Congestive cardiac failure: central blood pressure · 192 bone, arteriovenous fistulas, cor pulmonale, and beriberi. Here was near disaster for the backward failure theorists andaserious

Br Heart J 1987;58:190-203

Congestive cardiac failure: central role of the arterialblood pressure

St Cyres lecture 1986

PETER HARRIS

From the Cardiothoracic Institute, University of London, London

SUMMARY A review of the history of our knowledge and understanding of the peripheral oedemaof congestive cardiac failure points to the conclusion that an inability of the heart to maintain thearterial pressure is of central importance in this condition. Although the function of the circu-lation is to perfuse the tissues, the body monitors the adequacy of its perfusion, not throughmetabolic messengers carried from the tissues in the blood stream, but by sensing the arterialpressure; and the mechanisms evoked act to maintain the arterial pressure. In the short term thisis achieved by autonomic regulation of the heart and blood vessels; in the longer term the arterialpressure is maintained through an increase in the blood volume by a retention of salt and waterby the kidney. To support the latter process, intrinsic renal mechanisms are successivelymagnified by the renin-angiotensin-aldosterone system and by the activities of the sympatheticsystem and vasopressin. The natriuretic influence mediated through volume receptors and therelease of atrial peptide is overruled by the arterial baroreceptors, so that the body maintains thearterial pressure at the expense of an increase in blood volume.

In these ways the syndrome of congestive cardiac failure may be regarded as one which ariseswhen the heart becomes chronically unable to maintain an appropriate arterial pressure withoutsupport.

Early concepts of cardiac failure

Hope was probably the first to put forward a unifiedconcept of backward failure.' It was a concept basedon pathology as well as physiology. The over-worked ventricle first hypertophies and then dilates.As it dilates the blood gets dammed up behind it andan increased venous pressure is transmitted ulti-mately to the capillaries where oedema is formed.The concept of backward failure was widely

accepted until the last decade of the nineteenth cen-tury. But, in 1896, Starling, in his Arris and Galelecture, reported experiments on dogs in which heinjected oil into the pericardial sac.2 As the heart"failed" the pressure in the vena cava rose and thatin the aorta fell. To decide whether this was accom-panied by engorgement of the capillaries he placed aplethysmograph round one limb. This showedunequivocally that the volume diminished at the

Requests for reprints to Professor Peter Harris, The CardiothoracicInstitute, 2 Beaumont Street, London WIN 2DX.

same time as the aortic pressure decreased and thevena caval pressure increased.

Starling concluded that in failure, although thepressure in the great veins rose, the pressure in thecapillaries fell. If that were so, the only explanationthat he could see for the loss of liquid from the bloodinto the tissues was an increased permeability of thecapillaries; and the reason for their increased perme-ability had to be a loss of nutrition due to poor per-fusion. "In heart disease the capillary pressure is nothigher, but rather lower, than in a normal animal.The dropsy is entirely conditioned by the state of thecapillary wall."This theory of forward failure was championed by

Mackenzie: "The blood passes through the capillar-ies at a slow rate, impairs their nutrition, and allowstransudation to take place, which we call dropsy."So strongly did the great physician feel on this sub-ject that there is an entry "Heart failure, back-pressure theory, evil of," in the third edition of histextbook. "These views are the outcome of the dis-covery of auscultation," he writes, adding that in his

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Congestive cardiac failure: central role of the arterial blood pressure

opinion that discovery had "so far done more harmthan good."3

In the years that followed, attempts to investiatecapillary permeability with dyes failed to demon-strate any increase during cardiac failure. Mea-surements of the protein composition ofoedema liq-uid found that it was no different from normalinterstitial liquid. And direct measurements ofcapil-lary pressure by the technique of Landis eventuallyshowed that it was increased in cardiac failure.4 Thenormal pressure in digital capillaries held at the levelof the heart fell from about 35 mmHg in the arte-riolar limb to about 12 mmHg in the venous limb.In patients with congestive cardiac failure the pres-sure in the venous capillary limb averaged around33mmHg.

The blood volume

The argument went literally backwards and for-wards but by the second world war, when I becamea medical student, backward failure was the stan-dard teaching in London. And yet, looking back onnotes which I made at the time, it did not seem to bea complete explanation. The circulation could bedivided into two portions: the pulmonary and thesystemic. Failure of one ventricle meant simply thatblood was transferred from the portion in front of itto the portion behind it. The problem was that thevolume of the systemic portion was ten times that ofthe pulmonary. In the case of the left ventricle, itwas easy to imagine how blood transferred from thesystemic portion could flood the pulmonary portion.But, when the right ventricle failed, the most thatcould be transferred into the systemic portion wasthe total volume of the pulmonary portion, esti-mated to be less than a pint. In no way could thataccount for the many pints of anasarca that, in thosedays, were removed by Southey's tubes.Oedema of the lungs was, therefore, a special case.

