ventricular pressure in the dog, and they concluded contractility by the anesthetic agents and the surgical

Transcription

1 Jurnal f Clinical Investigatin Vl. 42, N. 7, 1963 STUDIES ON DIGITALIS. IX. EFFECTS OF OUABAIN ON THE NONFAILING HUMAN HEART By DEAN T. MASON AND EUGENE BRAUNWALD (Frnt the Cardilgy Brantch, Natinal Heart Institute, Bethesda, Md.) (Submitted fr publicatin December 31, 1962; accepted March 21, 1963) In spite f the widespread use f digitalis in clinical medicine and the extensive experimental wrk that has been carried ut with this drug, its actin n the nnfailing human heart still requires clarificatin. A variety f experiments n penchest, presumably nrmal, anesthetized dgs has clearly shwn that digitalis glycsides have a psitive intrpic actin (1-4). The applicability f these bservatins t the nrmal heart in intact human subjects is limited because the pssibility cannt be excluded that depressin f mycardial cntractility by the anesthetic agents and the surgical expsure f the heart mdified the respnse t the digitalis glycside in the animal experiments. Hemdynamic studies in subjects with nrmal hearts and in patients with heart disease withut cngestive heart failure have suggested that digitalis des nt imprve mycardial cntractility, and may even have a depressing effect, since its administratin results either in n change in the cardiac utput, r in a decline (5-9). It is nw clear that measurement f the cardiac utput alne des nt necessarily prvide an assessment f ventricular cntractility (10). The unavailability, in the past, f a reliable methd fr studying cntractility in the hearts f intact human subjects has been respnsible fr the lack f infrmatin cncerning the crucial questin f hw digitalis affects the nrmal, r the diseased but nnfailing human heart. Recently, Sarnff and Mitchell have defined mycardial cntractility as fllws: "When frm any given end-diastlic pressure r fiber length, the ventricle prduces mre external strke wrk and mre external strke pwer, an increase in ventricular cntractility is said t have taken place. Implicit in this definitin is an increased rate f develpment f tensin when cntractility increases" (11). Rushmer has als fund that an increased ventricular cntractility is reflected bvy an increase in the peak rate f develpment f intraventricular pressure (12). The bservatins f these and ther investigatrs (1, 4, 13-19) are all cmpatible with the view that the rate at which ventricular pressure rises during ismetric cntractin is determined by the cntractile state f the mycardium and by the cnditins under which the ventricle cntracts, i.e., the ventricular enddiastlic pressure, arterial pressure, and heart rate. In 1927, Wiggers and Stimsn demnstrated that digitalis resulted in a mre rapid rise f left ventricular pressure in the dg, and they cncluded that, like epinephrine, the glycsides imprve mycardial cntractin (1, 16). Measurement f the instantaneus rate f rise f intraventricular pressure in man has been fraught with 1105 cnsiderable difficulty because f the serius artifacts in the pressure tracings btained at cardiac catheterizatin by the standard catheter-manmeter systems. The recent develpment f a cardiac catheter with a high-fidelity micrmanmeter munted at its tip (20), hwever, has largely slved this prblem, since it is nw pssible with this instrument t recrd intraventricular pressure pulses faithfully and withut significant distrtin. In a previus cmmunicatin frm this labratry, the use f the cntinuusly cmputed rate f change f intraventricular pressure in assessing the functinal status f the heart in man was presented (21). The bjective f the present investigatin was t apply this technic in the determinatin f the effects f a cardiac glycside, uabain, n the nrmal and n the diseased but nnfailing human ventricle. SUBJECTS AND METHODS The effects f uabain were determined in a ttal f ten patients wh ranged in age between 14 and 45 years. The rate f change (dp/dt) in the right ventricular pressure pulse was studied in six patients after detailed clinical examinatin, as well as right and left heart catheterizatin, had been carried ut. Fur f these subjects, wh were referred because f precrdial systlic mur-

