass changed more dramatically with the increase in blood pressure. In contrast to these findings, studies by Hofmann et al (1981) performed in children and adolescents (aged 10-19 years) from a Dutch town, as well as in American teenagers (1982), did not detect a significant relationship between cardiac index and blood pressure. The authors concluded that it is not a hyperkinetic circulation that causes high blood pressure in children. Instead, they suggested that a gradual increase in total peripheral resistance, possibly due to high levels of circulating catecholamines, begins early in life, causing the changes in blood pressure over time. The Dutch Hypertension and Offspring Study, which has been ongoing since 1975, measured blood pressure in 10532 subjects, including 1642 parental couples (Van Hooft et al, 1993). By selecting groups of offspring with a maximal contrast in familiar predisposition, the authors established 40 children of two normotensive parents (NT/NT), 46 children with one hypertensive and one normotensive parent (HT/NT) and 60 children with two hypertensive parents (HT/HT) suitable for further study. During resting conditions, cardiac output was measured echocardiographically with simultaneous measurements of oxygen consumption, and blood pressure was measured by the cuff method. In addition, 24-hour blood pressure was recorded. Both the office readings and the 24-hour blood pressure values were significantly higher in the HT/HT group (mean 24-hour blood pressure: 120.3/72.0mmHg) as compared with the NT/NT group (mean 24-hour blood pressure: l15.6/67.2mmHg). The values for heart rate, cardiac index, oxygen consumption and calculated arteriovenous oxygen difference were similar between the two groups. Calculated total peripheral resistance was slightly, but significantly, higher in the HT/HT group than in the NT/NT group. These data therefore do not support the existence of a hyperkinetic circulatory system in the initial phase of essential hypertension but rather point to an increase in total peripheral resistance being the initial cause of the rise in blood pressure. The very low cardiac index values of about 1.81/min/m 2 reported in this study, which is approximately half the value reported in most previous studies obtained by invasive methods (Ohlsson, 1981), however, makes one ask whether the methods applied for haemodynamic measurements were accurate and reliable enough. Another large-scale offspring study is the Bergen Blood Pressure Study. By studying married couples for over 27 years, it was possible to establish a definite history of hypertension or normotension, and different types (HT/HT, NT/HT and NT/NT) of couples were characterized. Their offspring, who were somewhat older than in the Dutch study (34-40 years), repeatedly underwent monitoring of 24-hour blood pressure and heart rate, Doppler echocardiographic studies and measurement of various endocrine

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parameters. The blood pressure values were relatively similar to those in the Dutch study, being mildly higher in the HT/HT compared with the NT/NT offspring. Although none of the subjects in either study had definite hypertension, it seems very likely that, in both studies, some subjects will become hypertensives and others will not. A definite answer to this will be possible only by long-term follow-up. Furthermore, left ventricular wall thickness and left ventricular mass index was, in both studies, slightly increased in the HT/HT group versus the NT/NT subjects, indicating early cardiac structural adaptation to an increase in blood pressure.

