Br Heart 71994;72 (Supplement):S 22-27

Peripheral circulatory adaptations to pump failureof the heart

Helmut Drexler

Impairment of ventricular performance is theinitial step in the development of heart failure,but the symptoms and the reduced exercisecapacity cannot solely be explained by leftventricular dysfunction. The degree ofventricular dysfunction in congestive heartfailure (CHF) does not correlate with itsseverity-that is, indices of left ventriculardysfunction do not predict or correlate closelywith the functional state of patients with CHFas assessed by exercise tests.' Although rightventricular dysfunction has been linked to theseverity of symptoms and exercise intolerance,right ventricular failure seems to be a sec-ondary problem in most cases of clinical sys-tolic heart failure. There is evidence thatprognosis is associated with the degree of leftventricular dysfunction, extent of myocardialloss, and cardiac dimensions. Clinical symp-toms of heart failure usually emerge with theactivation of neurohumoral systems, in partic-ular the sympathetic system and the renin-angiotensin system. The study of leftventricular dysfunction (SOLVD) trial con-firmed that increases of plasma atrial natri-uretic peptide and noradrenalin occur early inthe disease and plasma renin activity increaseswith symptoms.2 Although numerous factorsare likely to be involved in the development ofsymptoms, the decrease in renal perfusionmay activate the renin-angiotensin system.Experimental data suggest that this alterationof renal haemodynamics emerges early in thecourse of heart failure. Sodium retention mayalso emerge early and compensate forimpaired left ventricular dysfunction byincreasing the preload. One important clinicalsymptom in chronic heart failure is earlyfatigue during physical activity, which has

1 Sympathetically mediatedvasoconstriction

2 Renin angiotensin systemplasma, local, tissueI I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~3 Vascular stiffness:

sodium content of vessel t

4 Endothelium dependentvasodilatation i, secondary tochronic reduced flow

5 Structural vascular alterations

Figure 1 Regional vascular compensatory vasoconstrictor mechanisms in congestive heartfailure.

been linked to impaired perfusion of skeletalmuscle during exercise. In patients withchronic heart failure, the increase duringexercise in blood flow to working muscle andthe oxygen consumption are less than those ofnormal people, whereas plasma lactate con-centrations are increased for each given work-load.3 Most of the reduction in maximal bloodflow during exercise occurs in oxidativeworking muscle.4 This impairment of meta-bolic vasodilatory capacity within skeletalmuscle during exercise has often been attrib-uted to excessive sympathetically mediatedvasoconstriction, activation of the plasmarenin-angiotensin system and more recently toincreased concentrations of endothelin(fig 1).5 It seems that endothelin concentra-tions play an important part in the pulmonarycirculation6 but its pathophysiological rele-vance in the systemic circulation remainsuncertain. Although these neurohumoral fac-tors exert potent systemic and regional vaso-constriction, they do not completely explainthe impairment of vasodilating capacity withinskeletal muscle in patients with chronic heartfailure. Impaired metabolic vasodilatationduring exercise cannot be restored by a block-ade with phentolamine.78 Similarly, a dose ofangiotensin converting enzyme (ACE) inhibitordoes not restore metabolic vasodilatation tonormal despite substantial reductions of plasmaangiotensin II and noradrenaline (norepi-nephrine) concentrations.9 This indicates thatblockade of the plasma renin angiotensin sys-tem by ACE inhibitors does not interfere withblood flow to working muscle during exercisein patients with CHF.9 10 After treatment withan ACE inhibitor for several months, a note-able increase in femoral blood flow duringexercise is found and is accompanied by animproved peak oxygen consumption.9 Thus,long-term ACE inhibitor treatment reversedthe inability of peripheral vessels to dilate.This is consistent with previous findings thatthe full beneficial effect of ACE inhibitortreatment in large scale trials emerges slowlywith time." Similarly, peripheral perfusionand skeletal muscle function take weeks ormonths to return to normal after cardiactransplantation.What are the mechanisms for the delayed

beneficial effects of ACE inhibitors or cardiactransplantation? It is important to note thatexercise tolerance in patients with heart fail-ure is not determined solely by central haemo-dynamics. One possible explanation could bethat the delayed effect ofACE inhibitors maybe partly due to its interference with the

Medizinische KlinikIII, UniversitatFreiburg, GermanyH DrexlerCorrespondence to:Dr Helmut Drexler,Medizinische Klinik III,Universitat Freiburg,Hugstetterstrasse 55, 79106Freiburg, Germany.

