The Mechanism of Adaptation of Left Atrial StretchReceptors in Dogs with Chronic

Congestive Heart Failure

IRVING H. ZUCKER, ALVIN M. EARLE, and JOSEPHP. GILMORE

From the Departments of Physiology and Biophysics, and Anatomy, University of Nebraska Collegeof Medicine, Omaha, Nebraska 68105

A B S T R A C T Chronic congestive heart failure(CHF) was induced in dogs by the construction ofan aorto-caval fistula below the level of the renalarteries. Aorto-caval fistula dogs showed signs of CHFwhich included ascites, hind limb edema, and pul-monary congestion. Ventricular catheterization indi-cated a significantly higher left ventricular enddiastolic pressure and lower maximum velocity of leftventricular pressure development/left ventricular enddiastolic pressure in CHF dogs when compared tosham-operated controls. Heart weight/body weightratios were significantly higher in CHFdogs. Electro-physiological recordings from medullated left atrialtype B receptors from the cervical vagus indicated adepressed sensitivity of these receptors in CHF dogswhen compared to sham-operated control dogs. For anygiven change in left atrial pressure, the dischargeof left atrial receptors was significantly reduced inCHFdogs compared with sham-operated controls. Themechanism for this depressed sensitivity was in-vestigated. Sonomicrometry of the left atrial appendageindicated a decreased compliance of the left atrialappendage in the dogs with chronic CHF. In addition,microscope examination of the complex unencap-sulated receptor endings taken from the left atrialendocardium indicated a marked alteration in receptormorphology. A loss of the end arborization was themost typical finding. It is concluded that chronicCHF brought about by an aorto-caval fistula resultsin a depressed left atrial stretch receptor responseand that both decreased left atrial compliance and

A preliminary report of the present investigation waspresented at the 49th Scientific Session of the AmericanHeart Association, 15-18 November 1976, Miami Beach, Fla.

Receivedfor publication 7January 1977 and in revisedform14 April 1977.

structural alterations in the receptor endings mayaccount for this depressed sensitivity.

INTRODUCTION

Alterations in salt and water metabolism during con-gestive heart failure (CHF)l are well known sequelaeof this disease process (1-4). The etiology of the al-tered fluid balance in CHF can be attributed to bothhemodynamic (1, 3, 5, 7) and hormonal factors (4, 8-11). Evidence has been presented by several investi-gators that the secretion of antidiuretic hormone(ADH) may be altered during CHFor related diseasestates (12-19).

Wood (20) suggested in 1963 that the polyuria whichoften accompanies attacks of paroxysmal atrial tachy-cardia may be related to the activity of left atrialstretch receptors. He noted that the polyuria was ab-sent in patients with chronic heart failure or mitralvalve disease.

Although the response of atrial stretch receptorshas been studied under a variety of acute situations(21-29), little is known about the discharge propertiesof these receptors under conditions in which the atriaare chronically distended. Greenberg et al. (30) demon-strated a depressed electrophysiological response ofatrial stretch receptors in dogs with tricuspid avulsionand pulmonary artery stenosis. They concluded that inCHF, impairment of salt and water homeostasis isdue, at least in part, to a decrease in type B atrialreceptor sensitivity. No attempt was made in theirstudy to delineate the mechanism of altered discharge

1Abbreviations used in this paper: ADH, antidiuretichormone; A-V, aorto-caval; CHF, congestive heart failure;dp/dt max, maximum velocity of left ventricular pressuredevelopment; LVEDP, left ventricular end diastolic pressure.

The Journal of Clinical Investigation Volume 60 August 1977-323-331 323

responsiveness nor were adequate sham-operated con-trols employed.

Because of the potential clinical importance of atrialreceptors in the control of salt and water balance,we decided to investigate receptor discharge duringchronic CHF in the dog. Using a model of high outputcardiac failure, left atrial stretch receptor activitywas analyzed electrophysiologically. We also under-took a study of atrial receptor morphology and atrialcompliance in an attempt to ascertain a possiblemechanism by which atrial receptor sensitivity isaltered.

