Hemodynamics in hypertension and heart failure

Hemodynamics in hypertension and heart failure

KEYNOTE ADDRESS Hemodynamics in Hypertension and Heart Failure PETER SLEIGHT, A glance at the reference lists in the recent major reviews of hyperte...

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KEYNOTE ADDRESS

Hemodynamics in Hypertension and Heart Failure PETER SLEIGHT,

A glance at the reference lists in the recent major reviews of hypertension and heart failure [l-15] will convince the reader of the impossibility of comprehensive cover in a short review. I will attempt to highlight the places in which agreement is broad but will also cover newer and less agreed upon data. HYPERTENSION Research into the behavior and distribution of the circulation in hypertension is bedevilled with many problems. First, until relatively recently there has been no good animal model of human essential hypertension. The spontaneously hypertensive rat model is very useful, with many resemblances, but these resemblances are not total [ 161. The different animal models, such as the Milan strain [6] in which a transplanted kidney will “carry” the hypertension to a normotensive recipient, the spontaneously hypertensive rat strain in which neurogenic factors are dominant, and the Dahl salt-sensitive strains, all point to the complexity of the issue. It seems very plausible that a similar heterogeneity exists in human hypertension. The second problem arises from the first. How do we subdivide populations? Pickering [ 171 rightly criticized the division of normal from hypertensive, showing that this was an artefact. Nevertheless, very few investigators express their data as a continuum, without arbitrary division between two groups. This is a pity. The debate over low and high renin hypertension, for example, has been greatly illuminated by such treatment of the data. Meade and his colleagues [ 181 examined the plasma renin activity in about 2,000 subjects and showed independent negative correlations with age and arterial pressure over the whole range of pressures. There was no clear dividing line between normal and abnormal. They suggested that the decrease in plasma renin activity with increasing arterial pressure was more likely a homeostatic consequence rather than a cause

M.D.

of hypertension. (The data also suggested that increased cardiovascular morbidity was associated with low rather than high renin levels.) This study emphasizes the power of the epidemiologic approach, in which the data are obtained from relatively unselected populations rather than from the selected patients referred to hospitals or special units. In addition to the misinformation resulting from biased samples, these hospital-based studies normally suffer from having an inadequate number of subjects. A final problem that is often overlooked is whether the pressure measured truly represents the subject’s real pressure. The effect of the defense or alerting reflex may give us quite erroneous data about the true blood pressure of the subject. In a recent trial [ 191 we recruited 59 subjects with a mean cuff blood pressure of 119 mm Hg (averaged over at least three readings in each). One third of these subjects turned out to have waking ambulatory intra-arterial pressures below 140190 mm Hg (Figure 1). Similarly, in the Australian trial of mild hypertension [ 201, almost half of the placebo-treated group became normotensive over the five years of study (in most, this fall occurred in the first few months). T. G. Pickering and his colleagues [21] found the greatest discrepancy between clinic cuff pressures and ambulatory cuff pressures in subjects with borderline values of pressure. If such effects can be observed with simple cuff measurement, it seems likely that quite important effects of the “defense” reaction might be seen with the most invasive procedures used to gather data on cardiac output and regional blood flow. Hollenberg et al [ 221 used a relatively mild verbal IQ test to show that subjects with essential hypertension had a greater increase in blood pressure and plasma renin activity, and a greater decrease in renal blood flow than normal subjects. Other confounding factors come from less obvious environmental stimuli. There is a clear relation to the

From the Cardiac Department, John Radcliffe Hospital, University of Oxford, Headington, Oxford, England. Requests for reprints should be addressed to Professor Peter Sleight, Cardiac Department, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DlJ, England.