2 106 DEAN T. MASON AND EUGENE BRAUNWALD murs, were cnsidered t have nrmal cardivascular systems. One patient, W.A., was studied 1 year fllwing successful clsure f an atrial septal defect, and the clinical and hemdynamic studies did nt reveal any abnrmalities. The sixth patient, R.B., had a small crnary arterivenus fistula emptying int the pulmnary artery. The pressures in the right side f the heart were within nrmal limits. There was n cardiac enlargement r diminished cardiac reserve, and the shunt int the pulmnary artery was s small that it culd nt be detected by the inhaled Kr" test (22) r by selective angicardigraphy. The effects f uabain n the dp/dt f the left ventricular pressure pulse was determined in fur patients wh had uncmplicated stium secundum atrial septal defects; the presence f the interatrial cmmunicatin permitted passage f the catheter int the left ventricle. Nne f these fur patients had ever experienced cngestive heart failure. Althugh they did nt have nrmal hearts, their left ventricular end-diastlic pressures were within nrmal limits (23), and their atrial septal defects were nt cnsidered t have placed an abnrmal hemdynamic burden n their left ventricles. All studies were perfrmed with the patient in the basal, pstabsrptive state. After placement f the catheter int the ventricle, 15 minutes were permitted t elapse fr the patient t reach a stable state. Three cntrl measurements f intraventricular pressures and the dp/dt f the right (r left) ventricular pressure pulse were then made at 5-minute intervals. Ouabain, 0.30 mg t 0.60 mg, representing dses ranging between.0076 mg per kg and.0126 mg per kg (average =.0096 mg per kg), was then infused thrugh the cardiac catheter ver a 10-minute perid. Measurements f ventricular pressure and dp/dt f the right (r left) ventricular pressure pulse were carried ut at 5-minute intervals fr the next 60 minutes. The methds f recrding intraventricular pressure and dp/dt have been presented in detail previusly (21). Briefly, a Telc intracardiac micrmanmeter was emplyed. This manmeter has been shwn t maintain a unifrm respnse t frequencies as high as 200 cycles per secnd (21). The dp/dt f ventricular pressure was cntinuusly determined with an R-C differentiating circuit having a time cnstant f 9.4 X 10' secnds, which prvided differentiatin f linear amplitude withut phase distrtin t 50 cycles per secnd (24). RESULTS TABLE I Circulatry effects f uabain* The results are presented in Table I. The means f the three values f the peak dp/dt de- Intensificatin Vent. Vent. f pre- Ouabain Cndi- peak Heart press. systlic Patient Age Weight Diagnsis dse tin dp/dt rate s/d dp/dt yrs kg mg mm Hg beats! mm Hg sec min Right ventricle J.B Nrmal 0.3 C / /2 M.P Nrmal 0.6 C /3 18/3 + J.M Nrmal 0.6 C /6 27/6 + W.B Nrmal 0.5 C /2 18/2 W.A POASD 0.4 C /4 30/4 R.B Cr. A-V fist. 0.5 C /3 20/3 Average C /3 23/3 Left ventricle V.Z ASD 0.6 C / /6 + L.F ASD 0.6 C 755 1, /4 114/4 R.N ASD 0.6 C 1,005 1, /3 104/3 R.M ASD 0.6 C /7 120/3 Average C 781 1, /5 109/4 *Abbreviatins: dp/dt =rate f change; vent. press. =ventricular pressure; s/d = systlic/diastlic; C =cntrl bservatin befre uabain; 0 = bservatin after uabain; + indicates intensificatin f presystlic dp/dt; - indicates n intensificatin f presystlic dp/dt; POASD = pstperative atrial septal defect; Cr. A-V Fist. = small crnary arterivenus fistula; ASD = atrial septal defect.

3 termined during the cntrl perid are shwn. There was little variatin amng these three values recrded in any given subject befre the infusin f uabain; the average deviatin f the single measurements frm the patient's mean value ranged frm 0 t 6.6% and averaged 2.0% f the mean value in the ten patients studied. In the six patients in whm the effects f bain n the right ventricular peak dp/dt were determined, the average values fr this variable during the cntrl perid ranged between 140 mm sc,., E O t 0~~~~~~~~~~~~~~ EFFECTS OF OUABAIN ON THE NONFAILING HUMAN HEART ua- E_ Y9 LO An every pa- The maximal value 30 ui 20.I _ PRESSURE IN PATIENT J.B. Hg per secnd and 291 mm Hg per secnd. increase in the peak dp/dt ccurred in tient, and the effect was usually appreciable by 10 minutes after the nset f injectin. The maximal increases were nted between 25 and 60 