Kinetocardiogram, Phonocardiogram, and Arterial Pulse Waves During Acute Hemodynamic Changes By Rosert C. Dappario, M.D., anp Epwarp D. Freis, M.D. HERE is currently a need for simple, atraumatic methods of assessing cardio- vascular status. The kinetocardiogram (KCG) and external recordings of arterial pulse waves represent possible approaches which have not yet been adequately explored. Both techniques have been applied in various cardiovascular disorders, but little information has been ob- tained on the effects of acute alterations in hemodynamics. Since it is possible to force the circulation in known directions by the ad- ministration of vasoactive drugs with specific hemodynamic actions, it seemed worthwhile to assess the effects of such acute changes on the KCG, carotid pulse contour, and the speed of transmission of the central arterial pulse wave. Such observations on the effects of known changes in hemodynamics should help clarify the interpretation of KCG and arterial pulse-wave tracings. Part I: The Kinetocardiogram Methods The subjects consisted of 28 males who were either normal volunteers or patients without car- diovascular disease, selected from the wards of the Veterans Administration Hospital. No pa- tients were acutely ill and none were suffering from chronic debilitating diseases. The subjects ranged in age from 25 to 48 years with a mean age of 37.4 years. Each received one to three drugs during the recording session. When more than one drug was used in the same subject, the short acting agents, such as amyl nitrite and angiotensin IJ, were given first and then sufficient From the Veterans Administration Hospital and the Department of Medicine, Georgetown University School of Medicine, Washington, District of Colum- bia. This study was done while Dr. Daddario was a trainee under a grant from the National Heart In- stitute, U. S. Public Health Service. Circulation, Volume XXXIV, September 1966 423 time was allowed for return of the KCG, pulse wave recordings, and blood pressure to control values before the next agent was administered. The kinetocardiograms were recorded accord- ing to the method of Eddleman? using two pick- ups, one in the K, and the other in the Ky posi- tion. These are similar in location to the electrode placements V, and V, of the standard 12-lead electrocardiogram. Lead I of the electrocardio- gram was used as a time reference. Recordings were made simultaneously through Sanborn am- plifiers and a direct writing multichannel oscillo- graph at a paper speed of 100 mm/sec. Blood pressure was measured in the upper extremity by the auscultatory method. Following the control tracings, various vaso- active drugs were administered. Synthetic angio- tensin II or methoxamine were used to increase total peripheral vascular resistance. Amyl nitrite or isoproterenol was administered to decrease total peripheral resistance and increase cardiac output and also myocardial contractility. Hex- amethonium was given to decrease myocardial contractility, cardiac output, and arterial pres- sure. All drugs except amyl nitrite (which was given by inhalation) were administered by slow intravenous infusion after dilution in 5% dex- trose solution. The infusion rates were regulated to obtain a significant change in arterial pres- sure as determined by frequent monitoring. Both the amplitude and the duration of the various components of the KCG were measured and expressed respectively as percentages of total cycle amplitude and cycle length. Changes were determined as differences in these percentages between the control and post-drug periods. Sta- tistical analysis of the changes following admin- istration of the various drugs was carried out by the signed ranks method.? Results Increased Left Ventricular Pressure Load Angiotensin II and methoxamine increase tota] peripheral resistance without an increase in cardiac output.3 They were used to impose an acute pressure Joad on the left ventricle. Despite considerable elevations of both sys- tolic and diastolic blood pressures, averaging DADDARIO, FREIS 424 Table 1 Changes in Precordial Movements Following Vasoactive Drugs Expressed as Per Cent of Cycle Amplitude Mean Ka No. of B.P. H.R. Right ventricular Drugs Subjs. change change movement* Systolic-retraction Mean No. No. Mean No. No. No. Sys. Dias. %o %) incr. decr. P (%) incr. decr. unch. P Angiotensin II 9 +47 +42, —18.9 +10.3 6 1 <0.05 —115 3 6 0 ns Methoxamine 9 434 +27 —26.1 — 88 3 6 ns + 3.0 6 3 0 ns Amy] nitrite 13t —27 ~-29 +445 + 1.0 4 6 ns + 4.0 6 3 1 ns Isoproterenol 14 +14 —35 +61.2 + 8.0 7 4 ms + 5.1 9 5 0 ns Hexamethonium 7 -i7 —22 +17.9 — 18 4 3 ns +17.0 5 2 0 ns *Not present in all subjects. +K, not obtained in three subjects after amyl nitrite. 47/42 mm Hg in nine subjects receiving angiotensin II, and 34/27 mm Hg in a similar number given methoxamine, there were no significant changes in the amplitudes of either the pre-ejection movement or the left ventricular thrust as recorded in the Ky position (table 1). The duration of the thrust was also essentially unchanged when ex- pressed as a percentage of the cycle length. The systolic retraction which occurs during left ventricular ejection fell significantly after both drugs (table I, figs. 1 and 2). The mean change was a reduction in systolic retraction of 13.9% (P <0.05) of the total cycle ampli- tude following angiotensin II, and 18.3% (P=0.01) after methoxamine. The right ventricular outward movement which preceded ventricular ejection as re- corded in the Ky position increased slightly during angiotensin IJ infusion (mean + 10.3, P <0.05) but showed no definite trend during methoxamine infusion. Systolic retraction de- creased in the K, position after angiotensin H, but the change was not significant. It remained essentially unchanged after methoxamine. Atrial waves were recorded in the K, position in five subjects receiving angiotensin II. The atrial wave increased in three subjects and decreased in two, the average change being + 8.3% of the total cycle amplitude. Atrial waves were