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The Splitting of the Second Heart Sound in Normal Subjects and in Patients with Congenital Heart Disease By MAURICE M. AYGEN, M.D., AND EUGENE BRAUNWALD, M.D. Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 with other forms of congenital heart disease (2) to provide hemodynamic-phonocardiographic correlations in these patients, (3) to demonstrate the effects of successful surgical closure of ASD on the splitting of the second heart sound, and (4) to present observations that provide an explanation for the mechanism of splitting of the second heart sound in normal subjects and in patients with ASD. Clinical Material ROUANET, in 1832, demonstrated that the second heart sound results from closure of the semilunar valves.1 In 1865, on the basis of clinical observations, Potain indicated that the second heart sound may be split into two components and that the degree of this splitting may vary with respiration.2 More recently the studies of Leatham and collaborators3 4 have focused considerable attention on the splitting of the second heart sound and, at the present time, precise characterization of this sound is of prime importance in auscultation of the heart. A physiologic basis for the interpretation of this auscultatory finding was first provided by Katz, in a study in which the timing of the dynamic events of the cardiac cycle in the two sides of the heart was determined, and slight asynchronv in the closure of the semilunar valves was noted.5 These observations were subsequently extended to human subjects with normal cardiovascular systems, in whom it was observed that pulmoniic valve closure followed aortic valve closure by 0.028 + 0.010 second.6 It is now well established that in normal subjects as well as in patients with many forms of heart disease, the time initerval between the sounds of aortic and pulmonary valve closure inereases with inspiration.3 4 7 It has been reported that in patients with atrial septal defects (ASD) this time interval is longer than in normal subjects during expiration and shows relatively little change during the respiratory cycle.8-10 The mechanisms responsible for these abnormalities are still under debate. The purpose of the present report is (1) to supply measurements of the effects of respiration and of the Valsalva maneuver on the second heart sound inl normal subjects, in a large series of patients proved to have ASD, as well as in patients F'rom the Cardiology Branch, National Heart Insti- This study is based on an analysis of the phonocardiograms obtained from 350 patients studied at the National Heart Institute between 1958 and 1961. The diagnosis was considered to be firmly established in every instance by means of detailed clinical examination and specialized studies. Right heart catheterization was performed on all patients with functional heart murmurs and congenital heart disease. In these patients the presence of a left-to-right shunt was detected by either the nitrous oxide1' or the inhaled Kr85 test.'2 In addition, all patients had dye-dilution curves further to characterize their circulatory shunts. The patients with aortic stenosis were all studied by left heart catheterization, which was generally carried out by the transbronchial, transseptal, or anterior percutaneous technic.13 The diagnosis was confirmed at operation in 194 of the 350 patients. The age range for each group of patients reported is presented in table 1. As indicated above, particular attention was directed to the effects of operation on the behavior of the second heart sound of patients with ASD. Preoperative and postoperative phonocardiograms were available for analysis in 31 patients, all of whom were operated upon with the aid of extracorporeal circulation; 29 had the ostium secundum or sinus venosus type of defect, while two had ostiumn primunii defects, i.e., a low atrial septal dedect with a cleft in the mitral valve. The postoperative phonocardiographic and cardiac catheterization studies were carried out 3 to 12 months after the operation. All phonocardiograms were taken on a SanbornTwin beam photographic recorder at a paper speed of 75 mm. per second ultilizing a logarithmic amplifying system. The recordings were obtained from the four valvular areas, and the tracing in whieh the second heart sound was most clearly defined tute, Bethesda, Maryland. 328 Circulation, Volume XXV, February 1962 329 SPLITTING SECOND HEART SOUND A2-P2 INTERVAL J+60 (mta I INSPI RATORY Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 -P2 1 +40 CHANGE OF INTERVAL -10 -lo -20 INSPIRATORY +10 CHANGE OF +20 +30 Q-A2 INTERVAL (msec) Figure 1 Effects the of inspiration abscissa, ordinate. snplitting normal with and on The of the who second from had the duration duration diagnoal subjects ASD on the of left of right ventricular systole of lines demonstrate the hea!rt sound. broken patients with pulmonary The ASD. artery puronary/systemic flow ratios less than was employed in the analysis. An electrocardiographic lead and indirect carotid pressure pulse were utilized for timing reference. Recordings were obtained during continuous spontaneous respiration and in many patients during and immediately Circulation, Volume XXV, February 1962 systole ventricular effects The mean solid triangles pressures 1.t/f.0, or line in along on width the separates represent eA.cess allong plotted inspiration diagonall plotted (Q-A2) (Q-P2) of most of the of the those patients 50 rm. Hg or both. after the Valsalva maneuver. In determining the time intervals between aortie and pulmonic valve closure, the longest interval recorded during inspiration and the shortest interval recorded during expiration in a single respiratory cycle AYGEN, BRAUNWALD 330 500 400 Table 1 Diagnosis and Age Distribution of Patients Studied I1 Number operNumber Ages (years) studied Range Average ated - 51 Normal I118 