abnormal coronary vascular response exercise dogs severe ... · hypertrophy; rv, right ventricular....

Abnormal Coronary Vascular Response to Exercise in

Dogs with Severe Right Ventricular Hypertrophy

PAUL A. MURRAYand STEPHENF. VATNER, Departments of Medicine,Harvard Medical School and Peter Bent Brigham Hospital, Boston,Massachusetts 02115; New England Regional Primate Research Center,Southboro, Massachusetts 01772

A B S T R A C T Measurements of right coronary arteryblood flow, aortic and right ventricular (RV) pressuresand heart rate were radiotelemetered during strenuous,spontaneous exercise in normal dogs and dogs withsevere RV hypertrophy induced by chronic (5-6 mo)pulmonary artery stenosis. With fixed pulmonic steno-sis, dogs with RV hypertrophy exhibited a decrease(P < 0.01) in arterial pressure during exercise. Underthese conditions, exercise increased right coronaryartery blood flow and decreased right coronary vascularresistance less (P < 0.05) in dogs with RVhypertrophycompared with normal. This attenuated response ofright coronary artery blood flow of dogs with RVhyper-trophy was not observed when arterial pressures re-mained at preexercise values during exercise. How-ever, regardless of changes in arterial pressures duringexercise, all dogs with RV hypertrophy demonstrateda striking postexercise coronary hyperemia (P < 0.01),suggesting a perfusion deficit of the hypertrophiedright ventricle during exercise. These results imply afundamental defect in the ability of the coronary cir-culation of the severely hypertrophied right ventricleto provide sufficient nutrient supply in the face of ele-vated metabolic demands of exercise.

INTRODUCTION

It is conceivable that the eventual decompensationof the hypertrophied ventricle to cardiac failure maybe the result of inadequate compensatory adjustmentsof the coronary circulation supplying the increasedcardiac mass. Pressure overload-induced right ventric-ular (RV)' hypertrophy is characterized by progres-

Dr. Murray is a National Institutes of Health PostdoctoralTrainee No. 5 F32 HL 05478-05. Address reprint requeststo Dr. Vatner.

Received for publication 24 March 1980 and in revisedform 5 January 1981.

'Abbreviations used in this paper: RVH, right ventricularhypertrophy; RV, right ventricular.

1314

sive, marked increases in blood flow per gram selec-tively to the right ventricle, without a significantchange in the ratio of capillary number to muscle fibernumber (1). These factors suggest that coronaryvascular reserve of the hypertrophied right ventriclemight be limited. Whereas this may not have significantconsequences at rest, it could have serious implicationsduring periods of elevated metabolic demand, as occurduring severe exercise, when increases in oxygen de-livery to the hypertrophied ventricle are primarilydependent on increases in coronary blood flow. Thecoronary vascular response to the cardiovascular stressof strenuous exercise has not been previously de-scribed in the presence of severe RV hypertrophy.The primary goal of the present study, therefore, wasto characterize both hemodynamic and coronary vas-cular adjustments of dogs with severe RVhypertrophyto spontaneous, free-ranging exercise. Because thecoronary vascular response of the normal right ventricleto this stress has not been previously characterized,it was also important to assess the responses to exercisein a separate series of normal dogs.

METHODS

Surgical preparation and induction of RV hypertrophy.11 mongrel dogs of either sex (conditioned and free of micro-filaria) were tranquilized with Tranvet-10 (PropiopromazineHCI; 0.1 imig/kg i.m.), intubated, artificially ventilated, anidprepared for sterile surgery. The heart was exposed via a leftthoracotomy in the fourth intercostal space. A heparin-filledTygon catheter (Norton Co., Tallmadge, Ohio) was implantedin the right ventricle, and an inflatable hydraulic occluder(20-26 mmID: Jones Co., Silver Springs, Md.) was placedaround the main pulmonary artery. The distal ends of thecatheter and occluder were exteriorized and positionedbetween the scapulae. All animals were placed on a 1-wkpostsurgical regimen of antibiotics.

A minimum of 3 wk was allowed for recovery from the ef-fects of this initial surgery. At this time, pressure-overloadRV hypertrophy was produced by gradual, chronic inflationof the hydraulic occluder previously implanted around themain pulmonary artery (1). A stable, peak RVsystolic pressure

J. Clin. Invest. © The American Society for Clinical Investigation, Inc. * 0021-9738/81/05/1314/10 $1.00Volume 67 May 1981 1314-1323

of 50 mmHg was achieved during the initial presentationof the pressure-overload. Over the succeeding 2 wk, inflationof the occluder was adjusted such that peak RV systolic pres-sure was at least 70 mmHg, and RV pressure and heart ratewere monitored on a biweekly basis thereafter. Subsequentchanges in RV pressure and all other measured variablesoccurred spontaneously in the presence of a consistentlyapplied stenosis of the pulmonary artery. The pressure over-load was sustained over a 5-6-mo period.