present in three subjects who were given methoxamine. Two subjects had increased atrial waves and one had decreased atrial waves, the average change being + 4.3%. The changes in the atrial wave after either agent were not significant. The durations of CONTROL | "ANGIOTENSIN ECG HEART SOUNDS Kl K4 CAROTID FEMORAL Figure 1 Simultaneous records of lead I of the electrocardio- gram, heart sounds, K, and K, positions of the kineto- cardiogram, and carotid and femoral pulse waves before and after raising the arterial pressure with infracenous infusion of angiotensin II. Paper spced was 100 mm/sec. Left ventricular thrust is indicated by the letter T. The systolic retraction wave following the thrust has disappeared after angiotensin I. The duration of the thrust is not increased as a percentage of cycle length, and the amplitude is unchanged. Circulation, Volume XXXIV, September 1966 ACUTE HEMODYNAMIC CHANGES 425 Ke Pre-ejection Left ventricular Systolic movement* thrust retraction Mean No. No. No. Mean No. No. Mean No. No. No. (%) incr. decr. unch. P (%) incr. decr. P C%) incr. decr. unch. P + 55 5 4 0 ns + 2.0 5 4 ns —13.9 1 7 1 < 0.05 — 2.3 4 2 0 ns + 0.6 4 5 ns —18.3 0 1 == 0.01 + 9.5 5 4 2 ns —29.3 1 12 <0.01 +25.2 Il 2 0 < 0.01 +14.0 7 2 0 ns “_ 98.2 3 11 = 0.01 +30.9 12 1 1 < 0.01 —14.8 0 3 1 ns —11.4 3 4 ns +29.2 6 1 0 < 0.05 either the atrial wave or the right ventricular movement were essentially unchanged. Increased Cardiac Output with Decreased Pressure Load Both amy! nitrite* and isoproterenol increase cardiac output and diminish total peripheral resistance. The increase in output is due primarily to increased heart rate rather than CONTROL ME THOXAMINE ECG HEART jo SOUNDS 4S K4 CAROTID : FEMORAL Figure 2 Records showing increase in P/F and I/F ratios of the carotid pulse (see text) during elevation of arterial pressure with methoxamine. Carotid-femoral trans- mission time difference decreased form 82 to 66 msec. Other notations as in figure 1. Circulation, Volume XXXIV, Septenber 1966 to stroke volume. The ventricular stimulation produced by amy] nitrite is probably reflex in origin secondary to the diminished arterial pressure whereas isoproterenol has a direct inotropic effect on the heart. The mean de- crease in arterial pressure following amyl ni- trite inhalation was 27/29 mm Hg. After isoproterenol, systolic pressure increased by an average of 14 mm Hg while diastolic pressure decreased by 35 mm Hg. Eleven of 13 subjects receiving amyl nitrite and nine of 14 subjects who were given isoproterenol exhibited pre-ejection move- ments in the records taken in the K, position. In the amyl nitrite group there was no sig- nificant change in amplitude of this deflection, five increased, four decreased, and two exhibited no change (table 1). In the nine subjects receiving isoproterenol, seven in- creased and two decreased, the mean change being + 14.08 (P<01) of the total cycle amplitude. The amplitude of the left ventricular thrust decreased significantly following both drugs. The mean reduction after amy! nitrite was 29.3% (P<0.01), and after isoproterenol it was 28.2% (P=0.01). The duration of the thrust expressed as a percentage of the cycle length shortened slightly after both drugs, but these changes were not significant. Fol- lowing amyl nitrite, the mean decrease was 2.0% of the total cycle length with 11 of the 13 subjects showing this response. In the 14 patients receiving isoproterenol, seven showed a decrease in duration, four an increase, and 426 three remained unchanged, the mean change being — 1.2% of the total cycle amplitude. The degree of systolic retraction during the left ventricular ejection phase of the cardiac cycle, as recorded in the K, position, increased (table 1, figs. 3 and 4). The increase in negative deflection averaged 25.2% (P <0.01) after amyl nitrite inhalation, and 30.9% (P<0.01) in the subjects receiving isopro- terenol. There were no significant changes in the recordings taken from the K, position following either amy] nitrite or isoproterenol. Decreased Left Ventricular Pressure Load and Output Hexamethonium lowers arterial pressure pri- marily by reducing cardiac output, the total peripheral resistance remaining essentially un- __GONTROL AMYL_ NITRITE ECG HEART SOUNDS Ki K4 GAROTID FEMORAL K Figure 3 Recordings before and after reduction of blood pres- sure with amyl nitrite showing increase in systolic re- traction and decrease in magnitude of left ventricular thrust in the K, position recording of the KCG. Other notations as in figure 1. DADDARIO, FREIS CONTROL ISOPROTERENOL _ ECG HEART SOUNDS KI K4 CAROTID Figure 4 Records showing disappearance of P maximum and reduction in I/F ratio of the carotid pulse wave fol- lowing infusion of isoproterenol. Other notations as in figure 1. altered. The only significant change in the KCG following hexamethonium was an in- creased systolic retraction in the K, position (table 1, fig. 5). The mean value for the amplitude of the left ventricular thrust de- creased 11.4%, but the response was too vari- able in the different subjects to be regarded as significant. Discussion The KCG abnormalities characteristically associated with chronic left ventricular over- load, as seen in patients with aortic valvular disease or hypertension, have been described by Davie and associates.