Established hypertension The characteristic haemodynamic disturbance in established essential hypertension of moderately severe degree (RR values between 160/100 and 180/115 mmHg; WHO stage I or II) is an increase in total peripheral resistance. Compared with normotensive controls and younger early-stage hypertensives, cardiac output is reduced, whereas heart rate is usually increased and stroke volume is normal or low (Frohlich and Pfeffer, 1975; Chau et al, 1977; Lund-Johansen, 1980). Echocardiographic studies typically show an increase in left ventricular wall thickness together with an impairment of diastolic left ventricular filling. Left ventricular systolic function is usually normal at this stage of the disease (Devereux et al, 1983). During exercise, total peripheral resistance in subjects with moderately severe hypertension is clearly higher than in age-matched normotensive controls and also higher than in younger borderline hypertensives (Sannerstedt, 1966). Exercise cardiac output is abnormally low owing to an insufficient increase in stroke volume, which is itself most probably due to reduced compliance of the left ventricle (Fouad, 1987). The more severe that arterial hypertension and hypertensive organ damage is (WHO stage II), the more pronounced is the increase in total peripheral resistance, often accompanied by a marked decrease in cardiac output and a reduction in stroke volume. Omvik and Lund-Johansen (1984) reported resistance index values of up to 6000 dyn/sec/cm-5/m2, which is almost three times the normal value in a group of subjects with very severe hypertension. One of the very few exceptions to this haemodynamic pattern has been documented by Ibrahim et al (1975), who presented a group of patients with severe hypertension and a high cardiac index. In the end stage, hypertensive disease is characterized by a marked increase in total peripheral resistance and a very low cardiac output. Left ventricular filling pressures, as well as the pressures in the pulmonary circulation, are increased, and left ventricular ejection fraction and maximal circumferential fibre shortening are reduced (Strauer, 1979). L O N G - T E R M C H A N G E S IN C E N T R A L H A E M O D Y N A M I C S The results from haemodynamic studies of hypertensives of different ages and stages seem to indicate that the circulatory pattern in essential

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hypertension undergoes a change from the typical 'high cardiac output, normal resistance pattern' in young age towards a 'low cardiac output, high-resistance pattern' in old age. As cross-sectional studies may be misleading owing to differences in methods and selection criteria, only longitudinal studies can detect the haemodynamic long-term changes that really evolve during the course of the disease. An overview of several longterm studies that have been published during the past three decades is presented in Table 2. Despite differences in patient selection and follow-up periods, all studies show a decrease in cardiac output and an increase in total peripheral resistance with no or only minor changes in blood pressure. Whereas most studies did not include control subjects, a study from Sweden by Andersson et al (1983) compared 33 borderline hypertensives with 22 normotensive controls (initial age 18-21 years). Central haemodynamics remained completely unchanged in the normotensive controls during the follow-up period of 5 years. In contrast, cardiac output decreased and total peripheral resistance increased slightly in the borderline hypertensive group. Similar to most other studies, blood pressure was unchanged. By subdividing the hypertensive subjects into hyperkinetic and non-hyperkinetic groups, the authors found that the hyperkinetic group showed a more marked reduction in cardiac index (from 4.5 to 3.31/min/m 2) associated with a greater increase in total peripheral resistance index, compared with the non-hyperkinetic group. Remarkably, Lund-Johansen has now been following 77 male patients with mild-to-moderate hypertension, recruited from the Bergen population survey (1967), for more than 20 years. Longitudinal determinations of central haemodynamics were performed not only at rest, but also during exercise (on a bicycle ergometer). Measurements included heart rate (by ECG), cardiac output (Cardiogreen method), blood pressure (brachial artery catheterization) and oxygen consumption (Douglas bag technique; determination of oxygen and carbon dioxide values by the microScholander method or by Beckman automatic gas analysers). At the initial haemodynamic study, most of the hypertensives who were less than 40 years old had only mild hypertension, which was not treated by antihypertensive drugs. However, almost all patients over the age of 40 received medication. The patients were then seen at yearly intervals until the follow-up studies 10 and 20 years later. In the younger age groups (under 40 years), resting blood pressure values did not significantly increase at 10-year follow-up but were elevated after 20 years. Cardiac index and stroke index significantly decreased at rest as well as during exercise after 10 years, and continued to fall during the second decade of follow-up, whereas total peripheral resistance at rest continuously increased. In the older age group (over 40 years), blood pressure increased both at rest and during exercise, along with a marked increase in total peripheral resistance and a decrease in cardiac output. At 20-year followup, despite satisfactory clinical blood pressure control, there had been further significant increases in total peripheral resistance index and decreases in cardiac index both at rest and during exercise (total peripheral resistance index -28% at rest and -19-65% during exercise; cardiac

