Cardiovascular Performance in Chronic Obstructive Pulmonary Diseases

Symposium on Obstructive Lung Diseases

Cardiovascular Performance in Chronic Obstructive Pulmonary Diseases Richard A. Matthay, M.D., * and Harvey]. Berger, M.D. t

Chronic obstructive pulmonary diseases (COPD), used here to describe a group of diseases (emphysema, chronic bronchitis, and cystic fibrosis) all of which have in common the physiologic defect of airway obstruction, may be associated with severe hemodynamic consequences. The primary cardiovascular complication in these diseases is the development of pulmonary artery hypertension. Hypoxic vasoconstriction, acidosis, reduction in the pulmonary vascular bed because of lung destruction or intercurrent pulmonary thromboembolism, and raised pulmonary venous pressure from left heart failure have been shown to contribute to the development and maintenance of pulmonary hypertension. Right ventricular hypertrophy develops in response to this increased afterload, and eventually right-sided congestive heart failure ensues. This article reviews cardiovascular function in chronic bronchitis, emphysema, and cystic fibrosis. Recent advances in detecting, quantifying and treating cardiovascular abnormalities, including pulmonary hypertension and right and left ventricular dysfunction, are emphasized.

PULMONARY ARTERY HYPERTENSION IN COPD It is critical to focus on pulmonary artery hypertension because it is the' principal cause of right ventricular enlargement and failure in chronic obstructive pulmonary disease. 27 • 194.231 It may be severe in obstructive lung diseases, and mean pressures of 80 mm Hg are not unusualP Since the normal mean pulmonary artery pressure is 20 mm Hg or less, this represents a fourfold increase, proportionately much greater than any encountered in the systemic circulation. Moreover, the right ventricle frequently is faced with a *Associate Professor of Medicine and Associate Director, Pnlmonary Section. Department of

Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.

t Assistant Professor of Diagnostic Radiology and Medicine and Director of Cardiovascular Imaging, Yale University School of Medicine, New Haven, Connecticut.

Supported in part by NHLBI Grant ROl H121960-03.

Medical Clinics of North America - VoI. 65, No. 3, May 1981

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pulmonary artery pressure which has risen rapidly in the course of an intercurrent, acute illness. The following discussion of pulmonary hypertension in COPD considers (1) pulmonary artery pressures and pulmonary vascular resistance at rest and exercise, (2) the etiology of pulmonary artery hypertension, and (3) noninvasive assessment of pulmonary artery hypertension.

Pulmonary Artery Pressures and Pulmonary Vascular Resistance at Rest and Exercise in COPD In 1941, Cournand and Ranges 56a applied the technique of right atrial catheterization to measure central circulatory pressures in man, and in 1946, Bloomfield and associates 28 described catheterization of the pulmonary artery. Subsequently, it was learned that in normal man pulmonary "wedge" pressures were almost identical to simultaneously measured pressures from the left atrium. 31 , 60, 116, 239 The "wedge" pressure usually is obtained by occluding blood flow through a branch of the pulmonary artery either through wedging the end of a cardiac catheter in the vessel or inflating a balloon surrounding the catheter. 24 , 31, 233 Pressure recorded at the tip of the catheter under "no flow" conditions reflect the pressure downstream within the vascular network at the site of the next freely communicating channels (i.e., the pulmonary capillaries or small pulmonary veins).177, 233 Markedly positive intrathoracic pressures, which develop with exhalation during exercise in the patient with COPD,148, 151, 195 are transmitted to the cardiac chambers. In addition, these positive pressures may be transmitted to the pulmonary circulation causing parallel changes in pulmonary arterial wedge pressure. Thus, pulmonary arterial "wedge" pressure is commonly elevated during exercise in COPDI30, 151 in the absence of left heart failure. However, Rice and colleagues l95 measured "wedge" pressures in patients with chronic bronchitis and emphysema at rest. They determined that the "wedge" pressure accurately reflects left atrial pressure in patients with COPD, except in a few cases of severe elevation in intrathroacic pressures which result in falsely high "wedge" pressure readings. Pulmonary vascular resistance 245 is determined by the inflow pressure in the pulmonary artery, the outflow pressure in the pulmonary veins or left atrium, and the blood flow through the lungs according to the equation: Pulmonary vasc:ular resistance (mm Hg/liter/min)

Pulmonary artery pressure (mm Hg)

Left atrial or "wedge" pressure (mm Hg)

Pulmonary blood How (liters/min)

