Journal of Clinical InvestigationVol. 42, No. 1, 1963

THE DYNAMICSOF PULSUSALTERNANS: ALTERNATINGEND-DIASTOLICFIBER LENGTHAS A CAUSATIVE FACTOR

By JERE H. MITCHELL,* STANLEYJ. SARNOFF, AND EDMUNDH. SONNENBLICKt

(From the Laboratory of Cardiovascular Physiology, National Heart Institute, Bethesda, Md.)

(Submitted for publication June 20, 1962; accepted September 8, 1962)

Pulsus alternans, first described by Traube in1872 (1), is characterized by an alternation be-tween weak and strong ventricular systoles witha regular rhythm (2-4). The electrocardiogramis usually normal but electrical alternans may bepresent (3, 5). Clinically, pulsus alternans mostfrequently occurs in the presence of myocardialdisease (3, 6), but may also be seen in spontaneoustachycardia without any apparent myocardial ab-normality (2, 7).

Various theories regarding the mechanism ofthis phenomenon have been postulated. Wencke-lach believed that extracardiac factors influencingthe degree of ventricular filling and therefore end-diastolic pressure and volume were the major de-terminants of alternation, the weak beat being initi-ated from a lower pressure and a smaller volume(8, 9). Straub's experiments led that investiga-tor to believe that the weak beat is initiated from asmaller volume but a higher pressure and that thiswas attributable to incomplete metabolic recoveryfrom the previous strong beat (10). A thirdview (11-15) holds that there is an alternate fail-ure of contraction of certain myocardial segments,a view which is still current (16, 17).

The obj ect of this communication is to presentevidence which appears to reconcile the views ofWenckebach and Straub. It will be shown thatthe weak beat can be initiated from either a lower,the same, or a higher end-diastolic pressure butthat, under the conditions of our experiments, thecommon denominator appears to be that the weakbeat occurs from a shorter end-diastolic length ofthe contractile element. Although these findingsdo not rule out the possibility that an alternatefailure of contraction of certain myocardial seg-

* Present Address: Established Investigator, AmericanHeart Association, University of Texas, SouthwesternMedical School, Dallas, Tex.

t Present Address: Department of Medicine, ColumbiaUniversity, College of Physicians and Surgeons, NewYork, N. Y.

ments may occur, pulsus alternans, as observed,is explicable without implicating this mechanism.A preliminary report of these observations hasbeen given (18).

METHODS

The data contained in this study were obtained fromthree experimental preparations. The first was a papil-lary muscle strip from the right ventricle of the dog.This was placed in a chamber containing a modifiedKrebs-Ringer solution and aerated with 95 per cent O.and 5 per cent CO2. Stimulation of the muscle was pro-vided by a Grass impulse generator. The preparation wasarranged so that changes in length and tension could becontrolled and recorded on a Sanborn direct-writingoscillograph (19).

In the second preparation, the dog was anesthetizedwith morphine, chloralose, and urethane (20). The chestwas opened, and ventilation was maintained with aStarling pump. Pressures were recorded in the leftatrium, left ventricle, and aorta with Statham straingauges, and heart rate was recorded with a Waters cardio-tachometer. The changes in length of a segment of leftventricular myocardium were measured by a myocardialsegment length recorder (21, 22). All values were si-multaneously recorded on an eight-channel Sanborn di-rect-writing oscillograph. The heart was paced from aGrass impulse generator by means of bipolar electrodesattached to the atrial appendage. In some experimentsthe carotid artery pressure was controlled by pump per-fusion (23).

The third preparation used was an isolated, supportedheart preparation in which a canine heart is isolated, butis perfused from a reservoir in which the blood is con-tinuously exchanged with that of a donor or support dog(24, 25). These preparations have been described indetail in the references cited.

RESULTS

Pulsus alternans in the papillary muscle strip.Pulsus alternans was repeatedly observed in fivepapillary muscle preparations of the dog rightventricle. A typical example of pulsus alternansoccurring in the isotonically contracting papillarymuscle is shown in Figure 1, upper panel. Thestimulus rate was increased from 30 to 60 per min-

55

JERE H. MITCHELL, STANLEY J. SARNOFF, AND EDMUNDH. SONNENBLICK

ute just before A. Pulsus alternans appeared atthis increased rate. The weak beat (B) occurredfrom a shorter initial length than did the strongbeat (C). As the increased rate of stimulation wascontinued and the increased myocardial contrac-tility developed, as is usual when the rate is ele-vated (25, 26), the intensity of the alternansabated. This diminution in the intensity of thepulsus alternans was accompanied by a gradualincrease of initial length before the weak beat.That an increased contractility had taken placeduring the period of higher frequency was indi-cated by the greater shortening in the first fewbeats after returning to the lower rate at D.