It could occur rapidly and could be readily expla-ined on mechanical grounds. The problem was, andis, the slowly developing oedema of the rest of thebody which is still generally referred to as right ven-tricular failure-this is the subject to which I shalladdress my comments during the remainder of thispaper.Another problem, pondered over in my notes, was

the total blood volume. "Plethoric", all the old clin-ical masters had said. But if either the backward orthe forward theory were correct the blood volumeshould diminish. Evidence suggesting the oppositehad been accumulating since the first world war5and was greatly supported by Wollheim's extensivemeasurements.6

Early in the second world war Isaac Starr pub-

lished the work that seemed to point in the rightdirection. He made a mechanical model which con-sisted of two pumps, designed to obey Starling'slaw, connected by pulmonary and systemic circuitsthe volume and resistance of which could beadjusted.7 He found that when he made one or bothof the pumps "fail" he could reproduce the hae-modynamic effects of cardiac failure only if heincreased the circulating volume or diminished thecirculatory capacity. From this he elaborated histheory of the "static" pressure in the circulation-the pressure which existed throughout the circu-lation when the pumps were stopped. Extendingthese ideas to man he found that the "static" pres-sure measured in newly dead corpses was muchhigher when there had been cardiac failure.8

Starr's observations strongly supported the evi-dence that capillary pressure was raised in con-gestive failure. But at the same time they showedthat the "static pressure" in a person without con-gestive failure was lower than the pressure in thevenous limb of the capillaries, which lent support toStarling's conclusion that when the cardiac outputwas abruptly reduced the capillary pressure fell.

Starling's conclusion also receives support from acommonplace observation. At the time of death theheart stops completely and yet tissue oedema doesnot occur in the succeeding hours even in the areas,for instance, round the eyes, where the tissue is laxand liable to accumulate liquid easily. This state ofaffairs is explained by a "static pressure" which isconsiderably lower than the colloid osmotic pressureof the plasma.So Starling was probably right in believing that

the capillary pressure fell in his dogs. His mistakewas to transfer this observation to patients with car-diac failure. "The dogs deceived him", as East saidof Lewis's work on bundle branch block.

The cardiac output

In the history of cardiology the period of the secondworld war is notable, above all, for the introductionby Cournand and Richards of the technique of car-diac catheterisation; this made immediately availablethe measurement of the cardiac output more accu-rately and securely than had previously been possi-ble. Many early studies showed the cardiac output tobe reduced in congestive cardiac failure, whichwould have pleased both the backward and the for-ward failure theorists. But shortly after came thediscovery of a group of conditions that clinicallyappeared to be associated with congestive cardiacfailure but in which the cardiac output wasincreased. The causes of this "high output failure"included anaemia, thyrotoxicosis, Paget's disease of

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bone, arteriovenous fistulas, cor pulmonale, andberiberi.Here was near disaster for the backward failure

theorists and a serious dilemma for the forward fail-ure theorists. If failure was caused by a diminishedsupply ofblood to the body how could the same syn-drome occur with a greatly increased blood supply?The answer was the definition which, with smallchanges in wording, appears today in every textbook of cardiology: "a state in which the heart failsto maintain an adequate circulation for the needs ofthe body ..."

Peripheral metabolism

What was left undefined was the nature of the needsof the body. What was this mysterious metabolicrequirement, the lack of which led to oedema?

Fuels for cells consist of oxygen, glucose, andfatty acids. Calculations of the turnover rate of thesethree fuels in the blood show that the turnover rateof oxygen is five or six times as high as that of theother two. Glucose and fatty acids enter the bloodthrough local streams which subsequently join themain flow. Only for oxygen is the point of entrydependent on the total cardiac output. The mostcritical need of the body referred to in the definitionmust, therefore, be the need for oxygen.But if in patients without metabolic disturbances

the circulation becomes inadequate to supply theneeds of the body it follows that the oxygen uptake isdiminished. Yet the early studies using the Fickprinciple had clearly shown that this was not so.10

The law of the heart

History is not one main road and we shall leave theblind alley into which much of the world of cardiol-ogy still finds itself and retrace our steps back to1915-the year of the law of the heart. ".... Themechanical energy set free on passage from the rest-ing to the contracted state depends ... on the lengthof the muscle fibre. This simple formula serves to'explain' the whole behaviour of the isolated mam-malian heart."'' The simplicity of the law aided bythe sheer arrogance of its title gave it an immediateauthority. It was widely welcomed by the backwardfailure supporters although, as we have seen, Star-ling himself was firmly committed to forward fail-ure. Note how Starling limited it to the isolatedheart. This important and severe limitation has beenwidely disregarded.The law takes no account of the processes of

hypertrophy and dilatation which are so importantin clinical disease. It ignores, also, the important roleplayed by the autonomic system. As Hamilton and

Harris

Richards were later to point out, "Without the coor-dinating stimulus of the central nervous system andthe hormonal control governed by this system, thetruly isolated heart seems to vary its pumping func-tion between that of a heart in a normal resting ani-mal and that of a heart in an animal moribund in thelast stages of shock."'12

The autonomic nervous system

The influence of the autonomic nervous system onthe heart was, of course, known to Starling, andmuch of our present understanding of it dates fromthe nineteenth century. However, it took a sur-prisingly long time before the relation between Star-ling's law and sympathetic drive was elucidated.This was the contribution of Sarnoff and Berglundwho showed that a heart could develop a whole fam-ily of Starling's curves depending on the degree ofsympathetic stimulation.'3An entirely new step forward was taken by Chid-

sey, working in Braunwald's laboratory. He showedthat the concentration of noradrenaline in theplasma increased much more in patients with con-gestive failure during exercise than it did in normalpeople.'4 The daily excretion of noradrenaline in theurine was also increased in these patients.'"The influence of the sympathetic system extended

not only to the heart but throughout the vascularsystem. At about this time Donald, Wade, andBishop were studying the redistribution of bloodflow to various regions of the body in cardiacpatients.16 They showed that the redistribution offlow in patients with cardiac failure was similar tothe redistribution seen during physical exercise innormal people. It comprised a reduction in bloodflow to the kidneys, gut, and skin, with preservationof flow to the myocardium and skeletal muscle. Thevasoconstrictor influence of the sympathetic systemon the renal circulation is especially important. Inheart failure the increased sympathetic activitycauses the renal blood flow to decrease dis-proportionately to the cardiac output.