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vascular tissue renin-angiotensin system,which reverses chronic structural alteration ofthe vessel. Experimental evidence indicatesthat angiotensin II induces hypertrophy ofcultured rat aortic smooth muscle cells.12Angiotensin II, endothelin, and noradrenalineseem to be involved in the activation of proto-oncogenes."3 This suggests that angiotensin IImay be involved in the proliferative process oftissues during growth (endogenous growthfactor). Recent findings indicate that ACEinhibition can reverse structural vascularalteration in a rat model of hypertension'4 to a

greater extent than can other antihypertensivedrugs. 5

Unfortunately, experimental and clinicalstudies investigating structural alterations inchronic heart failure are scarce and contradic-tory. Although some studies have indicatedthat structural abnormalities might occur atthe level of the resistance vessel'6 others didnot show such alterations.'7 The clinicalstudies usually have been confined to skinresistance vessels and may not be representa-tive of skeletal muscle resistance vessels.Small biopsies of skeletal muscle often allowexamination of only very small arterioles(<50 ,um), which may not play the main partin regulating blood flow. This seems also to betrue of resistance vessels that range from80-200 ,um. Other potential mechanismsinvolved in the impairment of metabolicperipheral dilatation in chronic heart failureinclude a vascular stiffness component owingto the increased vascular sodium content,which can be partly reduced with diuretictreatment in decompensated heart failure.'8Although it remains controversial whetherstructural changes occur in the microcircula-tion of skeletal muscle, flow dependent dilata-tion, and dilatation of large conduit vesselsinduced by glyceryl trinitrate are impaired inpatients with heart failure indicating thatthese patients have impaired relaxation of vas-cular smooth muscle and have impaired elas-tic properties of the large conduit vessels.'9This may have functional consequences

through a negative feedback on the pumpingperformance of the left ventricle.

Endothelial dysfunctionThe pivotal role of the endothelium derivedrelaxing factor on vascular tone is now recog-

nised. Nitric oxide, which accounts for mostof the biological activity of endotheliumderived relaxing factor, is continuouslyreleased from the endothelium, and this basalrelease of nitric oxide provides a constantcounteracting force to vasoconstrictor sub-stances such as noradrenaline or angiotensinII. Secondly, endothelium derived relaxingfactor can be released from the endotheliumupon stimulation-that is, by bradykinin or

ADP. Several pathophysiological conditionssuch as hypercholesterolaemia or hyperten-sion are associated with dysfunctionalendothelium-that is, either the basal or stim-ulated release of endothelium derived relaxingfactor is altered. Recent data from our labora-

tory and others showed that endotheliumdependent relaxation of the microcirculationof skeletal muscle in response to acetylcholineis impaired in chronic heart failure whereasthe vasodilating effect of glyceryl trinitrate ispreserved.2>22 Although the functional impor-tance of this finding remains unclear, it seemslikely that endothelial dysfunction in theperipheral circulation is involved in theimpairment of both reactive hyperaemia andincrease in blood flow in heart failure. Studieson the coronary circulation have shown thatinhibition of the synthesis of nitric oxidereduces the total reactive hyperaemia.The basal release of nitric oxide, which