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The American Journal of Medlclne

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F ;igure 1. Comparison of mean waking intra-arterial bloo d pressure in 59 untreated hypertensive subjects with the mean of three clinic cuff measurements. Open circles = those without electrocardiographic, roentgenographic, or optic fundal evidence of target organ damage. Reproduced with permission from [IQ].

room temperature at which the measurement is taken (Figure 2) [23]. Coffee drinking [24], particularly coffee drinking plus cigarette smoking [25], will raise arterial pressure markedly for about two hours. Nevertheless, when conditions are controlled, three cuff measurements appear to give a reasonable estimate of pressure 1261. Despite these caveats we do have evidence from the studies of, for example, Lund-Johansen [29-321 that there is a slow increase in blood pressure, a reduction in cardiac output, and an increase in total peripheral resistance over 10 to 15 years when the same subjects are studied serially, under the same conditions, and by the same investigator. All reviewers have pointed to the conflicting data in this topic. Much of the conflict probably arises from methodology, selection, and the play of chance with small numbers. Perhaps the new developments with noninvasive devices, such as Doppler ultrasound measurement of cardiac output and noninvasive continuous blood pressure recorders, will open the way to large-scale surveys of the hemodynamics of hypertension beginning in childhood. I will review the hemodynamic aspects of hypertension under several headings, while recognizing that many are closely interrelated. CARDIAC OUTPUT MEASUREMENT AND PLASMA VOLUME I have linked these together because of the well developed hypothesis that primary retention of salt and water lead to increased plasma volume [33-381. The higher cardiac filling pressures then resulted in in-

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creased cardiac output and hypertension. The gradual increase in total peripheral resistance over time was attributed to whole body autoregulation. This concept has come under increasing attack recently. Part of the problem is that the mechanism of the autoregulation can not be shown. Secondly, only a proportion of subjects show a high cardic output, Thirdly, cardiac output declines with age, and not all studies used aged-matched control subjects. Finally, measurement of solely resting cardiac output seems less reliable than the response to exercise. The resting cardiac output may, of course, be much more susceptible to the defense reaction than serial exercise measurements. Conway et al [39] and Lund-Johansen [29-321 have both shown in agematched subjects that, at any level of exercise, total peripheral resistance is higher in those with the higher pressures. The increase in cardiac output is less in hypertensive subjects. Tarazi et al [40] could find no evidence of an increase in plasma volume in hypertensive man; on the contrary, they did find a decrease that was proportional to the height of the pressure. They also increased the extracellular fluid volume in dogs by steroid therapy and showed an increase in cardiac output that was sustained with no evidence of autoregulation and increased total peripheral resistance [41]. Bing and Smith [42] similarly found no volume expansion, but they did find a normal relation between extracellular fluid and plasma volume. Korner [43] summarized the mounting experimental animal evidence against the autoregulation theory. In an impressive epidemiologic study of 319 teenagers from New England [44] cardiac output was measured by echocardiography and blood pressure by an automatic recorder. No evidence was found of an initiating high cardiac output in those with the higher pressures. Pressure was closely related to total peripheral resistance even at this young age. Although Lund-Johansen’s studies (cited previously) do show a decrease in cardiac output with time, the younger hypertensive subjects all showed an increased total peripheral resistance compared with normal. There was no evidence of a nervously induced “luxury” overperfusion. In those with a higher than normal cardiac output, oxygen consumption was also increased. Both could be the result of increased sympathetic discharge. Brod et al [45,46] recently restudied 12 subjects with renal disease from two to eight years after an initial hemodynamic investigation that had shown a hyperkinetic circulation. These subjects formed a subgroup of 32 initially normotensive subjects and were distinguished by an initially high plasma volume, high cardiac output, low forearm resistance, and low total peripheral resistance. In 11 of 12 subjects with this hyperkinetic state, hypertension had developed compared with only

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Figure 2. Seasonal trends for blood pressure for men in the three treatment areas of the Medical Research Council trial of mild hypertension. Means from about 12,000 subjects in each of the active treatment groups and 24,000 in the placebo-treated group. Note the decrease in pressure in the summer monfhs. Reproduced with permission from 1231.

