Pulmonary hypertension with special reference to its occurrence in congenital heart disease

Pulmonary Hypertension with Special .Reference to Its Occurrence in Congenital Heart Disease By CIIARLES K.

FRIEDBERG

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ULMONARY HYPERTENSION may occur without apparent cause (idiopathic, primary, solitary) or it may be secondary to congenital or acquired heart disease, bronchopulmonary disease or respiratory disturbances associated with hypoventilation. This presentation is concerned primarily with the pulmonary hypertension associated with congenital heart disease, since tile other etiologic forms of pulmonary hypertension are discussed in various articles in this symposium. The study of pulmonary hypertension associated with certain congenital cardiac lesions is of special interest and importance because it contributes to our understanding of the pathogenesis Of pulmonary hypertension, because the pulmonary hypertension modifies the clinical picture and prognosis and because it may alter the indications for and results of surgical therapy in these congenital lesions. Our recent increased knowledge of pulmonary hypertension is the outgrowth o f cardiac ~atheterization, which has enabled us to measure the pulmonary arterial blood-pressure. By wedging tile catheter into the most peripheral site of the pulmonary artery one determines the so-called pulmonary wedge pressure which, according to most investigators, is regarded as a measurement or reflection of the pulmonary venous pressure or of the left atrial pressure. Thus it is possible to determine whether pulmonary hypertension is associated with an obstructive disturbance in the pulmonary veins or left atrium or with left ventricular failure, as indicated by an elevated pulmonary wedge pressure, or whether the pulmonary hypertension is related to a vascular disturbance at or proximal to the pulmonary capillaries, as indicated by a normal pulmonary wedge pressure. Cardiac catheterization is also valuable in determining blood flow in the pulmonie as well as in the systemic circulations, thereby permitting the calculation of the pulmonic vascular resistance which is essential to understanding the significance of pulmonary hypertension. The normal pulmonary pressure averages 20/12 mm. Hg with a mean of approximately 15 mm. Hg. However, pressures up to 30 mm. Hg systolic are generally regarded as within tile range of normal. The pulmonary wedge pressure is usually 6 mm. Hg or less, but pressures up to 10 mm. Hg may be normal. CLASSIFICATION,OF PULhIONARY HYPERTENSION

Pulmonary hypertension may be classified etiologically according to the associated clinical disease, under five general headings: 1. Mitral stenosis or left-sided heart failure in which pulmonary hypertension follows a passive rise in pressure in the left atrium, pulmonary veins and pulmonary capillaries (passive pulmonary hypertension). Subsequently, changes in the pulmonary arterioles and smallest muscular arteries may contribute to the hypertension. 2. Chronic bronchopulmonary diseases, especially those associated with 356

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obstructive emphysema or diffuse alveolar-capillary fibrosis, in which the pulmonary vascular bed is sharply reduced in capacity by destruction, compression or fibrous replacement of pulmonary capillaries and in which the arterioles and small muscular arteries are narrowed by intimal fibrosis (obliterative pulmonary hypertension). When these diseases are associated with arterial hypoxemia, ano.,da further increases pulmonary vascular resistance and. pulmonary hypertension. Anoxia is regarded as the stimulus to vasoconstriction, which is reversible because correction of the hypoxemia lowers the pulmonary blood pressure (vasoconstrictive pulmonary hypertension). Pulmonary hypertension may occur in diseases of the chest wall (e.g., kyphoscoliosis), extreme obesity and in other conditions in which the bellows function of the lungs is impaired and alveolar hypoventilation and arterial hypoxemia result. 3. Recurrent or multiple pulmonary embolism or thrombosis. These usually obstruct muscular or segmental arteries (obstructive puhnonary hypertension). Healing and secondary changes may obscure the histologie evidence of embolism or thrombosis and produce intimal fibrosis and luminal narrowing interpreted as endarteritis obliterans. When the rise in pulmonary blood pressure appears excessive for the degree of organic reduction in the pulmonary vascular bed, a reactive vasoconst~'iction is postulated to account for the disparity. 4. Congenital heart disease, especially those lesions usually associated with septal defects or aortico-pulmonary communications and a left to right shunt with an increased pulmonary blood flow (hyperkinetic pulmonary hypertension). But such defects may also be associated with severe pulmonary hypertension and increased pulmonary vascular resistance, with little or no increase in pulmonary blood flow. The commonest congenital cardiac lesions in which pulmonary hypertension may be an important factor and which will be discussed in more detail are ventricular septal defect, patent ductus arteriosus and atrial septal defect, and less often aortic septal defect, ruptured aneurysm of an aortic sinus, partial anomalous pulmonary venous drainage, atrioventricular canal and mitral atresia. Pulmonary hypertension may also occur with lesions associated with cyanosis, including single" ventricle, single atrium, persistent truncus arteriosus, total anomalous pulmonary venous drainage and .transposition of the great vessels. Pulfnonary hypertension and vascular lesions may occur after anastomatic operations for the treatment of the tetralogy of Fallot. ~ 5. Idiopathic, primary or solitary pulmonary hypertension occurs in the absence of any known disease capable of affecting the pulmonary circulation. Lesions which narrow or obstruct the pulmonary arterioles and muscular arteries are found throughout the lungs. In some cases it may be impossible to exclude unrecognized recurrent pulmonary emboli as the cause of the observed lesions. PATIIOLOGY OF I)UL-~IONARY HYPERTENSION