accounts for the biological activity of endothe-lium derived relaxing factor,2' has been shownto contribute to the control of regional bloodflow in humans by the use of N-monomethyl-L-arginine (L-NMMA), a selective inhibitorof nitric oxide from L-arginine.4 In theabsence of notable vasoconstriction of conduitvessels, changes in blood flow indicate theresponse of resistance vessels. To identify theendothelium dependent vasomotor responseof large forearm conduit v small resistancevessels we used a novel ultrasound device todetermine forearmin arterial diameter accu-rately.2526 Simultaneously, blood flow velocitywas recorded by a Doppler velocity device inthe same vessel. By this method, the effects ofintra-arterial infusion of acetylcholine, L-NMMA, and glyceryl trinitrate on forearmconduit and resistance vessels were examinedin patients with chronic CHF and agematched healthy volunteers. Although theblood flow response to acetylcholine wasblunted in patients with CHF, the decrease inflow induced by L-NMMA was enhanced andthe response to glyceryl trinitrate was pre-served.21 As L-NMMA inhibits the basalrelease of nitric oxide, an exaggerated vaso-constrictor response in patients with heartfailure (compared with controls) is consistentwith the notion that the basal release of nitricoxide is increased in the peripheral circulationof patients with heart failure. Thus, endothe-lium dependent dilatation of forearm resis-tance vessels is impaired in patients withCHF, suggesting a reduced stimulated releaseof nitric oxide in response to acetylcholine.The basal release of nitric oxide seems to beenhanced, however, in a compensatory man-ner. As the dilator response to both acetyl-choline and glyceryl trinitrate involves theactivation of the guanylate cyclase system (ora non-specific effect of opposing constrictorforces) a generalised defect within the guany-late cyclase system cannot account for thisfinding. Thus in patients with heart failure,the stimulated release of endothelium derivedrelaxing factor seems to be attenuated result-ing in an impaired endothelium dependentrelaxation of resistance vessels. This does notestablish a general impairment of endothelialfunction or specifically an impairment of thebasal release of nitric oxide synthesised fromL-arginine. Indeed, blood flow after a highdose of L-NMMA was even more reduced inpatients with CHF than in normal people.

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Thus it seems that the stimulated and basalrelease of nitric oxide are dissociated inpatients with heart failure. The basal releaseof nitric oxide seems to be preserved or mayeven be enhanced in the peripheral circulationwhereas the stimulated endothelial dependentdilatation exerted by acetylcholine is blunted.The finding that forearm blood flow was sub-stantially reduced with L-NMMA withoutimportant changes in the diameters of largeconductance vessels in normal people sug-gests a preferential release or activity of nitricoxide in forearm resistance vessels comparedwith large conductance vessels in humans.Thus the basal release of nitric oxide seems toplay an important part in modulating tissueperfusion in distal resistance vessels in theforearm in heart failure but may be negligiblein conduit vessels, or other factors may over-ride this effect on vasomotor tone in largearteries.

Experimental evidence shows that long-term treatment with ACE inhibitors and phys-ical training improve endothelial dysfunctionin experimental heart failure.27 Preliminarydata indicate that training can improveendothelial function in patients with heartfailure.28 The beneficial effect of ACEinhibitors on endothelial function might bedue to the inhibition of the breakdown ofbradykinin, which is degraded by ACE.29Inhibition of the ACE mechanism mayincrease the local tissue concentrations ofbradykinin, which in turn stimulates therelease of nitric oxide (which accounts for thebiological activity of the endothelium derivedrelaxing factor) and vasodilating prosta-glandins.2930

Intrinsic alterations of skeletal muscle inchronic heart failureAlthough acute doses of vasodilators or posi-tive inotropes may improve blood flow toskeletal muscle during exercise, duration ofexercise and maximal oxygen consumption donot increase immediately after these drugs aregiven.31 This indicates that oxygen uptakewithin skeletal muscle during exercise cannotbe improved during short-term intervention inpatients with chronic heart failure even whenoxygen delivery is enhanced. This finding sug-gests that blood flow is shunted away fromactive muscle or that there are intrinsic alter-ations of skeletal muscle in chronic heart fail-ure, or both. We have noted previously thatthere might be a shift from oxidative skeletalmuscle to activation of more glycolytic work-ing muscle fibres4 again indicating a change inthe properties of the skeletal muscle itself.Muscle biopsies taken from patients withchronic heart failure showed moderate atro-phy (reduced muscle mass) and biochemicalalterations including a shift in the distributionof fibre type in skeletal muscle.3' Ultra-structural analysis of skeletal muscle biopsyspecimens has shown a reduced oxidativecapacity of the muscle as indicated by areduced volume, density, and reduced surfacearea of the cristae of mitochondria.34