* These changes con- sisted of an increase in the magnitude and duration of the left ventricular thrust recorded in the K, position. Davie and associates were unable to differentiate between the possible effects of hypertrophy, dilatation, or increase in work of the left ventricle as a cause of these abnormalities. In the present study acute Jeft ventyicular overloads were imposed by clevating total Circulation, Volume XXXIV, September 1966 ACUTE HEMODYNAMIC CHANGES CONTROL HEXAME THONIUM EGG HEART SOUNDS KI K4 CAROTID FEMORAL Figure 5 Records showing reduction in P/F and I/F ratios of the carotid pulse wave during reduction of arterial pressure after infusion of hexamethonium. Carotid- femoral transmission time increased from 68 to 76 msec. Other notations as in figure 1. peripheral resistance with angiotensin II or methoxamine. No significant changes were noted in cither the magnitude or duration of the Jeft ventricular thrust. The pre-ejection movement was similarly unaffected. These results are in contrast to the changes found by Davie and associates’ in patients with chronic overloads. This suggests that in pa- tients with long-standing hypertension and aortic valvular disease the increase in both amplitude and duration of the thrust is related not so much to the magnitude of the Joad but more specifically to its chronicity. The principal difference in the adjustment of the ventricle to a chronically imposed load as contrasted to an acutely imposed load is myocardial hypertrophy. Davie and associates™ did not find a significant correlation hetween the degree of thrust abnormality and cardio- megaly as determined by x-ray. However, it is well known that ventricular hypertrophy Circulation, Volume XXXIV, September 1966 427 in the absence of dilatation often cannot be detected in the x-ray. On the other hand, reduction in arterial pressure with amyl nitrite and isoproterenol resulted in a significant decrease in the mag- nitude of the left ventricular thrust and a slight but insignificant shortening of its thrust, each expressed as a percentage of the total cycle amplitude and duration, respectively. Hexamethonium resulted in a reduction in the magnitude of the ventricular thrust in some patients, but the responses were too variable to be regarded as significant. These results indicate that the magnitude of the thrust is relatively independent of increases in left ventricular load although reduction in pressure load may reduce the percentage magnitude but not the percentage duration of the thrust. In contrast, the changes in systolic retraction as a percentage of total cycle amplitude were consistent and significant with all of the acutely imposed alterations in left ventricular load. Systolic retraction decreased after angio- tensin IT and methoxamine and _ increased after amyl nitrite, isoproterenol, and hexa- methonium. Thus, the changes in systolic retraction were inversely related to the pres- sure loads imposed on the left ventricle. Since systolic retraction is an inward movement of the chest wall occurring during the period of ventricular ejection, it is proba- bly a reflection of the decrease in ventricular volume occurring during the phase of rapid ventricular ejection. An acute increase in the pressure load with angiotensin II reduces left ventricular emptying thereby increasing the end-diastolic volume of the ventricle.2 When ventricular volume is expanded, Jess shorten- ing of ventricular diameter will be required to expel a given stroke volume than when ventricular volume is reduced. If this inter- pretation is correct, the magnitude of the downstroke beginning at the peak of the thrust and ending at the completion of the systolic retraction wave should provide an indication of the approximate percentage change in left ventricular volume during the period of rapid left ventricular ejection. This suggestion obviously needs to be investigated under a 428 wide variety of clinical and experimental conditions before it can be accepted. ~ Summary A variety of vasoactive drugs were employed to produce acute hemodynamic alterations and their effects were determined on the kineto- cardiogram. The most consistent alteration was a change in the systolic retraction wave recorded at the Ks or apex region. Imposition of a left ventricular overload using angiotensin Il or methoxamine decreased the amplitude of the wave expressed as a percentage of the total cycle amplitude. Reduction of left ventricular pressure load, by using amyl nitrite, isoproterenol, or hexamethonium in- creased the degree of systolic retraction. These alterations in the magnitude of the downstroke from the peak of left ventricular thrust to the end of the systolic retraction wave may reflect percentage changes in left ventricular volume during this period. In contrast to patients with chronic hyper- tension or aortic valvular disease, the impo- sition of an acute left ventricular overload in normal subjects produced no significant change in the magnitude or duration of the left ventricular thrust expressed as percentages of the total cycle amplitude and duration, re- spectively. These results supply additional evidence that the duration of the thrust is a useful index of left ventricular hypertrophy. Part If: Changes in Arterial Pulse Waves Aside from the recording of changes in contour in aortic valvular and peripheral vas- cular occlusive disease, little use has been made of externally recorded arterial pulses in clinical medicine. Nevertheless, character- istic alterations in the shape of the carotid pulse occur with aging and hypertension.» 1 These appear to be related to the Joss of arterial distensibility associated with these con- ditions.) In addition, Katz and Feil’? and Weissler and associates’ have shown that the carotid pulse can be used as an indicator of alterations in left ventricular dynamics. In the present study, the effects of acutely induced changes in cardiac output or total peripheral vascular resistance were eyalu- DADDARIO, FREIS ated on various indices provided by simul- taneous recordings of the carotid and femoral pulse waves, heart sounds, and electrocardio- gram (ECG). Such studies might prove useful in the interpretation of alterations in these functions observed in different age groups and in the presence of cardiovascular disorders, Methods The subjects were the same as those de- scribed in Part I, the KCG and pulse waves be- ing recorded simultaneously, The arterial pulse- wave transducer has been described previously.