Tile nature and extent of the pulmonary vascular narrowirig and obstruction and the size and type of vessels chiefly affected in the various types of pul-

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monary hypertension listed above have been demonstrated by combined histologie study of one lung and pulmonary arteriography of the other at autopsy following injection of a radiopaque medium which penetrates to vessels with a diameter of 30 micra, just short of capillaries. 2 In cases of pulmonary hypertension there was a striking reduction in the pulmonary arterial bed, which was regarded as sufficient to account for the high vascular resistance and hypertension present during life. The combined arteriographie and histologie studies disclosed either obstructive lesions due to intimal proliferation or thrombus, or diffuse narrowing and indistensibility of the vessels, termed arterial contracture. The chief sites of involvement varied with the clinical type of pulmonary hypertension. In cases with recurrent embolism the lesions involved essentially the segmental, elastic arteries between 1.0 and 10 mm. in diameter. In congenital cardiac lesions tile muscular arteries 0.1 to 1.0 ram. in diameter were chiefly affected, in mitral stenosis, predominantly the arterioles less than 0.1 mm. in diameter, but also the small museular arteries between 0.1 and 0.2 ram. in diameter. In the cases of idiopathic pulmonary hypertension the arterioles and the muscular arteries 0.1 to 0.8 mm. in diameter were narrowed or occluded. Studies .by Heath e t al. ~ of the structural alterations of the arteries in pulmonary hypertension hffve disclosed a graded severity of lesions which were correlated with hemodynamie findings, as well as qualitative differences which permit a distinction between pulmonary hypertension present from birth and that which developed subsequently. In the fetus the elastie tissue in the media of the pulmonary artery trunk resembles that of the aorta, except for minor differences, and consists of tightly packed, long, uniform, parallel but somewhat crenated fibrils. Whereas this confignration persists in the adult aorta, the elastie tissue in the normal adult pulmonary artery becomes irregular, branching and fragmented. If pulmonary hypertension is present from birth, as may occur in ventricular septal defect or patent ductus arteriosus, the pulmonary artery in children and adults preserves the fetal type of medial elastic tissue; if pulmonary hypertension develops after infancy, as in atrial septal defect or mitral stenosis, the transformation of the pulmonary elastica'has already occurred and the normal adult configuration of the pulmonary artery elastic tissue is present. In subjects who have pulmonary hypertension since birth, there is marked medial thickening of the muscular pulmonary arteries (0.1 to 1.0 mm. in diameter) and the pulmonary arterioles (less than 0.1 mm. in diameter) have a thick muscular media such as occurs in the fetus, in contrast to the musclefree wall of the normal pulmonary arteriole. In atrial septal defect, without prominent pulmonary hypertension, there is a normal transition in infancy from the fetal thick-walled to the normal thin-walled, muscle-free pulmonary arteriole; in cases complicated by pulmonary hypertension a fetal-like thick muscular media develops. In both ventricular septal defect with pulmonary hypertension present from birth and atrial septal defect with pulmonary hypertension developing later, there is a progressive intimal proliferation of the arterioles and muscular arteries which is first cellular, then fibrotie, then finally fibroelastic with elastosis of the internal elastic membrane. The intimal thickening often leads to occlusion. But the intimal fibrosis in atrial septal

