EDITORIAL
REVIEW
~-
The Neurohormonal Hypothesis: A Theory to Explain the Mechanism of Disease Progression in Heart Failure MKTON
PACKER.
New Y”&
MD,
FACC
N of re\poc. bo, mevcably ihe parient experiences rubs~anl~al dsabdlly. for ho;pitalization
and cmergcncy
a recur~nr
need
care and. uamateiy.
death. No matter how stable the condition of 08 indwdual patient ma) appear initially. the underlying diwse progresw Respire the most careful anentian to the hemodynamic and clinical abnormalities of the syndrome. moot ritients who have heart failure will die of heart foilore. Although we believe that hemodynamlc factors play an essential role in caosmg the symptoms of heart failure. ae do not understand the factors responsible for progewon of the disease. Undoubtedly, heart failure may progrchs because of persistence or recurrence of its primary ~aure This concept exolains wbv heart failure worseos durine the continued ad&dstmtidn of a cardiotoxic drug or after the recurrence of myocardtal intarc:ma. io most patients. however. hext failure progwwes we” though !ke primary cause of left ventricular dysfunction is no longer prese :t ur active. Under these circumstances. heart failure advances because the original cause triggers endogeoous mechdnisma that (“ncc set into motion) lead to the :nei;“rable ia. tif myocardlal cells. The precise notore of tnese endogeoous mechanisms has not been defined. but for the lest 40 years. cardiclqists have assumed that the endogeoous facwr tkat X: responsible for disease aroeression in heart failure is identical t” the factor that i; re&msible for symptoms. namely. hrmadynamic stress. However. as we wili oemonstrate in this review, the results of recent studies do not support the kemadynamic hypothesis, but instead indicate that akernative mechanisms most play a primary role in advancing the disease process.
The Hemodynamic Hypothesis of Disease Progression According to the kemodynamic hypothesis. heart bilure progresses because hemodynamic stresses that are triggered by the initial injury t” the heart exert a deleterious effect on the circulation. Any loss of viable myocardiom is inevitably followed by a” increase in enddiastobc pressure and vol“me, as the heart attempts to maintain stroke volume ot a reduced ejection fraction. However, this increase in loading conditions (preload and afterload) constitutes an important hemodynamic stress for patients with hear! failure and may adversely affect both the functional and the structural inlegrity of the noninjured myocardium. Dtoing shon periods of time, the consequcnc~s of hemodynamic stress are primarily functional. Whereas an increase in preload and afterload leads to a” improvement in
cnrd:uc tunc~~un m the normal heart. a similar mcreze m ioadinp c”nd,r,ons adversely afiects the function of the !:::irng heart ‘Tlxs difference i\ related to an alteration in the re\pon‘~\cnc\\ And wnceptihility of the noninjured heart to strew after the loss of a \ienificant quantity of contractine myocardzum. The normal heart cat utilize an mcrease in prclmd I” enhance rysrohc ejection (Frank-Stw!ing mechamrm) and h;l\ do imrin5ic ability to “wrwme ao mcreace in afterload by augmenting contractde force lkomeometnc autore~~daoon~ (61. However. in the failing heart, increases in pre!old do n”t enhance )yst”lic performance lbecause the Frank-Starlmg curve IS both depressed and flattened) and the abnormal myocardwm cann”t increas: contractility in response t” an increase in afterload (51. Hence. any mcrease an imer\ m rhe fading heart will further impair cardiac function and !hus any intervention that ameliorates loading conditt”ns m hr2i: Liiure will augment cardiac performance. This pnnciple explains why drugs that reduce ventricular wall \IKIF gcncr41y improve the clinical rtatos of patients with heart fdilurc. However. hecause the functional consequences of hemodynamx ~trcss are readily revened when rhe aress is redwed. an increase in cvdiac preload and afterlwad cannot explain the inexorable progression of heart failure. Hence. a key assumption of the hemodynamic hypothesis is that a prolonged mcrease in hemodynamic stress in the impaired Ibear! leads I” an irrewrsihle rinrctwal deterioration of ventrulor function. Recent stud& 17.8) have shown that sustained increases in cardiac ~“loroe and pressure after acute myocardial injury can caose Trogresrive str~ctoral remodeling that is gaerally accompanied bjj a penoanent decrease in ventricular functiow Hence. a drug that reduces ventricular wall stress might not only improve cardiac performance and symptoms, but might also retard the pr”grGwe detenoration of cardiac woctore and funxion Land prolong life (9). Importantly, because ho:h positive isotropic agents and peripkelal vasodilators reduce reoiricu:ar watt stresh. it should not matter how kemodynamic improvement is ac$eved. Accordinp. to the kerndynamic hypothesis, both types of drug shouid retard the st”&al and functional consequences of hemodynamic stress and thereby exert a favorable effect on the natural history of heart failure.