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index -31% at rest and - 2 5 - 4 0 % during exercise). The reduction in cardiac index was mainly due to a fall in stroke index, but heart rate also decreased significantly by about 17% at rest and approximately 12% during exercise. Similar findings have been reported in other long-term follow-up studies. In general, the increase in blood pressure in mildly or borderline hypertensive subjects after 5-6 years is only very small, thus necessitating a longer follow-up period to demonstrate significant blood pressure rises. In another long-term study over a period of 20 years, Widimsky (1984) found that approximately 50% of young borderline hypertensives progressed to established hypertension. The number of haemodynamic studies in the very old (over 70 years of age) is relatively small. Terasawa et al (1972) compared the haemodynamic pattern at rest in 42 hypertensive subjects (blood pressure over 160/90 mmHg) with a mean age of 73 years, with 23 young (mean age 25 years) normotensive controls. As expected, cardiac index and stroke index were much lower, and total peripheral resistance index much higher, in the old hypertensives compared with normotensive controls. REGIONAL CIRCULATIONS More than three decades ago, Brod (Brod et al, 1962), who pioneered studies of haemodynamics in human essential hypertension, showed that the effect of different hypertensive disease stages on pressure-flow ratios (i.e. the calculated total peripheral resistance) in the various organ systems varied markedly. More recently, these findings have been confirmed by others. Renal circulation

In established hypertension, renal blood flow is usually reduced and renal vascular resistance increased. London et al (1984) compared renal blood flow, measured by ~32I-labelled hippuran, in 35 patients with sustained hypertension (mean blood pressure 183/100 mmHg) with 29 normotensive controls (mean blood pressure 133/73mmHg). Cardiac index was not significantly different in the two groups, but total peripheral resistance index was about 50% higher in the hypertensives than in the controls (2923 versus 1997dyn/sec/cm-Tm2) and renal blood flow was reduced in the hypertensive subjects (735 versus 853 ml/min/m2). The renal fraction of the cardiac output was slightly less in the hypertensives compared with the controls (20.8% versus 23.1%). These data were confirmed by de Leeuw and Birkenh~iger (1983) in 200 patients with uncomplicated essential hypertension. The nature and the site of the increased renal vascular resistance are still poorly understood, but mainly pre-glomerular vessels in the outer cortical zone seem to be affected by this increase in resistance. Findings in borderline hypertensive, have been more controversial. Whereas some authors (Hollenberg and Adams, 1971; Messerli et al, 1978)

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have found an increase in renal blood flow, Temmar et al (1981) reported renal blood flow to be within normal limits even in subjects with increased cardiac output. Bianchi et al (1979) found that renal plasma flow was increased in young, normotensive offspring from hypertensive parents, which raised the question of whether persons with an abnormally high renal blood flow form a special subgroup of pre-hypertensives.

Skeletal muscles In general, in patients with borderline hypertension and increased cardiac output, an increase in blood flow to skeletal muscles seems to be typical. With established hypertension, the vascular resistance increases and the blood flow falls. Takeshita and Mark (1983) studied young normotensive men with and without a positive family history of hypertension. They found that the minimum vascular resistance (after release from 10 minutes of brachial artery occlusion) was about 25% higher in subjects with hypertensive relatives, than in subjects with no family history and suggested that there might be a structural abnormality in the forearm vessels of the former group.

Splanchnic circulation In subjects with borderline hypertension and increased cardiac output, the hepatic blood flow was found to be normal (Temmar et al, 1981). In established hypertension, the vascular resistance in this part of the body was increased, as in the rest of the body.

Coronary circulation The information about coronary haemodynamics in hypertensive heart disease of different ages and stages is quite incomplete as the methods for measurement of myocardial blood flow require rather invasive procedures. For this reason, no systematic studies are available in children and adolescents. Strauer (1979) were able to demonstrate a reduction in the coronary reserve after vasodilation with dipyridamole in early-stage hypertensives. Nichols et al (1980) found an inverse correlation between maximal coronary blood flow and the degree of left ventricular hypertrophy. The metabolic reserve of the hypertrophic left ventricle in patients with essential hypertension is already impaired under resting conditions (Strauer and Mahmoud, 1985). Coronary blood flow during exercise has, however, not yet been studied extensively.