4 mo after initial presentation of the pressure-overload, asecond thoracotomy was performed through the fourth rightintercostal space. A segment (-2 cm) of the right maincoronary artery was dissected free of connective tissue andfat in a retrograde direction from the first major ventricularbranch to its aortic origin, for placement of an inflatable hy-draulic occluder (4 mmID) and a proximal Doppler ultra-sonic flow transducer. In four of the dogs, a solid-state pressuretransducer (P22: Konigsberg Instruments, Inc., Pasadena,Calif.) was inserted into the RV cavity via a stab wound inthe mid-anterior free wall. 3-4 wk later, an additional solid-state pressure transducer and a heparin-filled catheter werechronically implanted either in the descending thoracicaorta (four dogs) or abdominal aorta (seven dogs) through a1-cm longitudinal incision, and secured with three to fivesutures (4-0 silk, Ethicon Inc., Somerville, N. J.).

A separate group of 11 dogs with identical instrumentation,but not subjected to chronic pulmonary artery stenosis, servedas the control group.

Experimental measurements. Right main coronary arteryblood flow was measured with a CWDoppler ultrasonic flow-meter (2). The accuracy and reliability of this method of meas-uring coronary blood flow has been described previously indetail (3). At autopsy a catheter was inserted into the rightmain coronary artery via the ostium with its tip proximal tothe implanted flow probe. Flow probe calibration wasachieved in situ by perfusing blood through the catheter atknown flow rates. Aortic and RV pressures were measuredand telemetered from the implanted gauges (4, 5). Thesegauges were calibrated both in vitro and in vivo using theimplanted aortic and RV catheters attached to a Statham P23Db strain gauge manometer (Statham Instruments, Inc.,Oxnard, Calif.), which in turn was calibrated against a mer-cury manometer.

Experimental protocol. A period of at least 3 wk was al-lowed for full recovery from the effects of anesthesia andsurgery. At this time all the animals appeared healthy andvigorous. During the exercise period, instrumentation neces-sary for the continuous transmission of aortic pressure, RVpressure, and right main coronary artery blood flow signalsby radiotelemetry (described in detail previously) werecarried by each dog in a backpack (6, 7). The exercise regimenconsisted of each dog running freely behind a mobile record-ing van over a hilly, 0.3-mile course. Speeds of 25-35 miles/hwere achieved routinely by normal dogs during exercise.Whereas running speeds of dogs subjected to long term pul-monary artery stenosis were similar to normal dogs during theearly phase of exercise, some of these dogs were unable tomaintain peak speeds over the entire exercise course. How-ever, it is important to emphasize that the dogs with RVhyper-trophy exercised to their maximum capacity, as reflected bythe near collapse of these dogs at the end of the exercise run.

At autopsy, abdominal ascites and hepatic congestion werenot observed in those dogs with RV hypertrophy, indicatingthat these animals were not in congestive heart failure. Afterexcising the heart, the atria, great vessels, valves, large sur-face vessels, and epicardial fat were separated from the heartand discarded. The free walls of the right and left ventricleswere weighed separately, and the values for ventricular mass

to body weight ratio were computed using the body weight ofthe dog at the time of the initial surgery. RV wall thicknesswas measured at a consistent site in the mid-free wall andincluded trabecular muscles.

Data analysis. The experimental data were recorded(Honeywell model 5600 B, Honeywell, Inc., Denver, Col.)and played back onto a multichannel, direct-writing oscillo-graph (Gould-Brush Inc., Measurement Systems Div., Cleve-land, Ohio). A continuous record of RVderivative of pressurewith respect to time (dP/dt) was derived from the pressuresignal with an operational amplifier (National Semiconductor,Inc., Santa Clara, Calif.) connected as a differentiator. Meanaortic pressure and mean right coronary artery blood flow werederived using passive electronic filters with a 2-s time con-stant. Mean right coronary artery resistance was calculatedas the quotient of mean aortic pressure minus RVend-diastolicpressure and mean right coronary artery blood flow. A cardio-tachometer (Beckman type 9856, Beckman Instruments, Inc.,Fullerton, Calif.) triggered by the electrical signal from theaortic pressure pulse, provided instantaneous and continuousrecords of heart rate.