Testing the Hemodynamic Hypothesis Stud& with vasodilator drags. The first clinical test of the hemooynamic hypothesis was the first Veterans Affairs Heart Failure Trial IV-HeFT Trial) 110). Begun in 1978. the principal aim of this study was I” determine if drugs that reduce wall slress would reduce the risk ofdisease progression and thus prolong life in par:ents wirh heart failure. To trbl &is posbibiiity, ibr i”ve3uig*i”r~ urcd the uoiy wil:j active va~odilators available to them in the late 1970s: prozosrn and a combination of hydralazine and isosorbide dimtratc. Borh drug regimens were hemodynamicaliy eifeclive and produced similar decreases in ~:entricular prcload
and afrerload (t 1.121. Thus. ifthc hcmodynamic hypothesis was true. both vasodilators should have produced hvorable changes in the natural history of heart f&we. Interesttnclv. the V-HeFT trial showed that one-but not both-of the~;asodilator treatments was associated with a reduction m the mortality rate in patients with chronic heart failure. On the basis of the bemodynamic hypoiheris. the successful vaiodilator regimen reflected by pretreatment heart rate or circulating norcpinephrinc level, (51.521. Studies with positive and negative inctrapic agetats. If the hemodynamic hypothesis is correct. we might expect drogr with positive inotropic c~ccts to be benrficia! m heart faihoe and drugs wth nrg~tive inotroplc action. J have deleterious etTec!s. Such a concept has ilccn used to explain the adverse e&c+ ?f ~B)CIUIP. chkel blockers in chronic heat fadurc (16-20). However. the restdts of controlled clinical trials indicate that phosphooiesterare inhibitors !which enhance cardiac contractility) increase the mortality rate 126) and beta-blockers (which deprass cardiac contractilitv) prolonr life(50). lnterestmgly. lb; mechanisms by which th&eddrug~ influence mortality may be similar. Both primarily affect the total rr~;;&~~ iatc by &ir/i~g the risk of sudden death; beta-blockers reduce this rusk (50). whereas phorphodiesterare inhibitors increw it 153). ‘The two types of drugs also shore a common mode of action-thev bot!t exert profound effect:, on myocardial cyclic AMP: beta-blocker; reduce intracellular cyclic AMP, whereas phosphodiesterase inhibhors increase it. This parallelism suggests that the ncumbormonal and biochemical effects of drugs are a more important determinant of their influence on the niltuml htstory of heart fatlure than are their hemodyoamic actions. Similarly, the d&&us et%cts of oifedipine and diltiazem appear to be explained more comp!e!ely by neurohrrmonal octisatton than by the negative inotropic effects of these calcium channel biockcrs 154).
