Ventricular septal defect with pulmonary stenosis

The history

Sex distribution in Fallot tetralogy is approximately equal. The malformation recurs in families, has been reported in siblings including triplets, and in parents and offspring. ^, Two brothers with DiGeorge syndrome had Fallot tetralogy. Birth weight tends to be lower than normal, and growth and development are generally retarded. Hereditary cardiovascular defects in Keeshond dogs include typical Fallot tetralogy as well as isolated ventricular septal defect with pulmonary stenosis. Familial tetralogy has been associated with mutation of the jagged 1 gene, with NKX2.5 mutations, and with chromosome 22q11.2 deletion.

The tetralogy usually comes to light in neonates and infants. When the shunt is left-to-right, initial suspicion is a prominent systolic murmur. When the shunt is balanced, the murmur persists in addition to mild, intermittent, or stress-induced cyanosis. When the shunt is reversed, the prominence of the systolic murmur is inversely proportional to the degree of cyanosis (see Physical Findings ).

The clinical course in early infancy is often benign. Mild to moderate neonatal cyanosis tends to increase, but cyanosis may be delayed for months and is coupled with increased oxygen requirements of the growing infant rather than with progressive obstruction to right ventricular outflow. Patients seldom remain acyanotic after the first few years of life, and by 5 to 8 years of age, the majority of children are conspicuously cyanotic with cyanosis closely coupled to the severity of pulmonary stenosis. Infants with Fallot tetralogy and pulmonary atresia are mildly cyanotic or acyanotic when collateral flow is abundant.

In an analysis of survival patterns based on 566 necropsy cases of Fallot tetralogy, two thirds of patients reached their first birthday, approximately half reached age 3 years, and approximately a quarter completed the first decade of life. ^, The attrition rate was then 6.4% per year with 11% alive at age 20 years, 6% at age 30 years, and 3% at age 40 years. ^, Nevertheless, Fallot tetralogy remains the commonest cyanotic congenital heart disease after 4 years of age, and constitutes a large proportion of adults with cyanotic congenital heart disease. Fallot recognized this tendency when he wrote, “ We have seen from our observations that cyanosis, especially in the adult, is the result of a small number of cardiac malformations well determined. One of these cardiac malformations is much more frequent than others . . .” namely, the tetralogy to which he referred. The oldest Fallot patient was 36 years of age. Survivals between the fifth and seventh decades are uncommon but not rare. ^, A 64-year-old woman with the tetralogy was diagnosed in 1895 by G.A. Gibson, best known for his description of the continuous murmur of patent ductus arteriosus. In 1929, White and Sprague published an account of the American composer Henry F. Gilbert who lived a productive life to age 60 years. Another patient played cricket and football as a schoolboy and survived to age 62 years. Unrepaired patients have lived to age 75 years, 78 years, 84 years, and 86 years. In Fallot tetralogy with pulmonary atresia , survival without surgery is as low as 50% in 1 year and 8% in 10 years, but adequate collateral blood flow occasionally permits survival into adolescence and adulthood. ^{, , ,} One such patient lived to age 54 years, and another lived to age 55 despite acquired calcific aortic stenosis and regurgitation (see Fig. 15.14 B).

Pregnancy is poorly tolerated in females who reach childbearing age. The gestational fall in systemic vascular resistance increases the right-to-left shunt, and labile systemic vascular resistance during labor and delivery results in abrupt oscillations in hypoxemia. Fetal wastage is high, and live born infants are dysmature.

The neonatal right ventricle is well equipped to eject against systemic vascular resistance, because the non-restrictive ventricular septal defect permits decompression into the aorta. The right ventricle has been analyzed in terms of its inlet, apical trabecular and outlet portions. The apical trabecular portion took up the greatest portion of the overload, the outlet portion had decreased ejecting force, and the inlet portion was not significantly affected. Right ventricular failure is uncommon. However, biventricular failure in the first few weeks of life accompanies pulmonary atresia with excessive flow through large systemic arterial collaterals. Accessory tricuspid leaflet tissue that partially occludes the ventricular septal defect results in suprasystemic right ventricular systolic pressure and right ventricular failure. ^, Absence of the pulmonary valve (see later section) results in volume overload of the pressure-overloaded right ventricle. Systemic hypertension increases left and right ventricular afterload, and can induce right ventricular or biventricular failure. ^, Acquired calcific stenosis of the biventricular aortic valve imposes increased afterload on both the right and left ventricles (see Fig. 15.14 B). Regurgitation of a biventricular aortic valve sets the stage for right ventricular failure by imposing volume overload on the already pressure-overloaded right ventricle. Infective endocarditis on an incompetent aortic valve can result in catastrophic acute severe biventricular aortic regurgitation.