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defect precedes, whereas in ventricular septal defect it follows, the development of hypertrophy of the muscular media. Changes of graded severity were found in cases of chronic pulmonary hypertension associated with congenital septal defects and patent ductus arteriosus, the more severe histologic lesions correlating well with tile calculated pulmonary vascular resistance. 4 The progressive lesions denoting increasing severity were described as follows: Grade I--medial hypertrophy in arteries and arterioles without intimal changes in large ventricular septal defects and wide patent ductus arteriosus, cellular intimal proliferation in smallest arteries and arterioles in atrial septal defect; grade II--medial hypertrophy and cellular intimal proliferation; grade III--medial hypertrophy, intimal fibrosis and, in severe cases, early generalized vascular dilatation; grade IV--progressive generalized dilatation and occlusion by intimal fibrosis and fibroelastosis; grade V---appearance of other dilatation lesions, including vein-like branches of hypertrophied muscular arteries, cavernous lesions, angiomatoid lesions, hemosiderosis; grade Vl--necrotizing arteritis. In most patients with grade I lesions the mean puhnonary pressure was less than 35 mm. Hg; in all those with grade II or more severe lesions the pressure exceeded 45 ram. Hg. When thejaistologie grade of hypertensive vascular disease, based on the above criteria, wa~- related to the immediate change in pulmonary arterial blood pressure directly after closure of a defect in the atrial or ventricular septum, the pulmonary hypertension was found to be largely reversible in cases with lesions graded I to III, partially reversible in those with grade IV lesions, and irreversible in those with grade V and grade VI lesions. 5 These data suggested that pulmonary vascular resistance and associated hypertension are composed of functional and organic components, the latter becoming increasingly important as the changes of hypertensive pulmonary vascular disease become more severe. I)UL.~IONARY HYPERTENSION AND ITS RELATIONSttlP TO t)UL.MONAllY BLOOD FLOW AND RESISTANCE

The pulmonary blood flow in liters per minute is calculated from the oxygen consumption and tile arteriovenous oxTgen difference according to tlle following formula based on the Fick principle." Pulm. blood flow =

O., consumption (ml./min.) Arterial 0.2 content -- mixed venous 0.2 content (vol. %) X 10

To adjust for the difference in size of patients in order to obtain comparable values, the pulmonary blood flow is divided b); the surface area (in square meters) to give the pulmonary blood flow index. This is normally between 2.5 and 4.5 liters pe r minute per square meter. The pulmonary resistance is a value calculated by the following formula from the pulmonary blood flow, as determined above, and the pulmonary blood pressure measured by right heart catheterization: Pulmonary Vascular Resistance (dynes/sec./cm."~) Mean Pulm. Artery Press. (mm. Hg) -- Pulm. Wedge Press. (mm. Hg) (1332 X 60) -X Cardiac Output (L. per rain.) 1000

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This represents the pulmonary resistance i n the pulmonary arteries and arterioles. If the pulmonary wedge pressure used to represent left atrial pressure is not subtracted, the total pulmonary vascular resistance is obtained, and this includes the resistance in the pulmonary capillaries and veins, which may be increased because of left-sided valvular lesions and left heart failure. The normal pulmonary vascular resistance is 100 to 300 dynes/see./cm. -~. If the conversion factors 1332 X 60 are omitted in the above formula, the 1000 pulmonary resistance may be expressed as units, 80 dynes/see./cm. -5 being equal to 1 unit, and the normal.resistance being 1 to 4 units. It is apparent "from the above formula that tile pulmonary resistance is proportional to the ratio of pressure to flow and that an increase in resistance denotes a disproportionate rise in pulmonary arterial pressure relative to fow. From tile point of view of pulmonary arterial blood pressure, pulmonary hypertension denotes either an increase in both pulmonary resistance and flow, or an increase in one of these factors with no change or a diminution of lesser degree in the other. The formula indicates a linear relationslfip between increasing pulmonary blood pressure and flow for any given resistance, such as applies to steady flow in rigid tubes. Ho~fever, its applicability to l~ulsatile flo~v-'iri human blood vessels may be limited.G In the normal adult lung tl)e pulmonary vascular bed has a large reserve and may be distended by approximately three times the normal blood flow without a notable rise in pressure. This corresponds to the experimental observation that with normal flow the cross-sectional area of the pulmonary artery must be reduced to one-third its normal size before there is a noteworthy rise in pressure5 There is little relationslfi p between pressure and flow until the potential pulmonary vascular bed has been full); utilized, i.e., all of the open and potential vessels are fully distended. However, in the presence of severe vascular disease which has resulted in gross vascular narrowing, even normal flows may fully ntilize the pulmonary vascular bed and there may be a virtually linear relationship wherein increased blood flow results in a corresponding increase in pressure. Similarly, in the newborn lung there is a restricted pulmonary bed with narrow vessels functioning like rigid tubes; increases in flow induce relatively equivalent increases in pressure, s Moderate pulmonary hypertension may occur as a result of increased blood flow without abnormal pulmonary vascular narrowing and with no change or an actual reduction in pulmonary vascular resistance. However, severe pulmonary hypertension denotes narrowing or occlusion of pulmonary vessels and increased pulmonary vascular resistance. Increased pulmonary vascular resistance as calculated from the.formula previously mentioned is regarded as a more consistently reliable index of narrowing of the small pulmonary arteries or arterioles, organic or functional, than is the existence of pulmonary hypertension. PUL.~t6~'AnY VASOCOXSTnlCTIO.n There is uncertainty as to the relative importance of organic and functional narrowing of the pulmgnary ~r Bed in cases of pulm6nary hypertension