Control of the cardiovascular system by thecentral nervous system

In 1870 Dittmar, working in the laboratories of theself-effacing Carl Ludwig, found that the increase inblood pressure caused by stimulation of the sciaticnerve was retained in animals with pontine transec-tion but abolished when the medulla wasdestroyed.'7 Owsjannikow, from the same labora-tory, studied successive transections of the brainstem and discovered that the blood pressure beganto fall at the caudal border of the inferior colliculi



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Congestive cardiac failure: central role of the arterial blood pressureand reached the low pressure of a spinal animal withtransections below the obex. 8 Dittmar's furtherstudies located the region responsible for mainte-nance of the blood pressure in the ventral region ofthe lateral reticular formation.19

Later researches have shown a widespreadinvolvement of the reticular formation of the brainstem in the coordination and modulation of cardio-vascular responses, and this led to the general viewthat vasomotor control was diffusely mediated ratherthan located in a specific area. Recent findings have,however, indicated a specific and important role of aregion in the ventrolateral medulla-the site firstproposed by Dittmar over a hundred years ago. Thefirst clue came from observations that the applica-tion of a cold probe20 or pharmacological agents21 22to a specific area of the ventrolateral surface of themedulla could cause a precipitous fall in blood pres-sure. These observations suggested the existence ofa minute localised vasomotor region lying very closeto the surface of the medulla. Subsequent studieshave identified it as the rostral portion of the ventro-lateral reticular nucleus, corresponding to a group ofadrenaline-synthesising cells usually referred to asCl neurones.23 Neurones of the Cl area project tothe autonomic neurones of the intermediolateral col-umnn of the spinal cord.24 Electrical or chemicalstimulation of the Cl area leads to an increase inarterial pressure and heart rate and increased con-centrations of catecholamines and vasopressin in theplasma." Electrolytic lesions of the area cause a fallin arterial pressure to levels similar to those of aspinal preparation.26 The caudal portion of the ven-trolateral reticular nucleus consists of cells whichcontain noradrenaline (Al area). They project tomore rostral cardiovascular regions, including theCl area and have a depressant effect on the bloodpressure.27 28

At the beginning of this century, afferent fibrestravelling in the vagus and glossopharyngeal nerveswere traced to the nucleus tractus solitarius.29 In1932 Bronk and Stella demonstrated the existence ofthe baroreceptors which sense the stretch of the archof the aorta and the carotid sinus caused by the arte-rial blood pressure.30 The afferent baroreceptorimpulses end in the nucleus tractus solitarius fromwhich controlling relays pass to the Cl area of theventrolateral medulla to inhibit its tonic discharge tothe preganglionic sympathetic neurones of the inter-mediolateral column of the spinal cord. At the sametime relays pass from the nucleus tractus solitariusto the nucleus ambiguus and the dorsal nucleus ofthe vagus from which parasympathetic influencesare projected through the vagus nerve. In this way,an increased arterial pressure reflexly diminishescardiovascular sympathetic tone and, at the same

time, stimulates parasympathetic activity to slow theheart.

Similar stretch receptors, the "cardiopulmonaryvolume receptors", give rise to afferent dischargeswhich also travel through the vagus to the nucleustractus solitarius. These are stimulated by dis-tension of the atrium and other low pressure regionsand act to inhibit the sympathetic outflow from themedulla.

Control of the heart rate, cardiac output, andblood pressure is mediated also by regions of themid-brain, hypothalamus, and cerebral cortex, someof which have been described together by Hiltonas organising the "defence reaction."31 Thisphysiological response is made up of an increasedarterial pressure with an increased cardiac output,vasoconstriction in the gut, skin, and kidney, andvasodilatation in skeletal muscle.

Neuroendocrine mechanisms

The relation between the hypothalamus and thepituitary is central to the neuroendocrine control ofthe body. The posterior pituitary is an extension ofthe brain into which magnocellular neurones fromthe paraventricular and supraoptic nuclei descend,carrying oxytocin and vasopressin. Vasopressin hasboth antidiuretic and vasoconstrictive properties,although the effects of the latter on the arterial pres-sure are normally concealed by the action of the bar-oreceptors. In addition to its magnocellular popu-lation, the paraventricular region of thehypothalamus contains many parvocellular neu-rones. Some of these project to the medianeminence32 and are presumably concerned with theneural control of anterior pituitary hormone secre-tion through the hypophysial long portal system.Other parvocellular neurones of the paraventricularnucleus project to the nucleus tractus solitarius, theventrolateral medulla, and directly to the inter-mediolateral column of the spinal cord.33 -3 Thereare reciprocal connections between the para-ventricular nucleus and the nucleus tractus solitariusand A1 area36 and, through these, the para-ventricular nucleus may modulate the baroreceptorarc.Many peptides are synthesised within the central

nervous system. Several of them, including angio-tensin II, vasopressin, neurotensin, calcitonin gene-related peptide, and neuropeptide Y, have powerfulvasomotor effects elsewhere in the body, but theirfunction in the brain is largely unknown. The blood-brain barrier is, in general, impervious to peptidemolecules in the plasma, but, in certain small areasof the ventricular system, the capillary endothelialcells are fenestrated. These "circumventricular"

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organs may, therefore, be a pathway through whichplasma peptides, such as angiotensin II and vaso-pressin, can influence the central nervous system.

In addition to the influence of the hypothalamuson the release ofanterior and posterior pituitary hor-mones the central nervous system exercises a controlover the release of renin from the kidney (eitherdirectly through , receptors in the afferent arterioleor indirectly through renal arterial vasoconstriction)and over the release of adrenaline and noradrenalinefrom the adrenal medulla.