Isotonic exercise is accompanied by a fall in systemic vascular resistance in the face of fixed obstruction to right ventricular outflow, increasing venoarterial mixing and significantly influencing the dynamics of O ₂ uptake and ventilation. ^, Exercise-induced hypoxemia and increased carbon dioxide content stimulate the respiratory center and the carotid body, provoking hyperventilation that is subjectively perceived as dyspnea. ^,

Hypoxic spells , variously called paroxysmal hyperpnea, syncopal attacks, hypoxic or hypercyanotic spells, are dramatic and alarming features of Fallot tetralogy. A typical spell begins with a progressive increase in the rate and depth of breathing, and culminates in paroxysmal hyperpnea, deepening cyanosis, limpness, syncope, and occasionally convulsions, cerebrovascular accidents, and death. ^, Electroencephalographic abnormalities during a hypoxic spell are similar to those of hypoxic episodes of other causes. Peak incidence is between the second and sixth month of life with an occasional spell as early as the first month but comparatively few spells after age 2 years, and only rarely in adults. Spells in infants are typically initiated by the stress of feeding, crying, or a bowel movement, particularly after awakening from a long deep sleep. ^, However, attacks sometimes occur without an apparent precipitating cause, especially in deeply cyanotic infants, although spells are not necessarily related to the degree of cyanosis. Spells were originally attributed to infundibular contraction caused by sympathetic stimulation, which was believed to divert right ventricular blood into the aorta, but occurrence in patients with pulmonary atresia argued against this theory. It is now believed that vulnerable respiratory control mechanisms, which are especially sensitive after prolonged deep sleep, react to the sudden increase in cardiac output provoked by feeding, crying or straining, by initiating the following vicious cycle. ^, As heart rate and cardiac output increase, venous return increases in the face of fixed obstruction to right ventricular outflow, so the right-to-left shunt increases. Infundibular contraction reinforces this pattern but does not initiate it. The increased right-to-left shunt causes a fall in systemic arterial pO ₂ and pH, and a rise in pCO ₂ , a blood gas composition to which a sleep-sensitive respiratory center and carotid body overreact, provoking hyperpnea which in turn further increases the cardiac output and perpetuates the cycle. Supraventricular tachycardia and rapid atrial pacing initiate spells by inducing infundibular narrowing which increases the right-to-left shunt. Five mechanisms are therefore involved in the pathogenesis of Fallot spells: (1) an acceleration in heart rate, (2) an increase in cardiac output and venous return, (3) an increase in right-to-left shunt, (4) vulnerable respiratory control centers, and (5) infundibular contraction. Manual compression of the abdominal aorta can abort a spell by decreasing cardiac output and venous return. Squatting for relief of dyspnea is a time-honored hallmark of Fallot tetralogy ( Fig. 15.17 ). ^, In 1784, William Hunter made the following observations on the effects of posture: “Any hurry upon his spirits or brisk motion of his body would generally occasion a fit. And for some of the last years of his life he found out by his own observations that when the fit was coming upon him, he would escape it altogether, or at least take considerably from its violence or duration by instantly lying down upon the carpet on his left side, and remaining immovable in that position for about 10 minutes. I saw the experiments made with success.”