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of all etiologies. This problem is related to the controversial question as to the presence of variable vasomotor tone in pulmonary arteries. The pulmonary arterioles, the presumed site of maior resistance and vasomotor tone, is virtually free of smooth muscle, in contrast to the structure of systemic arterioles. Active constriction of small pulmonary arteries (arterioles) 10 to 25 micra in diameter in the rabbit have been demonstrated by plastic casts of the pulmonary bed. ~ Evidence for active vasomotor control of the pulmonary circulation has recently been critically reviewed by Daly 1~ and is discussed in this symposium by Marshall. u The rise in pulmonary blood pressure secondary to hypoxia has been attributed to pulmonary arterial vasoconstriction, but the mechanisms responsible for the latter are uncertain or undetermined.12-~ The limited pressor response to localized inspiration of low oxygen mixtures suggests a local vasoconstrictive response to anoxia. 15,~G Gorlin et al. 17 reported evidence of pulmonary vasoconstriction in man based on the observation of an aeute vasoconstrietive effect during stellate ganglion block in a case of primary pulmonary hypertension. Serotonin (5-hydroxyt~/ptamine) constricts the pulmonary arteries. 18 The pulmonary arterial pressor effect of infusing norepinephrine in m a n w a s found not to be due to increased pulmonary arterial resistance but to an increase in venous pressure, 19 a factor which may be responsible for other instances of inereascd pulmonary arterial pressure which have been attributed to pulmonary arterial vasoconstriction. Various types of evidence have been presented in favor of a vasoconstrictive or a functional element in the increased pulmonary vascular resistance associated with pulmonary hypertension. A substantial reduction in pulmonary hypertension and a diminution in calculated pulmonary vaseular resistance have been observed after surgical relief of mitral stenosis or the obliteration of a patent ductus or ventricular septal defect. The pulmonary arterial pressure has been reduced by inhalation of 100 per cent oxygen in cases of pulmonary hypertension of varied etiology,-"~ including those due to congenital heart disease. 3 A reduction in pulmonary artery pressure after administration of ganglion-blocking drugs was noted in patients with pulmonary hypertension, in cases of rheumatic heart disease~ and in those with emphysema.2z The sympatholytic drug tolazoline (Priscoline), injected intravenously, was reported to reduce pulmonary blood pressure in cases of idiopathie pulmonary hypertension,24 in eases due to emphysema and in cases associated with mitral stenosis, 2~ but not in patients with congenital heart disease and left to right shunts. -~6 The parenteral administration of 1 ipg. reserpine (Serpasil) produced a significant decrease in pulmonary arterial pressure and resistance, with no change in systemic blood pressure and resistance, in cases of mitral stenosis and ventricular septal defectY Recent studies have been concerned with the effect of acetylchol/ne, 1 to 2 mg. of which may be inieeted into the pulmonary artery where its action is brief and is dissipated before reaching the systemic circulation. A striking fall in pulmonary blood pressure without a fall in cardiac output occurred in many patients with pulmonary hypertension of varied etiology,2s.~-9 but not in patients with Eisenmenger's syndrome.3~ Acetylcholine was found to reduce

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or abolish the rise in pulmonary blood pressure which follows the inhalation of low-oxygen mixtures, zt In many of the studies reporting reduction in the level of a pulmonary hypertension following drugs, it is uncertain whether and to what extent the fall in pressure is due to a diminution in pulmonary resistance caused by release of vasoconstrictor tone, to changes in pulmonary blood flow or pulmonary venous pressure, to extravascular influences or to multiple mechanisms. With respect to acctylcholine, Soderholm and Werko z-" interpreted their observations as suggesting an interfcrence by the drug with an adiustment of the pulmonary vascular bed to an hypoxic stimulus. They did not regard it as necessary to postulate pulmonary vasoconstriction. PATIIOGENESIS OF PULMONARY HYPERTENSION LN CONGENITAL HEART DISEASE

