Festschrift for Sir John McMichael

The systolic murmur in hypertrophic obstructive cardiomyopathyand the nature of the obstruction

M. NELLEN M. S. GOTSMANCardiac Clinic, Department of Medicine, Groote Schuur Hospital,

and Council for Scientific and Industrial Research Cardiovascular-Pulmonary Research Group,Department of Medicine, University of Cape Town

PATIENTS with hypertrophic obstructive cardio-myopathy present with dyspnoea, angina pec-toris, palpitations, fatigue or syncope, but thesystolic murmur should draw attention to thecondition. The murmur begins after the firstheart sound, has a crescendo-decrescendo con-figuration and has its maximum intensity to theright of the mid-systolic point. It is best heardin the fourth left intercostal space, radiates tothe apex and base of the heart and has a harsh,low-pitched quality. It varies in intensity frommoment to moment-occasionally it is loud, atother times it may be soft or absent. Othernotable features on auscultation are the strikingfourth heart sound, a softer third heart sound,left and right-sided mid-diastolic flow murmursdue to inflow obstruction and occasionally para-doxical or partial paradoxical splitting of thesecond heart sound due to prolonged left ven-tricular ejection. An aortic early diastolic mur-mur is occasionally heard and may be due todistortion of the aortic valve ring by asymmetri-cal hypertrophy (Braunwald et al., 1954a, b;Tucker et al., 1966; Goodwin, 1967).We do not know whether the hypertrophy or

gradient in the cases where right ventricularinvolvement has been described either alone orwith left ventricular disease is sufficient to causea systolic murmur within the right ventricularsystem, but this is probable. In a recently des-cribed case of apparently purely right ventricularinvolvement, a harsh loud ejection systolic mur-mur was heard best at the left sternal borderand apex (Falcone, Moore & Lambert, 1967).However, even though no left ventriculargradient was found there may have also beeninvolvement of the left ventricle which may be-come more apparent in the future. The apicalsite of the murmur would, however, suggest aleft ventricular origin of the murmur even inthis case.While the systolic murmur may occur at a

time when there is no pressure gradient as shownby intraventricular phonocardiogram (Goodwin,1967), the intensity of the murmur appears fromour studies to vary with the gradient. That theincrease in gradient is associated with increasein systolic murmur intensity does not excludemitral incompetence as the cause of the murmurbecause the hypertrophy of the septum andpapillary muscle cause both the gradient andmitral incompetence. Mitral insufficiency almostinvariably accompanies hypertrophic obstructivecardiomyopathy (Wigle, Marquis & Auger, 1967)However, we agree with Goodwin (1967, 1968)that there are probably several reasons for thesystolic murmur in hypertrophic obstructive car-diomyopathy. Thus obstruction within the leftventricle, mitral incompetence and probablyturbulence within the strongly and rapidly con-tracting ventricle may all play a part in itsproduction.We have shown that amyl nitrite markedly

diminishes the regurgitant murmur of rheumaticvalvar mitral incompetence and that phenyl-ephrine intensifies the murmur (Vogelpoel et al.,1959; Beck et al., 1961). Amyl nitrite intensifiesthe systolic murmur in hypertrophic obstructivecardiomyopathy (Nellen et al., 1965) and increasesthe gradient (Wigle et al., 1964) and phenylephrineabolishes or markedly reduces the murmur andgradient; isoproterenol increases the gradientand murmur (Nellen et al., 1965). These findingsdo not rule out incompetence of the mitral valve(Fig. 1) as a factor in the production of thesystolic murmur. The cause of the mitral in-competence in hypertrophic obstructive cardio-myopathy is papillary dysfunction due topapillary and septal hypertrophy and not a purevalve mechanism. These drugs by altering theinternal diameter and mechanics of the obstruc-tive hypertrophy in the left ventricular chamberaffect the murmur in opposite directions to theireffect in pure valvar mitral incompetence.

89copyright.

on June 3, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.507.89 on 1 January 1968. D

ownloaded from

Postgraduate Medical Journal

Further support for the view that the obstruc-tion causes the mitral incompetence is that phar-macological abolition of the stenosis alsoabolishes the mitral incompetence (Wigle et al.,1967).

FIG. 1. Hypertrophic obstructive cardiomyopathy.The systolic murmur reflects the haemodynamic situationwith (a) amyl nitrite, (b) phenylephrine and (c) iso-prenaline. Pressure measurements in left ventricle andfemoral artery. Simultaneous external phonocardiogramshown in lower channel.

