Evaluation of the Role of Abana in Congestive Heart Failure A Double-Blind Study

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1 (Therp. Drugs (1992): 9, Jul./Dec., 23) Evlution of the Role of An in Congestive Hert Filure A Doule-Blind Study Antni, J.A., Prof. nd Hed, Dept. of Crdiology, nd Gulrg Hert Reserch Foundtion, Gulrg, Krntk Kulkrni, R.D., Prof. of Phrmcology, M.G.M. Medicl College, New Mumi, nd Antni, N.J., Gulrg Hert Reserch Foundtion, Gulrg, Krntk, Indi. ABSTRACT There were 3 ptients in this study, ll with chronic congestive crdic filure nd ged etween 3-75 yers. They were on low-dose digitlis nd diuretic, nd in Clss II or III of New York Hert Assocition (NYHA) criteri. Digitlis ws withdrwn nd then they were put on diuretic lone for 2 weeks. Then they were rndomly llocted into 2 groups for doule-lind, plceo-controlled 12-week tril with An. Mechnocrdiogrphy ws done t the edside efore tretment, fter 2 weeks nd t the end of 12 weeks tretment. Ptients on plceo nd diuretic showed further deteriortion of left ventriculr function. On the other hnd, those on An + diuretic showed significnt improvement in ll mechnoprmeters. By the end of the tril, ptients on An improved from Clss III nd II to Clss I of NYHA criteri. The vsodiltory, positive inotropic nd diuretic properties of An my hve rought out ll these desirle effects. INTRODUCTION Congestive crdic filure represents complex clinicl syndrome chrcterised y normlities of ventriculr function nd ccompnied y effort intolernce, fluid retention nd reduced longevity. There is grdul ut progressive impirment of myocrdil function occurring in ptient whose hert sustins pressure or volume overlod for prolonged period. Physiologiclly, hert filure my e defined s tht condition in which the hert is no longer le to pump n dequte supply of lood for the metolic needs of the ody t norml filling pressures of the ventricles, provided there is dequte venous return to the hert 1. The initil injury to the myocrdium results most commonly from infrction, myocrditis or toxins such s lcohol. However, the susequent development of hert filure is usully grdul process involving secondry compromise of initilly spred myocrdium enlisted to er the extr lod. Severl drugs hve een used singly or concurrently for the tretment of crdic filure ut the current therpeutic rmmentrium, crefully tilored to the individul ptient, hs filed to yield noteworthy rod results. Although drugs like digoxin, diuretics, vsodiltors nd sympthomimetic drugs re useful in lleviting the symptoms of congestive crdic filure, their long-term dministrtion cn e ssocited with serious toxic mnifesttions which necessitte their withdrwl. In view of the ove fcts, doule-lind, plceo-controlled study ws conducted to evlute the efficcy of An, sfe herominerl compound, s n djuvnt to diuretic therpy in congestive crdic filure 2.

2 MATERIAL AND METHODS Thirty ptients with chronic congestive crdic filure etween 3 nd 75 yers of ge were enrolled in the study. Selected ptients were on low-dose digitlis nd diuretic nd were in functionl clss II or III of NYHA (New York Hert Assocition) criteri. Before rndom lloction of the ptients into two groups, digitlis ws withdrwn from the ptients regimen with their consent, with the condition tht in cse of ny deteriortion of crdic function, rpid digitlistion would e done nd the ptients withdrwn from the tril. They were put on diuretic therpy lone for 2 weeks nd then rndomly llocted into two groups to receive either the ctive drug or identicl plceo dministered in doule-lind, plceo-controlled study. An/plceo ws dministered in the dose of 3 tlets twice dy for 12 weeks. The hert rte nd stndrd mechnoprmeters of ventriculr function, i.e. A mplitude, A wve durtion, LVET nd DP were studied serilly for evlution of An nd its comprison with plceo. Mechnocrdiogrphy is the edside method of evluting coronry rtery disese nd myocrdil performnce. It is the recording t 1 mm/sec speed of ECG, LV-pex crdiogrm (ACG), phonocrdiogrm (PCG) nd crotid pulse trcing (CPT) simultneously. It llows the evlution of the effects of crdic drugs in ptients more ojectively. The resultnt reduction in pre-lod, fterlod, nd myocrdil contrctility cn e specificlly studied nd the drug therpy cn e ojectively modulted 3. Mechnocrdiogrphy ws performed t the edside efore tretment, fter 2 weeks nd t the end of 12 weeks tril. Left ventriculr pex crdiogrphy ws performed ccording to the technique of Wyne nd Antni 3. ECG, crotid pulse trcing nd phonocrdiogrm were lso done (t 1 mm/sec) simultneously to otin non-invsive evlution of hemodynmics, glol LV function nd distolic function 2,3,4,5. Mechnocrdiogrphic recordings reflect the sudivisions of the crdic cycle nd the chnges in the pressure nd volumes in the ventriculr chmer 6. The recording technique is simple, esy to perform nd reproducile. With the ptient plced in the left lterl position, the chest piece of B-D stethoscope is strpped over the centre of the picl impulse nd connected through tue to trnsducer; nd led II of ECG is recorded for the timing purpose. The crotid pick-up is plced over the crotid rtery nd the contct microphone is strpped ner the pex. The oscilloscope is then interfced with multichnnel recorder to record the ACG, CPT nd phone. The clinicl sttus ws evluted every week for 12 weeks. During weekly follow-ups, the ptients were lso interrogted for side effects, if ny. In cse of ny deteriortion of crdic function, the ptient ws digitlised nd dropped from the tril. RESULTS Dt in Tle 1 show the effect of An nd diuretic on crdic function in ptients with chronic congestive crdic filure. The hert rte showed significnt increse fter 2 weeks of tretment with the diuretic. There ws rise in A wve mplitude nd durtion, which indictes left ventriculr distolic dysfunction. The exercise-induced ejection frction nd exercise time showed significnt reductions under the influence of diuretic therpy. The left ventriculr ejection frction showed significnt reductions under the influence of diuretic therpy. The left ventriculr ejection time showed deteriortion ut it did not rech the level of sttisticl significnce. No significnt chnge in doule product (DP) ws noticed. Tle 1: Effect of An on hert rte nd ventriculr function in ptients with congestive crdic filure Vlues: Men ± S.E. Prmeter Initil After 2 weeks After 12 weeks of tretment