The primary importance of anatomic reduction of the capacity of tile pulmonary vascular bed seems apparent in cases of pulmonary hypertension associated with obstructive emphysema and othcr pulmonary diseases as well as in cases associated with recurrent puhnonary embolism. But in pulmonary diseases, hypoxia, by'producing pulmonary vasoconstriction or by some other mechanism, is often responsible for acute gross increases in pulmonary ,arterial pressure, and, irl cases with arterial hypoxemia and high cardiac output, increased pulmonary flow-may be a contributing factor. Pulmonary hypertension following thromboembolism is not entirely due to anatomic reduction in the vascular bed caused by occlusion alone, but also by secondary oblitcrative lesions in tile vessels at sites removed from that of embolie impact. 33 In cases of mitral stenosis, pulmonary arterial hypertension initially appears to represent primarily a passive transmission of the elevated left atrial pressure, but the degree of pulmonary arterial hypertension often far exceeds that due to elevated left atrial pressure. There is pathologic as well as physiologic evidence indicating subsequent increased pulmonary vascular resistance due to possible vasoconstriction and to narrowing of the small pulmonary arteries and arterioles. This narrowing may serve to protect the pulmonary capillaries from excessive pulmonary blood flow, but tile mechanism of its development is uncertain. Tile pathogenesis of idiopathic pulmonary hypertension is discussed in this symposium by Whitaker and Heath. 34 In all of these etiologic types of pulmonary hypertension there is evidence, already mentioned, of a secondary, superimposed functional or vasoconstrictive factor which may in some cases be reversible, but which in others may be followed by organic vascular changes which are eventually irreversible. The congenital cardiac lesions associated with pulmonary hypertension offer interesting contrasts. The~e are essential hemodynamic differences between cases of ventricular septal defects and patent ductus arteriosus, on the one hand, and atrial septal defect on the other, suggesting correlations which may be important in the pathogcnesis of pulmonary hypertension. Severe pulmonary hypertension, with systolic pressure above 60 mm. Hg, and increased pulmonary resistance occur frequently in cases of large ventrieular septal defect and patent ductus arteriosus and relatively infrequently in cases of atrial septal defect. Yet in all three lesions there is an apparently

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similar communication between the systemic and pulmonary circulations, usually with a left to right shunt. Another striking difference is the finding of severe pulmonary hypertension in infants and young children with a large ventricular septal defect or a patent ductus, whereas severe pulmonary hypertension is very rare in children with atrial septal defect,z5 Correspondingly, Heath et al. 3 found pulmonary vascular lesions of grade II or greater severity in atrial septal defect only in patients beyond tile age of 25 years. These observations suggest that some common factor present from birth or early infancy in cases of ventricular septal defect and patent ductus arteriosus, but absent in atrial septal defect, is important in the pathogenesis of severe pulmonary hypertension with increased pulmonary vascular resistance and the associated vascular lesions. Tile cross-sectional area of the defect permitting a shunt is a determining factor in the occurrence of severe pulmonary hypertension with increased pulmonary vascular resistance, z~ But it does not explain the differences between the cases of atrial septal defect and those with ventricular septal defect or patent ductus. A small ventricular septal defect less than 5 inm. in diameter or a long narrow patent ductus of similar small diameter is virtually never associated with marked puhnonar.y hypertension; usually severe hypertension with pnlmonary vascular obstruction is found with a large septal defect or a short, wide ductus at least 1 cm. in diameter or i sq.cm, per sq.M. body surface,as But atrial septal defects of equally large or larger size are rarely associated with severe obstructive pulmonary hypertension except in adults. Neither can severe pulmonary hypertension with obstructive vascular lesions be attributed to voluminous pulmonary blood flows resulting from large left to right shunts through the septal or vascular communication'. Pulmonary blood flows, as large or larger than those in cases of ventricular septal defect or patent ductus, occur commonly with atrial septal defects. But the elevation in pulmonary blood pressure is slight or moderate in the latter and generally unaccompanied by an increase in calculated pulmonary vascular resistance or organic changes in the pulmonary arteries or arterioles. Even in cases of large ventricular septal defects or patent ductus arteriosus large left to right shunts with greatly increased pulmonary blood flows may be associated with only mild pu.lmonary hypertension and no obstruhtive vascular disease. In fact, tile size of the shunt and the pulmonary blood flow tend to be progressively less with increasing levels of pulmonary blood pressure. An essential difference in these congenital cardiovascular lesions is the direct transmission of the high systemic pressure to the pulmonary arteries by way of a shunt from the left to the right ventricle in cases of large ventrieular septal defect and directly from the aorta in cases of a wide pa{ent ductus; in cases of atrial septal defect blood is shunted at the low pressure of the left atrium. This difference suggests that the transmission of high pressure rather than huge flow to tile pulmonary arteries is the stimulus to the occurrence of a high resistance and occlusive lesions in the pulmonary arteries and arterioles and sustained, severe pulmonary hypertension.