}4 Tt consists essentially of a water-filled chamber sealed at one end with a compliant plastic mem- brane, and at the other by a metal diaphragm, on which two strain gauges are mounted. One of these transducers was used to record the carotid pulse. It was attached to the subject’s neck with an adjustable clamp previously de- scribed. Another similar transducer used to re- cord the femoral pulse was attached to a rigid support overlying the femoral triangle. The trans- ducer then was lowered over the artery and clamped in place at the overhead support. The measurements taken on the carotid pulse were based on the relative heights of three inflec- tions, two positive inflections or maxima occurring during systole followed by a negative inflection, the incisura. A line was drawn connecting the foot points at the beginning and end of a pulse cycle and perpendiculars were dropped from the three inflections. The ratio of the height of the second to that of the first maxi- mum (P/F ratio) and of the height of the incis- ura to the first maximum (I/F ratio) were cal- culated. The difference in pulse-wave transmission time between the carotid and femoral arteries was determined by using a magnifying lens as fol- lows: The steep ascending upslope of the wave was extrapolated downward until it intersected a horizontal line drawn between the foot points at the beginning and end of the cycle. The point of intersection was taken as the onset of the wave. The time difference between the onset of the carotid and femoral pulses during the same cardiac cycle was taken as the carotid-femoral transmission time difference. The ejection time was measured from the time of onset of the carotid wave, as defined above, to the minimum point of the incisura. The ejection time index (ETI) was calculated by the method of Weissler and associates!® which nor- malizes the ejection time with respect to heart rate. The isovolumic contraction time (ICT) was determined by measuring the time between the beginning of the first and second heart Circulation, Volume XXXIV, Septensher 1966 ACUTE HEMODYNAMIC CHANGES sounds and subtracting from this the ejection time. Low-frequency and low-amplitude vibra- tions preceding the first and second heart sounds were disregarded,!7 the onset of each sound be- ing taken as the first high frequency vibration of amplitude at least twice that of the background noise level. With respect to the first heart sound this point in time coincides with the onset of the steep rise in left ventricular pressure and does not take into account the slow initial phase of left ventricular contraction which lasts 10 to 20 msec. Thus ICT may be underestimated by this method but is probably satisfactory for compara- tive purposes. In some cases, following isoprotere- nol, the second heart sound was not clearly de- lineated. In the cases where it was recognizable after isoproterenol, the time interval between the beginning of the second heart sound and _ the carotid incisura remained unchanged from the control. Therefore, in cases of doubt, the onset of the second heart sound following isoproterenol was determined by subtracting the contro] time interval from the carotid incisura. The heart sounds were recorded with a San- born dynamic microphone and amplifier using a high-pass filter of 12 db per octave, and a nom- inal frequency cut-off of 100 cycles per second. The amplitude of the first heart sound was measured from peak to peak in millimeters, and the postdrug results were expressed as a per- centage of the control.!8 Tension period!® was measured from the time of onset of the QRS complex to the onset of the second heart sound, and from this interval the ejection time was sub- tracted. The Q-S, interval was taken as the time between the beginning of QRS and the onset of the first heart sound. The average of three con- secutive pulse cycles was used in all of the above measurements. Results The externally recorded carotid pulse char- acteristically displayed two positive inflections or maxima during systole. The first (F maxi- mum) was temporally related to the anacrotic bend of the aortic pressure pulse and to peak blood velocity, while the second (P maxi- mum) was related to peak aortic pressure.?° The ratio of the heights of P to F was previ- ously found to increase with age and hyper- tension. 1° 2° The ratio of I, the height of the incisura, to F, also increased. Angiotensin II and methoxamine elevate peripheral vascular resistance thereby raising hoth systolic and diastolic pressure.* The ratios of P/F and I/F were significantly increased Circulation, Volume XXXIV, September 1966 Table 2 Changes in Carotid Pulse Contour and Carotid to Femoral Transmission Time Following Vasoactive Drugs Carotid-femoral Transmission time differences Control I/F P/F % change +57.7 Heart rate Blood pressure (mm Hg) Diastolic Control 68.7 Systolic Control 118.0 126.6 No. of subjs. change (%) —18.9 —26.1 change —20.2 (msec) 64.5 change +45.3 Control 0.574 0.588 0.601 P < 0.01 Change Control 49.4 Change Drug < 0.01 < 0.01 0.919 446.5 9 9 13 14 Angiotensin II 0.01 < 0.01 67.7 -—118 = +181 66.1 < 0.05 < 0.01 < 0,01 +34.0 $38.3 <0,05 0.966 73.5 +266 +33.8 Methoxamine —46.2 —51.5 —21.5 27.0 744 -—294 444.5 0.966 * <0.01 414.2 126.7 Amy] nitrite ns < 0.05 — 54 + 8.7 66.6 73.1 —35.0 +61.2 0.934 * <0.01 0.562 0.844 0.465 120.5 122.6 Isoproterenol 21.6 69.1 < 0.05 < 0.05 +17.9 * 79.2 —17.1 7 Hexamethonium *P maximum disappeared in 8 subjects following infusion of amyl nitrite, in 10 following isoproterenol, and in one after hexamethonium. 429 430 DADDARIO, FREIS by both agents (table 2, figs. 1 and 2). By a(2eee , 6s8 egos . < ooo oe ooo contrast, amyl nitrite and isoproterenol de- VVVV 8 la NAVAN crease total peripheral resistance,*:* and these 3 agents produced a significant decline in P/F 3 : i eeaaqarnwe |e! g lod and I/F ratios (table 2, figs. 3 and 4). Hex- v et Sagres Bed wuoawS . . . a rat NON amethonium lowers blood pressure primarily Si++i tt j*} =e jy “oI by reducing cardiac output rather than by lowering peripheral resistance. This drug also Boley Oo ag wt produced a decrease in P/F and I/F ratios Bk Seats eae : ~ tm : = (6°. 