3 (n=3) of diuretic therpy (n=3) Plceo + diuretic (n=15) An + diuretic (n=15) Hert rte/min ± ± ± ± 2.2 e A -wve mplitude % ± ±.94 c 2.46 ± ±1.34 e A -wve durtion ± ± 3.6 NS ± ± 4.98 NS (msec) LVEF (%) ± ± 1.15 c 36.4 ± ± 2.51 e Exercise-induced ± ± ± ± 3.19 e ejection frction Exercise time (secs) 96.4 ± ± 4.64 c 56.4 ± ± 1.81 e LVET (secs) ± ± 4.75 NS ± ± 9.22 NS DP (mm Hg/min.) ± ± ± ± d p<.5, p<.1 nd c p<.1 s compred to the initil redings; NS -Non-significnt; d p<.1 nd e p<.1 s compred to plceo. When the ptients were put on plceo long with the diuretic for 12 weeks, there ws further deteriortion of left ventriculr function. The LV ejection frction, exercise-induced ejection frction nd exercise time were further decresed nd there ws rise in the doule product. On the other hnd, tretment with An nd diuretic showed significnt improvement in ll the mechnoprmeters. The A wve mplitude nd durtion were decresed significntly, wheres LV totl Figure 2: Effect of An on hert rte nd ventriculr function in ptients with congestive crdic filure 12 p<.5 p<.1 c p<.1 1 d p<.1 e p< d Hert Rte (/min) Iitil vlue A -Wve Amplitude (%) Pl ceo + Diuretic compred (Tle 1). c e A -Wve Durtion (millisec) Exerci se-in duced ej ectio n frction Diuretic Alone An + Diuretic e Percentge for LVEF Seconds for Exercise Time Figure 1: Effect of An on Ventriculr function (LVEF nd exercise Time) in ptients with congestive crdic filure Initil After 2 weeks Exercise Time Left Ventriculr Ejection Time (LVET) Iitil vlue Plceo + Diuretic Ap<.1 p< After 12 weeks LVEF An + Diuretic Plceo + Diuretic An + Diuretic Plceo + Diuretic ejection frction, exercise-induced ejection frction nd the exercise time were significntly incresed fter 12 weeks of tretment (Figures 1 nd 2). There ws slight increse in left ventriculr ejection time with significnt reduction in the doule product (Figure 3). These improvements in mechnoprmeters indicte improved left ventriculr relxtion nd etter distolic filling, with fll in oth prelod nd fterlod under the influence of An. Tchycrdi ws converted into norml sinus rhythm under the influence of An (Tle 1). Significnt improvements in ll the mechnocrdiogrphic prmeters were oserved when twelve weeks of tretment with An nd plceo were These oservtions were well sustntited y significnt improvement in the NYHA criteri (Tle 2). At the time of entry into the tril, the ptients were either in stge II or III of NYHA, ut y the end of twelve weeks of tretment with the diuretic plus An there ws significnt improvement in symptoms; ptients improved from stge III nd II to stge I. On the other hnd, tretment with diuretic nd plceo rought out significnt deteriortion in symptoms (Figure 4). (milliseconds) Figure 3: Effect of An on LVET nd DP (mm Hg/minute) Doule Product (DP) Diuretic Alone p<.5 p<.1 An + Diuretic