Atrial septal defect Pulmonic stenosis 30 Ventricular septal defect 68 Ventricular septal defect with pulmonic stenosis Tetralogy of Fallot Aortic stenosis Patent ductus arteriosus Total (msec) 300 200 _ 100 _A2- P2 O,L_ 14.2 27.1 14.1 20 11.9 40 2 23 12.0 5.8 13.7 12.8 3 3-9 4-32 2-41 0 80 6 30 13 194 I mr- v, 400 4-49 3-65 1-36 2-40 600 800 1000 1200 1400 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 PRECEEDING R-R INTERVAL (msec) Figure 2 Relationship between the preceding R-R interval and Q-P2, Q-A2, and A2-P2 in patient with ASD and atrial fibrillation. a were utilized for analysis. All measurements were made from the onset of the QRS and of each component of the second sound. The error of measurement was considered to be below 0.005 second. In the performance of the Valsalva maneuver the subject was asked to expire against a closed glottis with the chest in the mid-respiratory position for a period of several seconds, and then to relax without inspiring. The phonoeardiographic observations were carried out during and immediately after the Valsalva maneuver for a total of 8 to 10 cardiac cycles. Results Effect of Respiration on Q-A2, Q-P2, and A,-P2 In the 51 normal subjects the changes in the duration of the interval from the onset of ventricular depolarization to the aortic valve closure sound (Q-A2) during inspiration ranged from -20 msec. to +10 msee. and the average change was -5.2 msec. (fig. 1). Q-P2 increased during inspiration in all but one of these subjects. The maximum increase was 50 msec. while the average increase was 32.6 msee. The time interval between aortic and pulmonic valve closure (A2-P2) increased in all of the normal subjects, these increases ranging from 10 to 60 msee., with an average increase of 37.8 msec. In the patients with ASD a pattern differwas observed. The inspiratory increase of Q-P2 averaged only 4.6 msee. for the entire group, with an increase less thIan 20 msee. in 112 patients. Q-A2 showed no change during respiration in eight of the 118 patients, and in the remainder it increased or decreased up to 20 msec. The change in A2-P2 was much less during respiration than in the normal subjects. In 87 patients there was no change, and in 28 there was an increase of only 10 mnsee. In three patients the increase of A2-P2 equaled 40 msee., and they had either pulmonary hypertension (pulmonary artery mean pressure greater than 50 mm. Hg) or small left-to-right shunts. with pulmonary to systemic flow ratios less than 1.5/1.0 (fig. 1). Although Q-P2 and A2-P2 showed little change with respiration in patients with ASD, alterations in the duration of the preceding R-R interval resulted in significant changes in these time intervals. Phonocardiogramns were recorded at a constant respiratory position in four patients with ASD in whom atrial arrhythmias resulted in marked beat-to-beat variations in the R-R intervals. A representative result is plotted in figure 2 in which it is evident that as the preceding R-R interval lengthened, Q-P2 increased more than Q-Ao and, therefore, A2-P2 increased. ent from the normal Relationship between Heart Rate and the Duration of Systole The relationship between heart rate and the Circulation, Volume XXV, February 1962 331 SPLITTING SECOND HEART SOUND , ~~~I , 1 500 A 4501 _ 0- P2 ~~ A _ AM ~~~~~~~~A4 ^~~ INTERVAL 4001 DURING EXPIRATION (MSEC) A^aM A~~~~~~~~~ A A ~ ~~~A ~ A ~ , A Ab A _ /A AAA^t~AA @. A A~ AA AsA A< b * MA A A AAK ^ A/ a &//. A * A4 0 - @ * 0 A A A _ a 350[ A__- A < A * ~ * A A A Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 NORMAL 1 ASD 300 0 ~~~~~~~~~~ 130 120 100 110 90 80 60 70 50 HEART RATE/MIN Figure 3 Relationship between heart rate and and patients with ASD. Q-PI, recorded during expiration time interval from the onset of ventricular depolarization to the pulmonic valve closure sound (Q-P2) in normal subjects and in patients with ASD during expiration is shown in figure 3. It is clear that there is an inverse relationship between heart rate and Q-P2 in both groups of patients. The broken line outlines the highest values for Q-P2 encountered in the normal subjects. Although at any given heart rate there was considerable overlap between the values for Q-P2 in the normal subjects and in the patients with ASD, 62 of the 118 patients with this malformation had values of Q-P2, which exceeded the highest values observed in normal subjeets at similar heart rates. Similarly, 16 of the 30 patients with pure pulmonic stenosis (PS), 12 of the 67 patients with ventricular septal defect (VSD) and eight of the 10 patients with combined VSD and PS also had prolongation of Q-P2 above the greatest normal values. The other patients with the malformations listed above had values in the normal range. The Q-P2 and Q-A2 intervals in patients with congenital Circulation, Volume XXV, February 1962 in normal subjects aortic stenosis (CAS) and patent ductus arteriosus (PDA) also tended to be related inversely to the heart rate but showed no consistent deviation from the normal. Effect of Valsalva Maneuver A2-P2 on Q-A2, Q-P2, and In general, release of the Valsalva maneuexaggerated the effects of inspiration in normal subjects (fig. 4) but had relatively little effect on Q-P2, Q-A2, and A2-P2 in patients with ASD (fig. 5). In the normal subjects release of Valsalva increased Q-P2 by 15 to 75 msee. (av. = 40.7 msec.) ; Q-A2 changed by -30 to +10 msec. (av. = -9 msec.); A2-P2 increased by 20 to 80 msee. (av. = 49.7 msec.). In contrast, in the 42 patients with ASD studied, the change of Q-A2 after release of the Valsalva maneuver ranged from -20 to +20 msee. (av. = +1.4 msec.) ; the change of Q-P2 ranged from -10 to 50 (av. = +4.7 msec.) and A2-P2 increased by an average of only 3.3 msec. (fig. 6). Thus, it is evident that analysis of changes in Q-A2 and Q-P2 following release of Valsalva permits separation of ver 332 .L@sve t,;e>/'\+_^- A2 :LT.4 laCes. E NoE1 '.." :1 t" I .A AP S1 . r- -r ~~~~~~~~~- 1. -1 U . -- -. - . . . -N '. S -- - --N -1 7-1.4- Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 A2 LT. 4 t.C.S. :... J.1 -iNA _..I kA 6& I _1VOilk _- -- -- I rw -VP Iv"rm vr-I -- - I Ir y w ... 