Pulmonary circulation Even in patients with mild-to-moderate hypertension without clinical signs of heart failure, there is often an increase in pulmonary artery pressure (Atkins et al, 1977). As a consequence, the fight ventricle shows a reduced ejection fraction, causing functional impairment in both sides of the heart.

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What causes the rise in pulmonary artery pressure in subjects with mild hypertension is not definitely known. A centripetal redistribution of intravascular volume that occurs in the early stages of hypertension may be one explanation (Schmieder et al, 1995). Guazzi et al (1987) interestingly observed that stress tests such as arithmetic tests induced significant increases in lung arteriolar resistance in hypertensive patients but not in normotensive subjects. These results point to an over-reactive neural stimulation not only of the systemic vessels, but also of the pulmonary vessels. UNDERLYING FACTORS FOR THE HAEMODYNAMIC CHANGES IN ESSENTIAL HYPERTENSION Sympathetic nervous system Although it is generally believed that the increases in cardiac output, heart rate and oxygen consumption in early essential hypertension are due to an 'overactivity' in the sympathetic nervous system, this has been difficult to prove. Measurements of plasma or urinary catecholamine concentration could be misleading as they are influenced by many factors such as efferent neural activity, synaptic transmitter release, re-uptake mechanisms and regional blood flow (Folkow et al, 1983). By intraneural recordings of efferent sympathetic vasoconstrictor activity to skeletal muscle, Anderson and Mark (1989) found an increased sympathetic neural activity in borderline hypertensive subjects compared with normotensive controls. However, a recent study by Rea and Hamdan (1990) did not detect any difference in resting sympathetic outflow to muscle between borderline hypertensive subjects and a well-matched normotensive control group. The applied microneurographic technique in these two studies uniquely enables direct assessment of sympathetic activity at the pre-synaptic level but it is limited to measurements of neural outflow to skeletal muscle. If organ systems other than the muscles, such as the heart or kidneys, have to be studied, determinations of the organ-specific norepinephrine spillover rate would be the best index (Esler, 1985). Younger patients with essential hypertension had an increased renal norepinephrine spillover rate and elevated 24-hour norepinephrine levels (Tuck, 1986). Several investigators have found a positive correlation between plasma norepinephrine and total peripheral resistance or cardiac output. Izzo et al (1987) studied central haemodynamics and plasma norepinephrine levels in hypertensive subjects of different ages. They found that both age and increased sympathetic nervous system activation independently contributed to the decrease in cardiac output in these patients through their effects on systemic vascular resistance and afterload. Julius (1986) recently suggested that the haemodynamic abnormalities during rest seen in early essential hypertension are most easily described through neurogenic mechanisms. Various stress tests have been used to identify young persons who later develop hypertension. Falkner (1986) demonstrated a greater blood pressure and heart rate response in young subjects who later developed

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hypertension. These findings were considered to be consistent with a dysregulatory neurogenic component in the pathogenesis of essential hypertension. Furthermore, sodium-sensitive hypertensives have been found to be most sensitive to neurogenic stimuli (Koolen and van Brummelen, 1984). Thus the concept of 'hyperreactivity'--what causes it and whether it induces hypertension over time---deserves further study.

Blood volume and the capacitance vessels The increase in cardiac output seen in the early stages of essential hypertension seems to be due to a shift in the circulating intravascular volume toward the cardiopulmonary circulation, as indicated by a marked (20%) increase in central blood volume (Schmieder et al, 1995). This centripetal redistribution of the intravascular volume implies the active participation of the capacitance vessels, suggesting venous constriction in patients with early borderline hypertension. The underlying pathophysiological mechanism for this increase in peripheral venous tone may be an increase in sympathetic vasoconstrictor activity. Plethysmographic studies have also suggested a reduction in venous compliance, which seems to occur very early in the development of hypertension (Takeshita et al, 1982).