In contrast to the marked lessening in intensityor disappearance of the systolic murmur inhypertrophic obstructive cardiomyopathy withintravenous phenylephrine we have shown thatthe murmur of aortic stenosis is hardly affected.It usually lessens only slightly but may actuallyintensify-this may be a useful bedside test asthe two conditions may mimic each other(Nellen et al., 1965) (Fig. 2).The studies of Marcus, Perloff & DeLeon

(1964) and Hancock & Fowkes (1966) show thatinhalation of amyl nitrite is more useful thanisoproterenol as a provocative test for hyper-trophic obstructive cardiomyopathy. Inhalationof amyl nitrite has a greater effect than intra-venous injection of 2 mg of isoproterenol, ismore readily administered, has a briefer actionand is less likely to induce adverse effects suchas ventricular arrhythmias.

The effect of prompt squatting on the systolicmurmurPrompt squatting provides a simple bedside

method of acutely increasing venous return,effective filling pressure of the heart, stroke out-put and systemic arterial pressure and resistance(Sharpey-Shafer, 1955).We have therefore studied the effect of this

manoeuvre on the systolic murmur in twelvepatients with hypertrophic obstructive cardio-myopathy (Nellen et al., 1967), and we havecompared the effect of this manoeuvre in eightpatients witlh fixed valvar aortic stenosis and infive patients with mitral valvar incompetence asthe systolic murmurs in these cases may resemblethat of hypertrophic obstructive cardiomyopathy.

In hypertrophic obstructive cardiomyopathywe found that this manoeuvre abolished themurmur in three, and softened it markedly inseven. In one, the murmur softened slightly andin one the effect was variable (Figs. 3 and 4).In no case did the murmur intensify. In all thecases of valvar aortic stenosis and mitral in-competence the systolic murmur increased inloudness. To help in the assessment of the mech-anism of squatting we studied the effect of thisprocedure on the murmur of pulmonary steno-sis. The systolic murmur in this condition alsoquickly intensified on squatting. In this conditionthe increase in mean arterial pressure and inperipheral arterial resistance would not be ex-pected to increase the murmur, whereas in-crease in venous return and effective cardiac

F Systolic murmur

Control I Phenylephrine

Hypertrophicobstructive

cord iomyopothy

Aortic

stenosis

FIG. 2. Phenylephrine virtually abolishes the systolicmurmur in hypertrophic obstructive cardiomyopathy,and only slightly affects the murmur an aortic valvarstenosis.

90copyright.

on June 3, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.507.89 on 1 January 1968. D

ownloaded from

Festschrift for Sir John McMichael

FIG. 3. Hypertrophic obstructive cardiomyopathy:(a) standing, and (b) squatting. Phonocardiogram(MF = medium frequency) taken medial to the apex.The systolic murmur is virtually abolished on squatting.(Lead VI of the electrocardiogram is indicated in the toptracing. Each large square on the record indicates 0-05sec.)

filling pressure would do so. The same mech-anism would apply to the increase of systolicmurmur in valvar aortic stenosis and mitralvalvar incompetence. In the latter, increasedperipheral resistance could be an added factor.The increase in intensity of the systolic mur-

mur in hypertrophic obstructive cardiomyopathycan be explained by increased venous returnleading to increased left ventricular filling andincrease in end-diastolic volume-an effect simi-lar to a rapid infusion of blood or tilting thepatient into a head-down position (Braunwaldet al., 1964a, b; Shah et al., 1965; Mason,Braunwald & Ross, 1966). With larger intra-

3 Murmur abolished

7Murmur softensmarkedly

FIG. 4. Effect of squatting on the murmur of hyper-trophic obstructive cardiomyopathy in twelve patients.

ventricular volume, the gradient lessens due tothe increase in ventricular dimension whichreduces the degree of obstruction. Additionallythe raised arterial pressure and peripheral resist-ance, the bradycardia and reduction of leftventricular contractility would reduce thegradient and thus the intensity of the murmur.

The nature of the obstructionBraunwald et al. (1964a, b) attributed the

haemodynamic findings and the murmur to ob-struction of left ventricular outflow; Goodwin(1964) broadened the concept and added im-pedance to inflow in the right and left ventricleas a cause of the diastolic murmurs. Criley etal. (1965) questioned obstruction to the outflowregion and suggested that the hourglass silhouetteobserved at angiocardiography is a diastolicevent due to inflow of non-opaque blood fromthe left atrium. They proposed that the highventricular pressure gradients resulted from sus-

tained contraction and absence of flow inobliterated portions of the left ventricular cavity.The hypertrophied ventricle empties more com-

pletely and faster than the unobstructed normalventricle, with marked apical obliteration. Theyalso suggested that the systolic murmur is dueto mitral incompetence from abnormal align-ment of the papillary muscles in the greatlyhypertrophied left ventricle.