Pulsus alternans is also seen in the isometricallycontracting papillary muscle. Examples of thisare shown in Figure 1, middle and lower panels.In Figure 1, middle panel, the rate of stimulationwas increased from 40 to 80 per minute at A; fromthe same initial tension and external length, an in-crease in developed tension was established afterseveral beats (Bowditch staircase). At B, the

rate was decreased from 80 to 40 per minute, andthere was a slow decrease in the developed ten-sion. At C, the rate of stimulation was increasedfrom 40 to 120 per minute and pulsus alternansoccurred. The initial tension was higher beforethe weak beat. After several beats, the pulsusalternans almost disappeared, as did the alternationof initial tension. At D, the rate was decreasedfrom 120 to 40 per minute and there was a slowdecrease in the developed tension. When com-pared with the control values at the lower rate,the increased developed tension just after B and Dis an exhibition of the increase in contractilitywhich is induced during periods of increased stim-ulation rate as is seen in the intact isolated heart(25, 26).

Pulsus alternans in the isometrically contractingpapillary muscle is also shown in Figure 1, lowerpanel. The left portion of the tracing (section 1)was recorded at higher gain for emphasis on initialtension. The right portion of the tracing (section2) was recorded at lower gain for emphasis on de-

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FIG. 1. UPPER: ISOTONIC CONTRACTIONOF DOG PAPILLARY MUSCLE. Pre-load is 1.0 g; temperature is 250 C; iso-tonic shortening in millimeters (mm) shown on left; paper speed = 5.0 mmper second. MIDDLE: Temperature is250 C; isometric tension in grams (g) shown on left; paper speed = 2.5 mmper second. LOWER: Temperature is240 C; for section 1, isometric tension in grams (g) shown at left, and for section 2, isometric tension in grams (g)shown at right; paper speed = 1.0 mmper second.

56

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THE DYNAM'ICS OF PULSUS ALTERNANS

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veloped tension. The rate was 30 during A andchanged to 60 at B; initial tension alternation oc-

curred during C. The gain was decreased at Dand shows the alternation of developed tension.

The rate was then returned to 30 at E and wasre-elevated to 60 at F. Alternation of developedtension was present at the higher rate and not atthe lower rate.

57

JERE H. MITCHELL, STANLEY J. SARNOFF, AND EDMUNDH. SONNENBLICK

It was consistently observed throughout the ex-periments of the types shown above that small dif-ferences in initial tension (Figure 1, middle andlower panels) or in initial length (Figure 1, upperpanel) would produce marked alternation of eithertension development or shortening. Worthy ofnote is the fact that the weak beat always origi-nated from the higher initial tension with externallength constant in the isometrically contractingpreparations and from the shorter external lengthwith tension constant in the isotonically contract-ing preparations.

Pulsus alternans in the left ventricle. Certainhemodynamic findings in the same heart withoutand with pulsus alternans are shown in Figure 2,which is representative of those observed in thefive intact heart preparations studied. In Figure2, upper panel, pulsus alternans was not present.The heart rate was 115 per minute, and the totalcardiac cycle time was 520 msec. The durationof ventricular systole (from beginning of the risein left ventricular pressure until aortic incisura)for each beat was 250 msec. The duration of ven-tricular diastole (from beginning of aorta incisurato the rise in left ventricular pressure) was 270msec. For each beat, the left ventricular end-dia-stolic pressure, end-diastolic myocardial segmentlength, and end-systolic segment length were thesame. In Figure 2, lower panel, at a heart rate of175 per minute, pulsus alternans was present. The

total cardiac cycle time was 343 msec. The dura-tion of ventricular systole for the strong beat was238 msec, and that for the weak beat 220 msec.The duration of ventricular diastole was 123 msecbefore the strong beat and 105 msec before theweak beat. The weak beat occurred from a 2cm H20 lower, left ventricular, end-diastolic pres-sure and a shorter, left ventricular, end-diastolic,myocardial segment length than did the strongbeat. The left ventricular, end-systolic, myo-cardial segment length was longer after the weakbeat than after the strong beat. The atrial a wavewas higher before the weak beat than before thestrong beat.