Hence, if pulmonary blood flow is 6.3 liters/min, mean pulmonary artery pressure 14 mm Hg, and left atrial pressure 8 mm Hg, pulmonary vascular resistance is 0.95 mm Hg/liter/min. Table 1 compares normal pulmonary and systemic hemodynamic variables at rest and exercise in normal adult man. 177 Pulmonary artery pressures and pulmonary vascular resistance have been measured in several studies of patients with chronic bronchitis and emphysema at rest and during exercise. 41 , 79, 150, 151,207,235.242.253 In normal subjects, exercise causes a small increase in the pulmonary artery pressure (Table 1),

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Table 1. Comparison of Pulmonary and Systemic Hemodynamic Variables During Rest and Exercise of Moderate Severity in Normal Adult Man t REST CONDITION

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the increase appearing to be greater in the individuals over the age of 50 years. 65 , 67 In patients with COPD, mean pulmonary artery and right ventricular end-diastolic pressures frequently are elevated at rest and rise further with exercise. 61 , 73, 79, 10B,'117, 137, 212, 214, 235, 242 However, prior to the development of severe airway obstruction, these pressures may be abnormal only during exercise. BB ,235 Several investigators have studied the natural history of pulmonary artery pressure in patients with chronic bronchitis and emphysema. 33 , 127, 207, 213, 242-244 Weitzenblum et a1. 244 studied patients with COPD, mainly chronic bronchitis, who had arterial hypoxemia and moderate to severe obstruction of air flow. These patients had at least two right heart catheterizations up to 10 years apart (average, 5 years). Worsening of hemodynamic parameters was found to be mild and slowly progressive with mean pulmonary artery pressure increasing by 5 mm Hg in only 28 to 85 patients (33 per cent). In patients with hemodynamic deterioration, the final arterial oxygen tension was lower and the arterial carbon dioxide pressure higher than in the others.244 Boushy and North 33 reported minor hemodynamic changes in 136 patients with COPD studied an average of 25 months apart. Cardiac index decreased by 6 per cent and mean pulmonary artery pressure increased by 7 per cent. The changes were similar in patients with and those without emphysema. Finally, in a study of 35 patients with chronic bronchitis, Schrijen et a1. reached the same conclusions.213 Over a 3% year follow-up, the pulmonary hemodynamics changed little, even in patients with baseline elevations in pulmonary artery pressure.

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These three studies,33, 213, 244 including a total of 256 adults, suggest that there is a relatively slow progression of basal pulmonary artery pressure in chronic bronchitis and emphysema. This finding is in keeping with the overall clinical course of bronchitis and emphysema, namely a chronic, gradual evolution.

Etiology There are at least five potential causes of pulmonary artery hypertension in COPD (Table 2).11,27,94,107,109,111,123,146,152 The most common cause is increased pulmonary vascular resistance due to a reduction of the crosssectional area of the pulmonary vascular bed. This reduction can be due to a number of different pathologic processes, including loss of capillaries because of emphysema and occlusion of arterial lumina by pulmonary emboli. The major cause of a reduced pulmonary bed in patients with COPD is hypoxemia,27. 72, 86 the most potent pulmonary vasoconstrictor.82. 83. 85. 86, 87. 231 How hypoxia causes pulmonary arterial smooth muscle to constrict is unclear.86, 165 However, available information suggests two major alternatives: an indirect effect by which hypoxia causes cells in the pulmonary parenchyma to release vasoactive substances (e.g., histamine from mast cells), or a direct effect of hypoxia on pulmonary arterial smooth muscle. Other influences also may enhance hypoxic pulmonary vasoconstriction. For example, extrapulmonic reflexes or sympathetic stimulation (norepinephrine release) may augment the pressor response.t 65 Bishop27 emphasized that increased pulmonary vascular resistance results in structural changes in the pulmonary arteries, together with a functional and variable increase in vascular resistance. The structural and functional elements are closely interrelated, and their relative importance varies with the stage of the disease. Chronic hypoxemia leads to structural changes in the smaller pulmonary arteries consisting of muscularization of the pulmonary arterioles. 1l2 ,224 Substantial decreases in pulmonary artery pressure and pulmonary vascular resistance observed within 5 to 6 weeks of oxygen therapy suggests reversal of these structural changes. 5, 7, 27 In addition to structural changes, there also is a degree of active vasoconstriction which results in an acute, short-term variation in pulmonary artery pressure. 4, 6, 27 In chronic bronchitis, the degree of rise in mean pulmonary artery pressure correlates well with the amount of fall in arterial oxygen tension and arterial oxygen

Table 2.