METHODS

Mongrel dogs of either sex averaging 20.3±0.63 kg in weightwere used. They were anesthetized with intravenous pento-barbital sodium and divided into two groups. Group I con-sisted of 11 dogs which survived the establishment ofan aorto-caval fistula below the level of the renal arterieswhereas group II consisted of 8 dogs which were sham-operated.

A laparotomy was performed under sterile conditions,the intestines retracted, and the abdominal aorta and in-ferior vena cava dissected and isolated. After clamping theaorta and vena cava, an oval window varying in lengthbetween 10 and 15 mmwas cut in each vessel, and anasto-mosed using 5-0 Ethaflex suture (Ethicon, Inc., Somerville,N. J.). The vessels were occluded between 20 and 30 min.Sham-operated dogs were subjected to an identical procedureexcept that each vessel was opened and sutured closedwithout establishing an anastomosis. After surgery, eachdog was treated with 1.2 million U of Wycillin (WyethLaboratories, Philadelphia, Pa.) intramuscularly for 3 days.Of those animals in group I which survived the first 24-hrecovery period, the postoperative recovery course wasuneventful except for the slow development of CHF. Allanimals in group II survived with an uneventful post-operative course. Animals were weighed daily and checkedfor signs of pulmonary congestion, ascites, and peripheraledema. Animals were housed in outdoor runs adjoiningindoor cages, and fed standard lab chow and given waterad lib.

Before surgery, a left ventricular catheterization was per-formed. A high gain recording of left ventricular enddiastolic pressure (LVEDP) and the maximum velocity of leftventricular pressure development (dpldt max) were obtained.A similar catheterization was done at the time the acute ex-periment to be described below was performed. Cardiac out-put was measured by thermal dilution using the IL 601 car-diac output computer (Instrumentation Laboratory, Inc.,Lexington, Mass.) with a 5-French, flow-directed catheterin seven animals before surgery and at the time of theacute experiment.

When clinical signs of CHFwere evident in the dogs ofgroup I and after a similar length of time for the dogs ingroup II, each animal was prepared for recording atrialreceptor activity as described by us previously (25). Atransverse thoracotomy was performed in the fourth inter-costal space. The animal was placed on positive-pressurerespiration using room air supplemented with 100% oxygen.Left atrial pressure was measured using a catheter-tippedtransducer (Millar, Houston, Tex.) placed into the leftatrium through a small pulmonary vein. Aortic pressure wassimilarly recorded in the ascending aorta via a femoral artery.

Left atrial contractile force was measured using a Walton-Brodie strain gauge arch sutured to the left atrial appendage.A standard limb lead ECGwas also recorded. Blood gaseswere periodically monitored (Radiometer Co., Copenhagen,Denmark) and kept within normal limits. The left cervicalvagus was isolated, placed upon a black plastic platformunder warm mineral oil, and desheathed. Slips of the vaguswere cut centrally and placed upon bipolar platinum-iridium recording electrodes. The neural activity was ap-propriately amplified and the fiber continuously split until arecording was obtained from a single unit.

Each receptor was identified initially as an atrial receptorby its discharge pattern in relation to the aortic and leftatrial pressure pulse, the ECG, and left atrial contractileforce tracing. The response to occlusion of the aortic rootand pulmonary artery further identified the receptor as beingin the left or right atrium.

When the activity from an atrial receptor was identified,left atrial pressure was increased by intravenous infusion ofwarm isotonic saline in 50-ml increments. Recordings weretaken continuously during volume expansion. Usually twovolume expansions were performed for each receptor. Theanimal was hemorrhaged back to the control left atrialpressure between the first and second volume expansions.

The conduction velocity was measured in several animalsas follows: at the conclusion of the experiment, stimulatingelectrodes were placed around the left vagus in the chestabove the heart while recording from the unit in the neck. Thevagus was stimulated at a frequency far in excess of thenatural frequency of the receptor. Since several units wereusually evoked by this stimulation, a fast oscillographic traceindicated which of the several evoked potentials becameoccluded as the natural and stimulating pulses collided. Thelatency between stimulus artifact and evoked potential wascalculated as the conduction time. A length of thread placedalong the nerve between the stimulating and recordingelectrodes was measured to obtain the conduction distance.After determination of conduction time, the animals werebled, the heart opened, and the last receptor recorded fromin each animal was localized by punctate probing. In someanimals two receptors were studied. The first receptor waslocalized using vessel occlusion and selective probing in thebeating heart. 16 receptors were studied in the 11 CHFdogs and 14 receptors were studied in the 8 sham-operateddogs.

