Idiopathic Hypertrophic Subaortic Stenosis: I. A Description of the Disease Based Upon an Analysis of 64 Patients

Idiopathic hypertrophic subaortic stenosis (IHSS) is a disease characterized by marked hypertrophy of the left ventricle, involving in particular the interventricular septum and the left ventricular outflow tract. During systole, the hypertrophied muscle in the outflow tract often narrows this region sufficiently to produce obstruction to left ventricular ejection. Although the reports of Schmincke and of Bernheim early in this century indicate that IHSS has been recognized for many years, particular attention has been directed to the disease only during the last 7 years. In most instances left ventricular hypertrophy is asymmetric, but occasionally it is diffuse and the lumen of the outflow tract is reduced by the concentrically hypertrophied muscle. Marked enlargement of the papillary muscles and of the trabeculae carneae, deformation of the mitral valve by the thickened ventricular septum, and thickening of the anterior mitral leaflet are commonly noted. In many hearts the hypertrophied septum bulges into the right ventricular outflow tract as well as into the left. On microscopic examination, the muscle bundles in the left ventricle are often arranged in a bizarre fashion and are separated by clefts. Individual muscle fibers obtained from the left ventricle are often greatly thickened, but tend to be shorter than normal. There is an increase in the size and number of nerve fibrils and in the quantity of fluorescent material, presumably norepinephrine, in the affected muscle. Of the 64 patients with IHSS on which the present report is based, 67% were males and 33% were females. The patients with the familial form of the disease were distributed approximately equally between the 2 sexes. On the other hand, in the patients without a family history, 78% were males and only 22% were females. The average age was 25.7 years; the female patients were significantly older than the males. The discovery of a heart murmur was usually the first clinical manifestation of the disease. From a consideration of our patients, as well as those reported in the literature, it is evident that clinical findings may or may not be present at birth or in early childhood. The finding of a murmur before the age of 1 year in 9 of the 64 patients, and the reports of IHSS in a stillborn baby and in several infants, as well as the association of IHSS with congenital cardiac malformations, all support the concept that the disease may, at least in some instances, be congenital. On the other hand, in 20 of the 64 patients at least 1 detailed examination revealed no evidence of a heart murmur prior to the eventual discovery of the murmur, and in them it appears likely that many of the manifestations of the disease were acquired. Forty-eight of the 64 patients with IHSS were symptomatic, the most common symptoms being dyspnea, angina, dizziness and syncope. Although others have commented upon the absence of the clinical findings of congestive heart failure, clear evidence of cardiac decompensation was present in 14 of our patients. On physical examination the heart was usually enlarged, with a left ventricular lift. A double apical impulse was often palpable. Apex cardiograms usually showed an abnormally tall presystolic expansion wave ( a wave). A systolic thrill was palpable in approximately one-half of the patients and tended to be present more frequently in patients with severe than in those with mild obstruction. Paradoxical splitting of the second heart sound during the respiratory cycle was present in 22 patients, and in them the systolic pressure gradients were significantly higher than in those without this finding. A fourth heart sound was audible in almost all of the patients in sinus rhythm while a third heart sound was heard less frequently. Seven of the 64 patients had early systolic ejection sounds. An ejection type systolic heart murmur was heard in all patients, and was most prominent along the left sternal border or at the apex. The systolic pressure gradients were significantly lower in the patients in whom the murmurs were relatively soft than in those with louder murmurs. Although the electrical axis in the frontal plane was usually normal, left axis deviation was noted in 14 patients. Normal sinus rhythm was present in all but 2 patients, who had atrial fibrillation. The patients with normal P waves were generally asymptomatic, but patients with electrocardiographic findings of left atrial or combined atrial enlargement were usually markedly disabled by their disease. The classical WPW pattern was present in 2 patients, and in a number of others an incomplete form was seen with a shortened P-R interval and/or a delta wave and a normal QRS duration. The obstruction to left ventricular outflow tended to be significantly more severe in the 27 patients with delta waves than in the 37 patients without this finding. Sixteen patients exhibited abnormally deep and broad Q waves. This finding occurred significantly more often in patients with the familial form of IHSS than in those with the nonfamilial form. It is likely that these abnormal Q waves are related to gross septal hypertrophy rather than myocardial infarction. Although the voltage criteria for left ventricular hypertrophy in the precordial leads were usually satisfied, there was no correlation between the height of RV 5 or the sum of RV 5 and SV 1 and the magnitude of the systolic pressure gradient. On the conventional chest roentgenograms an abnormally large cardiothoracic ratio was noted in approximately one-half of the patients, and the left ventricle was considered to be enlarged in almost all of the patients, but the magnitude of the cardiothoracic ratio and the extent of the left ventricular enlargement did not correlate with the systolic pressure gradient or the functional classification of the patient. Aortic