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half the 20 subjects who were normotensive and normokinetic at the time of the first study. In these renal patients there was no correlation between cardiac output and oxygen consumption. The investigators concluded that this is evidence for a volume triggered hypertension. The difficulties in doing such serial studies necessarily lead to small numbers for comparison. This and the selection of subgroups make me cautious about their arguments. I believe that too much emphasis has been placed on the distinction between high output and high peripheral resistance. I am attracted to the idea that much essential hypertension could be explained by an increased sympathetic discharge. I will outline how this might have differential effects on resistance and output at different ages. PERIPHERAL

VASCULAR

RESISTANCE

In established hypertension an increased peripheral resistance is the key hemodynamic feature. This resistance appears to lie partly in small vessels at the arteriolar level [47] and partly in the change in im-

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pedance offered by a stiff vascular system [48]. We studied the distensibility of the forearm arteries in man and could find no difference in vessel wall stiffness when measured at the same transmural pressures in normal and hypertensive subjects [49]. This argued against any considerable structural change in the wall. As the transmural pressure increases with hypertension, the vessel wall becomes less distensible. O’Rourke [48] suggested that this causes a decreased amplification of the pressure wave as it reaches the periphery, and results in serious loss of energy and serious increase in the work of the heart; this may overshadow the changes in small arteries. Folkow and colleagues [50] and Sivertsson [51] have eloquently argued the importance of structural change in peripheral arterioles in perpetuating the hypertension. This hypet-trophy might well explain the lack of difference in sympathetic discharge seen in recordings from human muscle nerves of hypertensive and normotensive subjects [ 521. As well as structural changes, there appear to be metabolic and ionic differences in vascular smooth

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muscle [47,53]. Robinson et al [54] showed that intra-arterial injection of verapamil causes greater vasodilatation in the forearm resistance vessels of hypertensive men than of normal men. This was not simply a consequence of structural differences since injection of another vasodilator (sodium nitroprusside) had greater effects on normal vessels. They suggested that there is a difference in the functional properties (related to calcium and other ionic constituents of myocytes) and speculated that this may be related to altered membrane properties in hypertension. This may relate to the hypothesis of Poston et al [55] that these membrane abnormalities are caused by a circulating oubain-like inhibitor of sodium/potassium adenine triphosphatase (ATPase). Boon et al [56] in our laboratory used in vivo entry of rubidium (an analogue of potassium) into red cells and found increased entry of potassium into cells of hypertensive subjects. This is inhibited by oubain (in vivo) and so gives no support for a circulating oubain-like substance. This exciting in vivo work does support the general thesis of a change in membrane properties in hypertension. Differences in prostanoid metabolism in spontaneously hypertensive rats compared with Wistar Kyoto rats were recently reported by Doyle and his colleagues from Melbourne [57]. Paradoxically, in spontaneously hypertensive rats the ability to transform infused arachidonic acid into vasodilator prostanoids was enhanced, leading to more prolonged vasodepression. THE HEART The heart in hypertension is altered first by hypertrophy. This itself improves performance at high pressure but at the expense of reduced diastolic compliance [58], which may be responsible for the reduced output at higher workloads [59]. In man, coronary arterial disease further reduces coronary reserve. The mechanism of the cardiac hypertrophy is not fully understood. Ostman-Smith [60] proposed that sympathetic nerve stimulation is the trigger that switches on the metabolic processes in all forms of cardiac hypertrophy. In an interesting echocardiographic randomized study of the effect of beta-blockade or placebo therapy on cardiac hypertrophy in borderline hypertension, Larkin [61] showed that beta-blockade halted the development of hypertrophy, which continued in those receiving placebo therapy. The heart itself may be important in the genesis of hypertension. Liard [62] showed in dogs that cardiac sympathetic nerve stimulation, or intracoronary infusion of an inotrope, dobutamine, over seven days, will result in hypertension that is at first mediated by an increase in cardiac output but that is later accompanied by peripheral vasoconstriction.