Ross et al. (1966) showed the presence ofdefinite outflow-tract obstruction during systole,70% of the systolic blood volume is ejectedduring a period when a gradient is present,whilst 30% of the forward stroke volume isejected early when no significant pressure gradientis present. These workers showed that isometricpressure development and early ventricular ejec-tion proceed more rapidly than normally, thisearly systolic period being responsible for thesharp upstroke of the arterial pulse. Theseworkers have thus prepared a strong brief insupport of the postulate that an obstructive fac-tor exists in the haemodynamic hypertrophic leftventricle syndrome.The studies of Wigle et al. (1967) support the

views of Ross et al. (1966). These authors stressthe importance of the outflow tract as being thesite of obstruction in hypertrophic obstructivecardiomyopathy and show by retrograde andtrans-septal catheterization that the obstructionis caused by systolic apposition of the ventricularseptum and anterior leaflet of the mitral valve.They show how an abnormally high pressure atthe apex of the ventricular chamber can be ob-tained by 'imbedding' or 'catheter entrapment'in various conditions including hypertrophic ob-

Murmur softens slightly on propranolol

Variable response

91copyright.

on June 3, 2020 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.507.89 on 1 January 1968. D

ownloaded from

92 Postgraduate Medical Journal

structive cardiomyopathy (Wigle et al., 1967;Cross & Salisbury, 1963; Martin, Hackel &Sieker, 1963; DeBono, Proctor & Brock, 1965;Martin et al., 1965; White, Lewis & Criley, 1965;Morrow et al., 1965; Tobin et al., 1965; Wilsonet al., 1967). In these latter conditions (except forhypertrophic obstructive cardiomyopathy) theinflow tract pressure will equal the aortic pressurewhereas in hypertrophic obstructive cardiomyo-pathy the pressure is higher in the inflow tract thanin the outflow tract and aorta.

ConclusionsThere are probably several reasons for the

systolic murmur in hypertrophic obstructivecardiomyopathy. Obstruction within the left ven-tricle, mitral incompetence and turbulence withinthe strongly and rapidly contracting ventriclemay all play a part.The systolic murmur (and gradient) is

abolished or lessens markedly in intensity withintravenous phenylephrine, in contrast to the in-crease in loudness of the murmur of valvarmitral incompetence and little significant change infixed valvar aortic stenosis. In hypertrophic ob-structive cardiomyopathy amyl nitrite inhalationand intravenous isoproterenol intensify the mur-mur and the gradient. Amyl nitrite is probably thebest provocative test for the diagnosis of the con-dition-being safer and easier to administer thanisoproterenol and having a greater effect than theusual 20 ,ug dose of the latter 8-stimulatingcatecholamine.Prompt squatting has proved to be an excellent

bedside test in this condition-the systolic mur-mur never increases but is either abolished ordecreases markedly in intensity in most cases,in contrast to the intensification of the systolicmurmur of valvar mitral incompetence and fixedvalvar aortic stenosis.The obstruction causes a true gradient within

the outflow tract of the left ventricle and inter-feres also with papillary muscle function, caus-ing in most cases some mitral incompetenceThe problem of 'entrapment' or 'imbedding' ofthe catheter in the apex has been referred to.We would agree that although there is a tre-

mendous amount of information on the condi-tion of hypertrophic obstructive cardiomyopathy'The citadel holding the ultimate truth of thesyndrome, is still to be taken' (Burchell, 1966).

AcknowledgmentsWe wish to thank Professor V. Schrive and our colleagues

in the Cardiac Clinic, and our laboratory staff for assistancewith the catherization procedures, and Dr J. G. Burger,Superintendent of Groote Schuur Hospital, for permissionto publish. We acknowledge with thanks the continued

financial support of the Council for Scientific and IndustrialResearch and the City Council of Cape Town.

Figs. I and 3 are taken from Nellen et al. (1967) Brit. med.J. ii, 340, with permission of the Editor.

ReferencesBECK, W., SCHRIRE, V., VOGELPOEL, L., NELLEN, M. &SWANEPOEL, A. (1961) Haemodynamic effects of amylnitrite and phenylephrine on the normal human circula-tion and their relation to changes in cardiac murmurs.Amer. J. Cardiol. 8, 341.