inhibitors have produced disappointtng results. controlled !rds (55-58) have shown that long-term thenpy with dig. ^iiz rcL.c; sympwr,,a, p,u:ur~gs exerctse lulerance and decreases the risk of clinicat progression of heart failure. Why does digit& differ from other positive inotropic agents? Unlike cyclic AMP-dependent agents. digitalis reduces the activatton ofbcth the sympathetic nervous >ystem aod Ihe renm-angiotensitt systeiFl (59.60). This iaolabie neurohormonal effect is achieved iodependently of the drug’s hemodynamic actmns and is related to the abili!y of digitalis to restore the inhibitory effect of cardiac baroreceptars on sympathetic outflow from the central nervous system (59). The unique neurohormonal aclion of digitalis m&y expiin wily this drug aiTecrcacardiovascular morblaoy more
favorably than the cyclic AMP-dependent positive inotrapic agents t26.56.58). In cootrast. the hemodynamic hypotheses would have oredictcd suvcrior clinical results wth the cyclic AMP-depenbent agent\ iw~se both the be,*-a@tdand the phoaphodics;eraae mhibitors at&t cardiac contraetdity and the perapheral vasculature more favorably than digitali*. Conclusions Based on the studies cited in rhls review, can we conclude that there IS r~dFc~cnt cwience I,, accept the neurohornonal hypothesis and reject the hemodynamic hypothesis of heart faihw? Although the results of controlled trials strongly support the neumhormanal hypothesis. most of the dataare derived from studies usmg convening enzyme inhibitors. The hypothesis will be greatly strengthened if large-scale triols with betz.blockcrs and other neurohormonal antagonist3 show favortble effects on cardiovascular morbidity and mortality. Similarly. although the results of most controlled studies appear to refute the hemodynamic hypothcsts, tP_ evidence is not sufficient to completely reject an important role for hemodynamic factors ii the progression of heart failure. At Ieat one hemodvnnmicallv eR&ective drw ret+ men-a combination of hyhralazine -and isosorbid; diiiIrate-reduced the mortality rzte in the tist V-H&T study (IO). dnd the primary action of these two vasodilators is to improve cardiac function (by reducing preload and afterload and perhaps by increasing cardiac contractility [39.40]) and not to decrease the activilv of endoanous neurohormonal systems. Hence. it is like& that both neumhormonat and hemodvnamic factors are imrmtant but indca‘ndent determinant~ of disease progress& in heart fail&. If this concept proves to be valid. it will be highly desirable that future dr& for heart failure exert both favorable hemodynamic and ncurohormonal effects. Trials evaluating amlodipine, felodipine and tlosequinan. Such an approach is now being tested in several larg&cale. controlled. multicenter survival trials. .Amlodipitte and feltdtpine are new calcium chmmi) blocking drugs that decrease (rather than increase) the activity of the svmpathetic nervous system (61.621. In contrast to other calcium channel blockers. these drugs have been shown to lessen the symptoms and improve the exercise tolerance of patients with chronic heart failure in controlled clinical studies (62.63). Two large scale lrials have been initiated to evaluate the effect of these aeents on morbidttv and morlalitv: one with amlodioine (kospective Amlc&pinc Survival Evaluation LPRAI&l) and one with felodipmc (the third Veterans AtYaks Failure Trial [V-HeFT Ill]). Similarly, flosequinan is a new vasodilater with favorable tteurohormonal effects: the drug di!ates peripheral xteries nnd veins by interfering with the inositoltriphosphate pathway (64) and reduces ?yrrpathetic outflow to the heart. as demooslrwed hy conrroki studies of heart rate wriability (bS). In WE’ JBS! !” n?a?y other direct-acting vasodilators. controlled trials with Rosequinan have demonstrated favonble &cctr on symptoms ond cxcrcisz tolcr-
ante (66,671. A large scale controlled lrial evaluatmg the effect of Rosequinan on wrvival (Prospcctiw Flotequinx Longcvily Evaluation [PROFILE]) k now in progress. Fik nally. the elfects of dignahs. which exens both porilive inotropicand beneficral neurohormonai bmefit~. *n iuriiwl arc being evaluated in the Digirali~ inveatigawn clroup IDIGI study. If additional smdies confirmthe ncunhormonal hypolhesis, the theory nol only may change our treatment of hearr failure. but may ailer our fundamemal understanding of rhe disease. rhc ccotral message 01 the neurohormonnl hypoth~SIP is that hean failure is noi rimpiy a hemodynamio disorder and its physiologic abnormalma cannot be snmply assessed by lbe measurement of pressure. volume and flow Neurobormonal systems govern the functions of the heen and the circulation in both health and disease. The abday of the cardiovascular system to adapt to injury and ~oleratc stress is determined by the rekasc and interaction of !ocal and systemic neurohormonal signals and by change, in Ihe activation and effectiveness of their intracellular messengers (681. It is the interplay of these neurohormonal and hcmodynaic forces that defines the syndrome of heart failure.
42. Cohn IN, FmnoncisGS. Simon AR. Johnwn G and Ycicran$ Adnwmsirarmn Study Group. Response of plasma nDrepinephrine 10 long-term admrmrtratmn uf rnalapril or hydralaza~lrosorbide dmiiratc in hen! failure: V-HeFT II labwl. J Am Call Cardiol 1992:19(ruppl AI:ZI4A. 43. Cohn JN. Slmun A. Johnson CI, ard V.HePT Study Group. Rclalionrhrp ofplasma norepmephrmc ad plxma renin activity la mur&y m hcarrr failure: V-HcFT II labilrl. CrrculL~on 1991:841wppl llI:ll-310. 44. C~Tney TE. Braunw~ld 8. Importance of adrenergic nervw~ system in the suppoti of cwcuialory funcuon m pabeurs wilh cangt>twe heir1 failure. Am J hicd 1X13:34:320-4.