The measured variables were evaluated for data analysisover a period of at least 15-30 s while the dogs were standingquietly just prior to exercise, at two separate points duringthe exercise run, corresponding to one-tenth and two-tenths ofa mile of the exercise course, and at 1 and 5 min after theexercise period. The data were stored and statisticallyanalyzed with a PDP 11/34 computer (Digital EquipmentCorp., Maynard, Mass.). The area under the phasic rightcoronary artery blood flow signal was integrated utilizing thecomputer in order to evaluate the relative proportions ofblood flow occurring during systole and diastole for eachcardiac cycle. Stroke systolic right coronary artery blood flowwas defined as the blood flow occurring between the initialupstroke of RVdPldt and peak negative RVdPldt. Blood flowthroughout the remaining portion of the cardiac cyclerepresented stroke diastolic right coronary artery blood flow.In addition to the overall groups of normal dogs (n = 11) anddogs with RVhypertrophy and fixed pulmonic stenosis (n = 9),the response of the right coronary circulation to exercise wasalso assessed in subgroups of normal dogs (n = 3) and dogswith RVhypertrophy (n = 4) which did not change mean aorticpressure during exercise. The subgroup of fotur dogs with RVhypertrophy was composed of two dogs with RV hyper-trophy and fixed pulmonic stenosis, and two dogs with RVhypertrophy in which the pulmonic stenosis was released 1 dprior to the exercise period. Differences between morphologicand hemodynamic characteristics of nonnal dogs and dogswith RV hypertrophy were analyzed by Student's t test forunpaired comparisons (8). Changes in the measured variablesin response to exercise and differences in the measuredvariables during exercise among the different groups wereanalyzed by multivariate analysis of variance (8). Valuespresented represent mean+1 SEM.

RESULTS

Morphologic and hemodynamiccharacteristics of RVhypertrophy(Table I)Chronic pulmonary artery stenosis of 5-6 mo dura-

tion resulted in substantial hypertrophy of the rightventricle as evidenced by significant increases (P< 0.001) in RV free wall weight to body weight ratio,RV wall thickness, and RV free wall weight to left

Coronary Response of Hypertrophied Ventricle to Exercise 1315

TABLE IMorphology and Base-line Hemodynamnics

Normal RVH P*

(,= 11) (t= 9)

RV weight/body weight, glkg 1.69±0.14 2.59±0.15 <0.001RV thickness, mm 6.77±0.74 11.4+±0.82 <0.001RV weight/LV weight 0.50±0.03 0.83±0.04 <0.0001LV weight/body weight, glkg 3.21±0.24 3.67±0.32 NSRV systolic pressure, mmHg 34±2 114±4 <0.0001RVend-diastolic pressure, mmHg 4.4+0.4 10.0±)2.0 <0.05RVdPldt, mmHg/Is 946± 55 1298 ±72 <0.005Mean aortic pressure, mmHg 110±5 111±5 NSDiastolic aortic pressure, mmHg 85+4 93±3 NSHeart rate, beats/min 129±9 154+±7 <0.05

* P value for comparison between normal dogs and dogs with RVH.

ventricular free wall weight ratio. Moreover, in thefield prior to exercise, dogs with RV hypertrophy ex-hibited significantly elevated (P < 0.05) levels of RVsystolic and end-diastolic pressures, RV dPldt andheart rate compared to normal dogs, whereas values ofaortic pressure were similar in the two groups.

Hemodynamic and coronary vascularresponses to free-ranging exercise

NORMAL

Fig. 1 illustrates the response of a normal dog tospontaneous, free-ranging exercise. The summarizeddata are presented in Table II and Figs. 2 and 3.

Hemodynamic measurements (Table II). Exercisein normal dogs was associated with significant in-creases (P < 0.05) in mean aortic pressure, RV systolicand end-diastolic pressures, RV dPldt and heart rate.With the exception of RV end-diastolic pressure, thevalues of these measured variables remained signifi-cantly elevated (P < 0.05) 1 min following cessationof exercise, although RV systolic pressure, RV dPIdtand heart rate had returned towards preexercise levels.Only heart rate remained significantly elevated (P< 0.05) 5 min after the end of the exercise period.

Diastolic aortic pressure rose, but not significantly,with exercise.

Coronary vascular measurements (Figs. 2, 3). Meanright coronary artery blood flow increased (P < 0.001)rapidly and substantially from a preexercise level of25+2 ml/min with the onset of exercise, and remainedat this new steady-state level throughout the exerciseperiod. With cessation of exercise right coronary arteryblood flow decreased rapidly, such tnat by 1 min fol-lowing the end of exercise, blood flow was only slightlyhigher (33+3 ml/min) than preexercise levels. Con-versely, mean right coronary artery resistance de-creased by 3.13±0.65 mmHg/ml per min (P < 0.01)

during exercise from a preexercise level of 5.51±0.93mmHg/ml per min, and remained depressed through-out the exercise period. 1 min after exercise, rightcoronary artery resistance had already returned to pre-exercise levels. Thus, both hemodynamic and coronary