Taussig described the preference for certain postures other than squatting, namely, the knee-chest position, lying down, or sitting with legs drawn underneath ( Fig. 15.18 ). Parents may hold their breathless infant upright with its legs flexed against its abdomen ( Fig. 15.18 , panel #4). Young adults cross their legs during quiet standing or sitting, a relatively ineffective variation. Habitual squatters assume the position effortlessly (see Fig. 15.17 ). The mechanisms by which squatting exerts its beneficial effects are as follows: ^{, , ,} (1) Quiet standing after exercise-induced peripheral vasodilation predisposes to orthostatic hypotension and faintness, a tendency that is exaggerated in hypoxemic patients. Squatting counteracts orthostatic hypotension and diminishes or prevents post-exertion orthostatic faintness. ^, (2) Squatting increases systemic vascular resistance, diverts right ventricular blood into the pulmonary circulation, and increases the amount of oxygenated blood entering the left side of the heart. ^{, ,} The left ventricle delivers the larger volume of oxygenated blood into the systemic circulation, so systemic arterial pO ₂ and pH increase and pCO ₂ decreases, blunting the stimulus to the respiratory center and carotid body, and relieving hyperventilatory dyspnea. The effect of squatting on systemic venous return is an even more effective means by which hyperventilatory dyspnea is relieved. (3) Isotonic leg exercise reduces the oxygen saturation of venous effluent returning to the heart from the lower extremities. Squatting mechanically curtails lower extremity venous return, decreases the volume of unsaturated venous blood delivered to the heart, and increases the oxygen saturation of right ventricular blood. (4) Right ventricular blood shunted into systemic circulation has a higher oxygen content and pH and a lower pCO ₂ content. (5) The higher pO ₂ and pH and the lower pCO ₂ reduce the stimulus to the respiratory center and carotid body, and reduce the hyperventilatory dyspnea.

Recurrent hypoxic spells sometimes lead to brain damage and mental retardation. Cerebral venous sinus thromboses and small occult thromboses may become manifest after prolonged hypoxic spells. Hypernasal resonance or nasal speech (velopharyngeal insufficiency) may develop after repeated or prolonged spells because nasal resonance is compromised by improper approximation of the velum (soft palate) and the pharyngeal walls, a disturbance that has been ascribed in part to central nervous system damage caused by hypoxic spells.

Brain abscess and cerebral embolism add to the list of central nervous system complications. Iron-deficient erythrocytosis in patients younger than 4 years of age increases the risk of cerebral venous sinus thrombosis. Wheezing and stridor have been attributed to tracheal compression by an enlarged aorta. ^, A stenotic pulmonary valve and an incompetent aortic valve are substrates for infective endocarditis.

The physiological consequences and clinical course of a non-restrictive ventricular septal defect are favorably influenced by mild to moderate acquired obstruction to right ventricular outflow (see earlier and see Chapter 13 ). The clinical picture initially resembles an isolated non-restrictive ventricular septal defect with large left-to-right shunt (see Fig. 15.13 A). With the development of right ventricular outflow obstruction, excessive pulmonary blood flow and volume overload of the left ventricle are curtailed, ^{, ,} symptoms related to the left-to-right shunt diminish, and physical development improves. Obstruction to right ventricular outflow may progress sufficiently to reverse the shunt, resulting in late-onset cyanosis (see Fig. 15.13 B).

When a restrictive ventricular septal defect is accompanied by severe pulmonary valve stenosis, the clinical picture resembles isolated pulmonary stenosis with intact ventricular septum (see Chapter 10 ). A restrictive ventricular septal defect with mild pulmonary stenosis is associated with a conspicuous murmur and few or no symptoms, but with the risk of infective endocarditis.

Physical findings

Patients with cyanotic Fallot tetralogy are as a rule physically underdeveloped, and infants with excessive collateral arterial blood flow accompanying pulmonary atresia develop congestive heart failure and the catabolic effects of poor physical development.

Cyanosis varies from absent to severe and is symmetrically distributed. John Hunter described such a patient: “ I was consulted about a young gentleman’s health. From his infancy, every considerable exertion produced a seeming tendency to suffocation and a change from the scarlet tinge to the modena or purple. ” Cyanosis may become manifest only after crying, feeding, or exercise when the accompanying stress increases venous return to the obstructed right ventricle and augments the right-to-left shunt. When there is a history of squatting or an analogous posture, it is useful to have the patient or parent illustrate the posture so it can be witnessed by the examiner (see Figs. 15.17 and 15.18 ).