4 Tle 2: Effect of An on New York Hert Assocition (NYHA) criteri in ptients suffering from congestive crdic filure Vlues: Men ± S.E. Prmeter Initil (n=3) After 2 weeks of diuretic therpy (n=3) NYHA Clss 2.13 ± ±.9 p<.1s compred to diuretic therpy p<.1 s compred to plceo. After 12 weeks of tretment Plceo + An + diuretic diuretic (n=15) (n=15) ±.16 ±.16 DISCUSSION The gols of tretment of ptients with congestive crdic Figure 4: Chnge in NYHA criteri efore nd fter tretment with An filure re to improve the qulity nd durtion of life, i.e. 3.5 survivl. The present tretment ims t reduction of the hert s p<.1 3. p<.1 worklod which involves oth pre-lod nd fter-lod, 2.5 improvement of the hert pumping performnce nd control of 2. excessive slt nd wter retention. Unfortuntely, the drugs 1.5 ville t present re ssocited with much toxicity nd side 1. effects which necessitte their withdrwl. Digitlis tretment,.5 for exmple, is ssocited with crdic toxicity mnifested y Initil After 2 Wks Plceo + An + (n=3) of Diuretic Diuritic Diuretic rrhythmis nd hert locks. Bet-drenergic ntgonists my Therpy (n=15) (n=15) (n=3) induce or excerte congestive hert filure in susceptile (After 12 weeks of Therpy) individuls. They decrese the force of myocrdil contrction therey precipitting the filure. An, complex, herominerl preprtion, hs shown its eneficil effects in severl experimentl nd clinicl studies. Our erlier study 8 hs shown the eneficil effects of An in hypertension, IHD, nd improvement in ventriculr function nd nginl sttus. An contins importnt ctive ingredients such s Terminli rjun with known positive inotropic ction 9, Ashwgndh with dptogenic ctivity 1 nd Punrnv 11 with diuretic ctivity, esides others. An reduces the sensitivity of the hert to drenergic stimultion. Gulti et l., 7 hve shown the An cuses down-regultion of et-drenergic receptors. This effect is prticulrly desirle in protecting the hert from excessive sympthetic stimultion during stress. An lso cuses n increse in the force of contrction of the hert y n independent mechnism. This is in mrked contrst to the reduced force of contrction cused y the usul et-receptor locking drugs. The present study ojectively demonstrtes the eneficil effect of An on crdic function in ptients with congestive crdic filure. There ws significnt improvement in pump function in ptients on An, compred with ptients receiving the diuretic plus plceo. The hert rte significntly improved fter An therpy, wheres ptients receiving plceo showed deteriortion. A -wve mplitude nd durtion reflect distolic function. Significnt reduction in pre-lod, s judged y reduction of A -wve percentge, ws recorded in ptients receiving An. An lso reduced the fter-lod without significntly ltering the hert rte. The left ventriculr ejection frction hd significntly improved fter An therpy. It is ovious from this study tht mrked deteriortion of crdic function ws noticed when Digoxin ws withdrwn from the ptients nd this continued up to 12 weeks of tretment with plceo nd diuretics. When An ws dded fter withdrwl of Digoxin nd fter two weeks of NYHA Clss

5 tretment with diuretic lone, mrked improvement in hert rte nd ventriculr function ws noticed. The vsodiltory, positive inotropic nd diuretic properties of the ingredients of An my hve een responsile for these desirle effects in congestive hert filure without ny clinicl or electrocrdiogrphic dverse effects. REFERENCES 1. Hurst, Willis, J. nd Schlnt, Roert C., Pthophysiology of hert filure. In: The Hert, 7 th Interntionl Edition, Chpter 26, (199): p Antni, J.A. nd Wyne, H.H., Ejection phse indices y invsive nd non-invsive methods: An pex crdiogrphic echocrdiogrphic nd ventriculogrphic correltive study. Amer. J. Crdiol. (1979): 43, Wyne, H.H., Non-invsive techniques in crdiology, 1 st ed. (Reprint), Yer Book Medicl Pulisher Inc., Chicgo (1979): p Benchimol, A., Study of period of isovolumic relxtion in norml sujects nd in ptients with hert disese. Amer. J. Crdiol. (1967): 19, Weissler, A.M. nd Grrd, C.L., Jr., Systolic time intervl in crdic disese. Mod. Conc. Crdiovsc. Dis. (197): 5, Antni, J.A., Mechnocrdiogrm permits evlution of coronry rtery disese nd myocrdil performnce. Medicl Times, Gulti, O.D., Psnni, J.S., Hemvthi, K.G. nd Rjni, A.P., Effects of An, n Ayurvedic preprtion, on rit trium nd intestine. J. Ethnophrmcol. (1988): 24, Antni, J.A., Kulkrni, R.D. nd Antni, N.J., Effect of An on ventriculr function in ischemic hert disese. Jp. Hert J. (199): 31, Dwivedi, S., Somni, P.N. nd Udup, K.N., Crdioprotective effects of certin indigenous drugs in myocrdil ischemi in rits. Ind. J. Exp. Biol. (1988): 26, Bhrgv, K.P. nd Singh, N., Antistress ctivity in Indin medicinl plnts. J. Res. Edu. Ind. Med. (1985): 4, Mudgl, V., Comprtive studies on the nti-inflmmtory nd diuretic ction with different prts of the plnt Boerhvi diffus, Linn. (Punrnv). J. Res. Edu. Ind. Med. (1974): 9, 2.