22V VV The interval between the foot points of the 3 . : i So carotid and the femoral pulses was designated a alo neal? - . « . * 2 > as the carotid-to-femoral transmission time 3 FREY FY |S] g joaqrne : : S Spee Hod wr difference and was used to serve as an index of $ als raha : : : 3 elo Al ° pulse-wave velocity changes occurring in the Ol] & leFlo aeaa a . . : ma |*s aorta in response to the various vasoactive 7 5 ++ il it _ ° S . . > on agents. The transmission time difference in- 8 Eg jaAwmone : : . eye <= a Amaro to creased significantly following amyl nitrite § Ssleonane| SE |©wwwis * . eu and hexamethonium but not after isoproterenol Ss gg 3 2 SB S . . 2 oF oO (table 2). Both angiotensin II and methoxa- 3 : coe ‘ : : s mond mine decreased the transmission time signifi- 3 Dado a |22ee 3 sooo cantly. = MIS eSSs VVVV 8 The ejection time measured as the interval z VVVVV . . vy from the foot of the pulse wave to the incisura = gi} z 2 loo om --— » . + < increased after angiotensin IT and methoxa- 3 = : see sSi fe? [pense * : : vas q mine and decreased following amy] nitrite, a 8 e/3lah7 riya e [tt l! + hexamethonium, and isoproterenol (table 3). Si ag a : : . . . 2 = These changes in ejection time were approxi- 2 24 o©onor fo [rooen ) ‘ s Bgieesu4u5eny| |zz 4 2 mately inversely related to the alterations 8 ae B 5 5B 5 & &f |\S2RBS « th Ow ~ in heart rate produced by these agents. iy «og : : 7 : 3 The ejection-time index which normalizes 8 glannaa ow the ejection time with respect to heart rate’® § . Se/SQteh ns =e . - . 2 “ann remained essentially unchanged following ei = ey brat aa aVvv methoxamine, angiotensin I, and isoprotenerol | : wus SB 2 eslotwadn {table 3). It increased after amyl] nitrite é || = [Egle raca slog CANA (P<0.01) and decreased slightly following g oY SPs (PRS2LR : 3 im v hexamethonium (P< 0.10). Ea ; a bert i : : . . 3 g]lanewma . The isovolumic contraction time (ICT), & | S220 70 : ae . ag at measured by subtracting the ejection time 2 || San rs SQeesee from the interval between the two heart sounds S 288] . SEX 2aAanA . - : HyCZe) B/S SHAR] ME increased after angiotensin II and decreased wif & | @) bay 44 ~ a : . S ‘S after amy] nitrite and isoproterenol (table 3). 2 < oe OOQGr There was no significant change after methox- 8 Slo oa th zm . . : i rt amine or hexamethonium. The quotient of 3 zi ~~ diastolic pressure divided by ICT (DP/ICT) q g _ S et — provides an index of the mean rate of the left > " Sess _223 : . . . : : G-iG 8 oO fsa 96 ventricular pressure rise during the isovolumic > #eies BeEHeS an g SZage Egege contraction period.?? As calculated by this = SS _c& cL eek = wl pw aA aS yo me A . - . = sj 2@oaceés “Mos x > ¢ “ft v + 2 S E/ae 269 8 =aVYhos method, the rate of left ventricular pressure & 6\as328 S538 Circulation, Volume XXXIV, September 1966 ACUTE HEMODYNAMIC CHANGES rise for the 28 subjects during the contro] pe- riod averaged 2,043+1,280 mm Hg/sec. This index increased 19.5% (P<0.10) after isoproterenol and decreased 20.3% (P< 0.05) in the subjects given hexamethonium. There were no significant changes in this index fol- lowing amy] nitrite, angiotensin I, or methox- amine. The measurements of diastolic pres- sure by the auscultatory method during the peak action of isoproterenol probably were falsely low since the hemodynamic changes associated with this agent Jed to a persistence of the Korotkoff sounds. If the diastolic pres- sure had been recorded directly, the ratio of the latter to ICT probably would have been greater. Tension period is similar to ICT except that it also includes the period beginning at the time of onset of the QRS complex of the electrocardiogram. Tension period increased slightly after angiotensin II and methoxamine and decreased considerably after both amyl] nitrite and isoproterenol (table 3). Tension period did not change significantly following hexamethonium. The Q-S, interval, which is the period be- tween the beginning of QRS and the first heart sound, remained unchanged after angio- tensin II and methoxamine. It decreased after both amy] nitrite and isoprotorenol, the change being more marked with the latter drug (table 3, fig. 6). Following hexamethonium, Q-S; increased. The amplitude of the first heart sound in- creased after amyl nitrite and isoproterenol] with the greater change (mean +284%) oc- curring after isoproterenol (table 3 and fig. 6). The amplitude decreased after hexametho- nium and was insignificantly changed follow- ing angiotensin IJ and methoxamine. Discussion Aortic Wall Stiffness The changes in relative amplitudes of. the two systolic maxima observed in the carotid pulse produced by vasoactive drugs, have been described in a previous report.*° The height of the first positive inflection, or F max- imum, is related to the acceleration of the blood in the central arterial system during Circulation, Volume XXXIV, September 1966 431 early ventricular ejection. The height of the second or P maximum is related to the input impedance of the arterial system.2° The pres- ent study confirms and extends the former ob- servations. Elevation of input impedance by angiotensin II and methoxamine increased the second maximum probably by restricting sys- tolic runoff with resulting distention of the large arteries.2? The incisura, which was in- scribed soon after the second maximum, rose in association with the latter. These changes resulted in elevation of P/F and I/F ratios. Reduction of input impedance and wail ten- sion with the vasodilator drugs used in this study had an opposite effect on the P/F and I/F ratios. The velocity of the arterial pulse wave has long been used as an indicator of the changes in arteria] elasticity occurring with age and cardiovascular disease.?* 24 Past attempts to CRANGE - MSEC. Q ~ 5) INTERVAL +40 ° + +0 . : x ° . | «= 4] 8 * . q O beset Foe s e x 8 : a | & * w t -a ° * e | _.»..4 ° o $ a * » -@ CHANGE - PER CENT AMPLITUDE 51 +480 w +800 . i ° +30 eee le +280 : $ 160 --*%._4 s « +80 . 8 + * p ead i ° * --~-.4 . j F a x ~80 ANGIOTENSIN UL METHOXAMINE AMYL NITRITE ISOPROTERENOL HEXAME THON UM. Figure 6 Changes in the Q-S, interval and in the amplitude of the first heart sound following various drug-induced hemodynamic alterations. 