minutes (average = 42 minutes) fllwing the nset f the injectin f the drug. fr the peak dp/dt exceeded the average f the cntrl values by between 19 mm Hg per secnd and 177 mm Hg per secnd, an increase that averaged 63 mm Hg per secnd in the six subjects. Expressed as a percentage, the maximal value fr the peak dp/dt exceeded the average f the cntrl values by between 9.9 and 75.3%, an increase that averaged 31.5% f the cntrl values in the six subjects. The changes in the peak dp/dt fllwing the administratin f uabain t ne f these patients, J.B., are illustrated in Figure 1. In the fur patients in whm the effects f uabain n the left ventricular peak dp/dt were studied, the average f the peak values fr this variable during the cntrl perid ranged between 677 mm Hg per secnd and 1,005 mm Hg per secnd. An increase in the peak dp/dt ccurred in every patient and became maximal between 20 and 50 minutes (average = 33 minutes) fllwing the nset f the injectin f the drug. The maximal dp/dt exceeded the average f the cntrl values by between 180 mm Hg per secnd and 490 mm Hg per secnd (average = 277 mm Hg per secnd). Expressed as a percentage, the maximal peak dp/dt exceeded the average f the cntrl values by between 26.3 and 48.8% (average = 35.5%). The recrding f dp/dt befre and after uabain in ne f these patients, R.N., is illustrated in Figure 2. In five f the ten patients, a small presystlic elevatin f the ventricular dp/dt either became = TIME (MINUTES) FIG. 1. SEQUENTIAL MEASUREMENTS OF THE PEAK RATE OF CHANGE (dp/dt) OF RIGHT VENTRICULAR (RV) mre prminent fllwing uabain (Figure 3) r appeared fr the first time (Figure 4). These deflectins, which fllwed the P wave f the electrcardigram and ccurred during atrial cntractin, were fllwed by a return f the dp/dt t 0 befre its majr elevatin during ventricular cntractin. These deflectins were t small t be measured with accuracy. DISCUSSION During the past several years, increasing evidence has been btained which suggests that digitalis may exert a psitive intrpic effect n the nrmal and the diseased but nnfailing human heart. Weissler and Grde (25) and Weissler and Warren (26) have reprted that cardiac glycsides shrten the duratin f mechanical systle, as determined frm the phncardigram. In patients with heart disease but withut heart failure underging cardiac peratins, it has been

4 1108 DEAN T. MASON AND EUGENE BRAUNWALD RN. # CONTROL OUABAIN 0.6 mg mm. Hg/sec mm.hg/sec. j , f-1500 dp/dt mme dp/dt mm Hg/Sc H/Sl0 l500 LV 0. ~~~~~~~~mm Ḷ0 Hg EKG i 0 FIG. 2. RECORDINGS OF LEFT VENTRICULAR (LV) PRESSURE AND RATE OF CHANGE (dp/dt) BEFORE AND 30 MINUTES AFTER OUABAIN ADMINISTRATION. shwn that cardiac glycsides augment the frce arch was sewn t a segment f mycardium that f cntractin, as measured with a mycardial was stretched by apprximately 50% f its resting strain-gauge arch (27). Since the strain-gauge length, the reactins f the mycardial segment CONTROL RV J.M. # mm.hg/sec. / dp/dt 100- Hg/sec. 0 EKG 200 RVI dp/dt 100 OUABAIN 0.6 mg. Hg/sec. 0 / ~~~~~~~~a I76mmHg/sea EKG FIG. 3. RECORDING OF FIRST DERIVATIVE (dp/dt) OF RIGHT VENTRICULAR (RV) PRESSURE PULSE DURING CONTROL PERIOD (TOP) AND 25 MINUTES AFTER OUABAIN AD- MINISTRATION (BOTTOM). Letter a indicates the presystlic augmentatin f the dp/i dt during atrial systle, which became mre prminent after uabain.

5 EFFECTS OF OUABAIN ON THE NONFAILING HUMAN HEART might nt be representative f the reactin f the remainder f the ventricle. Furthermre, since the studies were carried ut in patients with heart disease, under the cnditins f general anesthesia with the chest and pericardium pened during ttal cardipulmnary bypass and with the heart empty, the direct applicability f these bservatins t the unanesthetized intact patient was, f necessity, limited. The demnstratin that digxin diminished the ttal pstexercise xygen debt f patients with heart disease but withut heart failure suggested the pssibility that digitalis may be helpful in the clinical management f sme f these patients (28). This study, hwever, als did nt reslve the questin f whether r nt digitalis stimulates the nrmal r near nrmal heart f intact, unanesthetized individuals. Accrdingly, the present investigatin was undertaken. In every