Structural changes in the left ventricle and in resistance vessels Recent data could demonstrate that cardiac structural changes occur before blood pressure is markedly elevated or total peripheral resistance increased (Schmieder et al, 1995). Thus early-stage-borderline hypertensives were reported to show an eccentric type of cardiac remodelling with increases in left ventricular mass and left ventricular end-diastolic diameter, most probably triggered by an increase in cardiopulmonary blood volume. As the disease continues and cardiac output decreases again, there is a change to the 'classic' form of concentric left ventricular hypertrophy in patients with established hypertension. Furthermore, it is well accepted today that, very early in the process of hypertension, even before wall thickness increases, there is an impairment in left ventricular compliance. Similarly, in spontaneously hypertensive rats, hypertrophy and reduced left ventricular compliance occur at a very early stage (Lundin and Hallb~ick-Nordlander, 1980). In humans with borderline or mild hypertension, total peripheral resistance is inappropriately high during measures that increase blood flow, such as heating and exercise or autonomic blockade (Julius, 1986). This 'residual' increase in total peripheral resistance is explained on the basis of an increase in wall-to-lumen ratio in the arterioles, similar to that which has been shown in spontaneously hypertensive rats (Takeshita et al, 1982).

T H E R A P E U T I C CONSIDERATIONS In general, treatment of hypertension should aim at normalization of both the central and the peripheral haemodynamic abnormalities to prevent the

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deterioration of cardiac pump function and the increase in arteriolar resistance. Careful selection of the haemodynamically appropriate antihypertensive drug is important as the various drug classes act quite differently on central haemodynamics at rest and during exercise. Also, owing to counter-regulatory mechanisms (such as a baroreflex-triggered increase in heart rate), the immediate haemodynamic effects of an agent may differ markedly from its long-term effects. Calcium antagonists, ACE inhibitors, alpha-receptor blockers and diuretics all lower blood pressure through a reduction in total peripheral resistance--achieved, of course, through very different mechanisms. All these classes of drug tend to normalize central haemodynamics during chronic treatment without reducing exercise tolerance. Peripheral as well as renal blood flow is maintained or even increased. The beta-blockers are different as they induce a reduction in exercise cardiac output, whereas total peripheral resistance does not seem to be reduced. Since most beta-blockers (without intrinsic sympathomimetic activity) reduce blood pressure as well as heart rate, they may substantially decrease the workload on the heart, thereby making a beta-blocker the drug of choice in hypertensive patients with angina pectoris. Hypertensive patients with heart failure seem to benefit most from ACE inhibitors, which strongly affect both preload and afterload. CONCLUSIONS Although haemodynamic investigations over the past three decades have brought many new insights, the 'initial phase' of essential hypertension is still not yet clearly defined. From a haemodynamic point of view, there is no uniform starting point. Increases in cardiac output, heart rate and oxygen consumption have been demonstrated in a large fraction of mildly hypertensive children, adolescents and young adults who, during long-term follow-up, remained hypertensive, with some increase in blood pressure over time. However, a high cardiac output phase is not present in all subjects, and essential hypertension may start by an increase in total peripheral resistance as well. The high cardiac output phase usually disappears over a 5- to 10-year period and the total peripheral resistance increases. Elderly hypertensives very rarely show an increase in cardiac output. The haemodynamic alterations in the early phase of essential hypertension may at least partially be induced by an increased activity of the sympathetic nervous system or by an imbalance between sympathetic and vagal tone. Echocardiographic studies have shown that left ventricular diastolic function is disturbed very early in the process of hypertension, even before wall thickness is increased. Systolic function is affected much later. The triggering mechanisms of the haemodynamic changes in essential hypertension are still not understood, nor is the question of why different groups of patients develop different haemodynamic patterns.

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Anti-hypertensive drug treatment should be tailored individually according to the haemodynamic disturbances behind the increased blood pressure. Thus the proper use of the various classes of anti-hypertensive agent should lead to a more physiological approach to the treatment of hypertension and, hopefully, to better tolerance and long-term results.

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