1. w _o. ; 4 :::.4:: Aa arrI A_ _+ . 5_ ," b:! * 8 A.. t s° wL t ..... I SL - L . AI A-- L f 8 A ........... .VA v -I rep)res(utatire phonocardl(fio('(firlrecorde(d i lrs.,left fourthi intercostal _T4 t..+.._... 4.ALV_A Figure 4 fromn a normal (top) aind the Valsalra mnurneuver (bottomii). SI, 1st heart x + ffi t 0 r -. t- I .. i + ? ._+_.. :PS. *03-06-51 A J 5_._ e 3 is F v i 4 4 s W .w _ - Y Ar --. ,}----5 ---- - - -Y A - e I. ... J ft CE :: ;:tv .. _ I~ _. .- -1.'i -.- 44 __48.z.... .A.. +, ^ ;i_ .1 -, - M--- rP , --1 I I 1. ... a * . A2 P2 E J AP2 A Pt St. It 717..-i-i ._°+AV: w;S-E AYGEN, BRAUNWALD s +. e ^4 t; .. ._.f, ,i,t X g subject during respiration sound; F,, ejection sound, LT. spa(e. normal subjects fromn patients with ASD. Again the )atieLlts with this malformation whose values were similar to those encountered in niormal subjects had severe pulrnonlary hypertenision or a very small left-to-right shunt. A2-P2 during the Respiratory Cycle Normal Subjects During expiration in normal subjects A2-P2} ranged from 0 to 40 msec., with anl average of 10.6 insee. (fig. 7). As already indicated, this time interval increased during inspiration in all these subjects. In general there was an inverse correlationl between A2-P2 dur- ing expiration and the augmenitation of this iinterval durinig inspiration (fig. 7). ASD, Preoperative In patieents with ASD the expiratory A2-P2 tended to be greater than in the normal subjects and averaoed 50.2 msee. The inspiratory augmentation of this interval was less than in normal subjects. One hundred and thirteen of the 118 patients with ASD had expiratory A2-P2 intervals of at least 30 msece. and an inspiratory auglmentation of less than 20 msee. but only one normal subject had an A2-P2 interval that fell withlin these limits. Of the five patients with ASD who did not fall into these Circulation. Volume XXV, February 1962 s -rrv 33 SPLITTING SECOiND HEART SOUND *~~~~E E il Ii -M rUT1fl7TTfflTTt~~~~LIii.tI 7 010 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 2 S M -Ak LT. S I S. i . im4w O' ,1. ... .... .... ... v VA J. 11 S m 0m A R S S m D -00A" .1 44 T.7- A %AI Figure 5 Phoi,iocai-diogram, recorded iiz the secoiid le ,ft intercostal space (LT. 2 i.c.s.) in a patient with ASD du?-iizg respiration (top) (iiid the Valsalra maiw?tcer (eenter). I'he bottom tracing shows a simitltaizeous iizdirect carotid pulse trachig ajid the broken vei-tical Iiiie above the incisura identifies A2- S-11, systolic ?nu)-?)zu?,; D.11, diastolic murmur. limits three had severe pulmonary y sion both or as small defined above oill a hyperten- left-to-right shunt, (flo,. 7). Circulation, Volume XXV, February 1962 or A2-P2duringr iiorirnal and immediately after release of The averacre values for n respiration, the Valsalva maneuver in the normal subjects 334 3AY GEN, BRAUNWALD Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 CHANGE OF Q -P2 INTERVAL 40 AFTER RELEASE OF VALSALVA | 0 0/ I0 -20 2 -0 +30 +20 0 + t0 -20 -30 -10 CHANGE OF Q-A2 INTERVAL AFTER RELEASE OF VALSALVAI(MSEC) Figure 6 Effects of release of the Valsalva maneuver on Q-A2, Q-P2, and A 2-P2. For explanation see legend of figure 1. and in the patients with ASD are summarized in figures 8 and 9. A SD, Effect of Operation At the time of the postoperative catheterizations it was observed that the left-to-right shunts had been completely abolished in 29 of the 31 patients with ASD. In the other two patients the magnitude of the shunit was reduced from the preoperative level but it had not been completelv eliminated. There was a distinct tendency for A2-P2 to return to normal limits following successful surgical dloCirculation, Volume XXV, February 1962 335 SPLITTING SECOND HEART SOUND INSPIRATORY INCREASE OF A2-P2 INTERVAL (msec) 40I& A,A * A.S.D. Normol 30 20 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 I0 I AA A 0 0 10 50 60 70 80 30 40 A2P2 INTERVAL DURING EXPIRATION (msec) 20 9( 0 100 Figure 7 A2-P2 during expiration, plotted along the abscissa, and the increase of this interval during inspiration, plotted along the ordinate. The absolute duration of A2-P2 during inspiration is equal to the sum of the two values plotted. sure (figs. 10 and 11). A decrease in A2-P2 during expiration occurred in 29 of the 31 patients; one of the two exceptions had pulmonary hypertension and normal splitting of the second heart sound prior to operation. Following complete closure of the defect the inspiratory increase of A2-P2 exceeded 10 msee. in 26 of the 29 patients. The two patients with residual left-to-right shunts exhibited a decrease in the expiratory A2-P2 interval from that observed preoperatively, but showed an augmentation of only 0 and 10 msec. respectively during inspiration (fig. 10). Thus, in the postoperative period both of these patients exhibited splitting of the second heart sound, which was indistinguishable from that observed in patients with unoperated ASD (fig. 7) but which could be differentiated from the pattern of splitting observed in those patients whose defects had been successfully closed. Circulation, Volume XXV, February 1962 Pulmonic Stenosis The expiratory A2-P2 interval and its augmentation during inspiration in the normal subjects and in the patients with pulmonic stenosis (PS) is plotted in figure 12. During expiration A2-P2 was less than 40 msee. in 46 of the 51 normal subjects and in all six of the patients with PS whose peak systolic pressure gradients between the right ventricle and pulmonary artery were less than 20 mm. Hg. In contrast A2-P2 during expiration equaled 40 msee. or more in all 24 patients with PS whose pressure gradients exceeded 20 mm. Hg. During inspiration the augmentation of A2-P2 was within normal limits in these patients (fig. 13). Aortic Stenosis, Patent Ductus Arteriosus During expiration A2 and P2 were fused and occurred synchronously in 38 of the 44 patients with congenital aortic stenosis (AS). In the other six patients A2 followed P2 by AYGEN, BRAUNWALD 336 Table 2 Systemic and Pulmonary Arterial Oxygen Saturation in Patients with ASD Patients Age (years) Arterial 02 sat. _ NORMAL P.A. 02 sat. P.A. 02 sat. during insp. during exp. 91.4 85.0 94.6 13 G.G. 82.7 77.2 93.2 7 F.D. 85.9 83.0 93.0 39 P.S. 91.5 90.0 22 99.0 H.J. 88.8 85.8 19 97.0 K.E. 90.0 88.8 8 92.9 M.M. 12 90.0 88.0 96.0 M.A. 88.0 94.0 84.0 9 L.B. 88.8 85.2 95.0 Mean ASD, atrial septal defect; Insp., inspiration; Exp., expiration. Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 20 to 40 msee., i.e., the A2-P2 interval was negative (fig. 14). In 21 patients with AS there was no inspiratory increase of A2-P2. In the others this increase ranged from 10 to 60 msee., as in the normal subjects. When the combination of A2-P2 during expiration and the change of this interval during ilnspiration are considered, it was observed that 29 of the 44 patients with congenital AS fell ontside the range encountered in the normal subjects (fig. 14). In 12 of the 15 patients with AS in whom A2-P2 fell into the normal range, the peak systolic pressure gradients between the left ventricle and brachial artery measured at left heart catheterization was less than 75 mmn. Hg. The behavior of the second heart sound in patients with PDA resembled that observed in patients with congenital AS. During expiration A2 and P2 were fused in eight patients, neaative in four, and positive in only one patient. When the combination of the expiratory A2-P2 and its change during inspiration was considered, seven of the 13 patients with PDA fell outside the range encountered in the normal subjects (fig. 14). Other Malformations In patients with ventricular septal defect (VSD), the relationship between the two components of the second heart sound was observed to fall into the normal range with only an occasional exception. There was a lower incidence of a single second heart sound dur- j *-EXPIRATION-|- - INSPIRATION MSECI 20 1--4 Q--p2 . ~ St.4I0.6 ,1 ~~ lo| o I ASD -EXPIRATION M II SECl_4- * - I - INSPIRATION t 2 3 4 5 6 HEART BEAT Figure 8 Average values for A2-P2 during respiration in normal subjects and patients with ASD. ing expiration in the patients with VSD and large left-to-riaht shunts than in the normal subjects. In 16 patients with PS, VSD, and a rightto-left shunt (tetralogy of Fallot) only one component of the second heart sound could be recorded; simnultaneous carotid pulse tracings ilndicated that this was the sound of aortic valve closure (A2). Effect of Respiration on Pulmonary Arterial Satur.-Ition in Patients with ASD Oxygen In order to elucidate the mechanism responsible for the relative constancy of A2-P2 during respiration in patients with ASD, blood samples were withdrawn from the pulmonary artery first during inspiration and then during expiration. Several respiratory cycles were required to obtain each sample, and the oxygen saturatiolns were determined by the manometric method of Van Slyke and Neill. In each of the eight patients studied, the pulmonary arterial oxygen saturation during expiratioln exceeded the saturationl during inspiration (table 2); the average difference in saturation was 3.6 per cent. The oxygen saturation of mixed venous blood proximal to the entry of the left-to-right shunt was calculated from the arterial oxygen saturation and Circulation, Volume XXV, February 1962 33S7 SPLITTING SECOND HEART SOUND Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 the pulmonary/systemic flow ratio determined by the Kr85 test.'4 Assuming the durations of inspiration and expiration to have been equal, it was then possible to calculate the shunt/ systemic flow ratio during both phases of the respiratory cycle. In each of the patients this ratio was greater during expiration (av. = 1.80/1.00) than during inspiration (av. = 0.64/1.00). Discussion In the present study the onset of ventricular depolarization (the Q wave of the electrocardiogram) was chosen as the reference point for all measurements, since this point can be easily recognized on all tracings. The time interval between the onset of ventricular depolarization and of closure of either of the semilunar valves (Q-A2 and Q-P2) actually represents the sum of three periods: (1) the interval between the onset of ventricular depolarization and the onset of ventricular contraction, (2) the duration of isometric ventricular contraction, and (3) the duration of ventricular ejection. The first two of these periods remain virtually constant under a wide variety of conditions and constitute only a small fraction of the total interval between the Q wave and the second heart sound. It is considered that in the absence of gross abnormalities of intraventricular conduction, changes in Q-P2 and Q-A2 represent changes in the duration of right and left ventricular ejection respectively. Consideration of the well-established fact that the duration of ventricular ejection varies directly with the stroke volume15 permits explanation of the observed effects of respiration and of the Valsalva maneuver on the splitting of the second heart sound in normal individuals. Inspiration augments the inflow,16 the effective filling pressure,'7 the end-diastolic volume,18 and the stroke output'9 of the right ventriele and has an opposite but smaller effect on the left ventricle.'9 This explains the prolongation of Q-P2 and the simultaneous shortening of Q-A2 during inspiration, resulting in an increase in A2-P2. It has been suggested by Boyer and Chisholm20 and more recently by Shafter2' that in normal Circulation, Volume XXV, February 1962 I I ASD -VALSALVA-1-POST VALSALVA- r--< 1~20 _ M SEC (gPZ - . I_ 51.9 