Exercise

Phasic AorticPressuremmHg

Mean Aortic

mmHg

120 ,; |7 1 1.!1!'1 I FfI1

Measic RightCoronary Rlowml/min

Mean RightCoronary Flow miji;l.i!lflbiml/min Siii

CoronaryResistancemmHg/ng/rnin i

Heart Ratebeats/ri

0.1s 20s

FIGURE 1 The effects of spontaneous, free-ranging exerciseare shown on the radiotelemetered measurements of phasicand mean aortic pressure and right coronary blood flow, meancalculated right coronary resistance and heart rate in a normaldog. Note that right coronary blood flow and resistanceincrease and decrease, respectively, rapidly with the onset ofexercise and return smoothly to preexercise levels followingthe exercise period.

1316 P. A. Murray and S. F. Vatner

TABLE IIHemodynamic Changes during Exercise and 1 and 5 Min Postexercise

Exercise* + 1 Min +5 Min

AMean aortic pressure, Normal 22±5t 22+64 6+6mmHg RVH -25+6t 13±5§ 1±5

P <0.001 NS NS

A Diastolic aortic pressure, Normal 7±3 9±2t -2±3mmHg RVH -25±5t 7±4 0±4

P <0.001 NS NS

ARVsystolic pressure, Normal 28±64 9±3§ -3±1mmHg RVH -12±9 43±94 0+3

P <0.01 <0.02 NS

ARVend-diastolic pressure, Normal 3.0±1.4§ -1.1±0.7 -1.9±0.8mmHg RVH 7.9±1.4t 7.5±2.24 -1.0±1.5

P NS <0.01 NS

ARVdPldt, mmHgls Normal 2,111+3474 778±2344 93±63RVH 857±346 1960±447t 160±48p <0.05 <0.07 NS

AHeart rate, beats/min Normal 163±114 61±71 27±9§RVH 101±13t 52±11t 8±6P <0.01 NS NS

P value for comparison between changes in normal and RVHgroups in response to exercise.* Changes in measured variables at 0.2 miles of exercise course.Symbols represent significant change of measured variables from control levels in each group inresponse to exercise (4P < 0.001; §P < 0.05).

vascular responses to exercise normally occurred rapidlywith the onset of exercise, were sustained throughoutthe exercise period, and returned smoothly to pre-exercise levels soon after cessation of exercise.

RVHYPERTROPHY

The response of a dog with severe RV hypertrophyto spontaneous, free-ranging exercise is illustrated inFig. 4. The summarized data are presented in TableII and Figs. 2 and 3.

Hemodynamic measurements (Table II). Whereasexercise was normally associated with an increase(P < 0.001) in mean aortic pressure, both mean anddiastolic aortic pressures decreased (P < 0.001) in dogswith RVhypertrophy. However, 1 min after cessation ofexercise, levels of mean aortic pressure were increased(P < 0.05) from preexercise values to a similar extentin both groups. In contrast to normal dogs, RV systolicpressure did not increase significantly during exercise.However, 1 min after exercise, RV systolic pressurewas markedly increased (P < 0.001) by 43+9 mmHgfrom preexercise levels, which was greater (P < 0.02)than the increment in normal dogs. RV end-diastolicpressure increased (P < 0.001) during exercise, butunlike normal dogs the increase (P < 0.001) was sus-

Exercise_

lMt +M

FIGuRE 2 Changes (Mean+ 1 SEM) in mean right coronaryblood flow are shown in response to exercise in normal dogs(0, - - -) (25+2 ml/min) and dogs with right ventricular hyper-trophy (RVH) (A, ) (59+11 ml/min). The increase in bloodflow during exercise is significantly attenuated in dogs withRVHcompared with normal. In contrast, whereas blood flow isalmost returned to preexercise levels 1 min after exercise innormal dogs, dogs with RVHexhibit a marked postexercisecoronary hyperemia. Values in parentheses represent pre-exercise levels of mean right coronary blood flow for therespective groups. Symbols represent statistically significantchanges (*P < 0.001; iP < 0.02) in blood flow from pre-exercise levels. P values represent comparisons betweenresponses of normal dogs and dogs with RVH.