Modifications ofthe autonomic nervoussystem

Evidence has been put forward that the baroreceptorresponse is diminished in patients with heart fail-ure.3738 A similar apparent diminution in bar-oreceptor response has been reported in normal peo-ple during exercise.3940 In both cases it seems likelythat this is an expression of a new setting of themedullary centres which diminish vagal outflow atthe same time as they increase sympathetic outflow.Changes in the autonomic system also occur in the

heart itself. There is a diminished response ofafferent nerve fibres to stretch in the atrium41 whichmay be due to an increased rigidity of the atrial wallor changes in the structure of the afferent endings.42A notable change in the myocardium is a profounddecrease in the content of noradrenaline.43-45 Itscause has been debated (see Rupp and Jacob46 forreview). In our experiments (unpublished data) thediminution in content has been specifically associ-ated with failure. In the presence of ventricularhypertrophy without failure the content of nor-adrenaline has remained unchanged while its con-centration has decreased simply because the volumeof myocytes has increased. The response of the ven-tricle to postganglionic sympathetic nerve stimu-lation has been found to be reduced in dogs withcardiac failure.47 This may in part be due to thediminished stores of noradrenaline but there is alsoevidence that there is a decrease in the density of1 adrenergic receptors in the myocardium.48

The kidneys

Soon after Starr's observations on "static pressure"Warren and Stead followed the course of events inpatients with heart failure whose cardiac treatmenthad been stopped.49 They found that the bodyweight and plasma volume started to increase beforethey could detect any increase in venous pressure.By now it was clear that the formation ofoedema andthe expansion of the plasma volume implied an

Harris

increase in the volume ofthe extracellular space. It isremarkable how long it took for this simple fact, soobvious to anyone who had seen the patients bloatedwith oedema, to become formally part of the conceptof failure.Now, therefore, attention swung to the kidney.

The scanty concentrated urine had been knownsince the time of Hippocrates and the routine testingfor "chlorides" in the urine with silver nitrate hadlong been used to teach students that chloride wasbeing retained. Merrill showed that the retention ofsodium in the urine was associated with a strikingdiminution in the renal blood flow.50 "Evidence of'forward failure' as primary cause of edema" is thesubtitle of the paper. But now "forward failure"refers to the kidneys not to vascular endothelium.At first it was thought that a simple decrease in

glomerular filtration rate in the presence of normaltubular reabsorption was sufficient to account forthe retention of sodium5' but more a careful mathe-matical analysis showed that there was a mysteriousincrease in tubular reabsorption.52 53

In fact, the decrease in glomerular filtration wasless than the decrease in renal blood flow and wasnot obvious until cardiac failure became clinicallysevere.52 In dogs with constriction of the thoracicinferior vena cava, glomerular filtration was actuallyincreased in the presence of severe sodium reten-tion.54 This was unlike what was known to happenwhen perfusion diminished in the isolated kidney.55Here, renal blood flow and glomerular filtrationwere both maintained as the perfusion pressure wasreduced from 180 to 80mmHg while below thatpressure glomerular filtration fell more precipitouslythan renal blood flow so that the filtration fractiondecreased. The high filtration fraction of cardiacfailure implied that the post-glomerular vascularresistance was increased disproportionately to thepre-glomerular resistance. Barger suggested thatthis would lead to an increased colloid osmotic pres-sure in the peritubular capillaries which would pro-mote tubular reabsorption of salt and water.56 Thismechanism (originally conceived by Carl Ludwig57)did not receive immediate acceptance; but sub-sequent work has led to the view that it is animportant factor regulating reabsorption from theproximal tubule and there is evidence that it func-tions in this way in congestive cardiac failure.58 59There is in addition abundant evidence of

enhanced distal reabsorption of sodium both in highoutput failure606' and in low output failure.62-64This is the region where aldosterone and, probably,atrial natriuretic factor exert their effects.

Renin-angiotensin-aldosterone

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cardiac failure was found by Singer and Werner whoobserved that the urine of patients with failure con-tained a sodium-retaining substance.65 This wassoon identified as aldosterone.66 Evidence of anincreased secretion of aldosterone into the bloodgrew both in patients and in experimental animals.67When one adrenal was removed and the other trans-planted to the neck the response of aldosterone toconstriction of the thoracic inferior vena cava wasnormal.68 Crossed circulation of blood from a dogwith a constricted vena cava to a normal dog causedan increased secretion of aldosterone.69 These stud-ies showed that the stimulus to the secretion ofaldosterone was humoral. Further studies withnephrectomy and the injection of renal extractsshowed that the agent came from the kidney, and itwas only a short step to identify it as renin and theimmediate humoral agent as angiotensin I1.70 Infact Merrill and his colleagues had already reportedan increased concentration of renin in renal venousblood of patients in cardiac failure in 1946, but itssignificance had gone unrecognised.The increased release of renin during renal

ischaemia had been known since Goldblatt et al'soriginal observations.7" Now this mechanism couldbe seen to be operating in cardiac failure. However,although the renal blood flow was known to bedecreased in cardiac failure, the control of therelease of renin from the juxtaglomerular cells wasfound to depend on the mean arterial perfusion pres-sure rather than on blood flow.72 This supportedTobian et al's theory that the release of renin wasdirectly regulated by the degree of stretch of thewalls of the afferent glomerular arterioles73; sub-sequent work has confirmed this mechanism. Inaddition, changes in the concentration of sodiumchloride ions in the region of the macula densa affectthe rate of release of renin. This mechanism under-lies the effects of a dietary restriction of salt and ofdiuretics which act by inhibiting the reabsorption ofchloride in the ascending limb of the loop of Henle.The direct effects of perfusion pressure, however,can be shown to operate when the macula isexcluded.74The relation between renal arterial pressure and