dilatation is an uncommon finding in IHSS and the presence of marked dilatation in a patient with obstruction to left ventricular outflow suggests that valvular or discrete subvalvular stenosis rather than IHSS is present. Intracardiac calcification was never noted. The thickness of the free wall of the left ventricle and the width of the left ventricular cavity were measured on angiographic films exposed in the frontal projection at the end of diastole. No patient with IHSS exhibited an abnormally wide left ventricular cavity, and in a significant number of patients the width of the left ventricular cavity was less than that observed in patients with normal left ventricles or in those with valvular or discrete subvalvular aortic stenosis. The free wall of the left ventricle was thicker than normal in almost every patient with IHSS, and in some the left ventricular wall was found to be thicker than in any patient with discrete obstruction. However, there was no correlation between the thickness of the left ventricular myocardium during diastole and the peak systolic pressure gradient. The shape of the left ventricular cavity was abnormal in the majority of patients; an inward concavity at the midportion of the right inferior margin being the most common finding. It is presumed that this results from the bulging of the greatly hypertrophied interventricular septum into the left ventricular cavity. A long subvalvular area of narrowing commonly appeared to be responsible for the obstruction. Mitral regurgitation was present in nearly one-half of the patients, who were significantly older, and tended to have more clinical disability and a higher left ventricular end-diastolic pressure than those without this finding. In patients with IHSS the arterial pulse rises sharply, the upstroke times in the indirect carotid arterial pulses averaging 0.062 sec. in IHSS, compared to a normal average value of 0.088 sec. A carotid pulse with two peaks in systole was recorded in 35 of the 47 patients with IHSS, and in the other 12 patients in whom there was only a single peak there tended to be little if any obstruction to left ventricular outflow. The first derivative of the arterial pressure pulse tended to be greater than normal in IHSS, and was always higher in patients with IHSS than in those with valvular aortic stenosis. The systemic arterial pressure was normal in the majority of patients. The pulmonary artery systolic pressure exceeded 30 mm. Hg in 16 patients. A systolic pressure gradient within the right ventricular outflow tract was recorded in 10 patients and the right ventricular end-diastolic pressure was abnormally elevated in 21 patients. The a wave was the most prominent wave in the right and left atrial pressure pulses in almost every patient. The resting cardiac index varied widely. The mean left atrial pressure was abnormally elevated in 18 of the 42 patients in whom it was measured, while the left ventricular enddiastolic pressure exceeded the upper limit of normal in 47 of the 64 patients. The peak systolic left ventricular outflow pressure gradient, measured in the basal state, exceeded 100 mm. Hg in 14 patients, ranged between 50 and 100 mm. Hg in 21 patients and between 10 and 50 mm. Hg in 15 patients. The other 14 patients did not exhibit significant obstruction to left ventricular outflow in the basal state. No correlation was found between the most common symptoms in IHSS and the severity of obstruction. A distinct notch on the ascending limb of the left ventricular pressure pulse was usually recorded and its level was approximately equal to the peak pressure distal to the obstruction. In addition to obstruction to ventricular outflow, IHSS is characterized by an abnormally low ventricular compliance, an important consequence of which is impedance of ventricular filling. Atrial hypertrophy results and atrial systole assumes a particularly important role in ventricular filling. One of the most important features of IHSS is the variability of the hemodynamic findings. In 28 patients in whom measurements of the systolic pressure gradient were carried out at intervals which averaged 24 months, the differences in the peak gradients averaged 25 mm. Hg. Large variations in the systolic pressure gradient also occurred in the course of a single study. Sometimes a significant systolic pressure gradient was recorded at the beginning of the catheterization but all hemodynamic evidence of obstruction disappeared with the passage of time; less frequently the opposite was noted. Forced slow respiration, discomfort or anxiety, elevation of the legs and general anesthesia all were shown to have striking effects on the severity of obstruction. These variations in the severity of obstruction constitute one of the most important characteristics of IHSS, and distinguish it from the other forms of heart disease with intracardiac or extracardiac obstruction to blood flow. Analysis of the postextrasystolic arterial pulse pressure response is a useful diagnostic test for IHSS. In normal individuals, and in patients with valvular or discrete subvalvular aortic stenosis, the cardiac cycle following a premature contraction is characterized by a ventricular contraction more forceful than normal, and the arterial pulse pressure in the cycle following the premature beat is greater than normal. Patients with IHSS share with normal subjects, and with patients with discrete obstruction to left ventricular outflow, this postextrasystolic augmentation of the force of left ventricular contraction. However, in 45 of the 57 patients with IHSS the arterial pulse pressure of the postpremature beat was abnormal, i.e., it did not exceed the pulse pressure of a control beat. Ten of the 12 patients with a normal postpremature contraction arterial pressure response had no obstruction or only trivial systolic pressure gradients. Patients with IHSS exhibit characteristic responses to a variety of vasoactive