Fe.- NomeA-RVH

FIGURE 3 Absolute levels (Mean 1 SEM) of mean rightcoronary blood flow and mean right coronary resistance areshown for normal dogs and dogs with RVH at control, attwo separate points during exercise corresponding to 0.1and 0.2 miles of the exercise course, and 1 and 5 min fol-lowing the end of the exercise period. Most striking is theexistence of a marked coronary hyperemia in dogs with RVHfollowing cessation of the exercise period. Symbols representsignficant changes of the measured variables from controllevels for the two groups (*P < 0.001; IP < 0.02; ifP < 0.05).P values represent comparisons between normal dogs anddogs with RVH.

tained 1 min after exercise. The increase in RVdP/dtduring exercise was significantly attenuated (P < 0.05)in dogs with RVhypertrophy. Furthermore, dogs withRV hypertrophy exhibited their peak increase (P< 0.001) in this variable immediately following exer-cise, at a time when RVdP/dt in normal dogs was re-turning towards preexercise levels. Heart rate in-creased to similar peak levels as occurred in normaldogs during exercise, but the increment was less (P< 0.01) in dogs with RV hypertrophy due to a higher(P < 0.05) preexercise level. Heart rate returnednormally towards control following the exercise period.

Coronary vascular measurements (Figs. 2 and 3).Preexercise levels of mean right coronary blood flowwere elevated (P < 0.001) to 59± 11 ml/min in dogswith RV hypertrophy. Note that the phasic waveformfor right coronary artery blood flow (Fig. 4) exhibits adiminished proportion of blood flow during systolecompared to normal (Fig. 1) and resembles the normalphasic waveform for left circumflex coronary arteryblood flow (1). The preexercise stroke systolic diastolicflow ratio was reduced significantly (P < 0.01) in dogswith RVhypertrophy (49±4%) compared with normal(85±8%). During exercise mean right coronary bloodflow increased only 26±6 ml/min in dogs with RVhypertrophy, which was significantly less (P < 0.05)than the increase of 45±5 ml/min in normal dogs. More-over, whereas the stroke systolic/diastolic flow ratioincreased (P < 0.01) in both groups during exercise,the ratio increased to a lower (P < 0.01) level in dogs

with RVhypertrophy (93+12%) compared with normal(155± 11%). 1 min after exercise, mean right coronaryblood flow was only slightly greater than preexerciselevels in normal dogs, whereas dogs with RV hyper-trophy exhibited a profound coronary vasodilation, inthat mean right coronary blood flow was increased(P < 0.001) by 57±6 ml/min from preexercise levels.At this time stroke systolic/diastolic flow ratios had re-turned to preexercise levels in normal dogs (100±12%)and dogs with RVhypertrophy (57±6%). It is importantto note that the absolute levels to which blood flowincreased were similar in the two groups during earlyexercise, slightly higher (P < 0.02) in dogs with RVhypertrophy during late exercise, and markedly higher(P < 0.01) in these dogs 1 min after exercise (Fig. 3).

Preexercise levels of mean right coronary artery re-sistance were significantly reduced (P < 0.001) in dogswith RV hypertrophy (1.95±0.28 mmHg/ml per min)compared to normal. Right coronary resistance de-creased less (P < 0.01), i.e., by 1.12±0.21 mmHg/mlper min, but reached lower (P < 0.02) absolute levels(0.83±0.12 mmHg/ml per min) during exercise com-pared to normal. Most striking, however, was the main-tenance of a prolonged postexercise decrease (P< 0.001) in resistance in dogs with RV hypertrophy,in contrast to the rapid return of resistance to pre-exercise levels in the normal group.

PARADOXICALCHANGESIN HEARTRATE DURINGEXERCISE IN DOGSWITH RV HYPERTROPHY

Heart rate increased significantly (P < 0.001) and tosimilar peak levels in both normal dogs and dogs withRV hypertrophy during exercise. However, as illus-trated in Fig. 4, a subset of dogs (n = 6) with RVhyper-trophy exhibited marked, paradoxical reductions inheart rate from peak levels during exercise. Thisresponse characteristically occurred in the mid-to-lateportion of the exercise run, when heart rate decreased(P < 0.001) in this subset of dogs from 297±3 to 150± 11 beats/min. Whenthe exercise period was repeatedon a subsequent day with four of these dogs followingthe preexercise administration of atropine sulfate,0.1 mg/kg, i.v., the reduction in heart rate late in theexercise period from a peak level of 280±7 beats/minwas not observed.

INFLUENCE OF PERFUSIONPRESSUREONCORONARYVASCULARRESPONSETOEXERCISE (TABLE III)

The extent to which the decrease in arterialpressure mediates the abnormal coronary vascularresponse to exercise in dogs with RV hypertrophywas assessed. The results are summarized in Table III.The coronary vascular response to exercise in a group


0 s0.2 S

Exercise

tt+*T1511tt t!!5 \ L-L tet~

10s 20s

FIGURE 4 Effects of spontaneous, free-ranging exercise on the meaisured variables in a dog withsevere RVH. In addition to the abnormal hemodynamic and coronary vascular adjustments toexercise that characterized the entire group of dogs with RVH, this is an example of one of a sub-set of dogs with severe RVH, which exhibited an abrupt, proonounced decrease in heart rate frompeak levels during the exercise period. Note the profound postexercise increase in right coronaryblood flow, as well as the prolonged return of right coronary resistance to preexercise levels fol-lowing the end of the exercise period.