plasma renin activity shows that little renin isreleased as the mean renal arterial pressure fallsfrom 100 to 85 mmHg.7s Thereafter the increase inplasma renin activity increases linearly down topressures of 50mm Hg. This implies that the intrin-sic afferent arteriolar stretch receptor system is, byitself, relatively unresponsive to a small fall in arte-rial pressure. The responsiveness of the system is,however, greatly increased by adrenergic stimuli,which act by increasing the threshold for reninrelease75 so that a small decrease in arterial pressure

can evoke a substantial release of renin. Both stimu-lation of renal sympathetic nerves and bloodborneadrenergic agents are effective and act througha receptors.

Electrical stimulation of the dorsolateral pons76and the lateral hypothalamus77 evoke renin releasethat can be prevented by denervatior& of the kidneys.The afferent limb of the reflex arises from the arte-rial baroreceptors and the cardiopulmonary "vol-ume" receptors described above.78 The two systemsmay be shown to conflict under experimentalconditions79 and, as discussed later, presumably doso in cardiac failure.The operation of the sympathetic system is not

necessary for the release of renin by the kidney inresponse to a decreased perfusing pressure but reninrelease is greatly enhanced by sympathetic stimu-lation. Thus the reflex control of the release of reninseems to be particularly important when arterialpressure changes slightly with physiological condi-tions such as posture80 and exercise.8' Even psycho-logical stimuli have been found to increase plasmarenin activity.82 Careful early studies had shownthat the sympathetic system, the baroreceptors, andvolume receptors and even the brain were not neces-sary to the renin-aldosterone response during con-striction of the thoracic inferior vena cava in ani-mals.67 This gave rise to the view that the nervoussystem was not a factor. But something which is notnecessary may still be used, and the present evidencesuggests that the nervous system has an importantrole in human disease in which the initial degrees ofcardiac disability are likely to be less severe.

In addition to stimulating the secretion ofaldosterone, angiotensin II has other importantproperties in cardiac failure; it is a powerful vaso-constrictor, it enhances adrenergic neuroeffectortransmission, and it is concerned with the sensationof thirst. Its constrictor properties are important inmaintaining the arterial pressure and may be thecause of the particular increase in post-glomerularvascular resistance.83

Early measurements ofboth aldosterone and reninactivity in the plasma were confusing. It seemed thatboth were increased in some patients but were nor-mal in others. The explanation came from theexperiments on dogs carried out by Watkins et al.84They showed that after constriction of the pul-monary artery or inferior vena cava "the initialresponse was a reduction in blood pressure, a rise inplasma renin activity, plasma aldosterone, and waterintake, and nearly complete sodium retention. In thedays after moderate constriction plasma volume andbody weight increased (with development of ascitesand oedema); blood pressure, sodium excretion,plasma renin activity, and plasma aldosterone

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returned to normal. In animals in which blood pres-sure was not restored, plasma renin activity andplasma aldosterone remained elevated throughoutthe period of constriction."This view of the endocrine response as something

which might be transient, rather than sustained, wasan important step forward. The renin-angiotensin-aldosterone system responds both in low output andin high output failure85 and the considerable num-ber of reports on the beneficial effects of convertingenzyme inhibitors testifies to the great importance ofthis system in clinical cardiac failure.

Argmiune vasopressin

Early studies showed that the urine of patients withcardiac failure contained an antidiureticsubstance86 87 but it was some years before anal-ytical techniques were adequate to show that plasmavasopressin concentration was increased.88 Thisfinding was consistent with the highly concentratedurine passed in cardiac failure, and the studies ofAnderson et al showed the role of vasopressin andthe mechanism through which its release is stimu-lated.89 Their experiments were carried out on dogssubjected to acute obstruction of the thoracic infe-rior vena cava. If the renal arterial pressure was heldconstant there was a fall in cardiac output and aorticpressure, a fivefold increase in urinary osmolality,and a dramatic reduction in free water clearance.Hypophysectomy greatly attenuated the response ofurinary osmolality and free water clearance if renalarterial pressure was held constant but, if renal arte-rial pressure was allowed to fall, there was a consid-erable decrease in free water clearance. From this itcould be concluded that the increase in urinaryosmolality was due almost entirely to vasopressin,while the decreased free water clearance was alsopartly determined by a diminished delivery to thedistal nephron. Constriction of the inferior venacava had no effect on urinary osmolality or free waterclearance in dogs that had intact hypophyses butdenervation of the baroreceptors. This indicatedthat the release of vasopressin during vena cavalconstriction was stimulated by a reduction inafferent baroreceptor impulses.

Constriction of the inferior vena cava, however, isunlike intrinsic failure of the heart in that the pres-sures affecting the low-pressure "volume" receptorsare diminished.84 The studies of Anderson et a189therefore suggest that in patients with cardiac dis-ease the stimulatory effect of a low arterial pressureon the release of vasopressin overrides the inhibitoryeffect of atrial distension. Such a predominance ofarterial baroreceptors over atrial stretch receptorsappears to be normal in primates.9091 It is unlikely

Harristhat the increased release of vasopressin in con-gestive failure is mediated through osmoreceptorssince the plasma osmolality is generally decreasedrather than increased.