56.2 *0 1 _ 0- 4 5 6 _ .1 I 2 3 HEART BEAT Figure 9 Average values for A2-P2 during and immediately after release of Valsalva in normal subjects and patients with ASD. individuals the inspiratory abbreviation of left ventricular systole is approximately equal to the prolongation of right ventricular systole. The observations on normal subjects presented in figure 1 are not consonant with these views. Of the average inspiratory increase of A2-P2 of 37.8 msee., 32.6 msec. or 86 per cent was contributed by prolongation of right ventricular systole and only 5.2 msee., or 14 per cent, by shortening of left ventricular systole. In only seven of the 51 subjects did the shortening of left ventricular systole during inspiration equal or exceed the prolongation of right ventricular systole. The observation that during respiration the duration of left ventricular systole is altered far less than the duration of right ventricular systole is also consistent with the experimental observations that the respiratory variations in the filling and stroke volume of the right ventricle exceed those of the left.'9 The abnormally wide splitting of the second heart sound in patients with ASD is a wellknown clinical sign.8 9, 22 It was suggested that the alterations in the pattern of right ventricular depolarization commonly observed in patients with this anomaly may account for AYGEN, BRAUNWALD 338 INSPI RATORY INCREASE OF 4 A -P INTERVAL (msec) 30 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 20 0 l0 50 80 60 70 40 (msec) AP2 INTERVAL DURING EXPIRATION 20 30 9l 0 100 Table 10 interval during expiration and the increase of this interval during inspiration in patients with ASD prior to and following operation. A2-P2 the delay in pulmonic valve closure. However, hemodynamic studies in patients with ASD and so-called "incomplete right bundle-branch block" have clearly established that there is no prolongation of the time interval between the onset of ventricular depolarization and of right ventricular contraction.9 23 In addition, the observations of Leatham8 and of Perloff and Harvey,24 have shown that following surgical closure of ASD the splitting of the second heart sound often demonstrates a normal pattern while the electrocardiographic changes characteristic of this malformation persist. As shown in figure 3, at any given heart rate, right ventricular systole tends to be longer in patients with ASD than in normal subjects. In patients with this malformation the stroke volume of the right ventricle is abnormally large and exceeds that of the left ventricle. All these considerations suggest that prolongation of right ventricular ejection is responsible for the abnormally wide split- ting of the second heart sound in these patients. Another important characteristic of the second heart sound in patients with ASD is that the wide splitting tends to show little variation during the respiratory cycle. Leatham and Gray observed no measurable change in the time interval between the two components of the second heart sound in 21 of 30 patients with ASD,8 whereas Shafter found that among 16 patients the maximum change with respiration was 29 msee.A In the present series of patients with ASD it was observed that in 87 there was no measurable change in A2-P2, and that in 30 there was an increase of 5 to 10 msec. The three patients with larger changes had severe pulmonary hypertension and only small left-to-right shunts (figs. 1 and 7). The mechanism for this tendency of the splitting of the second heart sound to show little, if any, variation during the respiratory cycle is not clear. Leatham and Gray considCirculation, Volume XXV, February 1962 339 SPIjITTING SECOND HEART SOUND MM Al Agl fP .T 'TTIM rrrTqM'W "I -ITIT -V-" " i L LiSui. T 'FM - -LA -A AA. f 44000-- --pON POST OP Vtu{-;:0Ii "Opt1' Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 1 I I- I Vp..A - ±AliLInAHLLLHnLd Inso 1 mm .- - "| Pa' Aa i I.--h nt -AiW.L- - a Vf]-' 11PPP1 -II 7l11F. ,.A - iFui971 I] .w I0 I1 TTIT,Fj Figure 11 Phonocardiogram recorded prior to (top) and folloving (center and bottom) szccessful surgical closure of an ASD. Preoperatively there is wide, fixed splitting of the second sound. Postoperatively the second sound is single during expiration and the Valsalva maneuver. ered the inequality of right and left ventricular outputs to be the responsible factor.8 It has also been suggested that in these patients the "overfilled" right ventricle cannot further au(gment its filling during inspiration and therefore does not inerease its stroke volume.24 If this hypothesis were correct, however, it would be anticipated that the duration of right ventricular ejection would be shortened when the systemnic venous return is impeded by prolonged expiration or by the Valsalva maneuver. It has been shown by Perloff and hTarvey24 as well as in figure 2, that the duration of right ventricular systole in patients with ASD does not always remain constant. Tn the presence of changes in the duration of diastole (lue Circulation, Volume XXV, February 1962 to atrial arrhythmias, Q-P2 and A2-P2 were found to increase with the R-R interval. In the same patients no variation in A2-P2 was observed throughout the respiratory eycle. Thus it is apparent that when changes in right ventricular fillinlg do occur in patients with ASD the duiration of righlt ventr-icular ejection and the degree of splitting of the second heart sound may be altered. Au alternative explanation for the tenideney to fixation of splitting of the, second heart sound in patients with ASD is that (duiring the respiratory cycle the two venous systems (systemic and pulmonary) that contribute blood to the right ventriele vary the manitude of their contributions reciprocally. As already mientioned, in normial subjects the in- AYGEN, BRAUNWALD QA0 7rl. r . .I 19 ^ l I lI I I 'I.