patient, an increase in the rate f intraventricular pressure develpment (peak dp/dt) was nted, and this finding is interpreted t indicate that the glycside exhibited a psitive intrpic effect. It is nw clearly appreciated that hemdynamic influences, besides the functinal state f the mycardium, can affect the peak dp/dt (4). These influences are the heart rate, the ventricular end-diastlic pressure and vlume, and the arterial diastlic pressure. Measurement f the peak dp/dt, hwever, is particularly suited fr assessing the intrpic actins f digitalis in nnfailing hearts, since this drug des nt appreciably alter these variables. Indeed, the slight slwing f the heart rate that ccurred in five f the ten subjects wuld, by itself, tend t diminish the peak dp/dt. Ventricular end-diastlic pressures remained unchanged after uabain. Ventricular end-diastlic vlume, hwever, was nt measured, and a change in this variable resulting frm an alteratin f ventricular cmpliance induced by uabain cannt be cmpletely excluded. The diastlic pressures in the pulmnary artery and the arta were nt measured in this investigatin. Hwever, the effects f acute digitalizatin n these pressures in patients withut heart failure have been reprted by a number f investigatrs (7, 29-32), and n cnsistent changes have been bserved. Althugh systlic systemic arterial pressure usually rises, the diastlic pressure shws little alteratin, presumably because f the cn- CONTROL mm Hg/sec. LV 750- dp/dt 500- L mm 2500 Hg/sec EKG LV75 mm Hg OUABAIN 06 mg. 780mm.Hg/sec. LV 750- dp/dt mm Hg/sec LV mm.h EKG FIG. 4. SIMULTANEOUS RECORDINGS OF LEFT VENTRICU- LAR (LV) PRESSURE AND OF LEFT VENTRICULAR RATE OF CHANGE (dp/dt) DURING CONTROL PERIOD (TOP) AND AFTER OUABAIN ADMINISTRATION (BOTTOM). The presystlic augmentatin f ventricular pressure, a, is barely perceptible befre uabain, but becmes clearly evident in the tracings recrded 35 minutes after the administratin f the drug. cmitant slwing f heart rate. Fr the reasns utlined abve, it is felt that the large and cnsistent elevatins f the peak dp/dt that were bserved in every patient can be attributed principally t a direct stimulating effect f uabain n ventricular cntractin. The develpment r intensificatin f a small, psitive ventricular dp/dt during atrial systle in sme patients suggests the pssibility that this drug als stimulates the frce f atrial cntractin, resulting in a mre rapid rise f intraventricular pressure during atrial systle. SUMMARY 1109 In fur patients withut heart disease and in tw patients with minimal cardiac abnrmalities and nrmal right ventricular functin, 0.30 t 0.60 mg uabain elevated the right ventricular peak rate f change (dp/dt) by 9.9 t 75.3%' (average = 31.5%) f cntrl values. In fur patients

6 1110 with uncmplicated atrial septal defects, in whm the left ventricular hemdynamic burden and left ventricular functin were nrmal, 0.60 mg uabain elevated the left ventricular peak dp/dt by 26.3 t 48.8% (average = 35.5%) f cntrl values. These bservatins in intact, unanesthetized subjects indicate that uabain is capable f stimulating the cntractility f the nnfailing and f the nrmal human heart. REFERENCES 1. Wiggers, C. J., and B. Stimsn. Studies n cardidynamic actins f drugs. III. Mechanism f cardiac stimulatin by digitalis and g-strphanthin. J. Pharmacl. exp. Ther. 1927, 30, Waltn, R. P., J. S. Leary, and H. P. Jnes. Cmparative increase in ventricular cntractile frce prduced by several cardiac glycsides. J. Pharmacl. exp. Ther. 1950, 98, Ctten, M. dev., and P. E. Stpp. Actin f digitalis n the nnfailing heart f the dg. Amer. J. Physil. 1958, 192, Wallace, A. G., N. S. Skinner, and J. H. Mitchell. Hemdynamic determinants f the maximal rate f rise f left ventricular pressure. Amer. J. Physil. In press. 5. Burwell, C. S., DeW. Neighbrs, and E. M. Regen. The effect f digitalis upn the utput f the heart in nrmal man. J. clin. Invest. 1927, 5, Stewart, H. J., and A. E. Chn. Studies n the effect f the actin f digitalis n the utput f bld frm the heart. III. J. clin. Invest. 