Atrial natriuretic peptide

Early electron microscopical studies had shown thepresence of specific granules in atrial myocytes, buttheir function was not suspected until de Boldshowed that the numbers of granules varied withchanges in water and electrolyte balance.92 Twoyears later he showed that atrial extracts had anatriuretic effect.93The active principle has now been identified as a

polypeptide and its amino acid sequence has beendetermined.9495 In the atrium it appears to beformed from the cleavage of a larger precursor mole-cule.96 Atrial natriuretic peptide is released inresponse to a high atrial pressure97 and the plasmaconcentration of the peptide has been found to beincreased in patients with congestive cardiacfailure.98The natriuretic effect appears to be located in the

distal tubules and collecting ducts.99 In the wholeanimal the effects of the peptide may be partly medi-ated through an inhibition of the secretion ofaldosterone and of the release of renin. In addition toits effects on the kidney, atrial natriuretic peptidehas been shown to be a vasodilator.'00

Distention of the atrium causes a release ofnatriuretic peptide and at the same time stimulatesnerve receptors that lead to an inhibition of sym-pathetic activity and a diminished release of renin.The two mechanisms, therefore, act together tolower systemic vascular resistance and increase theexcretion of sodium. But, clearly, the natriuretic andvasodilator effects of the peptide in patients withcardiac oedema are quite outweighed by the sodiumretention and vasoconstriction caused by sym-pathetic stimulation and activation of the renin-angiotensin-aldosterone system. It follows also thatthe stimulation of the sympathetic-renin-angio-tensin-aldosterone system by the low arterial pres-sure outweighs its inhibition by cardiopulmonaryvolume receptors.

Retention of saline is harmful

It may be supposed that the body reacts to a failingheart in a manner which will be beneficial. Forinstance, the retention of water by the kidneys maybe seen as a way of increasing the filling of the heartand, thereby, its output. And yet diuretics areprobably the most efficacious treatment we have.Vasoconstriction should maintain the blood pres-



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Congestive cardiac failure: central role of the arterial blood pressuresure and preserve flow to vital organs. Yet vaso-dilators are now widely used to treat cardiac failure.Similarly it might be argued that angiotensin II andaldosterone are beneficial; yet captopril andspironolactone are found to be helpful.

It seems that every time we thwart nature'sintentions, the patient improves. The explanation ofthis paradox is that the processes which are evokedduring cardiac failure originally evolved for somequite different purpose.101

Cardiac failure is a rare event. So exotic a condi-tion would not have any perceptible effect on thesurvival of the species. The powerful mechanismsthat we find in cardiac failure are more likely to haveevolved to deal with circumstances vital to everydaypreservation. Of these circumstances the two mostobvious are physical exercise and trauma.Unpublished studies carried out with colleagues

at the University of Brescia have shown that duringexercise plasma concentrations of several hormonesincrease in a sequential fashion: noradrenaline andadrenaline, vasopressin, and atrial natriuretic pep-tide, followed by renin activity and aldosterone.Measurements on patients with untreated myo-cardial infarction also showed an increase in all thesefactors.The neuroendocrine-renal response in both these

conditions is, therefore, similar to the response incongestive cardiac failure. The important differenceis in the length of time over which the stimulus ismaintained-minutes or hours for exercise, hours ordays for shock, weeks or months or years for cardiacfailure. The mechanisms that may be necessary forexercise or for survival in injury are harmful whenmaintained over prolonged periods because theylead to the retention of saline in the body. For thereason why the excessive retention of saline is harm-ful we have to go back far into evolutionary historyto the emergence of air-breathing animals1'o since itis the air-breathing lung that is so susceptible toflooding.

Cardio-neuro-endocrine links

Apart from the complicating presence of pain, thecondition of acute myocardial infarction is a highlyappropriate model of the immediate neuro-humoralresponse of the body to a suddenly diminishedpumping capacity of the heart. Already there is evi-dence of both increased sympathetic activity and itsassociated endocrine response.We have already discussed the links between a

stimulation of the sympathetic system and the endo-crine response. But what is the link between adiminished cardiac output and the stimulation of thesympathetic system?

There appear to be two main possibilities: meta-bolic and mechanical. First, the low cardiac outputmay lead to underperfusion ofthe tissues that releasesome intermediary substance into the blood stream.Second, the purely mechanical effects of a low car-diac output may give rise to the requisite afferentimpulses.

Is there ischaemia of the tissues in cardiac failure?We can say, as noted above, that the oxygen uptakeofthe body is undiminished at rest in congestive fail-ure; but the oxygen content of the mixed venousblood is abnormally low so that, in general, the tis-sues must be functioning at a lower Po2 than nor-mal. Nevertheless, the blood lactate in such patientsis normal at rest'02 and we can, therefore, concludethat, at rest, the supply ofoxygen is not rate-limitingfor ATP synthesis in the body as a whole.On the other hand, the concentration of lactate in

the blood increases to a greater extent than normalduring exercise in cardiac patients.'02 This may, inpart, be due to the glycolytic action of cate-cholamines (whose presence in excess during exer-cise of patients with cardiac failure has already beendiscussed) and in part to an inadequate supply ofoxygen. In the latter case, it might be reasonable tosuppose that a metabolic messenger was releasedinto the blood stream and stimulated either the heartor the central nervous system at some distant point.