Cytochrome c oxidase staining of the ultra-structural and biochemical measurement ofcitrate synthase showed a significantlyreduced concentration of the oxidativeenzymes (fig 2),3435 which suggests that theoxidative capacity of skeletal muscle is dimin-ished in severe chronic heart failure. In fact, aclose relation has been found between theoxidative capacity of working muscle, asassessed by cytochrome c oxidase or cristaesurface density of mitochrondria within theskeletal muscle and the peak oxygen con-sumption during exercise.'436 Thus exercisecapacity seems to be partly determined by thecondition of the working muscle.'7 The pat-tern obtained by nuclear magnetic resonancespectroscopy showed abnormal metabolism ofskeletal muscle, which supported the ultra-structural and biochemical findings.'8 Withnuclear magnetic resonance spectroscopy, itwas shown that the intracellular pH valuesduring exercise are much lower for a givenworkload in patients with severe heart failure.Moreover, during exercise, the concentrationsof plasma inorganic phosphate and phos-phocreatinine decreased much faster inpatients with heart failure than in normalpeople.38 39

Potential underlying mechanisms ofperipheral adaptationsMany experimental and human studies haveshown that exercise training induces impor-tant adaptations in skeletal muscle.40 Theseinclude increases in capillary supply, musclemass, mitochondrial content includingincreased activity of oxidative enzymes, and ashift in the distribution of fibre types-that is,a higher percentage of type I and IIA musclefibres that possess a higher oxidative capacitythan type IIB fibres. This adaptation of skeletalmuscle to training results in an increased res-piratory capacity of the muscle fibres accom-panied by metabolic consequences, such asslower use of muscle glycogen, greaterreliance on fat oxidation, and lower lactateproduction during exercise of a given inten-sity.40 In contrast, during prolonged immobili-sation, oxidative enzymes of skeletal muscle,muscle mass, and capillary density alldecrease below baseline values.41A3 As patientswith chronic heart failure usually restrict theirphysical activity, in part based on their physi-cians' advice, the hypothesis has been put for-ward that a deconditioning effect occurs intheir skeletal muscle.44 Consistent with thisconcept, bicycle training in patients withchronic heart failure has been shown toimprove exercise tolerance by peripheralmechanisms-for example, by delaying theonset of anaerobic metabolism.45 Traininginduced improvement of peripheral musclemetabolism seems to be independent of sys-temic adaptations. Both in normal people andpatients with heart failure, an exercise pro-gramme restricted to small muscle groups(such as forearm muscles) improves the meta-bolic state of skeletal muscle without alteringcardiac performance.46

Q<w coQ

11 = II : 11Oc Oc Oc.- - _ ,- -

Figure 2 Volume densityof mitochondria withcytochrome c oxidasepositive cristae. Group A,patients with severe heartfailure; group B, patientswith moderate heartfailure; group C, normalcontrols.