Causes of Pulmonary Artery Hypertension in Chronic Obstructive Lung Diseases

Increased pulmonary vascular resistance due to, Hypoxia-induced structural narrowing of pulmonary arteries Acidemia augmenting hypoxic vasoconstriction Alterations in intrathoracic pressures Increased cardiac output Increased pulmonary blood volume Increased viscosity of blood Raised pulmonary venous pressure

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saturation at rest and during exercise.41' 55, 77, 80, 235, 248 Moreover, oxygen therapy may cause a dramatic drop in pulmonary arterial pressure over a period of a few minutes during such episodes, suggesting the active nature of the vasoconstriction.6. 41. 251 The effects of changing the hydrogen ion concentration on pulmonary artery pressure and pulmonary vascular resistance are controversia1. 27 , 72, 111, 124 Acidosis has been shown to produce significant increases in pulmonary vascular resistance and to act synergistically with hypoxia. 72 An increase in arterial Pco 2 does not exert a direct effect. Instead, it seems to operate by way of the increase in hydrogen ion concentration that it induces. 165 Figure 1 illustrates the interplay of hypoxia and acidemia. At minor degrees of oxygen unsaturation, pulmonary artery pressure is relatively insensitive to hydrogen ion concentration, whereas it is extremely sensitive at high levels of unsaturation. 70 In contrast, when the pH is high, the pressor effect of hypoxia is blunted. Increased alveolar and transthoracic pressures can augment pulmonary vascular resistance and may be important in mediating local changes in resistance. 107, 123, 185,210 Harris et a1. 107 demonstrated that increased airway resistance and increased alveolar pressure can augment pulmonary vascular resistance or pulmonary arterial pressure in patients with chronic bronchitis. In these patients airway resistance was particularly increased during expira-

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tion. Along with the prolongation of expiration commonly observed in such patients, increased mean pressure in the alveoli causes compression of resistance vessels within the lung. 107 Thus, there appears to be a direct mechanical link between increased airway resistance and increased pulmonary vascular resistance in patients with chronic bronchitis. Robin and Gaudio 197 emphasized that the pulmonary vasculature is a low pressure, low resistance system which, under normal circumstances, is capable of accommodating large increases in pulmonary blood flow with only minor increases in pulmonary artery pressure (Fig. 2). Accordingly, in the normal vascular bed, no increase in pressure occurs until cardiac output is approximately 2.5 times greater than normal. However, in patients with a compromised vascular bed, small increases in flow may produce large increases in pressure over the entire range of physiologic cardiac outputs. An acute increase in total and central blood volume causes a rise in both pulmonary artery and pulmonary venous pressures. 4 • 27. 218 The effects of blood volume expansion of longer duration are not as well understood. 27 Although central blood volume is increased in patients with chronic bronchitis and 60

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congestive failure, and total blood volume is greater than normal, the two volumes increase approximately to the same extent, and their ratio remains unaltered. 6 The viscosity of blood is increased by erythrocythemia, which develops in some patients with COPD secondary to chronic hypoxemia. 27 Theoretically, increased viscosity leads to elevated pulmonary arterial pressure, but experimental evidence does not support this concept. When the packed cell volume of patients with chronic bronchitis was restored to normal levels by repeated venesection over a one week period, pulmonary arterial pressure did not decrease. 218 Raised pressure in the pulmonary veins and left atrium results in an equal rise in pulmonary arterial pressure, and subsequently to structural changes in the walls of small pulmonary arteries with narrowing of the lumina, causing a further elevation of pulmonary arterial pressure. 27 This sequence is familiar in mitral valvular disease or chronic left ventricular failure due to cardiomyopathy or coronary artery disease, which may be present concomitantly in patients with COPD.