of dogs with RV hypertrophy (i = 4) in which meanand diastolic aortic pressures were unchanged duringexercise was compared with: (a) the entire group ofnormal dogs (n = 11) in which mean aortic pressureincreased (P < 0.01) and diastolic aortic pressure wasunchanged during exercise; (b) a subgroup of thesenormal dogs (n = 3) in which mean and diastolicaortic pressures were unchanged during exercise; and(c) the entire group of dogs with RV hypertrophy(n = 9) in which mean and diastolic aortic pressuresdecreased (P < 0.001) during exercise. Preexerciselevels of mean aortic pressure were similar among allgroups. Preexercise levels of mean right coronary arteryblood flow were elevated (P < 0.001), and levels ofright coronary artery resistance were decreased (P

< 0.001) in the two groups with RVhypertrophy com-pared to the two normal groups. Mean right coronaryblood flow increased (P < 0.01) to a similar extentduring exercise in both normal groups. The subset ofnormal dogs that did not increase arterial pressureduring exercise failed to exhibit any degree of post-exercise coronary hyperemia. As might be expected,the RV hypertrophy group which maintained arterialpressure during exercise exhibited increases in bloodflow to significantly higher (P < 0.01) levels than theother three groups. However, despite this enhancedcoronary perfusion during exercise, the postexerciseincrease in blood flow was clearly evident in thisgroup, and actually rose to a higher (P < 0.001) levelthan that observed in those dogs with RVhypertrophy,

Coroniary Response of Hypertrophied Ventricle to Exercise 1319

TABLE IIIInfluence of Perfusion Pressure on Coronary Vascular Response to Exercise

Preexercise Exercise* +1 Min

Mean aortic pressure, mmHg

Diastolic aortic pressure, mmHg

Mean right coronary flow,ml/min

Mean right coronary

resistance, mmHg/ml per min

NormalNormal subgrouptRVHRVHsubgroup§RVHsubgroup:

vs. normalvs. normal subgroupvs. RVH

NormalNormal subgroupRVHRVHsubgroupRVHsubgroup:






110+5106±8111±5111±4

132+±8107+887±8

112± 10

NS P<0.01NS NSNS P<0.001

85+484±493±387±3

NSNSNS

25±224±159±1171±23

P < 0.001P < 0.001

NS

5.51±0.934.47±0.421.95±0.281.82±0.45

P < 0.001P < 0.001

NS

92±483±668±683±10

NSNS

P <0.02

70±669±885±12

133±17

P < 0.001P < 0.001P < 0.001

2.38±0.431.57±0.070.83±0.120.77±0.12

P < 0.001NSNS

* Values of the measured variables at 0.2 miles of exercise course.

I Normal subgroup comprised of three normal dogs where arterial pressure did not change during exercise.§ RVHsubgroup comprised of four RVHdogs where arterial pressure did not change during exercise.

which exhibited reductions in arterial pressure duringexercise.

DISCUSSION

Results from this study provide the first compellingevidence that dogs with severe RV hypertrophy havea strikingly abnormal coronary vascular response tofree-ranging exercise. The most distinguishing charac-teristic of this abnormal response to exercise is theappearance of a profound postexercise coronary hy-peremia (Figs. 2-4). The postexercise coronary hy-peremia is observed not only in dogs with RV hyper-trophy that undergo decreases in arterial pressure

during exercise, but is also noted in dogs with RV

hypertrophy in which arterial pressure is maintainedduring exercise (Table III). This response is stronglyindicative of a fundamental defect in the ability of thecoronary circulation of the hypertrophied right ventri-cle to sufficiently compensate for the elevated meta-bolic demands of exercise.

The postexercise coronary hyperemia suggests that a

perfusion deficit had been incurred by the hyper-trophied right ventricle during exercise. An analogousphenomenon has been reported recently in skeletalmuscle of anesthetized dogs (9, 10). These investigatorsobserved a "prolonged vasodilation" following cessa-

tion of electrical stimulation of in situ skeletal musclewhen arterial inflow was restricted to the contractingmuscle. It is also of interest that following brief periods