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SPLANCHNIC AND CAPACITANCE VESSELS The importance of venous tone in the control of venous return to the heart and cardiac output is increasingly recognized. Folkow and Mellander [63] showed that the known intrathoracic shift in blood volume in hypertension was caused by the sympathetic nerves, which raised venous tone. Safar et al [64] found evidence for increased central blood volume in borderline hypertension but not in established hypertension. The portal veins of spontaneously hypertensive rats generated greater contractile force in response to adrenergic stimuli than those in Wistar Kyoto rats [ 651. Similar results were seen in whole body or hindquarter preparations of spontaneously hypertensive rats, which showed a structurally reduced venous compliance together with no change in unstressed venous capacitance [66]. RENAL CIRCULATION AND SODIUM HANDLING Despite attractive, if oversimplified, concepts of a universal renal cause for hypertension based on pressure-diuresis abnormality [67], there is no clear evidence that the primary abnormality in essential hypertension is renal. On the other hand, it seems more probable that the kidney may be controlled by nervous [68,69] and other factors that obscure a simple pressure-related diuresis as seen in denervated or isolated kidneys. Winternitz and Oparil [70] showed that increased sodium loading in spontaneously hypertensive rats resulted in hypertension, which was accompanied by increased plasma and urinary epinephrine output. Similar neurogenically-mediated changes in forearm vasoconstriction occur with high salt feeding in man with borderline hypertension but not in normotensive subjects [71]. This surprising abnormality might be related to genetic differences in the handling of ions by cell membranes [ 72,731. Bomzon [74] recently reviewed the sympathetic control of the renal circulation-a circulation that takes about 20 to 25 percent of the cardiac output. He found no direct evidence that the renal sympathetic nerves are of paramount importance in the control of renal blood flow, but there is, of course, much evidence of their importance in modulating renal function and the renin-angiotensin system [75]. Collis and Vanhoutte [76] found norepinephrine release from renal sympathetic nerves to be greater in spontaneously hypertensive rats. The renal vasculature was more responsive to adrenergic stimuli in adult spontaneously hypertensive rats. The role of sodium in the genesis of essential hypertension is still ‘not clear. Population studies have been negative or even shown that hypertensive people have a lower sodium intake [77,78]. Intervention

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Relation of systolic

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pressure and exchangeable sodium (related to body surface area) in (a) moderately hypertensive subjects (r = 0.56; p < 0.00 I), (b) mildly hypertensive subjects (r = 0.25; p < 0.05}, and in (c) normal subjects (r = 0.04). The correlation was also significant in the 50 hypertensive patients who had never received treatment (r = 0.44; p < 0.0 1). Reproduced with permission from 1791.

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studies have been on small numbers of selected subjects. Any correlation between salt and blood pressure may possibly be confined to genetically susceptible subjects, but this remains to be proved. A collaborative study in Glasgow and Berne [79] on 121 normal and 9 1 hypertensive subjects has shown a positive correlation between blood pressure and total body sodium content in hypertensive but not normotensive subjects (Figure 3). This correlation was independent of age. It is not clear whether this is a primary cause or a secondary consequence of the hypertension, or whether this too reflects genetic differences in cell membrane transport.

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Genetic differences in the kidney are clearly important in the Milan rat [80]. The elegant experiments of Bianchi’s group [6] demonstrated that transplanted kidneys determine the blood pressure of the recipient rat. CEREBRAL CIRCULATION

The intracerebral blood vessels are generally recognized to receive little input from the sympathetic nervous system, although the latter may have some influence on the large extracerebral vessels [ 81,821. There is good evidence for cerebral autoregulation. The upper and lower pressure levels over which autoregulation