Receptor discharge was counted directly from the oscil-lographic recording (Visacorder 1858, Honeywell, Inc.,Minneapolis, Minn.) and atrial and aortic pressures wereanalyzed from the original record. The change in receptordischarge was correlated with the change in left atrial peakv wave pressure for spikes/cardiac cycle and spikes/minutewith the use of an IBM 1800 computer program (IBMCorp., White Plains, N. Y.). Student's t test and regressionanalyses were employed for statistical evaluation.

Measurements of left atrial appendage diameter were ob-tained in four animals using 5 MHz piezoelectric crystals(kindly supplied by Dr. H. L. Stone, University of Texasat Galveston) which. were sutured on to the left atrialappendage as close to the body of the atrium as possible.The ultrasound transit time between the crystals wasmeasured using a sonomicrometer (kindly supplied by Dr.A. M. Scher, University of Washington at Seattle). Thechange in left atrial pressure was plotted against the leftatrial appendage diameter. The slopes of the regressionequation for these points were compared for sham-operatedand CHFdogs.

At the end of the experiment the heart was removed,washed in saline, blotted, and then weighed. Blocks of

324 I. H. Zucker, A. M. Earle, and J. P. Gilmore

cardiac tissue, including the junction of the pulmonaryvein and the left atrium, were stained with methylene blueaccording to the Schabadasch procedure as described byMitchell (31). The tissue samples were coded so that thehistologist did not know from which group of dogs theyhad been obtained. Frozen, tangential sections of endo-cardium were cut at 40 ,m. Sections were mounted onslides using gelatin-alcohol (32), dehydrated, and thencovered to facilitate microscope examination.

RESULTSThe average length of time from establishment ofthe aorto-caval shunt to the recording of receptoractivity from the dogs in group I was 57.8+7.6 daysand 31.5+3.5 days for the dogs in group II. All CHFdogs showed signs of either ascites or peripheraledema and severe pulmonary congestion. All dogs ingroup II appeared healthy with no signs of ascites,edema, or pulmonary congestion.

Table I compares the hemodynamic data of CHFand sham-operated dogs. Some of the parametersshown in Table I were obtained from aorto-caval(A-V) fistula or sham-operated animals which werenot used for recording atrial receptor discharge.LVEDP was significantly elevated in CHF dogs,

whereas mean aortic pressure was significantly lowerin the CHF group. dp/dt max and dp/dt max/LVEDP were used as indices of contractility. Al-though dp/dt max was not significantly different inthe two groups of dogs, dp/dt max/LVEDP wassignificantly altered, being greatly reduced in theCHF dogs. Postmortem heart weights were signifi-cantly heavier in CHF than in sham dogs, indicatingsome degree of cardiac hypertrophy. Heart shadowsanalyzed from X rays taken before and after estab-lishment of the A-V fistula in two dogs showedmarked cardiac dilatation. The data presented in TableI along with the clinical data observed, describe apicture of chronic cardiac dilatation and hyper-trophy with a decrease in contractility.

Fig. 1 illustrates the response of a type B left atrialreceptor in a CHF dog (top) and a sham-operateddog (bottom). Panel A represents the control state,and panel B the volume-expanded state. In theCHF dog, resting left atrial pressure is high andaortic pulse pressure is elevated due to the low re-sistant A-V fistula. Atrial receptor discharge occursduring atrial filling (v wave of the atrial pulse) andceases before atrial contraction. In the CHF dog