Experimental evidence, however, is entirelyagainst such a hypothesis. First, the increase in heartrate occurs within a cardiac cycle,'03 an intervalmuch shorter than the circulatory time required forthe messenger. Second, substantially the sameincrease in heart rate and arterial pressure occurs innormal subjects whether or not the exercising limbis rendered ischaemic.'04'106There are, however, two organs in which a reduc-

tion in blood flow may have a specific effect-thekidney and the brain. A decrease in renal perfusionpressure associated with a reduced cardiac outputmay itself stimulate the release of renin and favourthe retention of saline by the kidney. The reductionof renal blood flow in cardiac failure is, however,proportionally greater than the reduction in cardiacoutput. 16 This is an indication of the importance ofthe increased sympathetic activity which magnifiesthe release of renin, as discussed above. A further,and little considered, result of a reduced renal bloodflow may be an increased production of erythro-poietin, since there is an increase in total red cellvolume as well as plasma volume in cardiacfailure. 07

The vasopressor effects of severe ischaemia of thebrain stem have been known since the last century.These effects have been shown to be mediatedthrough the rostral ventrolateral medulla; lesions in

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this area abolish the effects.'08 Cerebral blood flowtends to be protected in cardiac failure'6 and brainstem ischaemia has to be severe to have vasopressoreffects, so that the operation of this mechanism incardiac failure remains uncertain.

In the original experiments of Alam andSmirk'04105 discussed above, both the heart rateand the arterial pressure remained raised after exer-cise so long as the cuff stopping blood flow wasinflated. Subsequent investigators have confirmedthis observation with regard to the blood pressurebut not always with regard to the heart rate.'09 Alamand Smirk suggested that the afferent impulses arosefrom stimulation by some metabolite released fromexercising muscle fibres. Subsequent investigationshave pointed to potassium ions as the likely localmediator."0The existence of a reflex mechanism arising from

exercising muscles was shown directly in cats byCoote et al."l' Stimulation of the ventral root caus-ing tetanic contractions of the hind limb was accom-panied by an increase in the heart rate and arterialpressure. The cardiovascular response was notaffected by dividing nerves to neighbouring joints orskin but was abolished by neuromuscular blockadeor by cutting the dorsal roots. The afferent impulsestravel through small, slowly conducting fibres withfree nerve endings.'09 112 Some of these afferentfibres relay directly to the nucleus tractussolitarius"3 and may, therefore, be responsible forthe re-setting of the baroreflex arc which allows amoderate increase in arterial pressure during exer-cise. It will be remembered that Dittmar's experi-ments showed that the hypertension caused by stim-ulation of the sciatic nerve was retained despitetransection at the level of the pons. 7 In addition tosuch clear cut evidence of a cardiovascular influenceof muscle afferents, there is evidence, albeit lessstrong, that influences from the cerebral cortex alsohave a role.'09The experiments of Alam and Smirk'05 and oth-

ers, quoted above, not only demonstrate the exis-tence of a cardiovascular reflex from exercising mus-cle but also show that this reflex is unaffected byischaemia of the muscle. There is, therefore, no rea-son to believe that the increased sympatheticresponse to exercise in cardiac patients is caused byan increased afferent input to the medullary centres.Cortical and other higher influences may be oper-ating in evoking the defense reaction in these dis-tressed patients. Similarly more general somato-sensory afferents (for instance associated withdyspnoea or exhaustion) may have a direct influenceon the reticular formation of the brain stem."14 115Both these latter influences may act to re-set the cen-tral baroreflex mechanism, both during exercise and

Harrisat rest.By far the most obvious way, however, in which a

reduced cardiac output will magnify the sympatheticoutflow, during rest and exercise, is through the vas-cular stretch receptors. And, here, the influence ofthe arterial baroreceptors must dominate, since thedistension of the cardiopulmonary portion of thecirculation will inhibit, rather than stimulate, thesympathetic outflow.

A condition in which the cardiac output isinadequate to maintain the arterial pressure

All these different lines of argument converge on theconclusion that control of the arterial pressure is thekey link in the process of congestive cardiac failure.Present day opinion follows the view that in cardiacfailure the cardiac output is insufficient for the meta-bolic needs of the body. But the needs of the bodyare, as we have seen, being met. Neither is there anyevidence that the disturbances in energy pathwayswhich may be required to maintain these needs leadto some blood borne messenger or to any increase inthe afferent input from the limbs to the centralnervous system.Of course, the purpose of the circulation must be

to provide perfusion to the tissues. But the bodyassesses the adequacy of the circulation by sensingthe arterial pressure and not through metabolic mes-sengers from the tissues. The arterial pressure issensed by the juxtaglomerular cells and by the bar-oreceptors, and the sympathetic outflow whichresults from a reduction of baroreceptor inputmagnifies the response of the juxtaglomerular cells.

In this way, also, the mechanism of high outputfailure becomes apparent. All such patients have anabnormally low systemic vascular resistance eitherfrom vasodilatation or from arteriovenous shunts.Vasodilatation might be supposed to lead to oedemabecause the pressure at the arterial end of the capil-lary may be increased. This may well be a factor insome instances, but it cannot apply to the patientswith arteriovenous communications. The commonfactor is the tendency to low blood pressure. Closureof an arteriovenous fistula causes an increased bloodpressure and a prompt natriuresis.116 The differencebetween high output and low output failure is thedifference in the ability of the heart to respond to theincreased sympathetic drive.Oedema is commonly associated with vasodilator

treatment and may also be explained in this way.The oedema of cor pulmonale is always associatedwith the retention of carbon dioxide, which is apowerful vasodilator. In addition, a raised Pco2 inthe cerebral circulation specifically stimulates thevasomotor sympathetic outflow.



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Congestive cardiac failure: central role of the arterial blood pressureHypertension and cardiac failure: commonground

Scientific and clinical specialisation alike have led toa world wide separation between those whose inter-est is primarily the blood pressure and those whoseinterest is primarily the heart: different societies,different journals. What is astounding is that exactlythe same neurohumoral mechanisms are being stud-ied independently by both groups. One groupbelieves that these mechanisms are important in thecontrol of the blood pressure; the other that they areimportant in cardiac failure. This paradox seems tohave gone unremarked but is at once understandableif control of the blood pressure is the determiningfactor in cardiac failure.