Three different types of pulsus alternans in thesame intact heart preparation are shown in Fig-ure 3. The heart rate was 240 per minute, andthe total cycle time was 250 msec in all three ex-amples. In the left panel the duration of ventricu-lar systole for the strong beat was 200 msec andthat for the weak beat was 180 msec. The dura-tion of ventricular diastole was 70 msec before thestrong beat and before the weak beat was 50 msec.The weak beat occurred from a 2 cm H2O lower,ventricular, end-diastolic pressure. This is thesame type of pulsus alternans as seen in Figure 2,lower panel. In the middle panel, the weak andstrong ventricular beats occurred from the sameventricular end-diastolic pressure. The durationof ventricular systole for the strong beat was 190

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58

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THE DY.NAMIICS OF PULSUS ALTERNANS

FIG. 4. PULSUS ALTERNANSIN THE ISOLATED, SUPPORTEDHEART WITH CONTROLLEDCORONARYFLOW. L.V.D. = leftventricular diastolic pressure from 0 to 40 cm H2O. L.V. = left ventricular pressure for 0 to 250 mmHg. In theleft panel, pulsus alternans is present. In right panel, during the constant infusion of norepinephrine, pulsus alter-nans is not present. Paper speed = 100 mmper second.

msec and that for the weak beat was 180 msec.The duration of ventricular diastole before thestrong beat was 70 msec and that before the weakbeat was 60 msec. In the right panel, the durationof ventricular svstole for the strong beat was 190msec and that for the weak beat was 175 mnsec.The duration of ventricular diastole before thestrong beat was 75 msec and that before the weakbeat was 60 msec. In this instance, the weak beat

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occurred from a 2 cm HO higher, ventricular,end-diastolic pressure. Whether ventricular end-diastolic pressure was lower, the same, or higher,before the weak beat, the diastolic interval andthe ventricular end-diastolic, myocardial segmentlength were always shorter before the weak beat.

The effect of increasing ventricular contrac-tility on pdlsuts alternians. Pulsus alternans wasrepeatedly abolished in three isolated, supported

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FIG. 5. Int site HEART PREPARATION WITH CONTROLLEDCAROTID ARTERYPRESSURE. L.A. = left atrial pressure; A.P.= aortic pressure; L.V.D. = left ventricular diastolic pressure; C.S.P. = carotid sinus pressure. Heart rate heldconstant by atrial pacing. In left panel, during high carotid sinus pressure, pulsus alternans is present. Aortic flow= 1,200 ml per minute. In right panel, when the carotid sinus pressure is low, pulsus alternans is not present. Aorticflow = 2,400 ml per minute. Paper speed = 100 mmper second.

59

JERE H. MITCHELL, STANLEY J. SARNOFF, AND EDMUNDH. SONNENBLICK

heart preparations by the continuous infusion ofnorepinephrine. An example of this is shown inFigure 4, which was obtained from an isolated,supported heart with constant left coronary flow.Pulsus alternans was present in the left panel.The total cardiac cycle time for each beat was 375msec. The duration of ventricular systole for thestrong beat was 270 msec and that for the weakbeat was 200 msec. The duration of ventriculardiastole was 175 msec before the strong beat and105 msec before the weak beat. This was thetype of pulsus alternans in which the weak beatoccurred from a higher ventricular, end-diastolicpressure than did the strong beat. The ventriclewas clearly not completely relaxed at the end ofdiastole before the weak beat. The tracing in theright panel was obtained during the continuousinfusion of norepinephrine, and pulsus alterinansdisappeared. Again, the total cardiac cycle timewas 375 msec, but the duration of ventricular sys-tole was 180 msec and the duration of ventriculardiastole was 195 msec for each beat. The increasein the rate of development of tension and conse-quent shortening of systole induced by norepineph-rine allowed for an adequate diastolic interval afterthe strong beat.

Pulsus alternans was induced and abolished byvarying carotid sinus pressure, an interventionknown to modify ventricular contractility (23),in three intact heart preparations. An exampleof this is shown in Figure 5. Heart rate was heldconstant by atrial pacing. In the left panel, dur-ing high carotid sinus pressure, pulsus alternanswas present. For each beat, the total cardiac cycletime was 345 msec. The duration of ventricularsystole for the strong beat was 235 msec, and thatfor the weak beat was 200 msec. The durationof ventricular diastole before the strong beat was145 msec, and 110 msec before the weak beat.The weak beat occurred from a slightly higherventricular end-diastolic pressure than did thestrong beat. In the right panel, during low caro-tid sinus pressure and the consequent reflex sym-pathetic stimulation (23), pulsus alternans disap-peared. Aortic pressure and flow increased.Again the total cardiac cycle time was 345 msec,but the duration of ventricular systole was 225msec, and the duration of ventricular diastole was120 msec for each beat.