TABLE IHemodynamics of CHFand Sham-Operated Dogs

CHF Sham

Body weight, kg

Heart weight, g

Heart weight/kg body weight

Mean arterial blood pressure, mmHg

LVEDP, mmHg

dp/dt max, mmHgls

dp/dt max/LVEDP, per s

Cardiac outputBefore A-V fistula or sham operation,

liters/min

After A-V fistula or sham operation,liters/min

20.0±0.96* 20.6+0.73(11)t (8)

212.7±10.8 152.0±7.2(11) (8)

10.8±0.66(11)

98.3±6.8(11)

24.4±8.6(7)

2,150.8±206.6(7)

7.4±0.35(8)

121.4±7.2(8)

4.8±0.93(6)

1,920.7±130.8(6)

90.5± 16.3 659.5±282.4(6) (6)

2.80±0.81(5)

4.37±0.83(5)

2.53±0.31(2)

1.92±0.26(2)

* ±+1 SEM.t Numbers in parentheses refer to thewas made.

number of animals on which each measurement

NS

P < 0.0005

P < 0.0025

P < 0.025

P < 0.025

NS

P < 0.05

NS

P < 0.0025

Left Atrial Receptor Adaptation 325

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depicted in Fig. 1, control atrial receptor dischargeis 5 spikes/cardiac cycle. After raising left atrialpressure by approximately 5 cm H2O (from 20 to 25cm H20), atrial receptor discharge increased to 10spikes/cardiac cycle. The sham-operated dog depictedin Fig. 1 had a control left atrial pressture of about12 cm H2O, and atrial receptor discharge increasedfrom 3 to 9 spikes/cardiac cycle, with an increase inleft atrial pressure of only 2 cm H20. The controlleft atrial pressures shown in Fig. 1 and those recordedin each animal are not necessarily the control leftatrial pressures which existed in the closed-chestanimal. Since various amount of fluid were adminis-tered to each animal in the process of identifyingthe volume responsiveness of the units isolated, it isfelt that the LVEDP obtained in the closed-chest,nonfluid-loaded animals (Table I) is a better indica-tion of the true resting left atrial pressure. Themean change in discharge/cardiac cycle versus themean change in left atrial v wave pressure is shownin Fig. 2. Note that for any given change in leftatrial pressure, the sham-operated dogs had a substan-tially higher change in discharge when compared tothe CHF dogs. These two curves are significantlydifferent from each other at each point depicted.Conduction velocity was measured in five fibers,four from CHFanimals and one from a sham animal.Mean conduiction velocity was 18.9±2.9 m/s (range

326 1. H. Zucker, A. M. Earle, and J. P. Gilmore

9.8-25.8 m/s for all fibers, agreeing with previousvalues obtained by Paintal (33) for myelinated typeB atrial receptors.

Fig. 3 shows the relationship between left atrialappendage diameter and the change in left atrialfilling pressure over a wide range of pressures. Twonormal dogs are compared with two CHF dogs. Theslope of the regression lines for the two normal dogsand the slopes of the regression lines for the twoCHF dogs are not significantly different from eachother. However, the common slopes for the two nor-mal animals are significantly different from the com-mon slopes of the two CHF animals (P < 0.001)using a t analysis for the comparison of slopes (34).

Fig. 4 shows six representative receptors from sham-operated (A) and CHF dogs (B). The receptors fromsham-operated dogs show the characteristic complexunencapsulated endings originally described byNonidez (35). Each ending appears as an arboriza-tion extending as a ball-like structure from its axon.In contrast, the endings obtained from CHF dogsshow a loss of the typical complex unencapsulatedending seen in the normal or sham-operated dog.The axons appear prominent but the ball-like arboriza-tion is either completely absent or appears as com-pressed and disoriented structures. A receptor endingsuch as those displayed here from the sham-operatedgroup was never seen in any CHFdog.

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DISCUSSION

The A-V fistula model used in the present experimentsresulted in the production of consistent CHF as evi-denced by the high LVEDP, cardiac hypertrophy,and dilatation as well as the clinical evidence citedpreviously. In addition to the hemodynamic altera-tions presented here, the animals in the presentstudy were retaining sodium markedly and were

unable to excrete a volume load (unpublished ob-servation).