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But it is not clear why some large ventricular septal defects or patent dueti, which allow a large left to right shunt and should seemingly result in the transmission of the systemic blood pressure to the pulmonary arteries, are not accompanied by severe pulmonary hypertension and increased pulmonary vascular resistance. With respect to very small defects there is probably sufficient obstruction to the shunt to cause a large gradient between the left and right ventricle or between the aorta and pulmonary artery, thus preventing either a large shunted blood flow or the transmission of the high systemic blood pressure. Perhaps somewhat larger defects permit a greater shunt and blood flow yet are sufficiently obstructive to prevent the transmission of systemic blood pressure. Swan et al. zs have shown that there is marked increase in flow as the gradient across a ventricular septal defect diminishes from high levels, and that as the gradient approaches zero there is often a sharp reduction in blood flow and a great increase in pulmonary vascular resistance. But no such graded quantitative relationship between tlle size of the defect, pulmonary blood flow and degree of hypertension has been demonstrated, and there is, on the contrary, evidence of considerable over!apping. Variations in-'puhnonary blood pressure and resistance in cases with large defects may depend not only on the exact size of the defect but also on different responses of pulmonary arteries to an increased blood flow or transmitted high pressure. The occurrence of severe puhnonary hypertension with increased pulmonary vascular resistance in congenital cardiovascular lesions has been related to persistence of the fetal state of the pulmonary arteries. 39 Instead of the involution to thin-walled vessels with lower resistance after the lungs are expanded with air after birth, the thick, muscular fetal pulmonary vessels are presumed to persist as a result of the transmitted high pressure of the shunted blood. This theory appears to be supported by the finding of severe puhnonary hypertension and increased pulmonary vascular resistance in infancy or early childhood in some cases of ventricular septal defect or patent ductus. On the other hand the observations of Brotmacher and Campbell aU indicate that pulmonary hypertension in ventricular septal defect increases with age, and that patients with moderate hypertension and little increase in pulmonary vascular resistance may eventually develop severe pulmonary hypertension, great increase in pulmonary vascular resistance and cyanosis due to a reversal of tile shunt. In such cases one would have to assume that normal involution of fetal arteries had occurred after l~irth, but that increased pulmonary arterial resistance recurred de nouo as a result of the increased pulmonary blood flow. Since the fetal pulmonary vessels are relatively indistensible and offer a small, fixed pulmonary bed with high resistance to blood flow, they should behave like rigid tubes. One would then expect that even moderately large defects, associated with an increased pulmonary flow but without transmitted systemic blood pressure, should produce a linear rise in pulmonary blood pressure which would prevent involution of fetal vessels to vessels of low resistance. There is little evidence from serial catheterization

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studies to indicate that pulmonary hypertension in ventricular septal defect or patent ductus arteriosus rises progressively, and in some reported cases there was no change in pressure over a period of seven years. 4~ More extensive studies with much longer periods of observation arc necessary to determine whether severe pt, lmonary hypertension with increased pulmonary vascular resistance develops at or shortly after birth or whether it develops or increases progressively over a period of years. Since severe pulmonary hypertension with increased vascular resistance does occur in some patients with atrial septal defect, it is apparent that the transmission of tile high systemic blood pressure is not essential for such development. Tiffs suggests that either an increased puhnonary flow or the modest elevation of pulmonary blood pressure resulting from the increased blood flow may stimulate an increase in pulmonary resistance and gross elevation in pulmonary blood pressure. But because of the lesser intensity of this stimulus in comparison to that of transmitted, high systemic pressure, such developments require two or three decades or more. However, even with advanced age, increased pulmonary resistance with severe pulmonary hypertension is not an invariable consequence of atrial septal defect and large pulmonary blood flow. Apparently the large pulmonary blood flow resulting from the shunt in atrial septal defect does not prevent a fall in the high resistance of the fetal pulmonary vessels after birth. Or else such involution occurs soon after birth before a large left to right shunt develops. In conclusion, it appears that a large septal defect or patent ductus beyond a critical size is a prerequisite to the development of severe pulmonary hypertension with increased pulmonary vascular resistance. If there is a free transmission of systemic arterial pressure to the pulmonary arteries, high pulmonary vascular resistance with severe hypertension is present from birth as a persistence of the fetal state or it develops rapidly after involution of tile fetal pulmonary arteries. However, an increased pulmonary blood flow or the associated slight hypertension may also stimulate high pulmonary resistance over a period of many years. Since the pulmonary blood pressure and resistance may be reduced in some cases by administering 100 per cent oxygen, or injecting acetylcholine or by surgical correction of the defect, it has been postulated that the initial stimulus of elevated pulmonary blood pressure or flow has induced a reactive vasoconstriction, or an increase in tone or arterial contraction or constriction which increases pulmon~y resistance and sustains a greatly elevated pulmonary blood pressure. Finally, as indicated by pathologic studies, this persistent arterial constriction induces organic narrowing or occlusion of the small pulmonary' muscular arteries or arterioles of progressive severity, which may eventually cause irreversible pulmonary hypertension. To account for differences in pulmonary vascular response, one may invoke the theory of Evans and ShortZ that fibrous and fibroelastic intimal thickening occur in those vessels which are predisposed by a congenital weakness (hypoplasia) of the media. But this assumption appears unnecessary in view Of the regularity with which proliferative intimal