130+ 10120±11125±7127±7

NSNSNS

92+496±+10

100±5103±5

NSNSNS

33±328±3

116±11151±20

P < 0.001P < 0.001P < 0.001

4.58±0.694.32±0.190.95±0.110.77±0.09

P < 0.001P < 0.001

NS

of myocardial ischemia induced by coronary arteryocclusion, the resultant reactive hyperemia is asso-ciated with a transient overshoot in myocardial func-tion above preischemic levels in the region renderedischemic (11). This overshoot in function was pre-vented by inhibiting the reactive hyperemia by gradu-ally releasing the coronary occlusion (11). Moreover,a postexercise augmentation of left ventricular functionassociated with coronary hyperemia was observed ina prior study conducted in this laboratory, in whichthe normal increase in left main coronary inflow wasrestricted during exercise (12). These prior studies(9-12) lend support to the hypothesis that the post-exercise coronary hyperemia observed in the presentstudy was most likely mediated by the accumulationof myocardial metabolites secondary to inadequateoxygen supply during exercise. However, an alterna-tive explanation could be that the coronary hyperemiais due to an increase in oxygen demand consequentto elevated levels of RV systolic and end-diastolicpressures and dP/dt that were observed immediatelyfollowing exercise in dogs with RVhypertrophy. Thisis a less likely explanation, since there was no obviousneed for RV pressure and dP/dt to rise following, asopposed to during, exercise. Furthermore, the in-creases in pressure and dP/dt occurred at a time whenheart rate was falling rapidly back to preexercisecontrol levels.

The mechanism(s) responsible for the apparentaccumulated perfusion deficit of the hypertrophiedright ventricle during exercise are likely multifactorial.In part, the attenuated right coronary vascular re-sponse during exercise (Fig. 2) could be related tothe elevated preexercise levels of right coronary bloodflow, or could be secondarily related to the smallerincrements in heart rate and RV dP/dt in dogs withRVhypertrophy during exercise (Table II). Increasedextravascular compression of the coronary vasculaturesupplying the hypertrophied right ventricle couldserve to limit the extent of the increase in blood flowduring exercise. The lower level to which strokesystolic/diastolic flow ratio increased during exercisein these dogs would appear to support this possibility.Additionally, the decrease in coronary perfusionpressure during exercise in dogs with RV hyper-trophy with a fixed pulmonic stenosis almost cer-tainly attenuated the magnitude of the increase in rightcoronary artery blood flow during exercise. This issupported by the observation that right coronaryartery blood flow increased to significantly higherlevels during exercise in dogs with RV hypertrophyin which arterial pressure was sustained during theexercise period (Table III). However, a decrease incoronary perfusion pressure cannot be entirely respon-sible for the abnormal coronary vascular response toexercise, because the most prominent feature of this

response (i.e., the postexercise coronary hyperemia)was also observed in those dogs with RVhypertrophythat did not exhibit reductions in either mean ordiastolic arterial pressures during exercise (Table III).Previous studies from this laboratory (13, 14) havedemonstrated that dogs in chronic right heart failureexhibit augmented alpha adrenergic constriction ofperipheral vascular beds during free-ranging exercise.Moreover, alpha adrenergic activation during exercisecan attenuate the normal coronary vascular responseto exercise (7). Thus, it could be postulated that anenhancement of coronary alpha adrenoceptor activa-tion may limit the extent of the increase in rightcoronary artery blood flow during exercise in thesedogs with RV hypertrophy. But perhaps the mostlikely mechanism for the abnormal coronary vascularresponse to exercise is that coronary vasodilatorcapacity of the hypertrophied right ventricle is sig-nificantly reduced. A recent study from our laboratoryprovides supportive evidence for this hypothesis (15).In that investigation (15) maximal coronary vasodilatorcapacity (response to adenosine infusion) of thehypertrophied right ventricle was found to be reducedsignificantly. This reduction was most prominent in theendocardial layer of the hypertrophied right ventricle.This diminution in maximal coronary vasodilatorcapacity likely limits the ability of the coronary vascula-ture supplying the hypertrophied ventricle to suffi-ciently increase nutrient supply in the face of markedlyelevated levels of metabolic demand, which are asso-ciated with the cardiovascular stress of free-rangingexercise.

Whereas RV hypertrophy is characterized by amarked increase in blood flow per gram of ventricleat rest (1), blood flow to the hypertrophied left ventriclehas been shown to be either modestly reduced (16-19),unchanged (20-24), or only slightly increased (25).Moreover, in contrast to the results of the present study,coronary vascular adjustments to exercise of the hyper-trophied left ventricle appear to be largely normal(21, 22, 26-28). Although slight degrees of relativeendocardial underperfusion during exercise have beenreported (21, 22, 28), similar changes were observedin the non-hypertrophied control group (22, 28). Onepossible explanation for the divergent results betweenthese studies and the present study is the differencein the ventricle being subjected to the chronic pressureoverload. It should also be noted, however, that thosestudies concerned with the coronary vascular responseof the hypertrophied left ventricle measured discretechanges in myocardial blood flow (radioactive micro-sphere technique) during less strenuous treadmillexercise, whereas the present investigation involvedcontinuous measurements of right coronary arteryblood flow (Doppler ultrasonic technique) duringspontaneous, severe, free-ranging exercise.