~~~~~~~~~~~~~~~~~~~~~~~~~~~ 50 I * Normal Pulmonic Stenosis Gradient>20mm Hg 0 Pulmonic Stenosis Gradient < 20 mm Hg I 60 I @00 I NSPIRATORY 40 INCREASE OF AiPINTERVAL RMSEC) 30 * * l0 _ °- ON oW we *t @0 20 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 10 I 0 0 0 000 0 000 0 0 0 00 0 0 0 0 000 OSO @0 O 00 II I I. 0 10 20 30 40 50 60 70 80 90 100 A2-P2 INTERVAL DURING EXPIRATION (MSEC) Figure 12 A2-P2 during expiration and increase of this interval during inspiration in normal subjects and patients with PS. The broken vertical line separates the majority of these patients. flow of blood into the right heart from the systemic venous bed is augmented during inspiration and a decline in filling of the left side of the heart takes place simultaneously. It is suggested that this sequence of events is not disturbed in patients with ASD. If one considers that in these patients the two atria form a common reservoir for the filling of the ventricles, then the effect of inspiration on the stroke volume of the ventricles would be determined by the net effect of inspirations on the inflow into this common atrial reservoir. When the inspiratory augmentation of the systemic venous return is balanced by an equal decrease in pulmonary venous return, no significant inspiratory change of inflow into the atrial reservoir, of ventricular filling and discharge and, therefore, of Q-P2, Q-A2, and A2-P2 would be expected. Indeed, no change in these intervals was observed in 63 of the patients with ASD studied. However, if there is a net augmentation of inflow into the atrial reservoir during inspiration, an increase of the filling and discharge of the ventricles and a prolongation of both Q-A2 and Q-P2 would be expected; in 25 of the patients with ASD there was an inspiratory increase of both Q-P2 and Q-A2. If the inspiratory decline in pulmonary venous filling exceeds the simultaneous augmentation of right ventricular filling, then a shortening of the duration of ventricular ejection would be expected; this occurred in only two patients. Under all circumstances, the exact distribution of blood between the two ventricles depends on the relative compliance of these chambers during diastole.25 If, as described above, respiratory variations in the magnitude of the inflow of blood from the systemic and pulmonary venous beds into the atria takes place, it would be anticipated that variations in the magnitude of the left-to-right shunt would also occur. Suggestive evidence that the left-to-right shunt actuCirculation, Volume XXV, February 1962 341 SPLITTING SECONI) HEART SOUND Az00030000: A2V82 s P2 LT. 2: S,i. t9t . C4Sp ' 2 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 : .I. P2 ' SI $;M ::P* 00-87-67: :N Figure 13 A representative phonocardiogramn -ecordled from a patient with PS. AlIthough there tz signtificant splittinzg of the second sounid during expiratio, A 2-P2 increases further during inspiration. ally diminishes duringr inspiration and becomes augmented duLring expiration xwas provided by the observation that in patielnts with ASD the oxygetn saturationi of blood withdrawn from the pulmonary artery during expiratioln exceeds the saturation of blood withdrawn duringc inspiration (table 2). In conclusion, these considerations woould suggest that the relative constaiicy of the splitting of the secoind heart sound ini patienits witlh ASD is not due to ani inability of the right ventricle to augment its stroke output during inspiration,24 but it is postulated that the conistancy of splittincr is due to reciprocal changes in the magnitude of the left-to-right shunt and Circulation, Volume XXV, February 1962 the systemic venous inflowv into the right ventriele duLring respiration. Reg,ardless of the exact meehanism underlying the variations in the splitting of the seconid heart souncd, precise auseultatory anid phonocardiographic analyses of the effects of niormal respiration and of the Valsalva maneuver on this sounid are of areat clinieal value. In additionl to indicatin-g the time of closure of the pulmonic alid aortic valves, the relative intenisities of the two compolnen-ts of the seconid heart sounld provide some informatioln regardingr the relative levels of pressure in the pulmonary artery and aorta. The width of splitting, duriin expiration and the mag- AYGEN, BRAUNWALD 342 7n IU -- 60 I I I I I II * Normal A A.S. o P.D.A. - * I. 50 INSPIRATORY INCREASE OF 401 A2-P, INTERVAL D. (msec) 301 II A. 0 0 0 ~~~~I AA 1 A 0 * *0 L__ .----' 20 m AO A A A Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 1l- I so I I XI. a &£ * S! i: MAAI As -50 I IIa I -30 -10 -40 -20 Ai P. INTERVAL A) I 10 20 I i 30 40 50 DURING EXPIRATION (msec) Figure 14 A2-P2 interval during expiration, and the increase of this interval during inspiration in normal subjects and in patients wtith AS and PDA. WVhen A2 followed P2 the A2-P2 interval was considered to be negative. All values to the left and below the broken line were outside of the normal range. nitude of the changes in this time interval during inspiration can generally be appreciated by careful auscultation, but pholiocardiographic tracings are necessary for precise measurements. In the vast majority of patients with ASD the inspiratory increase o A2-P2 is 10 msee. or less. An increase of 10 msec. was found in only two of 51 normal subjects, and it would seem appropriate to designate a change of A2-P2 up to 10 msee. during normal respiration as "fixed splitting" of the second heart sound. It is of interest that the three patients with ASD who did not demonstrate fixed splitting did not have the hemodynamic features that are typical for ASD; all three had very small left-toright shunts and one also had severe pulnmonary hypertension. In normal subjects the Valsalva maneuver tends to exaggerate the changes in Q-P2, Q-A2. and A2-P2 observed during quiet respiration (figs. 4, 6, and 9), but this maneuver does ilot abolish the "fixed splitting" of the second sound in patients