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Although these findings suggest that thealterations in skeletal muscle of patients withchronic heart failure are due to decondition-ing, other potential factors should not be dis-missed. Mancini et al suggest that decreasedcaloric and protein intake may be a main con-tributor to skeletal muscle atrophy.'2 It wouldbe interesting to see whether or not there is arelation between indices of muscle atrophyand caloric intake. Depressed caloric intakemay be an important factor in certain subsetsof patients, particularly patients with alcoholiccardiomyopathy. Given the frequent lack ofsigns of malnutrition, however, other factorsare likely to be involved in the development ofmuscle abnormalities. These factors mayinclude increased free radical activity,47increased sympathetic tone, or monocyte acti-vation associated with increased plasma con-centrations of tumour necrosis factor.4849 Thismonocyte activation, possibly linked to astimulated renin-angiotensin system in severeheart failure,49 may cause endothelial dysfunc-tion50 and adversely affect muscle metabolismand function.5' Indeed, there is evidence thatin patients with cardiac cachexia the net nega-tive protein balance across leg tissue is associ-ated with an increased rate of myofibrillarprotein breakdown.52 Endothelial dysfunction,which has been shown to emerge in patientswith heart failure,2' may further compromiseskeletal muscle function by affecting its bloodflow. Long-term ACE inhibition improvesblood flow to skeletal muscles and oxygenextraction during exercise.9 Also, preliminarydata indicate that ACE inhibitors partiallyreverse ultrastructural abnormalities of skele-tal muscle in patients with heart failure.'4Experimental evidence suggests that long-term ACE inhibitor treatment reduces vascularinfiltration by monocytes and macrophagesand restores endothelial function.53 54 Some ofthese findings support the view that alter-ations of skeletal muscle in heart failure are,after all, the consequence of impaired cardiacfunction. It has been speculated, however,that a generalised myopathy may occur in asubset of patients with dilated cardiomyopa-thy.55 56 Dunnigan et al found that youngpatients with cardiomyopathy who developedeither ventricular tachycardia or heart failurehave histological abnormalities of skeletal andcardiac muscle, in particular, atrophy of typeII skeletal muscle fibres.55 Caforio et alreported histological alterations characterisedby selective atrophy of type 1 fibres, that aresimilar to those found in congenital and idio-pathic myopathies and are unrelated to car-diac functional New York Heart Associationclasses.56 Thus, common underlying factors-for example, genetic or autoimmune disor-ders-that affect both cardiac and skeletalmuscle may be operating in a subset ofpatients with dilated or hypertrophic car-diomyopathy. These divergent morphologicalfindings are based on qualitative histologicaland ultrastructural analysis of upper armskeletal muscle in a limited number of youngpatients without clinically overt myopathy.5556In contrast, in most reports evaluating weight

bearing calf muscle, the abnormalities weresimilar in patients with heart failure whetherdue to coronary artery disease or to dilatedcardiomyopathy, suggesting that in most casesthe reduced oxidative capacity of skeletalmuscle is related to the state of heart failureand its severity.The impact of impaired blood flow during

exercise on these skeletal muscle alterationsremains unclear. Subsequent studies withnuclear magnetic resonance spectroscopy aswell as skeletal muscle function tests inpatients with chronic heart failure showedthat these abnormalities, under ischaemicconditions, were unrelated to different rates ofblood flow to the working muscle during exer-cise.57-59 This does not exclude the fact thatrepeated episodes of reduced blood flowwithin skeletal muscle may be involved in thedevelopment of skeletal muscle alterations,despite the fact that these alterations, oncedeveloped, can be shown regardless of mea-sured flow during the assessment of musclefunction59 or metabolism.5758The alterations of the peripheral circulation

in chronic heart failure are similar to thosefound after prolonged physical inactivity. Incontrast, opposite changes can be found afterintense training-that is, in athletes. Severalsmall studies have documented that a trainingprogramme can reverse at least some of theadverse peripheral changes.4560 Based on thetheoretical considerations, physical traininghas a great potential to improve the clinicalstate of patients with heart failure. Beforewidespread recommendations can be madethe safety of training in patients with heartfailure needs to be shown in large populationsof patients. In particular, the impact ofphysicaltraining on cardiac function needs to be testedvigorously. Although some animal studies byScheuer et al indicate that training mayimprove the myocardial phenotype andimprove cardiac performance, these studieswere almost exclusively performed in rats.6' 62The myocardium of rats has specific proper-ties distinct from the human myocardium,and more importantly, coronary artery diseasein humans usually complicates matters. In theend, there may be an interaction between car-diac performance during exercise and the pro-gressive perfusion deficit in skeletal muscleduring exercise. It is now established that theforce frequency relation is substantiallyaltered in human heart failure-that is, twitchtension of the failing heart decreases withincreased heart rate (peak twitch tension50-70 beats/min), whereas the peak twitchtension in the normal myocardium is 130 to140 beats/min. Thus the increase in heart ratein normal people during exercise is associatedwith increased cardiac output but thismyocardial inotropic reserve cannot berecruited in the failing heart and may beinvolved in the impaired perfusion duringexercise. Recent data from our laboratoryindicate that the impaired force frequencyrelation during exercise is related to an alteredcardiac phenotype of the expression of thesarcoplasmatic reticulum ATPase. Future

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studies, by integrating cardiac, pulmonary,reflex, vascular, and skeletal muscular aspectsshould be able to delineate the compositealterations responsible for the clinical syn-drome of heart failure.

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