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occurs are reset upwards in hypertension [83]. This emphasizes the need for caution in lowering arterial hypertension too rapidly by treatment [ 841. HOMEOSTATIC MECHANISMS A review of the hemodynamics of hypertension demands consideration of the important control mechanisms; whether or not these are secondarily deranged or whether they might in some circumstances have a primary role. We have already seen how one of these-the defense reaction-can alter both the blood pressure and important regional vascular beds such as the kidney. There is abundant evidence of impaired baroreflex control of the circulation in hypertension [lo]. This is more readily shown for heart rate control [85] than for control of peripheral blood vessels, but Bevegard et al [86] have produced evidence that the gain of the baroreflex control of peripheral vasculature is also reduced in hypertensive man. Baroreflex dysfunction on the afferent side may be counterbalanced by increased sympathetic effector tone as a result of hypertrophy of vascular smooth muscle. Recent studies from our laboratory have shown a striking negative correlation between baroreflex sensitivity and control of arterial pressure during daily life, measured by ambulatory recording [87]. The role of impaired baroreflexes in hypertension and, indeed, the whole concept of neurogenic hypertension as a result of baroreceptor denervation have been questioned by Guyton’s group [88]. This has been discussed at length [ 10,891. I believe that the results

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RATE

Figure 4. The mean difference (3~SE) in blood pressure (L) and heart rate (r) responses to stress of noise or vibration between nine pairs of spontaneously hypertensive rats and normal control rats (NCR), and between 18 Milan hypertensive strain rats (MHS) and their normal controls (NR). Changes in heart rate are expressed as percentages from resting heart rate. Reproduced with permission from 1981.

of their denervation experiments show that, although in the denervated animals taken as a group, over-all there was only a small increase in arterial pressure, individual animals show clear evidence of sustained hypertension [ 881. These are counterbalanced by others showing hypotension [88]. Possibly, these hypotensive animals have had extensive sympathetic motor denervation in the course of the extensive stripping of aortic baroreceptor afferents. More recent work with a limited baroreceptor denervation in the rat [90] has produced sustained hypertension. Baroreflex inhibition by higher centers can be readily seen during mental arithmetic in man [91]. A combination of atheroma-induced carotid and aortic baroreceptor “splinting” and/or central “defense” reaction [92,93] resetting of the baroreflex would be a plausible mechanism for the alterations to renal and splanchnic vascular beds seen in essential hypertension, in addition to changes in centrally mediated nonbaroreflex changes in autonomic tone. SYMPATHETIC NERVOUS SYSTEM IN HYPERTENSION A review of the evidence for or against a role for the sympathetic nervous system in hypertension is beyond the scope of this review. There is, nevertheless, much to suggest overactivity, particularly in younger hypertensive subjects [94-971. Such overactivity provides an attractive hypothesis for the changes in hemodynamics seen in hypertension in man. In the young subject, sympathetic stimulation affects both the heart

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and the blood vessels with an increase in cardiac output

and then later hypertrophy of vascular smooth muscle. This increase in afterload tends to damp the output down. This process is aided by the development of cardiac hypertrophy, which limits diastolic compliance and hence cardiac filling and output. As the stimulus to peripheral vessels continues, structural changes (hypertrophy) amplify the response to a given level of sympathetic nerve traffic which, therefore, need not be so intense. The end result is an increased vascular resistance, normal cardiac output, and “normal” sympathetic nerve activity producing amplified effects on hypertrophied arteriolar smooth muscle in muscle, splanchnic, and renal circulations. This does not rule out the distinct possibility of genetic differences in reactivity, as seen in rats (Figure 4) 1981. HEART FAILURE Interest in the hemodynamics of heart failure has followed the recent use of vasodilators and other agents to reduce the afterload of the failing heart (for reviews see the series of articles on vasodilators [99] .) We may define heart failure as failure of the cardiac pump to deliver an adequate blood supply to meet the metabolic demands of the body. Initially, it is apparent only on exercise, leading to dyspnea and fatigue. Later it is apparent at rest, with orthopnea, edema, and CheyneStokes respiration. Many of the manifestations are due to fluid retention by the kidney; one must bear in mind other causes of fluid retention, such as acute nephritis that may mimic heart failure, with edema, increased jugular venous pressure, and pulmonary edema. Here, however, the cardiac output is found to increase normally with exercise [ 100,lO l] . The pathophysiology of heart failure is less controversial than that of hypertension, with many of the features a direct result of reflexly increased sympathetic drive to organs not affected by exercise [ 1021 and particularly to the kidney [ 141, which in turn leads to renal vasoconstriction, release of renin, and increase in angiotensin II in the blood [ 1031. This has complex and far-reaching effects: (1) direct peripheral vasoconstriction and increase in peripheral resistance; (2) central nervous effects, which lead to a direct increase in sympathetic tone and a reflex increase due to inhibition of the baroreflex arc: (3) peripheral sympathetic increase, due to the greater release of norepinephrine for a given nerve traffic [ 1041; (4) central stimulation of thirst receptors; (5) increase in fluid retention by the kidney as a result of the angiotensin-stimulated increase in aldosterone; and (6) renal vasoconstriction. Many of these mechanisms promote the formation of edema (see Figure 5) [ 1021. The triggering increase in renal sympathetic stimulation probably results from both arterial and cardio-