Noninvasive Identification of Pulmonary Artery Hypertension in COPD Chest radiographic determination of pulmonary artery hypertension in cardiovascular disease, mitral stenosis in particular, has been described. 46 , 153, 169, 171, 191, 192, 216, 227 However, few studies have compared plain chest radiographic findings and pulmonary artery pressures in patients with COPD. 47,118 A recent study164 established that the presence of pulmonary artery hypertension (mean pulmonary artery pressure > 20 mm Hg) can be identified in patients with chronic bronchitis and/or emphysema by measuring the widest diameter of the right and left descending pulmonary arteries on the plain chest radiograph (Fig. 3). The right descending pulmonary artery (RDPA) was enlarged (> 16 mm Hg)8, 44 in 43 of 46 patients (93 per cent) with an elevated mean pulmonary artery pressure, and the left descending pulmonary artery diameter (LDPA) also was enlarged (>18 mm) in 43 of 46. 164 Combining increased RDPA and increased LDPA diameter measurements permitted correct identification of 45 of 46 cases (98 per cent) with pulmonary artery hypertension, including all 26 with a mild elevation of mean pulmonary artery pressure (21 to 30 mm Hg). Thus, analysis of right and left descending pulmonary artery diameters on the plain chest radiograph is a sensitive method to detect the presence of pulmonary artery hypertension in chronic obstructive lung diseases.

THE RIGHT VENTRICLE IN COPD As stated, the major cardiac burden in chronic obstructive pulmonary diseases is upon the right ventricle. Pulmonary artery hypertension and increased pulmonary vascular resistance in these diseases leads to cor pulmonale, 30, 61, 77, 78, 88, 231 which is defined by the World Health Organization as right ventricular enlargement resulting from disorders that affect either the structure or function of the lungs. 252 According to this anatomic-pathologic

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Figure 3. Left, Posterior ante rior chest radiograph of a patient with severe chronic obstructive pulmonary disease and pulmonary artery hypertension (mean pulmonary artery pressure 48 mm Hg). Arrows outline an enlarged right descending pulmonary artery, 22 mm in widest diameter (normal :516 mm). Also, note the enlarged left main pulmonary artery. Right, Lateral chest radiograph illustrates (arrows) enlarged left descending pulmonary artery, 24 mm (normal :518 mm).

definition, the right ventricle must be enlarged, but mayor may not be hypertrophied. Clinically, it is important to distinguish pulmonary artery hypertension (the load the right ventricle bears) from cor pulmonale (adaptive right ventricular enlargement) and cor pulmonale with right ventricular failure. This distinction may be difficult. When overt right heart failure occurs with distended neck veins, enlarged liver, and peripheral edema in patients with electrocardiographic evidence of right ventricular enlargement, the diagnosis is obvious. However, many individuals with pulmonary artery hypertension and right ventricular enlargement do not have classic clinical signs or electrocardiographic criteria for right ventricular enlargement. Recently developed non invasive techniques, including thallium-201 myocardial imaging,21,54 gated equilibrium blood pool imaging,22, 23, 230 and first-pass radionuclide angiocardiography,16, 17, 19, 68, 162, 163, 230, 254 and echocardiography119, 120, 122, 147, 202 offer promise in identifying clinically occult right ventricular enlargement, hypertrophy and dysfunction in patients with chronic obstructive lung disease. This section reviews (1) incidence and prevalence of cor pulmonale, (2) determination of right ventricular enlargement in COPD, (3) right ventricular hemodynamics in chronic bronchitis and emphysema, and (4) right ventricular hemodynamics in cystic fibrosis.

Incidence and Prevalence of Cor Pulmonale (Pulmonary Heart Disease) Several clinical entities lead to pulmonary artery hypertension and to cor pulmonale, including recurrent pulmonary thromboembolism, pulmonary

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vasculitides, fibrosing alveolitis, and the obstructive pulmonary diseases. However, in many countries, including the United States, chronic obstructive pulmonary diseases are the most common causes of cor pulmonale. 126 In a British study, 40 per cent of patients with chronic bronchitis and emphysema showed anatomic evidence of cor pulmonale at autopsy,113 In the United States, 10 to 30 per cent of patients admitted to the hospital for congestive heart failure have decompensated cor pulmonale. 126 Overall in the United States decompensated cor pulmonale constitutes 30 to 40 per cent of clinical heart failure. BB Cor pulmonale also is a common complication of cystic fibrosis of the pancreas. 35. 203. 204. 221. 22B