DISCUSSION

There is nothing in the above data which makesit possible to decide whether or not an alternatefailure of contraction of certain myocardial seg-ments occurs during pulsus alternans. The datamake it possible, however, to introduce a unifyingelement in the conceptual approach to this problemwithout resort to this unknown variable. It isclear from the above data that in pulstus alternansthe weak beat can occur from a lower, the same,or a higher ventricular end-diastolic pressure.What appears to be a common denominator is thatthe initial fiber length is, at least tinder the condi-tions of these experiments, always shorter beforethe weak beat.

At any particular moment in time, the relationbetween pressure and volume (or fiber length) inthe ventricle will be determined by the complianceof the ventricular myocardium and the volume ofblood it contains. These two variables can beheld to account reasonably completely for the ob-served phenomena. In a ventricle which has notyet lost the increased stiffness it acquired duringthe preceding systole at the time of the subse-quent systole, the pressure in it will be higher forany given end-diastolic volume or fiber lengththan if relaxation had been complete. In a ven-tricle which is completely relaxed, the end-diastolicvolume and fiber length will be importantly influ-enced by small absolute changes in the time avail-able for inflow if the diastolic period available forinflow is short, as is usually the case with pulsusalternans.

Lendrum, Feinberg, Boyd, and Katz (27) andSiegel and Sonnenblick (28) have recently dem-onstrated pulsus alternans in an isovolumic ven-tricle. The former group were apparently im-pressed by the occurrence of the ventricular "al-ternans phenomenon unassociated with changes infiber length." Siegel and Sonnenblick made twoobservations of note. Using their index of changesin the basic state of the myocardium (28), theyfound that the myocardium did not appear to al-ternate its basic state in the weak and strong beats.Further, using high gain for recording ventriculardiastolic pressures, they found that the weak beatin the alternating isovolumic ventricle consistentlyoriginated from a higher end-diastolic pressure.

60

THE DYNAMICSOF PULSUSALTERNANS

Relevant to the finding of these two groups arethe data in the papillary muscle experiments shownabove (Figure 1). The explanation of the al-ternating shortening in the isotonically contractingpapillary muscle (Figure 1, upper) is clear: theweak contraction originated from a shorter initialfiber length. In the isometrically contracting papil-lary muscle, in which the external length was fixed.the weak contraction originated from a higherinitial tension, that is to say, from a state of in-complete relaxation. There is no way at presentof assessing the extent to which a muscle stripwhich is fixed at both ends has an internal geo-metric rearrangement which influences effectivemuscle fiber length during the relaxation phase.Further, there may be dead tissue at or near eitherend of the muscle at the point of fixation whichintroduces a compliance of unknown parametersinto the over-all system. Most important. how-ever, is the possibility that, although the externallength is fixed, a muscle in which the tension hasnot completely subsided almost certainly has a dif-ferent distribution of stretch in its internal ele-ments, i.e.. contractile element and series elastic(29, 30), than is the case when the resting tensionis fully achieved. In the former case, when theresting tension is higher, the length of the con-tractile element can confidently be expected to beless than in the latter case when the resting ten-sion is lower. Thus the shorter length of the con-tractile element which is present before the weakbeat accounts for the diminished force of contrac-tion.

The contractility of the ventricular myocardiumappears to be an important element in determiningwhether or not pulsus alternans will occur. Thisis consonant with the observation that this phe-nomenon is most often seen in the diseased heart(3, 6). In the present study, pulsus alternans wasfound to occur when the continuous level of myo-cardial contractility was such that, at a given im-posed heart rate, stroke volume, and aortic pres-sure, there was not an adequate time for diastoleafter the strong beat. The inadequate diastolictime after the strong beat did not allow a com-parable period either for complete relaxation, orfilling, or both. Whenventricular contractility wasincreased, svstole shortened, and the diastolic pe- 1

riod thereby prolonged (Figures 4 and 5), pulsusalternans was abolished.

These considerations reconcile the views ofStraub, who felt that the weak beat always origi-nated from a higher end-diastolic pressure becauseof an inadequate period for ventricular relaxation(10), and those of Wenckebach, who felt that theweak beat always originated from a lower end-diastolic pressure because of less filling (8, 9).The above represents a synthesis of these views,since it was shown that pulsus alternans can occurfrom either a lower or higher end-diastolic pres-sure and further, that as both Wenckebach andStraub would agree, the weak beat is initiatedfrom a shorter end-diastolic fiber length. It isnot necessary to postulate a fractionate deletionof contractions during the weak beat in order toexplain the observed findings.