Fallot tetralogy is associated with a number of distinctive phenotypes: CATCH 22 monosomy 22q11.2, ^, Down trisomy 21, ^, velocardiofacial (Shprintzen-Goldberg) syndrome, Goldenhar syndrome (oculo-auriculo-vertebral dysplasia), absence of thumb and first metacarpal, absence of a pectoralis major muscle (congenital pectoral dysplasia or Poland syndrome) ( Fig. 15.19 ), pentalogy of Cantrell, ectrodactyly, syndactyly, brachydactyly with hypoplasia of the ipsilateral hand, underdevelopment of the left arm secondary to an isolated left subclavian artery, hypoplasia of a hand, dextrocardia, and situs inversus.

The arterial pulse is normal irrespective of the severity of pulmonary stenosis (see Fig. 15.15 C and D). When the shunt is balanced, the left ventricle maintains a normal stroke volume, and when there is severe pulmonary stenosis or atresia, a reduced left ventricular stroke volume is supplemented by right ventricular blood ejected directly into the aorta. A brisk arterial pulse with wide pulse pressure is reserved for large systemic arterial collateral flow or aortic regurgitation.

An accurate estimate of the right ventricular outflow gradient requires little more than the bedside determination of blood pressure. Right ventricular systolic pressure is systemic (see Fig. 15.15 C and D), so the stenotic gradient is the difference between the cuff brachial arterial systolic pressure and an estimated pulmonary arterial systolic pressure of 15 to 25 mm Hg, depending on age and the severity of pulmonary stenosis. The estimate is further refined by taking into account that pulmonary arterial pressure is lowest when cyanosis is severe, and normal when cyanosis is mild.

The neonatal right ventricle has an inherent capacity to eject against systemic resistance without extra help from its atrium. In Fallot tetralogy, resistance to right ventricular discharge is at, but not above, systemic because the non-restrictive ventricular septal defect permits decompression into the aorta (see Fig. 15.15 C and D). The right ventricle maintains its neonatal capacity to eject at systemic resistance without increasing its filling pressure. Accordingly, the right atrium is not required to increase its contractile force, so the jugular venous pulse is normal in height and wave form (see Fig. 15.15 B). If accessory tricuspid leaflet tissue partially occludes the ventricular septal defect, right ventricular systolic pressure exceeds systemic (see Fig. 15.16 ), and the jugular A wave becomes prominent. With systemic hypertension, the right ventricle contracts from an increased end-diastolic fiber length induced by forceful right atrial contraction which is reflected in the jugular venous pulse as an increase in the A wave. Acquired stenosis of the biventricular aortic valve has a similar effect on the right ventricle and right atrium. A minor feature of the jugular venous pulse is related to a persistent left superior vena cava. The left jugular pulse is then more prominent than the right. ^,

In 1839, James Hope described an “increase of pulsation at the inferior part of the sternum as a sign of right ventricular hypertrophy.” The right ventricle in Fallot tetralogy ejects at systemic pressure with little or no increase in its force of contraction. Accordingly, the accompanying precordial impulse is gentle, analogous to the impulse of a normal neonatal right ventricle. The right ventricular impulse is relegated to the fourth and fifth left intercostal spaces and subxiphoid area because the stenosis is infundibular (see Fig. 15.15 D). A left ventricular impulse is conspicuous by its absence because the left ventricle is underfilled. Abundant flow through large systemic arterial collaterals augments left ventricular filling, but even then, a left ventricular impulse is seldom palpated. Subinfundibular stenosis or double-chambered right ventricle (see Fig. 15.12 ) relegates the right ventricular impulse to the fifth left intercostal space and subxiphoid area.

A dilated right aortic arch (see Fig. 15.6 ) reveals itself by an impulse at the right sternoclavicular junction. The aortic component of the second heart sound is often palpable in the second left intercostal space because a hypoplastic or atretic anterior pulmonary trunk is all that guards the enlarged aortic root. Systolic thrills do not originate at sites of severe stenosis because right ventricular blood flow is diverted from the pulmonary trunk into the aorta. In acyanotic Fallot tetralogy, the lesser degree of obstruction permits sufficient flow across the stenotic site to generate a thrill.