Right Ventricular Enlargement Because right ventricular enlargement occurs most commonly in association with chronic elevations in pulmonary artery pressures, an analogy has often been made between the left ventricle in systemic hypertension and the right ventricle in pulmonary hypertension. 165 The normal right ventricle is a thin-walled, distensible muscular pump that accommodates considerable variations in systemic venous return without large changes in filling pressures. BB Its geometric configuration makes this chamber well suited for ejection of relatively large volumes of blood with minimal myocardial shortening. However, when pulmonary artery pressure and pulmonary vascular resistance increase, the right ventricle does not adapt well to the development of high intracavitary pressures. 165 In contrast, the left ventricle is better able to handle an increase in a pressure load. Figure 4 illustrates this point by contrasting the effects of increasing preload and afterload on right and left ventricular function. 165 In the left-hand panel, stroke volume is plotted as a function of various afterloads that were produced by actively constricting the main pulmonary artery and aorta in the dog. 2. 3 Small increments in pulmonary artery pressure are associated with sharp decreases in right ventricular stroke volume. In con-

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trast, the left ventricle, which normally works against high pressures, continues to maintain stroke volume despite substantial increases in systemic arterial pressure. The right-hand portion of Figure 4 demonstrates the effects of increasing preload. These ventricular function curves were obtained by volume infusions into the atria of dogs. 59 , 209 There are marked differences in the respective ventricular stroke work that occurs as right and left ventricular pressures are increased. For a fourfold elevation in filling pressure, the inqrease in left ventricular work was approximately five times that of the right. Under normal physiologic situations, the pulmonary vasculature provides little resistance to the right ventricular outflow. However, in response to chronic pressure overload imposed by pulmonary artery hypertension, the right ventricle becomes enlarged llO , 112, 113, 170 (Fig. 5). This enlargement mainly involves the free ventricular wall rather than the inflow and outflow tracts. Pre-terminally, an acute episode of severe hypoxia often exaggerates the degree of pulmonary hypertension and imposes an acute afterload on the right ventricle leading to dilatation of this chamber. Thus, cor pulmonale with right ventricular failure and systemic venous congestion results from pressure overloading of the right ventricle; the high resistance, constricted, and often restricted vascular bed acts as a peripheral stenosis to outflow. Three noninvasive techniques for determining the presence of right ventricular enlargement (RVE) or hypertrophy in patients with obstructive

Figure 5. Photomicrograph of the heart illustrating right ventricular enlargement and hypertrophy in a patient with cor pulmonale. (Number key: 1, right ventricular free wall; 2, left ventricular free wall; 3, interventricular septum; 4, right ventricular chamber; 5, right ventricular papillary muscle; and 6, tricuspid valve.) The right ventricular free wall is markedly thickened, approximately 2.5 cm widest diameter (normal 5 5 mm). Also, the right ventricular chamber and papillary muscles are significantly larger than the left ventricular chamber and papillary muscles.

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airway disease include scalar electrocardiography, vectorcardiography, and thallium-20l myocardial imaging. Electrocardiography. Scalar electrocardiographic criteria for right ventricular enlargement are listed in Table 3. 121 • 136. 152, 165, 172, 197 If a distinctive pattern of RVE is present in patients with COPD, the degree of cardiomegaly probably is severe. However, the standard criteria for RVE have been met in only one third of patients with chronic bronchitis and emphysema who had RVE at autopsy!97 Thus, the scalar electrocardiogram is insensitive in detecting RVE when cor pulmonale complicates obstructive airways disease. 103 , 136, 172, 197 Electrocardiographic evidence of RVE may be inconclusive at the point of early yet significant increments in the mass of the right ventricle in COPD because of such factors as changes in total lung capacity and rotation or displacement of the heart. 92, 103 Criteria for RVE may occur transiently with episodes of acute respiratory decompensation in COPD, heralding the onset of marked pulmonary artery hypertension and thus increased right ventricular afterload. 136 Kilcoyne and associates 136 studied 200 patients with COPD and were able to demonstrate that when the arterial oxygen saturation fell below 85 per cent and mean pulmonary artery pressure was 25 mm Hg or greater, one or more of the following changes would develop on the electrocardiogram: (1) a rightward shift of the mean QRS axis of 30" or more from its previous position; (2) inverted, biphasic, or flattened T waves in the right precordial leads; (3) depressed ST segments in leads 11, Ill, and a Vf; and (4) incomplete or complete right bundle branch block. With an increase in arterial saturation, these alterations disappeared. Electrocardiographic features of prognostic irliportance in severe chronic airway obstruction have been outlined by Kok-Jensen. 14o In a study of 288 patients, survival was very poor in individuals with a QRS axis of +90 to 180" and an amplitude of the P wave in lead' 11 of 0.20 mVor more; only 37 and 42 per cent, respectively, of the patients with these changes were alive after 4 years.