In the present experiment, the ability of left atrialstretch receptors in CHF dogs to respond to eleva-tions of left atrial pressure was reduced comparedto sham-operated controls (Figs. 1-2). We have pre-

viously demonstrated (25) an exquisite sensitivity ofleft atrial stretch receptors in the dog. This sensi-tivity was not reduced by acute induction of heartfailure produced by administration of propanolol or

pentobarbital sodium or by acute coronary arteryocclusion (26).

The present experiments extend the findings ofGreenberg et al. (30). Their studies showed a de-pressed atrial receptor responsiveness to increasesin central venous pressure during volume expansion indogs with tricuspid avulsion and pulmonary arterystenosis as compared to normal dogs. Sham-operatedcontrols were not used in the above study so that

the nonspecific effects of surgery could not be ruledout as a causative factor. In addition, no attemptwas made to locate the receptors from which theseworkers recorded. Although the mechanism of the de-pressed atrial responsiveness was not investigated,the authors indicated that a possible explanation isthe failure of the atrium to stretch beyond a certainpoint because of pericardial tamponade. This obviouslycannot be a causative factor in the decreased sensi-tivity of atrial receptors in the present experimentssince our dogs were open chest with the pericardiumremoved at the time atrial receptor activity was re-corded. Greenberg et al. (30) also raise the possi-bility that altered sympathetic drive in CHF mighthave influenced the sensitivity of atrial receptordischarge. Again, we must reject this hypothesissince we have previously shown that efferent cardiacsympathetic nerve stimulation has no direct effecton type B left atrial receptor discharge (24).

One obvious mechanism by which the sensitivityof left atrial stretch receptors can be reduced in CHFis by loss of atrial compliance. Zehr et al. (19) re-ported that ADH levels fail to rise when dogs withexperimental mitral stenosis were subjected to a non-hypotensive hemorrhage. Histological sections of theleft atrium indicated endocardial hypertrophy andossification. The consequence of these changes wouldmost likely be a stiffer and less compliant atrium.

Left Atrial Receptor Adaptation 327

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Using Whitney strain gauges Eliahou et al. (36) dem-onstrated a decrease in atrial pulsation at a high fillingpressure. These observations were confirmed by Payneet al. (37) using sonomicrometry. Paintal has sug-gested that atrial stretch receptors respond to theamplitude or atrial pulse pressure rather than thepeak or static pressure reached during atrial filling(21). Wecould not confirm this finding in our previouswork which showed that the best correlate to type Batrial receptor discharge is the peak v wave pressure(25). This is in agreement with the study of Arndt et al.(38) who could demonstrate a velocity component toatrial receptor discharge only at high levels of stretchand at rapid frequencies of stretch in vitro. Eventhough atrial pulsations decrease with progressivevolume expansion (37), the static levels of atrialstretch also increase and one would expect receptordischarge to increase up to some plateau as indeedit does in the normal animal. Payne et al. (37)plotted the relationship between left atrial end diastolicdiameters and the change in the left atrial pressturefor two consciouis dogs on two separate occasions.At low end diastolic diameters the change in leftatrial end diastolic pressure was low and it increasedsharply at high end diastolic diameters. One wouldexpect that at a high atrial end diastolic diameter thecompliance of the atrium would be diminished.

In the present experiments, sonomicrometry of leftatrial appendage diameter in two thoracotomized,sham-operated dogs and two thoracotomized CHFdogsindicated that the appendage was less compliant inthe CHF dogs compared to the sham-operated dogs(Fig. 3). This diminished compliance could explainthe high left atrial pressures and the altered receptordischarge in CHF.

In a recent study published in Russian, Anjuchovskijet al. (39) observed a depression of right atrial type-Breceptor discharge in cats with CHFdue to pulmonaryartery stenosis. Based upon pressure diameter meas-uremiients of the right atriuim, these workers con-cluded that the depression of receptor dischargewas most likely brought about by a decrease in rightatrial compliance, an observation essentially con-firmed in the present investigation.