with ASD (fig. 5). In the normal subjects the mean increase of A2-P2 during inspiration equaled 37.8 msec.: this time interval increased to an average of 49.7 msec. followinlg the Valsalva maneuver. In conitrast, A2-P2 increased by a mean value of only 3.3 msee. both during inspiration and following the Valsalva maneuver in patients with ASD. During auscultation this maneuver has been found to be helpful in distinguishing patients with ASD from those subjects who on clinical examination tend to show little variation in A2-P2 during normal respiration. We have encountered five patients without ASD, includinog two subjects without cardiovascular disease, who demonstrated "fixed splitting" of the second heart sound during normal respiration phonocardiographically and in whom greater changes in A,-P. were Circulation, Volume XXV, February 1962 SPLITTING SECOND HEART SOUND 343 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 RSS 03-39-46 Figure 15 phonocardiogroim recorded from a potifrt with sevecre A-S. There is paradoxicual splitting of the seco U]c heart sotmd, wcih issi.iigle during inspirationz but sRplit: dar iM, etpitrotion. Thle carotid pulse (l()w(owi trajing) shows thait A2 follows' P2. A representative observed following the Valsalva manieuver. Exaggeration of the chainge in splitting of the second hieairt sounid by this mnaneuver has also beeni of conlsiderable aid during cardiac auseultation of patients witlh unlusuiallyv wide splitting of this sounid during expiration. In such patients any given change in A%-P2 is far more difficult to appreciate by auseultation than a simailar chalnge iln patients Awitl shorter A2-P2 initervals. In the iilmmediate postoperative period following repair of an ASD somne patients show little, if any, change of A2-P2 during, nornail] resliration. These patienlts also showed a norinal increase of A2-P2 followingr the Valsalva maneuver. When studied 3 to 12 mnonths following operation the seconid heart sound tended to exhibit a normal patternii during quiet respiration in those latients in whioi the defects Awere closed. In two patients wvithi residual slhun-ts, however, distinctly ahbnormal splittingy persisted. Thlus, phonocardiocraphic study in the posto)erative period is a useful technici itl the elinical iassessm-iient of patienits with ASD (fig. 10). In the patients with moderate or severe PS and an initact ventricular septum, A2-P2 durCirculation, Volume XXV, February 1962 iLglr expiratioil tended to be prologlmd al(li iti the samne racrne as observed in patients with ASD. The patients with PS showed a greater increase in this initerval during inspiration, however, than did those with ASD. In both patients with PS and fixed splitting of the seconid heart sound, illustrated in figure 12 a nornmal increase of A2-P2 occurred following, the Valsalva maneuver. These results are in agrreement with those of Leathamn and Weitzman26 and of other inivestigators.27 9 As in patients with ASD with a small shuint, muildl degrees of PS generally result in nornial splitting of the second heart souiid. The increased resistance to riglht ventricular ejeetioni in these patients is apparently the cause of the prolongation of Q-P2 and the abnrormnally wide splittinig of the second heart sournd. When a VSD is associated wit]l obstructioi-i to right ventricular outflow, tliere is only a tendency to abnormnal prolongationi of A2-P1 durinicg expiration in those patienits with a large left-to-right shunit. When the obstruetion to right ventricular ejection is severe anid there is a large right-to-left slhunt (tetralogy of Fallot) tlhe pulmonarv elosuire sotund eaninot usually be recorded. 344 Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 In patients with obstruction to left ventricular outflow, there is a tendency to prolongation of left ventricular ejection,30 and this is reflected either in reversal of the normal sequence of semilunar valve closure or simultaneous valve closure during expiration (figs. 14 and 15). In those patients in whom the sequence is reversed, prolongation of Q-P2 and abbreviation of Q-A2 occur during inspiration, resulting in narrowing of the P2-A2 interval. This abnormality has been termed "paradoxical" splitting of the second heart sound, and it is also evident in some patients with patent ductus arteriosus (fig. 14) in whom the prolongation of left ventricular ejection is presumably related to the increased stroke volume of the left ventricle. Summary The characteristics of the second heart sound were analyzed in 350 phonocardiograms recorded from patients in all of whom the diagnosis was proved either at operation or by detailed catheterization studies. A2-P2 during expiration averaged 10.6 msec. in normal subjects. Q-A2 changed little during inspiration, with an average decrease of only 5.2 msee., while Q-P2 increased by an average of 32.6 msec. The average increase of A.-Po during inspiration was therefore 37.8 msec. In patients with ASD, A2-P2 during expiration averaaed 50.2 msee. and the inspiratory change in Q-P2 averaged only 4.6 msec. In 115 of 118 patients with ASD the inspiratory inerease of A2-P2 ranged from 0 to 10 msee. Following successful surgical closure 29 patients with ASD developed the normal inspiratory augmentation of A2-P2; in the two patients in whom the defect was not completely closed the relatively constant A2-P2 noted preoperatively persisted. Release of the Valsalva maneuver exaggerated the inspiratory increase of A2-P2 observed in normal subjects but did not modifv this interval in patients with ASD. Analysis of the effect of release of the Valsalva maneuver on A2-P2 was helpful in separating patients with ASD from normal subjects. Evidence was presented that the relative constancy of the splitting of the second heart AYGEN, BRAUNWALD sound in patients with ASD is due to reciprocal changes in the magnitude of the left-toright shunt and the systemic venous inflow into the rigrht ventricle during respiration. In patients with moderate or severe pulmonary stenosis, A2-P2 during expiration was longer than in normal subjects and in the same range as in patients with ASD. However, patients with PS showed a normal augmentation of A2-P2 during expiration. In patients with congenital AS, and those with PDA, left ventricular ejection tended to be prolonged with reversal of the normal sequence of semilunar valve closure or simultaneous closure of these valves during expiration. Acknowledgment The cooperation of Dr. Andrew G. Morrow and of the staff of the Clinic of Surgery, National Heart Institute, is gratefully acknowledged. References 1. ROUANET, J.: Analyse des bruits du coeur. Paris thesis, No. 252, 1832. 