Table 3. Electrocardiographic Changes Characteristic of Right Ventricular Enlargement in Chronic Cor Pulmonale with Obstructive Disease of the Airways" 1. Isoelectric P waves in lead I or right axis deviation of the P vector 2. P-pulmonale pattern (an increase in P-wave amplitude in 11, Ill, aV,) 3. Tendency for right axis deviation of the QRS 4. RIS amplitude ratio in V, < 1 5. Low-voltage QRS 6. S,Q3 or S ,S2S3 pattern 7. Incomplete (and rarely complete) right bundle branch block 8. RIS amplitude ratio in V. > 1 9. Marked clockwise rotation of the electrical axis 10. Occasional large Q wave or QS in the inferior or mid-precordial leads suggesting healed myocardial infarction "The first seven criteria are suggestive but nonspecific; the last three are more characteristic of right ventricular enlargement in obstructive disease of the airways. (From Holford, F. D., in Fishman, A. P., ed.: Pulmonary Diseases and Disorders. New York, McGraw Hill, 1980. Reproduced with permission.)

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Vectorcardiography. The vectorcardiogram is apparently more sensitive than the scalar electrocardiogram for detecting right ventricular enlargement in obstructive lung diseases. The vectorcardiogram is a threedimensional construction of the instantaneous mean cardiac vector at any point throughout the cardiac cycle. 103. 250 The horizontal plane is the most important in evaluating RVE. In severe RVE, the horizontal loop is oriented rightward and anteriorly toward the anatomic position of the right ventricle; it is inscribed in a clockwise fashion. 103 Chou et aP1 found vectorcardiographic criteria for RVE in 80 of 97 patients (83 per cent) with COPD, atrial septal defect, or mitral stenosis and pulmonary hypertension. Wilson et al. 250 correlated vectorcardiographic changes with hemodynamic measurements in 32 patients with COPD and no scalar electrocardiographic evidence of RVE. The extent of rightward terminal QRS forces on the vectorcardiogram was significantly greater in patients with abnormal hemodynamic data at rest and during exercise than in those with normal rest and exercise results. In this study, the vectorcardiogram provided an indirect method of detecting, if not quantifYing, hemodynamic abnormalities. Thallium-201 Imaging. A nuclear medicine technique sutiable for determining the presence of right ventricle hypertrophy in obstructive airway diseases is thallium-201 myocardial imaging. 21 • 54.135.141.190.254 Distribution of this radiotracer is determined by regional myocardial blood flow and myocardial mass. 190 At rest, the vight ventricle normally is not visible but the left ventricle is clearly visualized because of its greater mass. The right ventricle commonly is demonstrated during the augmented right ventricular blood flow that is produced by exercise. Cohen et al. 54 first noted that in patients with pulmonary artery hypertension the right ventricle was visualized at rest. Thickening of the right ventricular free wall was apparent when pulmonary artery hypertension and RVE were severe. In subsequent studies,21. 135. 141 resting thallium-201 imaging has been evaluated in a variety of patients with right ventricular volume and pressure overloading. The presence of right ventricular visualization was related to elevated right ventricular systolic pressure and pulmonary vascular resistance. Moreover, Rabinovitch et al. 190 demonstrated in the chronic hypoxic rat with right ventricular hypertrophy myocardial thallium-20l uptake directly reflected myocardial mass and thus can be used to quantifY the severity of hypertrophy. The significance of right ventricular visualization on thallium-20l images in COPD has been evaluated recently in 71 patients with chronic bronchitis and/or emphysema (Fig. 6).21 Analysis of computerized thalium-201 images was compared to resting right ventricular ejection fraction, scalar electrocardiograms, and pulmonary function. Of 11 patients with electrocardiographic evidence of right ventricular hypertrophy/54. 170 9 had marked right ventricular thallium-20l uptake and 2 had mild uptake, Patients with marked right ventricular thallium uptake had significantly greater right ventricular dysfunction (Le., depressed right ventricular ejection fraction), arterial hypoxemia, and airway obstruction than patients with normal thallium-20l images. Of 23 patients with marked right ventricular uptake, 20 had an abnormal ejection fraction, but only 9 had right ventricular hypertrophy on the electrocardiogram. 21 In contrast, only 3 of 19 patients with normal thallium-20l

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Figure 6. Resting thallium-201 myocardial perfusion images in a patient with chronic obstructive pulmonary disease. Images are shown in the anterior (A), 45° left anterior oblique (B), and left lateral (C) positions. Note the marke d right ventricular thallium-201 uptake seen in all three positions. Using quantitative computerized analysis, the right ventricular to background ratio for thallium-201 was 1.6: 1. The patient had an abnormal right ventricular ejection fraction (37 per cent). (From Berger, H. J., and Matthay, R. A.: Amer. J. Cardiol., in press. Reproduced with permission.)

images had an abnormal right ventricular ejection fraction and none had electrocardiographic evidence of right ventricular hypertrophy. These data suggest that marked right ventricular uptake on thallium-201 images in COPD may be an early indicator of right ventricular hypertrophy and right ventricular performance abnormalities.