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lesions with high-flow resistance can be induced in the experimental animal by creation of a large anastomosis between a large systemic artery and the pulmonary artery. 4"~ CLINICAL FEA~aaES A N D PROBLEMS RELATED TO P U L M O N A R Y HYPERTENSION LW CONGENITAL HEART DISEASE

The clinical features due to pulmonary hypertension, per se, are essentially identical, regardless of etiology, and are best observed in pure form in cases of idiopathic pulmonary hypertension, z4 In cases of congenital heart disease these features modify the symptoms and signs of the basic lesion and may dominate the clinical picture. The symptoms and signs of lesions such as the septal defects or patent ductus arteriosus are not usually significantly altered by tile moderato degree of pulmonary hypertension, due to increased pulmonary blood flow associated with a left to right shunt, but which is not associated with a substantial increase in pulmonary vascular resistance. On the other hand, severe pulmonary hypertension with greatly increased pulmonary vascular resistance may itself lead to right ventricular hypertrophy and failure; or to a reduction, elimination or reversal of gradient across tile defect, t.hus alteringthe character of murmurs and producing arterial hypoxemia and its consequences. The commonest symptom o f severe pulmonary hypertension with intense pulmonary vascular resistance is dyspnea or fatigability on exertion, presumably due to a limited cardiac output and arterial hypoxemia. Other characteristic symptoms include angina pectoris, etfort syncope, cyanosis, hemoptysis and eventually right-sided congestive heart failure. The angina pectoris may be due to restricted cardiac output and to hypertrophy and ischemia of the right ventricle. Since effort syncope is also characteristic of idiopathic pulmonary hypertension without a shunt, it is probably due to an inadequate cardiac output and consequent cerebral anoxia or to a vasodepressor reflex rather than to an increased right to left shunt and arterial hypoxemia during exercise. Cyanosis denotes that tile rise in pulmonary and right ventrlcular pressure is great enough to cause a right to left shunt. Polycythem!a and clubbing may appear if the hypoxemia is severe enough and prolonged. In patent ductus arteriosus with a right to left shunt the cyanosis is more intense in the lower than the upper extremities and more in the left than the right hand since most of the unoxygenated blood is shunted through the ductus to the descending aorta with some transport to the adjacent left subclavian artery. Hemoptysis is a characteristic late and sometimes terminal symptom, not exclusiqely due to the pulmonary hypertension since it is very uncommon in idiopathic pulmonary hypertension. The hemoptysis is directly due to pulmonary infarction following pulmonary thrombosis. Although pulmonary arteriosclerosis secondary to pulmonary hypertension may be a predisposing factor, the thrombosis appears to be directly related to the polycythemia. The murmurs characteristic of the congenital cardiac lesions are modified b y the high pulmonary blood pressure. A systolic murmur replaces the con_tirluous machinery murmur of patient ductus arteriosus. In ventricular septal