432 characterize the elasticity of the aorta in pre- cise quantitative terms from pulse-wave ve- locity data have not been accepted because of many indeterminable factors such as varia- tions in wall structure in different portions of the aorta, difficulties in accurately measuring the vessel length between the pickups, visco- elastic properties of the arterial walls, and other variables. Nevertheless, the available evidence suggests that pulse-wave velocity may serve as an approximate index of arterial elasticity of sufficient accuracy to be useful clinically.?*: 24 In the present studies the carotid-femoral transmission time difference was used to deter- mine whether the speed of propagation of the pulse wave through the aorta would change in the expected direction with alterations in aortic wall stiffness. Both angiotensin II and methoxamine increase aortic wall tension as indicated by the rise in systolic and diastolic pressures. As would be expected under such circumstances, the transmission time difference was consistently shortened. On the other hand, lowering of both systolic and diastolic pres- sures with amy] nitrite or hexamethonium de- creased aortic wall tension and lengthened carotid-femoral transmission time, again dem- onstrating that changes in the stiffness of the aortic wall were reflected in the speed of pro- pagation of the pulse wave. The inconsistent changes which occurred in the pulse-wave transmission time during iso- proterenol may reflect opposing influences on the pulse-wave velocity. This drug de- creased diastolic pressure which would reduce the speed of transmission. However, aortic blood velocity rises considerably after iso- protereno] which, as pointed out by Bramwell and THill,?® will cause an equal increase in the velocity of the pulse wave. The present study employed the method of external pulse-wave recording using drugs as hemodynamic forcing functions, One purpose was to determine whether certain character- istics of these waves could be used as indices of the extent of changes in central arterial wall structure which are known to occur with advancing age.'!:?* The results indicate DADDARIO, FREJS that both contour changes in the carotid pulse wave and transmission time through the aorta can be used as indices of alterations’ in cen- tral arterial wall stiffness. Furthermore, both indices have been shown to change character- istically with advancing age although the cor- relation shows considerable spread.’” 2 24 The use of several criteria of central arterial wall stiffness recorded simultaneously, such as carotid pulse contour and_ carotid-femoral transmission time differences, should increase the reliability of the method. Cardiac Function Another purpose of this study was to deter- mine whether externally applied transducers can be used as a measure of cardiac perfor- mance. Weissler and associates'® found a re- duction in left ventricular ejection time index (ETI) in normal subjects given digitalis which they attributed to the inotropic effects of the drug. In the present study, ETI re- mained unchanged except for a slight increase following amyl nitrite, and decrease after hexamethonium. These small variations may be due to alterations in stroke volume follow- ing use of these agents. Stroke volume falls after hexamethonium® and may rise after amyl] nitrite, although the increase in cardiac output produced by amy] nitrite and isoproterenol is due primarily to an elevation in heart rate rather than in stroke volume.*:® The ejection- time index did not seem to provide an ac- curate reflection of ventricular contractility in the present study since the index was insig- nificantly altered after isoproterenol, a drug which considerably augments ventricular pow- er. Following digitalis, the contraction is not only more powerful but also is more sus- tained whereas after administration of isopro- tcrenol contractile force is increased but the contraction period is shortened. Thus, ETI by itself does not appear to express changes in myocardial contractility under all circum- stances. The isovolumic contraction time (ICT) re- fers to the interval between the closure of the mitra] valve and the opening of the aortic valve. Frank and Kinlaw,?? using the same in- direct method employed in the present study, Circulation, Volume XXXIV, September 1966 ACUTE HEMODYNAMIC CHANGES found an average ICT of 49 msec in normal subjects with a standard deviation of con- secutive cycle variation of 4.0 msec. In the present series ICT averaged 38.3 msec. The difference may be due at least in part to the somewhat lower diastolic pressure of 72.1 mm Hg in the present series as contrasted to an average value of 80.7 mm Hg in Frank and Kinlaw’s subjects.?7 Katz and Feil,’? who also employed the same method, concluded that ICT was an index of the velocity of ventricu- lar contraction. Reeves and associates,?* using the left ventricular and aortic pressure pulses, also related ICT to myocardial contractility. If ventricular power remains unchanged, ICT should rise or fall with corresponding changes in aortic diastolic pressure since ejec- tion begins at the moment that Jeft ventricular pressure exceeds aortic pressure. ICT in- creased with angiotensin II and methoxamine and decreased following amyl nitrite and isoproterenol. ICT did not shorten significant- ly after hexamethonium despite a reduction in diastolic pressure suggesting that ventric- ular power had decreased under the influence of ganglionic blockade. An attempt was made to find a regression equation that would nor- malize ICT with respect to diastolic pressure because of the apparent relationship between diastolic pressure and ICT. However, the correlation coefficient between diastolic pres- sure and ICT in the 26 subjects during the control period was only 0.47. This degree of scatter was considered too great to make such normalization useful. The ratio of diastolic pressure to ICT (DP/ICT) should provide an index of the mean rate of rise of left ventricular