BRAUNWALD, E., LAMBREW, C.T., ROCKOFF, S.D., Ross, J.& MORROW, A.G. (1964a) Idiopathic hypertrophic sub-aortic stenosis 1. A description of the disease based uponan analysis of 64 patients. Circulation, 30, 3 (Suppl. No. 4).

BRAUNWALD, E., OLDHAM, H.N., JR, Ross, J., JR, LINBART,J.W., MASON, D.T. & FORT, L. (1964b) Circulatoryresponse of patients with idiopathic hypertrophic sub-aortic stenosis to Nitroglycerin and to the val salvamanoevre. III. Circulation, 29, 422.

BURCHELL, H.B. (1966) Pressure differences and obstructionof left ventricular outflow. (Editorial). Circulation, 34, 556.

CRILEY, J.M., LEWIS, K.B., WHITE, R.I. & Ross, R.S. (1965)Pressure gradients without obstruction-a new concept of'hypertrophic subaortic stenosis'. Circulation, 32, 881.

CROSS, C.E. & SALISBURY, P.F. (1963) Functional subaorticstenosis produced in animals. Amer. J. Cardiol. 12, 394.

DEBONO, A.H., PROCTOR, E. & BROCK, R. (1965) Dynamicobstruction ofthe left ventricle. Its production and abolitionby drugs in normal animals. Guy's Hosp. Rep. 114, 4.

FALCONE, D.M., MOORE, D. & LAMBERT, E.C. (1967) Idio-pathic hypertrophic cardiomyopathy involving the rightventricle. Amer. J. Cardiol. 19, 735.

GOODWIN, J.F. (1964) Hypertrophic obstructive cardio-myopathy. Brit. med. J. i, 1527.

GOODWIN, J.F. (1967) Disorders of the outflow tract of theleft ventricle. Brit. med. J. ii, 461.

GOODWIN, J.F. (1968) Mitral regurgitation in congestivecardiomyopathy. Postgrad. med. J. 44, 62.

HANCOCK, E.W. & FOWKES, W.C. (1966) Effects of amylnitrite in aortic valvular and muscular subaortic stenosis.Circulation, 33, 383.

MARCUS, F.I., PERLOFF, J.K. & DELEON, A.C. (1964) Use ofamyl nitrite in the hemodynamic assessment of aorticvalvular and muscular subaortic stenosis. Amer. Heart J.68, 468.

MARTIN, A.M., HACKEL, D.B. & SIEKER, H.O. (1963) Intra-ventricular pressure changes in dogs during hemorrhagicshock. Fed. Proc. 22, 259.

MARTIN, A.M., JR, HACKEL, D.B., SPOCH, M.S., CAPP, M.P.& MIKAT, E. (1965) Cineangiocardiography in hemorr-hagic shock. Amer. Heart J. 69, 283.

MASON, D.T., BRAUNWALD, E. & Ross, J., JR (1966) Effectof changes in body position on the security of obstruc-tion to left ventricular outflow in idiopathic hypertrophicsubaortic stenosis. Circulation, 33, 374.

MORROW, A.G., VASKO, J.S., HENNEY, R.P. & BRAWLEY,R.K. (1965) Can outflow obstruction be induced within thenormal left ventricle. Amer. J. Cardiol. 16, 540.

NELLEN, M., BECK, W., VOGELPOEL, L., SWANEPOEL, A. &SCHRIRE, V. (1965) The effect ofamyl nitrite, phenylephrineand isoproterenol on the systolic murmur in hypertrophicobstructive cardiomyopathy. S. Afr. med. J. 39, 304.

NELLEN, M., GOTSMAN, M.S., VOGELPOEL, L., BECK, W. &SCHRIRE, V. (1967) Effects of prompt squatting on thesystolic murmur in idiopathic hypertrophic obstructivecardiomyopathy. Brit. med. J. ii, 340.

RosS, J., JR, BRAUNWALD, E., GAULT, J.H., MASON, D.T. &MORROW, A.G. (1966) The mechanism of the intra-ventricular pressure gradient in idiopathic hypertrophicsubaortic stenosis. Circulation, 34, 558.

copyright. on June 3, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.44.507.89 on 1 January 1968. Dow

nloaded from

Festschrift for Sir John McMichael 93

SHAH, P.M., AMARASINGHAM, R. & OAKLEY, C.M. (1965)Haemodynamic effects of changes in blood volume inhypertrophic obstructive cardiomyopathy. Brit. Heart J.27, 83.