47. En~lemeierRS.O’Connr,,,~,~~~shR.RddN, S‘w,lon PJ. GunnsrRM. Improvement m sympta,ns md exercix tolerance by mctoprolo, in patients with dibaed cardiomyopathy: a double.bhnd. mndomired. plrcebo-controlled Ina,. C,rc~lll,on 1985:72:5,6-46. 48 Gilhen EM. Anderson JL. Ueiwhmrn D. et ill. Longaerm Pblacker vasodilalor lhcnpy mrproves cardiac function in idiowihic dilated cardiomyopulby: ii double-blind. randomized wdy of bwndnlol wrtu, placebc. Am J Med 1990:88:223-9. 49. Olsen S,.. Gilher, EM. Rcnlund DG. Me&y PC. “olkn,m K. O’Connell JB, Yanowilz FD. Brislox MR. Carvedilol improver left vcnlncular funclmn m idropathic dilated csr&oe!yopathy (abs,rl. Gnularios 1991: wruppt l1):ll-sM. SO. Chadda K. Goldstein S. Byingon R. Curb JD. E&I of propranolol after acute nryocarrlidl infvclian in patents with congcstivr hean failure. Cwculation 1986:73:5%,O. 51. Gilher, El. Mwmn~ L. AndersoanJL. Woo& SL. Br~ww MR. Can response lo Pblockcr therapy m idiopathic dilated cardiomynpalhy br predicred by baseline onramelers ,abswl Clrculmion ,98B:R0~aupp, ,,I: 11.671
57. DiUk:xaR.Sb&eraiB. Ku~lukW,rta,. Acampar~ranoiorul mdrmunc, dieoxm. and their cumbmation in rhe ~reaimeor of patient\ wilh chrome hear, fadure. N Enc, J Med 1989.320 6%K3. 58. Packer Id. Gheorghtade ht. Young JB. el al Randomzed. double.b,,nd. placebo-cordroiled. wilhdrawa, atudv of d;gxin in patitnls with chrome l!can Lilure trealrli wilh convellinwrzyme inhiblmrs labsIr). J AmCoIl CwdiOl lW?:,9lrupp, A,:260A. 59. Fe~gusonDW. Rep WJ. Srnden J: Roach PJ. Kempf IS. Kienrlc MC Sympatho-iuhhbilory rurponres 10 digiralir &vm~der in hcarl farlure pirtientr: thrccl evidence fram sympathetic ncurd rccwding~ CtrculaLion 19R9:80:6%-77 M). Covrl AB. Schaer CL. S&y JE. Laragh IH. Cody RJ Supprecr’oo 01 the rain-angiolensin ~ywrn by m%venouadigoxin in chroniccangeswe hear! failure. Am I Mcd 19R3:75:4&7. 61. Kassis E. Ammrp 0. l.w-lerm clinical. hcmodynamic. ugiogrupb;.. and neurohurmonal rewonw to varodilrlion wtlh fclodipiw in aatienrs
62. Pvcker M. Nicod P. Khandhenil ER. el al. Rnndumwd. rnullic~nl~r. double-bhnd. placebo-cowaired evalua~on ofamlodipmern paliws wh ml!d.to-rwderdtr hai falure labrtr 1. J Am Colf Cardiul 1991;11:?14A. 63. Ounrelrw, PHJM. Kudze CEE. “a” Brureen A. er al. Effwacv of ft,lxhpine in congestive hear! failure. Eur Iit% J 1989:10.154-64. DB. pharmacology offlosrquinan. Am Heart J 1991:12,:974-83. 65. Biaklsy PF. NurrLiata E. Hauon P. Proicou G. Cody RI. Floraquinan augmenls parusympathelic tone and alterwater sympalhctx drive in congestive heart failure: demonswation by analysis of hear! ra,e variabiliiy tabnr) 1 Am Co11Cardml 19yz:l%supp, AI:,47A. bb Packer M. Naiahara KA. ELyam U. e1 a,. Randomized. muil,mxnlei. double-blind. pIacebo.cumrolled study of the efficacy of Rosesuinan. a new. lasgarting vsrodilator drug. in~palienlr with chronic he& fadure Isbswl. Circulation l9yo:S2lsuppl ll1kl1,-323. 67. Pi,, 8. on behalf 01 the R&cl I, Study Group. A randomized. mullicewr. doublc.Mind placebo comrallea rludy of Lhe ei%ca~y of t&equinan in p&ems wrlh chronic hew failure labar). Circulation IW,: wruppl 111:11-31I. 68. Packer M. Neuruhnrmonal interdclions and adapralions in congerlive hear, failure Cxculvtion l%R:77rl21-30
54. Yam
’
REVIEW
~-
The Neurohormonal Hypothesis: A Theory to Explain the Mechanism of Disease Progression in Heart Failure MKTON
PACKER.