pressure during the initial phase of ventricular contrac- tion. Both Reeves and associates*’ and Rush- mer** have indicated that the maximum rate of pressure rise in the left ventricle (maxi- mum dp/dt) is closely correlated with other indicators of myocardial contractility. Landry and Goodyer*! have shown recently in dogs that DP/ICT correlated closely with maxi- mum dp/dt measured directly in the left ven- tricle. Their average control value was approx- imately 2,300 mm Heg/sec by both methods. Circulation, Volume XXXIV, September 1966 433 They also observed changes in the rate of rise of ventricular pressure after beta-adrenergic stimulation, and use of a ganglion blocking drug and methoxamine that were similar to those observed in the present studies in man. Gleason and Braunwald®° measured the max- imum rate of left ventricular pressure rise directly in man. These investigators also found that it increased significantly following iso- proterenol but remained unchanged after methoxamine. In the control state, they found that maximum left ventricular dp/dt varied between 841 and 1,696 mm Hg/sec. This range is considerably lower than is indicated by the mean value of 2,043+ 1,280 mm HG/sec found in the present study, obtained by the indirect method. Their patients had valvular lesions or septal defects and, there- fore, probably did not have entirely normal ventricular dynamics. Another factor produc- ing the higher values in the present series is that the end-diastolic pressure in the left ven- tricle was assumed to be zero. The onset of the first heart sound also is sometimes indistinct due to low frequency vibrations which precede the closure of the mitral valve. This difficulty can be avoided by measuring total systole including clectrical systole from the onset of the QRS complex to the beginning of the second heart sound. The difference between this interval and the ejec- tion period as determined from the carotid pulse has been called the tension period.’® The latter changed in the same direction as ICT in all instances except that the magnitude of the change was not as great. Thus, although easier to determine, tension period is a less sensitive index of changes in the pre-ejection phase of systole than is ICT. In the absence of mitral stenosis, the Q-S, in- terval may provide a useful index of contractil- ity. It shortened considerably after administra- tion of isoproterenol, moderately following amyl nitrite, increased with hexamethonium, and remained unchanged following angioten- sin IJ and methoxamine. The latter two agents are believed to have little or no inotropic effects on the heart. Isoproterenol and amyl 434 nitrite stimulate adrenergic activity, the for- mer directly, and the Jatter through reflex action, while hexamethonium blocks sympa- thetic nerve transmission, Sakamoto and associates,!® who used the directly measured maximum dp/dt as an index of left ventricular contractility in closed chest dogs, found that percentage changes in the peak-to-peak amplitude of the first sound var- ied directly with changes in ventricular con- tractility induced by a variety of procedures and pharmacological agents. The results of the present study in man are consistent with their conclusion and suggest that changes in ven- tricular contractility can be estimated by this simple method. Unfortunately, due to chest configurations, degrees of adiposity and other factors, variations occur in the transmission of the heart sounds among different subjects making comparisons between subjects invalid by this method. However, in studies of drug effects or other acute procedures on ventricu- lar contractility in the same individual, the amplitude changes in the first heart sound may provide an attractively simple method for assessing this important cardiodynamic variable. Summary The effects of drugs that produce known hemodynamic alterations were assessed on ex- ternally recorded pulse waves, heart sounds, and the relationship of these to each other and to the electrocardiogram. The shape of the carotid pulse and the caro- tid-femoral pulse-wave transmission time dif- ference showed changes that could be related to alterations in central arteria} distensibility. The ratio of the second to the first positive in- flection, and of the incisura to the first positive inflection of the carotid pulse wave, increased following use of drugs which raised mean ar- terial pressure and decreased after those which lowered blood pressure. The carotid-femoral transmission time difference decreased with vasopressor agents, increased with amy] nitrite and hexamethonium, and showed no consis- tent change after isoproterenol. Left ventricular ejection time, measured from the carotid pulse, changed in relation to DADDARIO, FREIS heart rate, increasing with cardiac slowing and decreasing when the rate accelerated. The ejection time index remained unchanged ex- cept for a slight increase following amyl ni- trite and a decrease after hexamethonium. Alterations in isovolumic contraction time approximately paralleled changes in diastolic pressure. The ratio of diastolic pressure to isovolumic contraction time provides an in- dex of the rate of rise of left ventricular pres- sure. The quotient of diastolic pressure divid- ed by isovolumic contraction time increased with adrenergic stimulation (isoproterenol ) and decreased after ganglion blockade. It was not significantly changed by angiotensin II, methoxamine, or amyl nitrite. The interval between the onset of QRS and the beginning of the first heart sound (Q-S;), shortened considerably after isoproterenol and moderately following amyl nitrite. It increased after hexamethonium and remained essentially unchanged following angiotensin II or methox- amine. These results suggest that the Q-S, interval may reflect ventricular contractility in the absence of mitral valvular disease. The amplitude of the first heart sound ap- peared to be a sensitive indicator of ventricu- lar contractility increasing with isoproterenol and amyl nitrite, decreasing with hexamctho- nium and remaining unchanged following use of angiotensin II or methoxamine. Conclusions: Parts I and II The present studies indicate that external transducers may provide important informa- tion on structural and functional alterations in the cardiovascular system. The following in- dices appear to merit further study: 1. Percentage change in left ventricular vol- ume during the interval from the onset to the peak rate of left ventricular ejection. This is estimated in the Ky position of the kinetocar- diogram from the magnitude of the down- stroke beginning at the peak of the left ventricular thrust to the end of the systolic retraction wave expressed as a percentage of the total cycle amplitude. 