The physiology of Fallot tetralogy is nicely reflected in the accompanying auscultatory signs. Ejection sounds originate in a dilated aorta (see Figs. 15.6 A and 15.7 A), and are therefore important auscultatory signs of severe pulmonary stenosis or atresia ( Figs. 15.20 through 15.24 ). ^{, ,} The aortic ejection sound is maximum at the upper right sternal border, but when loud, it is heard along the left sternal border and toward the apex. The ejection sound may selectively decrease with inspiration (see Fig. 15.20 ) even though it originates in the aortic root rather than in the pulmonary valve (see Chapter 10 ). Pulmonary ejection sounds are absent because the stenotic bicuspid pulmonary valve is not sufficiently mobile (see Fig. 15.3 ).

Nearly 50 years before the Fallot report, James Hope wrote: “A loud superficial murmur with the first heart sound in the third left intercostal space may proceed from a contraction of the pulmonary orifice or from an opening out of the right ventricle into the left ventricle, or from both these lesions conjoined. When these lesions coincide with cyanosis, the double lesion is almost positive and an increase of pulsation at the inferior part of the sternum, indicative of right ventricular hypertrophy is a corroborative circumstance.” The murmur that Hope described referred to cyanotic Fallot tetralogy, and originated at the site of stenosis rather than across the ventricular septal defect ( Fig. 15.25 ). The murmur is maximum in the third left intercostal space because the stenosis is infundibular. Subinfundibular stenosis results in a lower location of the murmur. The duration and configuration of the systolic murmur are determined by the balance between resistance at the site of stenosis and resistance in the systemic vascular bed. Changes in this balance are reflected in changes in the length and loudness of the systolic murmur. These auscultatory signs are closely coupled with the severity of pulmonary stenosis (see Fig. 15.21 ). A holosystolic murmur extending up to the aortic component of the second heart sound reflects a left-to-right shunt across the ventricular septal defect (see Fig. 15.21 B). As pulmonary stenosis increases, the shunt murmur becomes decrescendo, diminishing and ending before the aortic component of the second sound (see Fig. 15.21 C). When the shunt is balanced, the ventricular septal defect is silent, and the previously obscured pulmonary stenotic murmur emerges (see Fig. 15.21 D). A further increase in the degree of pulmonary stenosis diverts right ventricular blood into the aorta and away from the pulmonary trunk, so the pulmonary stenotic murmur becomes shorter and softer (see Fig. 15.21 E). Severe pulmonary stenosis is reflected in an even shorter and softer systolic murmur and by an ejection sound that is generated in the dilated aortic root (see Fig. 15.21 F). Pulmonary atresia abolishes right ventricular-to-pulmonary arterial flow and abolishes the pulmonary stenotic murmur. An aortic ejection sound may be followed by no murmur at all (see Fig. 15.21 G) or a trivial mid-systolic murmur into the dilated aorta.

During hypoxic spells, pulmonary arterial blood flow sharply declines, the pulmonary stenotic murmur shortens and softens, and with loss of consciousness, the murmur disappears. ^, Vasoactive drugs induce analogous changes by altering systemic vascular resistance. ^, Pressor agents increase systemic vascular resistance and increase the resistance to right ventricular discharge into the aorta. The right-to-left shunt decreases, right ventricular blood is diverted into the pulmonary artery, and the pulmonary stenotic murmur becomes louder and longer. Amyl nitrite has the opposite effect, inducing a decrease in systemic vascular resistance, a decrease in resistance to right ventricular discharge into the aorta, a decrease in flow into the pulmonary trunk, with softening and shortening of the stenotic murmur ( Fig. 15.26 ).

Continuous murmurs are auscultatory signs of pulmonary atresia and occur in over 80% of such patients (see Figs. 15.20 and 15.22 through 15.24 ). Continuous murmurs originate in direct and indirect systemic arterial collaterals (see earlier), and therefore do not occur in Fallot tetralogy with pulmonary stenosis in which collaterals are confined to bronchial arteries (see Fig. 15.6 B). The intensity of continuous murmurs ranges from grade 3/6 to soft and easily overlooked, especially at nonprecordial sites. Continuous murmurs are heard beneath the clavicles, in the back, to the right and left of the sternum, and in the right and left axillae (see Figs. 15.22 through 15.24 ). Thoracic locations vary from patient to patient, and from time to time in the same patient. ^, Continuous murmurs may peak before and after the second heart sound (see Figs. 15.22 and 15.24 ) or may be more prominent in systolic, as with other arterial continuous murmurs (see Fig. 15.23 ), creating the mistaken impression of a long intracardiac systolic murmur especially if the murmur is located at the left sternal edge.