SHARPEY-SCHAFER, E.P. (1955) Effects of squatting on thenormal and failing circulation. Brit. med. J. i, 693.

TOBIN, J.R., BLUNDELL, P.E., GOODRICH, R.G. & SWAN,H.J.C. (1965) Induced pressure gradients across infundi-bular zone of right ventricle in normal dogs. Circulat. Res.16, 162.

TUCKER, R.B.K., BARLOW, J.B., ZION, M.M. & GALE, G.E.(1966) Hypertrophic obstructive cardiomyopathy inJohannesburg. Proceedings, Fifth World Congress onCardiology, 1966, p. 197.

VOGELPOEL, L., NELLEN, M., SWANEPOEL, A. & SCHRIRE, V.(1959) The use of amyl nitrite in the diagnosis of systolicmurmurs. Lancet, ii, 810.

WHITE, R.I., LEWIS, K.B. & CRILEY, J.M. (1965) Non-obstructive nature of isoproterenol-induced left ventri-cular pressure gradients in dogs. (Abstract). Circulation,32, suppl. 11, 11.

WIGLE, D.E., CHRYSOHOU, A. & LENKEI, S.C.M. (1964) Theeffect of peripheral vasodilatation in muscular subaorticstenosis. (Abstract). Amer. J. Cardiol. 13, 144.

WIGLE, D.E., MARQUIS, Y. & AUGER, P. (1967) Muscularsubaortic stenosis. Initial left ventricular inflow tractpressure in the assessment of intraventricular pressuredifferences in man. Circulation, 35, 1100.

WILSON, W.S., CRILEY, J.M. & Ross, R.S. (1967) Dynamicsof left ventricular emptying in hypertrophic subaorticstenosis. Amer. Heart J. 73, 4.

A modified index of phosphate excretion

B. E. C. NORDIN L. BULUSUMedical Research Council Mineral Metabolism Research Unit,

General Infirmary, Leeds

THERE are several ways of looking at the excre-tion of phosphorus, or for that matter of anyelement in the urine. For certain purposes, it ismost appropriate to consider the total daily orweekly excretion and relate it to the dietaryintake and faecal output as part of a balancestudy, the object of which is to establish whetherthe subject is in negative or positive balance ona particular dietary intake. In the study of kid-ney stone disease, the important criterion isprobably the concentration of the different phos-phate ion species in the urine and these can becalculated from a knowledge of urinary pH andtotal phosphorus concentration (the organicphosphorus content of the urine being neglig-ible). In relation to many other aspects of cal-cium and phosphorus metabolism, however, thephysiological parameter of particular interest isthe tubular reabsorption of phosphorus, both be-cause it is a large factor in the regulation ofthe plasma phosphorus level and because it isunder the control of the parathyroid glands.

There are various ways of assessing tubularreabsorption of phosphorus, the simplest beingthe measurement of phosphate clearance (whichIs inversely related to tubular reabsorption)(Kyle, Schaaf & Canary, 1958) and the mostsophisticated the measurement of the maximumtubular reabsorptive capacity (Anderson & Par--sons, 1963). Between these extremes is thephosphate/creatinine clearance ratio which in-

dicates the proportion of filtered phosphate thatis not reabsorbed by the tubules; it tends to beraised in hyperparathyroidism and reduced inhypoparathyroidism (Milne, Stanbury & Thomp-son, 1952; Nordin & Fraser, 1954).

Unfortunately, the phosphate/creatinine clear-ance ratio is itself governed not only by tubularfunction but also by the filtered load of phos-phorus itself since there is a very high correla-tion between the plasma phosphorus level andthe phosphate/creatinine clearance ratio in nor-mal subjects (Lambert, van Kessel & Leplat,1947). For this reason, Nordin & Fraser (1960)suggested that any particular value of CpI/C,rshould always be related to the plasma phos-phorus level and that the extent to which theobserved value differed from the predicted valuecould be used as a measure of tubular re-absorption of phosphorus. They called this valuethe phosphate excretion index, established thelimits + 0-09 and showed that higher valueswere associated with states of hyperparathyro-idism and low values with states of parathyroidinsufficiency.The general validity of the phosphate excre-

tion index has since been confirmed. It isgenerally raised in primary hyperparathyroidism(Nordin & Smith, 1965) and frequently also inthe secondary hyperparathyroidism of osteo-malacia (Nordin & Fraser, 1960), renal failureand high phosphate feeding (Smith & Nordin,

copyright. on June 3, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.44.507.89 on 1 January 1968. Dow

nloaded from