Right Ventricular Hemodynamics in Chronic Bronchitis and Emphysema Data obtained at right heart catheterization have provided a broad overview of right ventricular hemodynamics at different stages in the evolution of chronic bronchitis and emphysema. 41 , 71. 77. 134, 165. 247. 24B Patients with relatively mild obstructive lung disease without severe hypoxemia generally have normal mean right atrial and left ventricular end-diastolic pressures, low to normal cardiac outputs, normal or slightly elevated pulmonary artery pressures, and slightly elevated pulmonary vascular resistances at rest4 l • BB. 134. 165 (Table 1). With mild steady state exercise, pulmonary artery pressure rises and right ventricular end-diast~lic pressure and stroke work increase. 41. 79. 130, 137,235 Relating end-diastolic pressure to stroke work suggests that these patients operate on an extension of the normal right ventricular function curve. 134, 165 At this point, clinical or electrocardiographic evidence of right ventricular enlargemem is absent. 41 However, acute right ventricular failure can develop in these patients if respiratory failure is precipitated by a pulmonary infection. 165 As the obstructive ventiliatory impairment worsens, the hemodynamic alterations also are accentuated. When severe chronic hypoxemia develops, usually in association with chronic hypercapnia, there is moderate pulmonary hypertension at rest, which becomes more severe during exercise in association with abnormal right ventricular filling pressures,t35. 165 Cardiac output tends to be normal. or slightly elevated at rest but increases little with exercise. At this point, mean pulmonary artery pressures can reach 60 to 80 mm Hg, and these individuals are likely to show clinical and electrocardiographic changes usually ascribed to cor pulmonale (Table 3).165 Right ventricular failure is associated with an expanded circulating blood volume.6 However, in contrast to left ventricular failure, the pulmonary blood volume/total

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volume ratio remains essentially normal (approximately 10 per cent of the total) even though red cell mass may be considerably increased. 165. 208 Both circulating plasma volume and lung water increase,'65. 208 and both have been shown to decrease when pulmonary artery pressure is lowered with therapy.'65 In addition to cardiac output and central circulatory pressure measurements obtained at cardiac catheterization, relatively noninvasive measurements of ejection fraction have provided important information regarding biventricular performance in COPD. Ejection fraction is that portion of end-diastolic volume which is ejected per beat, or stroke volumelenddiastolic volume. During the past 6 years, several investigators have utilized quantitative radionuclide angiocardiography for determining ejection fraction at rest and during exercise in CO PD. 16. 18. 19. 23. 52. 53. 68. 69. 70. 159. 162. 163. 181. 222. 226 Two techniques have been used commonly, first-pass radionuclide angiocardiography and equilibrium gated blood pool imaging. '6. 22. 155. 156. 220 Employing the first-pass radionuclide technique, the most widely utilized in COPD patients, analysis is made from regional time-activity curves during the initial20-second transit of a radionuclide bolus through the central circulation (Figs. 7 and 8).16.19.22.23.155.156.254 Studies are obtained after peripheral venous injection of technetium 99m radiotracers. Both right and left ventricular ejection fraction are obtained from the same study.'6 Right Ventricular Ejection Fraction at Rest. In studies from our laboratory, right ventricular ejection fraction (RVEF) initially was evaluated at rest in 36 patients with chronic bronchitis (Fig. 9).16 It ranged from 19 to 71 per cent, and was abnormal « 45 per cent) in 19 of these 36 patients. All 10 patients with clinical evidence of decompensated cor pulmonale manifested abnormal right ventricular performance. Of 26 patients without clinical TIME - ACTIVITY CURVES