Several groups have recently described the responseof atrial stretch receptors whose activity travels upsmall diameter (c fiber) fibers in the vagus nerve.These fibers have low conduction velocities (lessthan 2 m/s) and are relatively unresponsive tochanges in atrial pressure (40, 41). Since we meas-ured conduction velocity in several fibers and allwere far above 2 m/s and averaged very close to

that reported for myelinated atrial receptors by others(21), it does not appear that we were selectivelyrecording from c fibers in our CHFdogs.

The study of Greenberg et al. (30) eludes to the factthat a change in the sensitivity of atrial receptordischarge could have come about by a structuralresetting of receptor endings. A precedence has beenestablished for morphological alterations in cardio-vascular stretch receptors under sustained stretch bythe work of Angell-James (42). She found degenera-tion and fragmentation of aortic baroreceptor endingsin several rabbits with sustained renal hypertension.These results confirm those of Abraham (43) andHilgenberg (44). In the present study, vital staining ofleft atrial receptors indicated similar degeneration andfragmentation of the receptor ending in CHF. Thechronic stretch that these endings were subjected tois a similar condition to the sustained hypertensionof the aortic baroreceptor studies cited above. Thehistology of the receptor endings from our sham-operated dogs is similar to that described in a varietyof species by Miller and Kasahara (45). The mor-phology of atrial receptors in the human describedby Johnston (46) is similar to that seen in the presentstudy for the CHFgroup of dogs; that is, the distinctend arborization is absent and the endings appear morediffuse than those described by Miller and Kasaharafor monkey, dog, cat, and lamb (45) and those ob-served in the sham-operated group in the presentstudy. Although Johnston used post-mortem material,he did not state whether or not any cardiac pathologywas present in these patients, an important con-sideration in view of the present findings. Diffuseendocardial nerve nets have also been described inthe atrium (45, 47). The receptors that we observedin the dogs with CHF do not have the interlacingappearance characteristic of nerve end niets. It istherefore most likely that the endings shown in thepresent experiments are single degenerated uinencap-sulated left atrial receptors.

Since the secretion of ADHunder normal conditionsappears to be in part governed by mechanorecep-tors located on both the high and low pressure sideof the circulation (48-53), alterations in the activity ofthese receptors could potentially alter the secretionof ADH.

Cardiac dilatation and hypertrophy are the hallmarksof both high and low cardiac output chronic CHF.According to the schema proposed by Gauier andHenry (54) and others, increased left atrial pressureincreases left atrial stretch, thereby stimulating leftatrial stretch receptors of the type first described by

FIGURE 4 Light micrographs of left atrial receptors from sham-operated dogs (A) and fromCHFdogs (B).

Left Atrial Receptor Adaptation 329

Nonidez (35) and subsequently characterized bymany others (45-47). The increased activity of thesereceptors would enter the brain via the vagi andreflexly inhibit the release of ADH, thereby increasingwater excretion, which in turn would cause a decreasein plasma volume returning left atrial pressure tonormal. In addition to the modulation of ADHsecretion, enhanced left atrial stretch receptor activityhas been shown to depress renal efferent sympatheticnerve activity (55, 56), an effect that would increaserenal blood flow and glomerular filtration rate, therebyenhancing the ability of the kidney to reduce plasmavolume. In spite of the potent stimulus on leftatrial stretch receptors in CHF, ADH titers remainhigh and renal blood flow remains low (12, 14-19).

It is concluded from the present study that the de-creased sensitivity of left atrial stretch receptors indogs with CHF is the result of alterations in atrialcompliance and of morphological changes in the re-ceptor endings themselves. Atrial receptor adaptationmay be responsible for the inappropriately high plasmaADH levels and may contribute to the peripheraledema, ascites, and hyponatremia often seen inpatients with chronic CHF.

ACKNOWLEDGMENTSThe authors express their gratitude for the expert technicalassistance of Dr. Morris Ellington, Mrs. Adah Earle, Mrs.Phyllis Anding, and Mr. John Dietz. Wealso would like toacknowledge the surgical assistance of Dr. John Latenser.

This research was supported by a grant-in-aid from theAmerican Heart Association and National Institutes of Healthgrant HL 13427.

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