2. POTAIN, M.: Note sur les dedublements normaux des bruits du coeur. Bull. et m6m. Soc. med. hop. Paris 3: 138, 1866. 3. LEATHAM, A., AND TOWERS, M.: Splitting of the second heart sound in health. Brit. Heart J. 13: 575, 1951. 4. LEATHAM, A.: Splitting of the first and second heart sounds. Lancet 2: 607, 1954. 5. KATZ, L. N.: The asynchronism of right and left ventricular contractions and the independent variations in their duration. Am. J. Physiol. 72: 655, 1925. 6. BRAUNWALD, E., FISHMAN, A. P., AND COURNAND, A.: Time relationship of dynamic events in the cardiac chambers, pulmonary artery and aorta in man. Circulation Research 4: 100, 1956. 7. MCKUSICK., V. A., REAGAN, W. P., SANTAS, G. W., AND WEBB, G. N.: The splitting of heart sounds. Am. J. Med. 19: 849, 1955. 8. LEATHAM., A., AND GRAY, I.: Auscultatory and phonocardiographic signs of atrial septal defect. Brit. Heart J. 18: 193, 1956. 9. WOOD, P.: Discussion of splitting of P2 in ASD. Brit. Heart J. 20: 267, 1958. 10. McKusicK, V. A.: Cardiovascular Sound in Health and Disease. Baltimore, The Williams and Wilkins Company, 1958. 11. SANDERS, R. J., AND MORROW, A. G.: The diag- nosis of circulatory shunts by the nitrous oxide test. Circulation 18: 856, 1958. Circulation, Volume XXV, February 1962 SPLITTING SECOND HEART SOUND Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 12. SANDERS, R. J., AND MORROW, A. G.: The identification and quantification of left-to-right circulatory shunts. A new diagnostic method utilizing the inhalation of a radioactive gas, Krm. Am. J. Med. 26: 508, 1959. 13. MORROW, A. G., BRAUNWALD, E., AND ROSS, J., JR.: Left heart catheterization: An appraisal of techniques and their applications in cardiovascular diagnosis. Arch. Tnt. Med. 105: 645, 1960. 14. SANDERS, R. J., CoopyR, T., AND MoRRow, A. G.: An evaluation of the nitrous oxide method for the quantification of left-to-right shunts. Circulation 19: 898, 1959. 15. BRAUNWALD, E., SARNOFF, S. J., AND STAINSBY, W. N.: Determinant of duration and mean rate of ventricular ejection. Circulation Research 6: 319, 1958. 16. BRECHER, G. A., AND HUBAY, C. A.: Pulmonary blood flow and venous return during spontaneous respiration. Circulation Research 3: 210, 1955. 17. LAUSON, H. D., BLOOMFIELD, R. A., AND COURNAND, A.: The influence of the respiration on the circulation in man. Am. J. Med. 1: 315, 1946. 18. BOYD, T. E., AND PATRAS, If. C.: Variations in filling and output of the ventricles with the phases of respiration. Am. J. Physiol. 134: 7, 1941. 19. SHULER, R. H., ENSOR, C., GUNNING, R. E., Moss, W. G., AND JOHNSON, V.: The differential effects of respiration on the left and right ventricles. Am. J. Physiol. 137: 620, 1942. 345 20. BOYER, S. H., AND CHISHOLM, A. W.: Physiologic splitting of the second heart sound. Circulation 18: 1010, 1958. 21. SHAFTER, H. A.: Splitting of the second heart sound. Am. J. Cardiol. 6: 1013, 1960. 22. BARBER, J. M., MAGIDSON, O., AND WOOD, P.: Atrial septal defect. Brit. Heart J. 12: 277, 1950. 23. BRAUNWALD, E., DoNoso, E., SAPIN, S. O., AND GRISHMAN, A.: Riglht bundIle branch block. Hemodynamic, vectorcardiographic and electrocardiographic observations. Circulation 13: 866, 1950. 24. PERLOFF, J. K., HARVEY, W. P.: Mechanisms of fixed splitting of the second heart sound. Circulation 18: 998, 1958. 25. DEXTER, L.: Atrial septal defect. Brit. Heart J. 18: 209, 1956. 26. LEATHAMT, A., AND WEITZMAN, D.: Auscultatory and phonocardiographic signs of piulmonary stenosis. Brit. Heart J. 19: 303, 1956. 27. ABRAHAMS, D. G., AND WOOD, P.: Pulmonary stenosis with normal aortic root. Brit. Heart J. 13: 519, 1951. 28. CREVASSE, L., AND LOGUE, R. B.: Valvular pulmonic stenosis: Auscultatory and phonocardiographic characteristics. Am. Heart J. 56: 898, 1958. 29. VOGELPOEL, L., AND SCHRIRE, F.: Auscultatory and phonocardiographic assessment of pulmonary stenosis with intact ventricular septum. Circulation 22: 55, 1960. 30. GRAY, I. R.: Paradoxical splitting of the second heart sound. Brit. Heart J. 18: 21, 1956. The Early History of Instrumental Precision in Medicine The true rate of advance in medicine is, however, not to be tested by the work of single men, but by the practical capacity of the mass. The truer test of national medical progress is what the country doctor is. How useful, how simple, it seemed to count the pulse and respiration, or to put a thermometer under the tongue, and yet it took in the one case a cantury, and in another far more, before the mass of the profession learned to profit by the wisdom of the few.-S. WEIR MITCHELL, MD., Transactions of the Congress of American Physicians and Surgeons held at Washington, D.C., 1891. New Haven, The Congress, 1892, p. 180. Cfrcuiation. Volume XXV. February 196* The Splitting of the Second Heart Sound in Normal Subjects and in Patients with Congenital Heart Disease MAURICE M. AYGEN and EUGENE BRAUNWALD Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017 Circulation. 1962;25:328-345 doi: 10.1161/01.CIR.25.2.328 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1962 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. 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