1932, 11, Harvey, R. M., M. I. Ferrer, R. T. Cathcart, and J. K. Alexander. Sme effects f digxin n the heart and circulatin in man; digxin in enlarged hearts nt in clinical cngestive failure. Circulatin 1951, 4, Rdman, T., C. A. Grcxyca, and B. H. Pastr. The effect f digitalis n the cardiac utput f the nrmal heart at rest and during exercise. Ann. intern. Med. 1961, 55, Gdyer, A. V. N., A. Chetrick, and A. Huvs. The effect f Lanatside-C n the respnse f the human cardiac utput t walking exercise. Yale J. Bil. Med. 1960, 32, Sarnff, S. J., and E. Berglund. Ventricular functin: I. Starling's law f the heart studied by means f simultaneus right and left ventricular functin curves in the dg. Circulatin 1954, 9, Sarnff, S. J., and J. H. Mitchell. The cntrl f the functin f the heart in Handbk f Physilgy, Sectin 2: Circulatin. Washingtn, D. C., American Physilgical Sciety, 1962, p Rushmer, R. F. Effects f nerve stimulatin and hrmnes n the heart; the rle f the heart in DEAN T. MASON AND EUGENE BRAUNWALD general circulatry regulatin in Handbk f Physilgy, Sectin 2: Circulatin. Washingtn, D. C., American Physilgical Sciety, 1962, p Frank, 0. On the dynamics f cardiac muscle. Amer. Heart J. 1959, 58, Pattersn, S. W., H. Piper, and E. H. Starling. The regulatin f the heart beat. J. Physil. (Lnd.) 1914, 48, Wiggers, C. J. Studies n the cardidynamic actins f drugs. I. The applicatin f the ptical methds f pressure registratin in the study f cardiac stimulants and depressants. J. Pharmacl. exp. Ther. 1927, 30, Wiggers, C. J. Studies n the cardidynamic actins f drugs. II. The mechanism f cardiac stimulatin by epinephrin. J. Pharmacl. exp. Ther. 1927, 30, Reeves, T. J., L. L. Hefner, W. B. Jnes, C. Cghlan, G. Priet, and J. Carrll. The hemdynamic determinants f the rate f change in pressure in the left ventricle during ismetric cntractin. Amer. Heart J. 1960, 60, Siegel, J. H., and E. H. Snnenblick. A dynamic index characterizing alteratins in the basic state f cardiac muscle. Circulat. Res. In press. 19. Tlman, R. A., and P. G. Yung. Slpe changes f ventricular pressure curves cmpared with ventricular functin curves. Fed. Prc. 1961, 20, Laurens, P., P. Buchard, E. Brial, C. Crnu, P. Basculard, and P. Sulie. Bruits et pressins cardi-vasculaires enregistres in situ 'a l'aide d'un micrmanmetre. Arch. Mal. Ceur 1959, 52, Gleasn, W. L., and E. Braunwald. Studies n the first derivative f the ventricular pressure pulse in man. J. clin. Invest. 1962, 41, Braunwald, E., A. Gldblatt, R. T. L. Lng, and A. G. Mrrw. The kryptn8" inhalatin test fr,the detectin f left-t-right shunts. Brit. Heart J. 1962, 24, Braunwald, E., E. C. Brckenbrugh, C. J. Frahm, and J. Rss, Jr. Left atrial and left ventricular pressures in subjects withut cardivascular disease: bservatins in eighteen patients studied by transseptal left heart catheterizatin. Circulatin 1961, 24, Nble, F. W. Electrical Methds f Bld-pressure Recrdings. Springfield, Ill., C. C Thmas, 1953, p Weissler, A. M., and H. E. Grde. New bservatins n the effects f digitalis n ventricular systle in nrmal individuals (abstract). Clin. Res , Weissler, A. M., and J. V. Warren. Digitalizatin: an evaluatin f the dse-respnse curve f deslanside in man (abstract). Circulatin 1962, 26, Braunwald, E., R. D. Bldwell, L. I. Gldberg, and A. G. Mrrw. Studies n digitalis. IV. Obser-

7 EFFECTS OF OUABAIN ON THE NONFAILING HUMAN HEART 1111 vatins in man n the effects f digitalis preparatins n the cntractility f the nn-failing heart and n ttal vascular resistance. J. dlin. Invest. 1961, 40, Kahler, R. L., R. H. Thmpsn, E. R. Buskirk, R. L. Frye, and E. Braunwald. Studies n digitalis VI: reductin f the pst-exercise xygen debt with digxin in patients with cardiac disease withut heart failure. Circulatin 1962, 27, Selzer, A., H. N. Hultgren, C. L. Ebnther, H. W. Bradley, and A. 0. Stne. Effect f digxin n the circulatin in nrmal man. Brit. Heart J. 1959, 21, Williams, M. H., Jr., L. R. Zhman, and A. C. Ratner. Hemdynamic effects f cardiac glycsides n nrmal human subjects during rest and exercise. J. appl. Physil. 1958, 13, Dresdale, D. T., Y. Z. Yuceglu, R. J. Michtm, M. Schultz, and M. Lunger. Effects f Lanatside C n cardivascular hemdynamics; acute digitalizing dses in subjects with nrmal hearts and with heart disease withut failure. Amer. J. Cardil. 1959, 4, Selzer, A., and R. 0. Malmbrg. Hemdynamic effects f digxin in latent cardiac failure. Circulatin 1962, 25, 695.