Ferrer, Harvey, Cournand, and Richards (4)suggested that a variation in end-diastolic fiberlength might not be a relevant mechanism. In apatient with mild right ventricular alternans, theydid not feel that they observed substantial alterna-tions in end-diastolic pressure. However, perusalof Figure 11 of their paper (the only tracing whichwas obtained during breath-holding) shows thatthe strong beat was initiated from a right ventricu-lar, end-diastolic pressure which was several centi-meters of H20 higher than that which was presentbefore the weak beat. This is most marked in thefirst four of the six beats of their tracing, and it isin these beats that the alternation of right ventricu-lar systolic pressure is greatest. A change of ven-tricular end-diastolic pressure of one or two cmH,0 can make a substantial difference in the end-diastolic fiber length and the stroke work of thesubsequent beat (21, 31). This interpretationof their data is strengthened by the recent observa-tions of Gleason and Braunwald, who studied serialvolume changes with biplane selective angiographyduring four consecutive beats in a patient withleft ventricular alternans (32). They not onlyfound that the left ventricular volume was smallerbefore the weak beat, but that there was a goodcorrelation between the end-diastolic volume andthe subsequent volume ejected.

Katz and Feil postulated that end-systolic vol-ume is smaller after the strong beat and that al-ternation of the diastolic period of filling was not

61

JERE H. MITCHELL, STANLEY J. SARNOFF, AND EDMUNDH. SONNENBLICK

a relevant variable (33). That end-systolic vol-ume is smaller after the strong beat was demon-strated by Straub (10) and by Wiggers (34)with biventricular oncometry, in the patient ofGleason and Braunwald (32), and by the segmentlength tracings shown above. It is self-evidentthat, if end-systolic volume is smaller and the in-flow period and gradient the same after the strongbeat, end-diastolic pressure and fiber length willbe lower before the weak beat. This must beconsidered a relevant variable in pulsus alternans,but the tracings shown above make it unwise toexclude variations in the time available for ven-tricular relaxation and filling.

SUMMARY

The data presented above and a considerationof the references cited seem to make possible a con-ceptual simplification of the phenomenon of pulsusalternans. The available evidence indicates thatthe weak beat is initiated from a shorter end-diastolic fiber length than is the strong beat,whether the end-diastolic pressure is lower, thesame, or higher. This can be brought about by aninadequate diastolic period for ventricular relaxa-tion, ventricular filling, or both, relative to the in-flow volume required to produce any given end-diastolic fiber length from any given end-systolicvolume. In this study, pulsus alternans occurredwhen the continuous level of myocardial contrac-tility was not sufficient for a given imposed heartrate, stroke volume, and aortic pressure to allowan adequate time for diastole before the weak beat.Pulsus alternans was abolished when an increasein myocardial contractility was induced by norepi-nephrine infusion or by reflex cardiac sympatheticnerve stimulation.

ACKNOWLEDGMENT

We gratefully acknowledge the valuable technical as-sistance of Mrs. Carrie Scott and Mr. Frank Perry.

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2. Lewis, T. The Mechanism and Graphic Registrationof the Heart Beat. London, Shaw and Sons, 1925.

3. Friedberg, C. K. Diseases of the Heart, 2nd ed.Philadelphia, W. B. Saunders Co., 1956.

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9. Wenckebach, K. F. Die unregelmassige Herztaitig-keit und ihre klinische Bedeutung. Berlin, Engle-mann, 1914.

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11. Gaskell, W. H. On the rhythm of the heart of thefrog, and on the nature of the action of the vagusnerve. Phil. Trans. B. 1882, 173, 993.

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21. Linden, R. J., and Mitchell, J. H. Relation betweenleft ventricular diastolic pressure and myocardialsegment length and observations on the contri-bution of atrial systole. Circulat. Res., 1960, 8,1092.

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THE DYNAMICSOF PULSUS ALTERNANTS

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23. Sarnoff, S. J., Gilmore, J. P., Brockman, S. K.,Mitchell, J. H., and Linden, R. J. Regulation ofventricular contraction by the carotid sinus. Itseffect on atrial and ventricular dynamics. Circulat.Res. 1960, 8, 1123.

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28. Siegel, J. H., and Sonnenblick, E. H. A dynamicindex characterizing the basic state of the myo-cardium. Circulat. Res. In press.

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33. Katz, L. N., and Feil, H. S. Clinical observationson the dynamics of ventricular systole. IV. Pulsusalternans. Amer. J. med. Sci. 1937, 194, 601.

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63