New Y”&
MD,
FACC
N of re\poc. bo, mevcably ihe parient experiences rubs~anl~al dsabdlly. for ho;pitalization
and cmergcncy
a recur~nr
need
care and. uamateiy.
death. No matter how stable the condition of 08 indwdual patient ma) appear initially. the underlying diwse progresw Respire the most careful anentian to the hemodynamic and clinical abnormalities of the syndrome. moot ritients who have heart failure will die of heart foilore. Although we believe that hemodynamlc factors play an essential role in caosmg the symptoms of heart failure. ae do not understand the factors responsible for progewon of the disease. Undoubtedly, heart failure may progrchs because of persistence or recurrence of its primary ~aure This concept exolains wbv heart failure worseos durine the continued ad&dstmtidn of a cardiotoxic drug or after the recurrence of myocardtal intarc:ma. io most patients. however. hext failure progwwes we” though !ke primary cause of left ventricular dysfunction is no longer prese :t ur active. Under these circumstances. heart failure advances because the original cause triggers endogeoous mechdnisma that (“ncc set into motion) lead to the :nei;“rable ia. tif myocardlal cells. The precise notore of tnese endogeoous mechanisms has not been defined. but for the lest 40 years. cardiclqists have assumed that the endogeoous facwr tkat X: responsible for disease aroeression in heart failure is identical t” the factor that i; re&msible for symptoms. namely. hrmadynamic stress. However. as we wili oemonstrate in this review, the results of recent studies do not support the kemadynamic hypothesis, but instead indicate that akernative mechanisms most play a primary role in advancing the disease process.
The Hemodynamic Hypothesis of Disease Progression According to the kemodynamic hypothesis. heart bilure progresses because hemodynamic stresses that are triggered by the initial injury t” the heart exert a deleterious effect on the circulation. Any loss of viable myocardiom is inevitably followed by a” increase in enddiastobc pressure and vol“me, as the heart attempts to maintain stroke volume ot a reduced ejection fraction. However, this increase in loading conditions (preload and afterload) constitutes an important hemodynamic stress for patients with hear! failure and may adversely affect both the functional and the structural inlegrity of the noninjured myocardium. Dtoing shon periods of time, the consequcnc~s of hemodynamic stress are primarily functional. Whereas an increase in preload and afterload leads to a” improvement in
cnrd:uc tunc~~un m the normal heart. a similar mcreze m ioadinp c”nd,r,ons adversely afiects the function of the !:::irng heart ‘Tlxs difference i\ related to an alteration in the re\pon‘~\cnc\\ And wnceptihility of the noninjured heart to strew after the loss of a \ienificant quantity of contractine myocardzum. The normal heart cat utilize an mcrease in prclmd I” enhance rysrohc ejection (Frank-Stw!ing mechamrm) and h;l\ do imrin5ic ability to “wrwme ao mcreace in afterload by augmenting contractde force lkomeometnc autore~~daoon~ (61. However. in the failing heart, increases in pre!old do n”t enhance )yst”lic performance lbecause the Frank-Starlmg curve IS both depressed and flattened) and the abnormal myocardwm cann”t increas: contractility in response t” an increase in afterload (51. Hence. any mcrease an imer\ m rhe fading heart will further impair cardiac function and !hus any intervention that ameliorates loading conditt”ns m hr2i: Liiure will augment cardiac performance. This pnnciple explains why drugs that reduce ventricular wall \IKIF gcncr41y improve the clinical rtatos of patients with heart fdilurc. However. hecause the functional consequences of hemodynamx ~trcss are readily revened when rhe aress is redwed. an increase in cvdiac preload and afterlwad cannot explain the inexorable progression of heart failure. Hence. a key assumption of the hemodynamic hypothesis is that a prolonged mcrease in hemodynamic stress in the impaired Ibear! leads I” an irrewrsihle rinrctwal deterioration of ventrulor function. Recent stud& 17.8) have shown that sustained increases in cardiac ~“loroe and pressure after acute myocardial injury can caose Trogresrive str~ctoral remodeling that is gaerally accompanied bjj a penoanent decrease in ventricular functiow Hence. a drug that reduces ventricular wall stress might not only improve cardiac performance and symptoms, but might also retard the pr”grGwe detenoration of cardiac woctore and funxion Land prolong life (9). Importantly, because ho:h positive isotropic agents and peripkelal vasodilators reduce reoiricu:ar watt stresh. it should not matter how kemodynamic improvement is ac$eved. Accordinp. to the kerndynamic hypothesis, both types of drug shouid retard the st”&al and functional consequences of hemodynamic stress and thereby exert a favorable effect on the natural history of heart failure.