There are several aspects of the methodology andthe interpretation of results that require discussion.First, it should be noted that measurements of rightcoronary artery blood flow do not reflect the totalperfusion of either the normal or hypertrophied rightventricle. Whereas the right coronary artery providessubstantial blood supply to the central core of the RVfree wall, up to 37% of total perfusion of the normalright ventricle, primarily the blood flow to peripheralmargins, originates from the left coronary artery (29).It could be argued that the attenuated increase in rightcoronary artery blood flow during exercise in dogswith RV hypertrophy is the result of enhanced per-fusion of the hypertrophied right ventricle from theleft coronary artery. However, this is not a likelyexplanation for several reasons. First, the fractionalcontribution of the right coronary artery to total perfu-sion of the right ventricle is greatly enhanced fol-lowing the development of RV hypertrophy (29).Second, in the presence of right main coronary arteryocclusion, absolute levels of perfusion of normaland hypertrophied right ventricles originating from theleft coronary artery are similar (29). Moreover, if per-fusion of the hypertrophied right ventricle had beensufficiently augmented by blood flow from the leftcoronary artery, then the postexercise right coronaryhyperemia would not have been observed.

It is also important to note that measurements ofright coronary artery blood flow do not permit an assess-ment of possible transmural variations in blood flowduring exercise to the hypertrophied right ventricle.However, it must be emphasized that the flow meas-uring technique utilized in this study has permittedcontinuous measurements of right coronary arteryblood flow in the field by radiotelemetry techniquesat a time when the dogs were exercising at maximumlevels of capacity. It is under these conditions ofsevere cardiovascular stress that a markedly abnormalresponse to exercise has been detected in dogs withRVhypertrophy.

It is recognized that there is a fine line betweenanimals with severe RVhypertrophy alone, and thosewith hypertrophy and failure in combination. Thesedogs did not exhibit the more apparent signs of rightheart failure, i.e., abdominal ascites, liver congestion,peripheral edema, or markedly elevated levels of RVend-diastolic pressure at rest. However, these dogs diddemonstrate significant hemodynamic abnormalities(decreases in aortic and RV systolic pressures and anincrease in RVend-diastolic pressure) during exercise,and it is, therefore, possible that the cardiovascularstress of exercise was sufficient to precipitate acutecardiac failure.

An additional point of interest was the marked, slow-ing of heart rate from peak exercise levels prior to cessa-tion of exercise observed in some of the dogs with RV

hypertrophy. This abrupt slowing of heart rate wasblocked by atropine, indicating that the efferent limbof this response can be ascribed to activation of theparasympathetic nervous system. This is a paradoxicalresponse, because exercise is normally associated witha withdrawal of parasympathetic activity. Althoughspeculative, it is possible that a perfusion deficit ofthe hypertrophied right ventricle during exercise re-sults in the production of a myocardial metabolite,which in turn could activate ventricular mechano-receptors or peripheral arterial or cardiac chemo-receptors during exercise. In this regard, it is interest-ing that a recent preliminary study (30) has reportedthat the intracoronary injection of prostaglandinsinduces hypotension and reflex bradycardia, insteadof the expected tachycardia mediated by arterialbaroreceptors. A cardio-coronary reflex parasympa-thetic coronary vasodilation elicited by chemicalstimulation of cardiac receptors (i.e., the Bezold-Jarischreflex) has also previously been reported (31), and maycontribute a component of the postexercise coronaryhyperemia observed in some of these dogs with RVhypertrophy.

In conclusion, results of this study provide evidencethat coronary vascular adaptations to the stress of spon-taneous, free-ranging exercise are markedly abnormalin dogs with severe RV hypertrophy. These findingssupport the concept that compensatory adjustments ofthe coronary circulation of the severely hypertrophiedright ventricle may be insufficient to supply adequatelevels of nutrient supply during periods of elevatedmetabolic demand of the hypertrophied right ventricle.This inadequate coronary vascular response is mostlikely responsible for the state of near collapse ob-served in the dogs with hypertrophy immediately post-exercise and may be causally related to the pathogene-sis of congestive right heart failure.

ACKNOWLEDGMENTSThe authors gratefully acknowledge the engineering assist-ance of A. Sherman, J. Bienstock, and R. Thomas.

This work was supported in part by U. S. Public HealthService grants HL 23724, HL 15416, and HL 20552, and bygrant 80 1048 from the American Heart Association.

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abnormal coronary vascular response exercise dogs severe ... · hypertrophy; rv, right ventricular....

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