Arterial pressure, cardiac output, andexercise

A look back over evolutionary history shows that thearterial pressure and the cardiac output took a sud-den jump together when the warm-blooded animalsemerged.0'° With a high cardiac output and a supe-rior air-breathing respiratory apparatus the mam-mals and birds were able to make full use of theenergy available from oxidation in their red muscles.In this way they have developed the surpassingcapacity for physical activity which has been a mainorigin of their success. For this purpose the circu-lation has to provide for a sudden massive increase inblood supply to the exercising muscles. This isachieved by a great capacity for an increased outputand by vasodilatation in the exercising muscle andvasoconstriction in other regions.

I have argued elsewhere that it is these require-ments of physical exercise which have necessitatedthe extraordinarily high arterial pressure of themammals and birds.'0' The combination of a highresting arterial pressure, together with an immensecapacity for vasodilatation in skeletal muscle, allowsa sudden massive increase in cardiac output withonly a moderate increase in left ventricular emptyingpressure. Thus the links between the cardiac outputand the arterial pressure are archetypal and havetheir origins in the requirements for physicalactivity.

It may not, therefore, be surprising that the effectsof physical exercise are specifically important inpatients with a limited cardiac output. The ther-apeutic effect of rest in such patients was well knownto our predecessors but has largely been forgotten bya generation obsessed with the cult of physicalfitness. Physical exercise, as we have seen, evokes thesame neuroendocrine response as is found in cardiacfailure and, as judged by the concentration ofplasma

noradrenaline, the response to physical exercise isespecially increased in cardiac patients.During exercise, as discussed above, afferents

from the exercising limbs and, probably, commandsfrom higher centres re-set the medullary cardio-vascular control system to permit an increased heartrate and arterial pressure. The diseased heart isunable to increase its output to the normal extent inresponse to autonomic control. During exercise,therefore, it is unable to increase the arterial pres-sure to the extent demanded by the medullary con-trol system. The massive and largely locally medi-ated vasodilatation in the exercising muscles mayeven lead to a fall in arterial pressure. In the absenceof an adequate modulatory baroreceptor input, theinhibitory influence of the nucleus tractus solitariuson the vasomotor elements ofthe reticular formationand perhaps specifically the Cl area may be pre-sumed to be diminished so that the outflow to thepreganglionic sympathetic neurones of the inter-mediolateral column of the spinal cord is increased.The neuroendocrine response in congestive fail-

ure may well, therefore, be intermittent, accordingto the state of physical activity of the patient. Thiswould in part explain why isolated blood samplesmay fail to show abnormal concentrations ofhormones and why a chronic re-setting of thebaroreceptor arc does not seem to occur.

Finally, it will be noted that all the changes in theperipheral autonomic system, reviewed above, willexacerbate the condition of congestive failure. Dimi-nution of the baroreceptor response will reduce theinhibitory control which this exerts on the vaso-motor centres. A decreased responsiveness of atrialreceptors will reduce the afferent input whereby adistended atrium reduces sympathetic outflow. Alack of responsiveness of the myocardium to post-ganglionic sympathetic stimulation will reduce theincrease in output that is necessary to maintain theblood pressure.

Conclusion

The evolution of a high cardiac output in the warm-blooded animals has provided a surpassing capacityfor physical activity supported by oxygen. The oxy-gen uptake of exercising muscles is met by a massivecapacity for local vasodilatation and by an increasein cardiac output. The co-evolution of a high restingarterial pressure permits the increase in cardiac out-put to take place during exercise with a relativelystable left ventricular emptying pressure.Although the function of the circulation is to per-

fuse the tissues, the body monitors the adequacy ofits perfusion, not through metabolic messengers car-ried from the tissues in the blood stream, but by

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sensing the arterial pressure. A damaged heartbecomes progressively less able to maintain the arte-rial pressure, at first during exercise and ultimatelyat rest. When this happens the body responds in thestereotyped manner for which it has beenprogrammed by natural selection to maintain thearterial pressure during exercise or trauma.

In the short term this is achieved by autonomicregulation through the baroreflex arc, the centralcontrol of which is modulated by afferents from thelimbs and instructions from higher centres. In thelonger term the arterial pressure is maintainedthrough an increase in the blood volume by reten-tion of saline by the kidney. To this end local renalmechanisms are successively magnified by the renin-angiotensin-aldosterone system and by the activityof the sympathetic system and vasopressin. In car-diac failure the natriuretic influence mediatedthrough volume receptors and the release of atrialnatriuretic peptide is overruled by the arterial bar-oreceptors so that the body maintains the arterialpressure at the expense of an increase in bloodvolume.The increase in blood volume is, therefore, the

result of "forward failure". But the distribution ofthe excess volume of blood is determined by themechanical forces of "backward failure". Thus boththese processes raise the pressure in the peripheralcapillaries so that liquid is expelled into the tissuespaces to form oedema.

In these ways the arterial pressure has a centralrole in congestive cardiac failure and that syndromemay, with little exaggeration, be regarded primarilyas one which arises when the heart is chronicallyunable to maintain an appropriate blood pressurewithout support.

I am glad to acknowledge the longstanding supportof the British Heart Foundation.

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Congestive cardiac failure: central blood pressure · 192 bone, arteriovenous fistulas, cor pulmonale, and beriberi. Here was near disaster for the backward failure theorists andaserious

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