Testing the Hemodynamic Hypothesis Stud& with vasodilator drags. The first clinical test of the hemooynamic hypothesis was the first Veterans Affairs Heart Failure Trial IV-HeFT Trial) 110). Begun in 1978. the principal aim of this study was I” determine if drugs that reduce wall slress would reduce the risk ofdisease progression and thus prolong life in par:ents wirh heart failure. To trbl &is posbibiiity, ibr i”ve3uig*i”r~ urcd the uoiy wil:j active va~odilators available to them in the late 1970s: prozosrn and a combination of hydralazine and isosorbide dimtratc. Borh drug regimens were hemodynamicaliy eifeclive and produced similar decreases in ~:entricular prcload
and afrerload (t 1.121. Thus. ifthc hcmodynamic hypothesis was true. both vasodilators should have produced hvorable changes in the natural history of heart f&we. Interesttnclv. the V-HeFT trial showed that one-but not both-of the~;asodilator treatments was associated with a reduction m the mortality rate in patients with chronic heart failure. On the basis of the bemodynamic hypoiheris. the successful vaiodilator regimen reflected by pretreatment heart rate or circulating norcpinephrinc level, (51.521. Studies with positive and negative inctrapic agetats. If the hemodynamic hypothesis is correct. we might expect drogr with positive inotropic c~ccts to be benrficia! m heart faihoe and drugs wth nrg~tive inotroplc action. J have deleterious etTec!s. Such a concept has ilccn used to explain the adverse e&c+ ?f ~B)CIUIP. chkel blockers in chronic heat fadurc (16-20). However. the restdts of controlled clinical trials indicate that phosphooiesterare inhibitors !which enhance cardiac contractility) increase the mortality rate 126) and beta-blockers (which deprass cardiac contractilitv) prolonr life(50). lnterestmgly. lb; mechanisms by which th&eddrug~ influence mortality may be similar. Both primarily affect the total rr~;;&~~ iatc by &ir/i~g the risk of sudden death; beta-blockers reduce this rusk (50). whereas phorphodiesterare inhibitors increw it 153). ‘The two types of drugs also shore a common mode of action-thev bot!t exert profound effect:, on myocardial cyclic AMP: beta-blocker; reduce intracellular cyclic AMP, whereas phosphodiesterase inhibhors increase it. This parallelism suggests that the ncumbormonal and biochemical effects of drugs are a more important determinant of their influence on the niltuml htstory of heart fatlure than are their hemodyoamic actions. Similarly, the d&&us et%cts of oifedipine and diltiazem appear to be explained more comp!e!ely by neurohrrmonal octisatton than by the negative inotropic effects of these calcium channel biockcrs 154).