2. Left ventricular hypertrophy from the magnitude and duration of the left ventricular thrust. Circulation, Volume XXXIV, September 1966 ACUTE HEMODYNAMIC CHANGES 3. Left ventricular contractility either from the Q-S, interval or the estimated mean rate of rise of left ventricular pressure as derived from the ratio of diastolic pressure to the isovolumic contraction time (DP/ICT). Changes in contractility in the same individual due to drugs or other factors may be estimated simply from percentage changes in the ampli- tude of the first heart sound. 4, Central arterial distensibility from the contour of the carotid pulse as well as the carotid-femoral transmission time difference. Acknowledgment The authors wish to thank Mr. Joseph C. Strong for his valuable technical assistance. References ]. Eppteman, E. E., Jn.: The kinetocardiogram— ultra Jow frequency precordial movements. In Cardiology, suppl. 1, edited by A. A. Luisada. New York, Blakiston-McGraw, 1963, p. 3. 2. Marintanp, D.: Elementary Medical Statistics. Philadelphia, W. B. Saunders Co., 1963, p. 973. 3. Aviano, D. M.: Pharmacologic approach to the treatment of shock. Ann Intern Med 62: 1050, 1965. 4. Pervorr, J. K., Cotvin, J., AnD De Leon, A. C.; Systemic hemodynamic effects of amyl nitrite in normal man. Amer Heart J 66: 460, 1963. 5. Dopnce, H. T., Lorn, J. D., anp Sanpier, H.: Cardiovascular effects of isoproterenol in nor- mal subjects and subjects with congestive heart failure. Amer Heart J 60: 94, 1960. 6. Freis, E. D., eT at.: Hemodynamic effects of hypotensive drugs in man: JJI. Hexamethoni- um. J Clin Invest 32: 1285, 1953." 7. Davie, J. C., Lancriey, J. O., Dopson, W. H., AND EppLeMAN, E. E.: Clinical and kineto- cardiographic studies of paradoxical precor- dia] motion. Amer Heart J 63: 775, 1962. 8. Ecxsrein, J. W., anp Wenpuinc, M. G.: Com- parative effects of norepinephrine and angio- tensin on left ventricular performance in in- tact dogs. Circulation 28; 714, 1963. 9. Friart, J.: La morphologie du sphygmogramme carotidien dans J’arterisoclerose: Etude prelimi- naire. Acta Cardiol (Brux) 15: 557, 1960. 10. Doxtas, A. S., Taytor, H. L., anp Keys, A.: Carotid pressure plethysmograms: Effects of age, diastolic blood pressure, relative body weight and physical activity. Arch Kreislauf- forsch 36: 49, 1961. 11. Hatiockx, P., axp Benson, I. C.: Studies on Circulation, Volume XXXIV, September 1966 12. 13. 14, 15. 16, 17. 18. 19. 435 the elastic properties of isolated human aorta. J Clin Invest 16: 595, 1937. Katz, L. N., anp Fem, H. S.: Dynamics of auricular fibrillation: Ventricular systole: Arch Intern Med 32: 672, 1923. Wreiss_er, A. M., Game, W. G., Grove, H. E., Couen, S., AND ScHOENFELD, C. D.: Effect of digitalis on ventricular ejection in normal hu- man subjects. Circulation 29: 721, 1964. Davis, M., Gitmore, B., anp Freis, FE. D.: Im- proved transducer for external recording of arterial pulse waves. IRE Trans Biomed Electronics 10: 173, 1963. . Gitmore, B. L., AND Frets, E. D.: Effect of amyl nitrite on the height of the pulse wave incisura in atherosclerotic patients. Angiology 15: 219, 1964, Weisscen, A. M., Harris, L. C., anp WHuire, G. D.: Left ventricular ejection time index in man, J Appl Physiol 18: 919, 1963. Counzuan, T., Messer, A. L., Rappaport, E. E., AND SpracuE, H. B.: Initial vibrations of the first heart sound. Circulation 3: 730, 1941. SaKkaMoTo, T., Kuskawa, R., MacCanen, D. M., AND Luisapa, A. A.: Hemodynamic deter- minants of the amplitude of the first heart sound. Circulation Research 16: 45, 1965. BLUMBERGER, K., AND Meiers, S.: Studies of cardiac dynamics. In Cardiology, vol. 2, part 4, edited by A. A. Luisada. New York, Blakis- ton-McGraw, 1959, p. 372. Freis, E. D., Heatu, W. C., Lucusincer, P. C., AND SNELL, R. E.: Changes in the carotid pulse with age and hypertension. Amer Heart J 71: 757, 1966. : Lanpry, A. B., JR., AND Goonyer, A. V. N.: Rate of rise of left ventricular pressure: In- direct measurement and physiological signifi- cance. Amer J Cardiol 15: 660, 1985. Perrrson, L. H.: Dynamics of pulsatile blood flow. Circulation Research 2: 127, 1954. Hatiock, P.; Arterial elasticity in man in rela- tion to age as evaluated by the pulse wave velocity method. Arch Intern Med 54: 770, 1934. Haynes, F. W., Evuis, L. B., anp Wess, S.: Pulse wave velocity and arterial elasticity in arterial] hypertension, arteriosclerosis and_re- lated Amer Heart J 11: 385, 1936. BraMweELL, J. C., ano Hinz, A. V.: Velocity of the pulse wave in man. Proc Roy Soc (Biol) 93B: 298, 1922. Moret, P. R.: Modifications de lelasticité ar- terielle avec VPage. Bibl Cardiol 15: 40, 1964. Frank, M. N., ann Kintaw, W. B.: Indirect measurement of isovolimetric contraction time and tension period in normal subjects., Amer J Cardiol 10: 800, 1962. conditions. 436 28. Reeves, T. J., Herner, L. L., Jones, W. B., Cocuian, C., Prieto, G., AND CARROLL, J.: Hemodynamic determinants of the rate of change in pressure in the left ventricle during isometric contraction. Amer Heart J 60: 745, 1960. DADDARIO, FREIS 99. Rusumer, R. F.: Initial ventricular impulse, po- tential key to cardiac evaluation. Circulation 29: 268, 1964. . 30. GiEeason, W. L., anp Braunwa p, E.: Studies on the first derivative of the ventricular pres- sure in man. J Clin Invest 41: 80, 1962. Circulation, Volume XXXIV, September 1966