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defect, there is usually an abbreviated systolic murmur of low intensity and no thrills instead of the classic, loud, long murmur and frequent thrill. The pulmonary systolic ejectio,a murmt, r and the diastolic murmur at the lower left border of the sternum or apex commonly heard with septal defects are usually absent when the pulmonary vascular resistance is very high. But a pulmonary ejection click is frequent and is probably directly relate~ to the high vascular resistance. In the majority of cases there is a pulmonary diastolic murmur (Graham-Steele) due to the high pulmonary blood pressure. The second pulmonary sound is accentuated. In contrast with the normal electrocardiogram, that of left ventricular hypertrophy and that of biventricular hypertrophy seen in cases of patent ductns arteriosus or ventricular septal defect without severe pulmonary hypertension, the pattern of right ventricular hypertrophy is common when the pulmonary vascular resistance is greatly increased. Whereas all tlle small branches as well as tile main trunk and large pulmonary arteries appear enlarged on roentgenologic examination in the cases with normal pressures or moderate hypertension due to increased blood flow, in cases with severe pulmonary hypertension and greatly increased resistance the peripheral lung fields are clear (ischem.ie) due to ,_3 .disparity between tile small peripheral and enlarged proximal vessels. 43 The presence of severe pulmonary hypertension is usually regarded as indicating a serious complication or an advanced stage of the abovementioned congenital cardiac lesions and implying an unfavorable prognosis. Right heart failure may be the eventual consequence of severe pulmo,mry hypertension and right ventricular hypertrophy. The possibility of pulmonary arterial thrombosis and infarction is a serious danger. However, there is little actual evidence to prove that a patient with a large septal lesion or a wide patent ductus arteriosus with severe pulmonary hypertension has a less favorable outlook than one with a large left to right shunt and only moderate pulmonary hypertension. The presence of high pulmonary vascular resistance and severe pulmonary hypertension raises problems as to indication and contraindication of surgical treatment for the basic congenital defect. It is often urged that patients with large defects and high pulmonarylblood flows but with low pulmonary vascular resistance Be operated on early before high resistance and severe pulmonary hypertension develop. But it is still unproved that the cases of ventricular septal defect or patent ductus with high pulmonary blood flows and relatively little hypertension are later transformed into cases with high pulmonary resistance, severe hypertension and normal or diminished pulmonary blood flow. The greater average age of those patients with ventricular septal defect who have high pulmonary vascular resistance than Of those with a normal vascular resistance may indicate that the former patients live longer rather than that their condition represents a later and more unfavorable stage in the life history of ventricular septal defect. Similarly it is urged that patients with ventricular septal defects or patent ductus and high pulmonary resistance and blood pressure be operated on early before there is a fllrther increase in resistance and pulmonary h>,per-

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CHARLES K. FIUEDBERG

tension. But there is little evidence from catheterization studies of such a progressive rise in resistance and pressure; rather, the high resistance and pressure appear to develop shertly after birth. On tile other hand, histologie studies do suggest that organic changes and obstruction increase with time and that the less severe and presumably earlier lesions are reversible; the later and more severe are not. The clinical observation of the development of cyanosis indicating a reversal of shunt must also be interpreted as being due to an increase in pulmonary vascular resistance and pulmonary hypertension. Our greatest experience with surgery for congenital heart disease with the high resistance type of pulmonary hypertension concerns cases of patent ductus arteriosus. There is general agreement that the ductus should be closed, despite puhnonary hypertension if tile puhnonary blood pressure is below the aortic, or if the pressures are virtually equal, provided there is only an intermittent small shunt in either direction.44 However, the mortality has been higher than 50 per cent when there is a substantial shunt from right to left. Usually final decision in doubtful cases is made at operation by observing the effect of repeated temporary occlusion of the ductus. A fall in pulmonary blood pressure is an iudi.cation for occlnsion, whereas tachycardia, systemic hypotension or increased pulmonary hypertension is a contraindication. It is probable that the experience with patent ductus and pulmonary hypertension may be applied to similar cases of ventricular septal defect. Although there is a substantially higher mortality in cases with severe pulmonary hypertension than in those with moderate hypertension or relatively normal pulmonary blood pressure, good results may be obtained in many of the former group. On the other lmnd, operation is probably contraindicated in cases with a significant right to left shunt when this is due to se~'ere ~ulmonary hypertension associated with high pnlmonary vascular resistance-Some investigators have used the electrocardiogram45 and pulmonary biopsies 46 as guides to indication for surgery in the presence of pulmonary hypertension with ventricular septal defect or patent ductus arteriosus. Various two-stage technics have been advised for surgical correction of the ventricular septal defect with severe pulmonary hypertension, including the preliminary production of a pulmonary stenosis .7 or the creation of a temporary artificial ductus. 4s In cases of atrial septal defect clinical and hemodynamie studies do indicate that the development of increased pulmonary vascular resistance and severe pulmonary hypertension is a progressive process with eventual reversal of shunt. Present evidence discloses that in the majority of cases of atrial septal defect with severe pulmonary resistance and hypertension causing a consistent right to left shunt, closure of the defect is fatal. 49 Thereh~re operative intervention is indicated before this stage i~ reached. REFERENCES

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