inhibitors have produced disappointtng results. controlled !rds (55-58) have shown that long-term thenpy with dig. ^iiz rcL.c; sympwr,,a, p,u:ur~gs exerctse lulerance and decreases the risk of clinicat progression of heart failure. Why does digit& differ from other positive inotropic agents? Unlike cyclic AMP-dependent agents. digitalis reduces the activatton ofbcth the sympathetic nervous >ystem aod Ihe renm-angiotensitt systeiFl (59.60). This iaolabie neurohormonal effect is achieved iodependently of the drug’s hemodynamic actmns and is related to the abili!y of digitalis to restore the inhibitory effect of cardiac baroreceptars on sympathetic outflow from the central nervous system (59). The unique neurohormonal aclion of digitalis m&y expiin wily this drug aiTecrcacardiovascular morblaoy more
favorably than the cyclic AMP-dependent positive inotrapic agents t26.56.58). In cootrast. the hemodynamic hypotheses would have oredictcd suvcrior clinical results wth the cyclic AMP-depenbent agent\ iw~se both the be,*-a@tdand the phoaphodics;eraae mhibitors at&t cardiac contraetdity and the perapheral vasculature more favorably than digitali*. Conclusions Based on the studies cited in rhls review, can we conclude that there IS r~dFc~cnt cwience I,, accept the neurohornonal hypothesis and reject the hemodynamic hypothesis of heart faihw? Although the results of controlled trials strongly support the neumhormanal hypothesis. most of the dataare derived from studies usmg convening enzyme inhibitors. The hypothesis will be greatly strengthened if large-scale triols with betz.blockcrs and other neurohormonal antagonist3 show favortble effects on cardiovascular morbidity and mortality. Similarly. although the results of most controlled studies appear to refute the hemodynamic hypothcsts, tP_ evidence is not sufficient to completely reject an important role for hemodynamic factors ii the progression of heart failure. At Ieat one hemodvnnmicallv eR&ective drw ret+ men-a combination of hyhralazine -and isosorbid; diiiIrate-reduced the mortality rzte in the tist V-H&T study (IO). dnd the primary action of these two vasodilators is to improve cardiac function (by reducing preload and afterload and perhaps by increasing cardiac contractility [39.40]) and not to decrease the activilv of endoanous neurohormonal systems. Hence. it is like& that both neumhormonat and hemodvnamic factors are imrmtant but indca‘ndent determinant~ of disease progress& in heart fail&. If this concept proves to be valid. it will be highly desirable that future dr& for heart failure exert both favorable hemodynamic and ncurohormonal effects. Trials evaluating amlodipine, felodipine and tlosequinan. Such an approach is now being tested in several larg&cale. controlled. multicenter survival trials. .Amlodipitte and feltdtpine are new calcium chmmi) blocking drugs that decrease (rather than increase) the activity of the svmpathetic nervous system (61.621. In contrast to other calcium channel blockers. these drugs have been shown to lessen the symptoms and improve the exercise tolerance of patients with chronic heart failure in controlled clinical studies (62.63). Two large scale lrials have been initiated to evaluate the effect of these aeents on morbidttv and morlalitv: one with amlodioine (kospective Amlc&pinc Survival Evaluation LPRAI&l) and one with felodipmc (the third Veterans AtYaks Failure Trial [V-HeFT Ill]). Similarly, flosequinan is a new vasodilater with favorable tteurohormonal effects: the drug di!ates peripheral xteries nnd veins by interfering with the inositoltriphosphate pathway (64) and reduces ?yrrpathetic outflow to the heart. as demooslrwed hy conrroki studies of heart rate wriability (bS). In WE’ JBS! !” n?a?y other direct-acting vasodilators. controlled trials with Rosequinan have demonstrated favonble &cctr on symptoms ond cxcrcisz tolcr-
ante (66,671. A large scale controlled lrial evaluatmg the effect of Rosequinan on wrvival (Prospcctiw Flotequinx Longcvily Evaluation [PROFILE]) k now in progress. Fik nally. the elfects of dignahs. which exens both porilive inotropicand beneficral neurohormonai bmefit~. *n iuriiwl arc being evaluated in the Digirali~ inveatigawn clroup IDIGI study. If additional smdies confirmthe ncunhormonal hypolhesis, the theory nol only may change our treatment of hearr failure. but may ailer our fundamemal understanding of rhe disease. rhc ccotral message 01 the neurohormonnl hypoth~SIP is that hean failure is noi rimpiy a hemodynamio disorder and its physiologic abnormalma cannot be snmply assessed by lbe measurement of pressure. volume and flow Neurobormonal systems govern the functions of the heen and the circulation in both health and disease. The abday of the cardiovascular system to adapt to injury and ~oleratc stress is determined by the rekasc and interaction of !ocal and systemic neurohormonal signals and by change, in Ihe activation and effectiveness of their intracellular messengers (681. It is the interplay of these neurohormonal and hcmodynaic forces that defines the syndrome of heart failure.
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54. Yam
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