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Major factors leading to peripheral edema in congestive failure. Reproduced with permission from [ 1021. vgure

5.

pulmonary baroreceptors [ 105,106]. It is certainly extremely effective. This was well shown experimentally by Vatner and his colleagues (Figure 6) [ 1071. This severe reduction in renal blood flow and glomerular filtration is responsible for the clinical symptom of nocturia. At night, sympathetic tone is reduced in sleep [108]. There is recent evidence that in heart failure renal blood flow is diverted away from the superficial cortical nephrons to the deeper nephrons, whose loops of Henle reach further into the renal papilla and produce a more concentrated urine [ 14,109]. The mechanism of this shift in intrarenal blood flow is not fully understood. Another force for fluid retention is afferent glomerular arterial constriction, which increases colloid osmotic pressure in peritubular capillaries, again favoring retention of fluid. The kidney is paramount in the altered physiology of heart failure. Many of the reactions we have discussed are quite appropriate for the decrease in intravascular pressure due to hemorrhage (the probable evolutionary reason for these mechanisms). They are not appropriate for heart failure in which the primary abnormality lies in the heart itself [ 1 lo]. It is true that fluid retention increases cardiac filling pressures; unfortunately, however, the failing heart responds rather poorly to further increases in filling. This explains why converting enzyme inhibition has many attractions in the treatment of heart failure [ 111,113]. The correction of the renal

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The American Journal of Medicine

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HEART FAILURE DENERVATED

INNERVATED

ARTERIALPRESSURE

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RENALFLOW VELOCITY

RENAL FLOW CALCULATEDRENAL

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Figure 6. Typical renal response to severe exercise in a dog with experimentally induced congestive heart failure. Note the severe reduction in renal blood flow and the increase in renal resistance in the innervated kidney (left panel) that is largely but not completely relieved by surgical denervation (right panel). Reproduced with permission from [ 1071.

fault is very effective in combating the difficult hyponatremia seen in prolonged diuretic treatment [ 1141. The failure of contractility of the heart can best be aided by correction of mechanical, metabolic, or endocrine causes. If these are not correctable, inotropes can be used to stimulate pump function. In general this is disappointing, perhaps because of the diminished beta-adrenergic receptor density and effectiveness recently shown by Bristow et al [ 1151 I or because of depleted myocardial catecholamine stores [116,117].

Therefore, the emphasis is now on reducing the afterload on the heart muscle in order to aid ejection. This effect can be achieved by both conventional vasodilator [ 1181 and converting enzyme inhibition, provided that postural hypotension can be avoided. The hemodynamic derangements of both hypertension and heart failure are powerfully influenced by effects on the renal circulation. Converting enzyme inhibition has given us a powerful toolto attack these common and closely interrelated conditions.

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