drugs. The intravenous administration of rapidly acting cardiac glycosides resulted in large and consistent increases in the pressure gradient and diminutions in the size of the stenotic orifice. Similarly, isoproterenol intensified the obstruction in 8 out of 9 patients in whom obstruction was present in the basal state, and provoked the development of a systolic pressure gradient in 7 others. Nethalide, a beta adrenergic blocking agent, prevented these effects of isoproterenol. Methoxamine or phenylephrine consistently abolished the obstruction in patients with IHSS, while nitroglycerin either intensified the obstruction or provoked the development of a systolic pressure gradient. The circulatory response to exercise in the supine position was determined in 14 patients. The left ventricular end-diastolic pressure rose abnormally in all of them, by an average of 13 mm. Hg. The normal small increases in stroke volume and stroke work occurred in only 3 patients. During exercise, the calculated effective orifice size of the left ventricular outflow tract diminished in 5 of the 9 patients in whom it was determined; in several patients the obstruction became even more severe 2 to 3 minutes after discontinuation of the exercise. This intensification of obstruction could be diminished by the prior administration of Nethalide. The Valsalva maneuver also augmented the systolic pressure gradient or provoked the development of obstruction. In contrast, in patients with discrete obstruction to left ventricular outflow, the Valsalva maneuver tended to reduce the magnitude of the pressure gradient. Since the obstruction in IHSS results from systolic contraction of the hypertrophied muscle which constitutes the walls of the left ventricular outflow tract, the systolic volume of the left ventricular cavity, the force of left ventricular contraction and the transmural pressure which distends the outflow tract during systole are the principal determinants responsible for alterations in the severity of obstruction. The reduction in ventricular volume produced by the Valsalva maneuver, isoproterenol, nitroglycerin, amyl nitrite and muscular exercise tends to intensify the obstruction while the increase in the contractile state of the myocardium produced by a premature contraction, drugs with positive inotropic actions, or muscular exercise have similar effects. Conversely, the increase in ventricular volume produced by bradycardia, and the distension of the outflow tract produced by an increase in arterial pressure diminish the severity of obstruction. Relatively small changes in the anatomical configuration of the left ventricular outflow tract and in the patient's circulatory state can determine the presence or absence, as well as the severity of obstruction to left ventricular outflow in IHSS, but the same fundamental disease process may be present in patients with and without obstruction. Analysis of the natural history revealed that the course of IHSS is extremely variable. In general, however, the disease is a progressive one and there is an interval of at least 3 years between the discovery of a murmur and the development of the first symptom. Disability usually advances slowly, and in most patients several years of mild limitation precede the onset of moderate or marked symptoms. Occasionally, symptoms actually diminish or disappear spontaneously with the passage of time. Six of the 64 patients died as a consequence of their disease: 2 patients died suddenly, 2 died after having been in severe congestive heart failure, 1 died as a consequence of diagnostic investigation, and the sixth as a result of operation. All of these patients were symptomatic prior to death. Review of the literature indicates that sudden death occurs in a significant proportion of patients with IHSS, and appears to be more frequent in those with the familial than in those with the nonfamilial form of the disease. It may occur in patients who were previously asymptomatic, as well as in patients who had been severely limited prior to death. Twenty-three of the patients in this series were considered to have the familial form of the disease, and these patients were members of 11 separate family groups. Analysis of these families indicated that IHSS is transmitted in a non-sex-linked, autosomal dominant fashion, without genetic anticipation. The etiology of IHSS has not been defined. Although it has been suggested that an abnormal position of the anterior mitral valve leaflet may be responsible for IHSS, it now appears that this uncommon malformation may produce obstruction to left ventricular outflow and secondary ventricular hypertrophy but that it is an entity distinct from IHSS. A history of hypertension has been reported to antecede the development of IHSS in several patients, and it seems likely that the presence of left ventricular hypertrophy secondary to hypertension accelerated the obstruction to left ventricular outflow. The severity of left ventricular hypertrophy in patients with a discrete obstruction is not always a direct function of the severity of the obstruction, and in some patients the left ventricle becomes hypertrophied with a less intense stimulus than in others. It is possible that IHSS represents an extreme form of this process, and that muscular hypertrophy is evoked by a normal left ventricular systolic pressure. Although there has been considerable debate concerning the precise temporal relationship between left ventricular hypertrophy and obstruction to left ventricular outflow, it now appears likely that hypertrophy precedes and is responsible for the obstruction in IHSS. The possibility must be considered that an abnormal sequence of contraction of the major structural units of ventricular muscle may be responsible for the development of the disease, and it has also been suggested that there is a relationship between the hyperkinetic heart syndrome and the eventual development of IHSS.