The murmur of tricuspid regurgitation is reserved for the occasional adult with right ventricular failure caused by systemic hypertension or acquired aortic stenosis, or in the occasional patient with suprasystemic right ventricular pressure due to partial occlusion of the ventricular septal defect by tricuspid leaflet tissue.

Diastolic murmurs are caused by aortic regurgitation, or much less frequently by absent pulmonary valve (see later section). The aortic regurgitant murmur is typically high-frequency decrescendo, beginning with the prominent single aortic component of the second heart sound (see Fig. 15.23 A). Continuous murmurs from collateral circulation obscure the murmur of aortic regurgitation. A brisk arterial pulse may result from abundant collateral flow rather than aortic regurgitant flow. However, conspicuous cyanosis with a brisk arterial pulse favors aortic regurgitation, because arterial collaterals large enough to cause bounding pulses are also large enough to increase pulmonary arterial blood flow and minimize the cyanosis. Large collateral arteries that deliver abundant pulmonary blood flow occasionally cause a mitral mid-diastolic murmur (see Fig. 15.23 A). Rarely, a bicuspid pulmonary valve is incompetent, generating a delayed medium-frequency diastolic murmur of low-pressure pulmonary regurgitation (see Fig. 15.23 B).

The pulmonary component of the second heart sound is soft or absent because right ventricular blood preferentially enters the aorta, so pulmonary blood flow and artery pressure are abnormally low. A delay in the pulmonary component is due to the relatively long interval required for high right ventricular systolic pressure to fall below the low pulmonary arterial diastolic incisura, and to delayed relaxation of the infundibulum that contributes to late pulmonary valve closure by supporting the column of blood in the pulmonary trunk after the right ventricle has begun to relax. ^,

With mild or absent cyanosis, a soft delayed pulmonary component can be detected (see Figs. 15.21 C and 15.25 ). ^, When cyanosis is marked, the pulmonary component is typically inaudible, and with pulmonary atresia, there can be no pulmonary component because there is no functional pulmonary valve. Amyl nitrite inhalation reduces pulmonary arterial flow still further, so an audible pulmonary second sound disappears (see Fig. 15.26 ). ^, Inaudibility also results from thickened bicuspid pulmonary leaflets that preclude brisk closing excursions. In 1866, Thomas Peacock wrote. “The aorta is unusually large and from the powerful reaction on the valves during diastole of the heart, a loud ringing second sound is heard on listening at the upper part of the sternum.” Peacock’s loud ringing second sound was the loud aortic component ( Fig. 15.27 ; see also Fig. 15.24 ).

Fourth heart sounds are exceptional because the force of right atrial contraction is not increased. Third heart sounds rarely occur on either side of the heart because right ventricular failure is uncommon and left ventricular filling is reduced. With systemic hypertension, right ventricular or biventricular failure may be accompanied by third and fourth heart sounds. With pulmonary atresia and large systemic to pulmonary arterial collaterals, increased blood flow across the mitral valve sometimes generates a left ventricular third sound and a short mid-diastolic murmur (see Fig. 15.23 ).

Auscultatory signs in severe pulmonary valve stenosis with a restrictive perimembranous ventricular septal defect are similar to, if not identical to, the auscultatory signs of severe isolated pulmonary stenosis. Suprasystemic right ventricular systolic pressure abolishes the left-to-right shunt through the ventricular septal defect, so a long pulmonary stenotic murmur exists alone. A loud long pulmonary stenotic murmur is also heard when accessory tricuspid leaflet tissue partially occludes the ventricular septal defect (see Fig. 15.16 ).

Mild pulmonary valve stenosis with a restrictive ventricular septal defect results in auscultatory signs dominated by the holosystolic murmur of the ventricular septal defect. Suspicion of coexisting pulmonary valve stenosis depends on the presence of a pulmonary ejection sound and a right ventricular impulse.