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D. Figure 8. Traced outline of contrast angiographic studies in 6 normal patients without evidence of cardiovascular disease. The right ventricle (RV) is shaded. The left ventricle (LV) also is noted. These diagrams were obtained directly from contrast angiographic studies in the anterior projection. Note the wide variation in the shape and configuration of the normal right ventricle. This variability in right ventricular shape makes quantitative contrast angiographic determination of right ventricular volumes and ejection fraction extremely difficult. In contrast, the first-pass radionuclide technique, by obtaining ejection fraction from relative changes in count rate, is not dependent upon major geometric assumptions concerning the shape and configuration of the right ventricle. (Modified with permission from Dotter, C. T., and Steinberg, I.: The normal angiocardiogram. In Dotter, C. T., and Steinberg, I., eds.: Angiocardiography. New York, Harper and Brothers, 1953.)

evidence of cor pulmonale, 9 also had a depressed RVEF.16 In a follow-up period of a minimum of 1.5 years, 4 of these patients with abnormal right ventricular performance at rest subsequently developed acute respiratory failure and decompensated cor pulmonale. In contrast, none of the patients with normal RVEF developed evidence of right-sided heart failure during the same period. These data suggest that radionuclide-determined RVEF can identify clinically occult right ventricular performance abnormalities and can also detect a population at risk for developing frank right heart failure. Other studies utilizing first-pass radio nuclide angiocardiography have confirmed these data by demonstrating depressed RVEF at rest in patients with chronic bronchitis and/or emphysema and no clinical evidence of decompensated cor pulmonale. 18 t. 222 Perhaps at this point, appropriate therapeutic intervention designed to decrease right ventricular afterload would lead to improvement in prognosis. The degree of obstructive ventilatory impairment in patients with chronic bronchitis, assessed by forced expiratory volume in one-second (FEV l ), was related to evidence of right ventricular dysfunction at rest measured by the first-pass radio nuclide technique. 16 A similar relationship was found between the severity of arterial hypoxemia and abnormal right ventricular performance. 16 Thus, severe abnormalities in FE VI and arterial oxygen tension (P a02) appear to be indirect indicators of augmented right ventricular af-

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Figure 9. Right ventricular ejection fraction in 50 normal control subjects without evidence of cardiopulmonary disease and in 36 patients with chronic obstructive pulmonary disease (COPD). The means ±2 standard deviations (SD) is shown for the normal group. Using ±2 standard deviations, the lower limit of normal is 45 percent. Note the wide variation in ejection fraction values for patients with COPD. Nineteen of the patients demonstrated abnom'ial right ventricular performance at rest, and all 10 patients with a history of decompensated cor pulmonale (*) had an abnormal right ventricular ejection fraction. (From Berger, H. J., Matthay, R. A., Loke, J., et al.: Amer. J. Cardio!., 41 :897-905, 1978. Reproduced with permission.)

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terload in COPD. Since the ejection fraction detennination is highly afterload dependent, a relationship understandably exists between abnonnal RVEF and depressed FEV I and P a 0 2. Right Ventricular Ejection Fraction During Exercise. As stated earlier, right ventricular dysfunction often becomes apparent only during exercise in COPD.88 ,130,145,226,235 Using cardiac catheterization techniques, elevated pulmonary artery, pulmonary capillary wedge and right ventricular end-diastolic pressures have been demonstrated during exercise. 128, 130, 151, 235 Right and left ventricular ejection fractions also have been evaluated during exercise with radionuclide angiocardiography l7, 20, 162, 181 (Figs. 10 to 12). Of 30 patients with COPD, 23 (77 per cent) demonstrated an abnonnal right ventricular ejection fraction response to submaximal upright bicycle exercise (Figs. 11 and 12).162 Yet, RVEF was abnonnal at rest in only 8 of these patients. Abnormal right ventricular responses were demonstrated even in some patients with mild airway obstruction. Altered right ventricular afterload due to pulmonary artery hypertension likely is the major factor modulating the right ventricular response to exercise rather than abnonnalities in myocardial contractility. Accordingly, it is important to stress that abnonnal right ventricular exercise reserve in COPD may be a nonnal physiologic response to augmented afterload rather than an indication of intrinsic right ventricular myocardial dysfunction. Increased pressure

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Figure 10. Right ventricular (RV) and left ventricular (LV) ejection fraction at rest and during exercise in 25 normal control subjects without cardiopulmonary disease. Overall means are shown at the sides of each panel. Right and left ventricular ejection fraction increased by at leat 5 percent in all subjects, irrespective of protocol. (From Matthay, R. A., Berger, H. J., Davies, R. A., et al.: Ann. Intern. Med., 93:234-239, 1980. Reproduced with permission.)

on pulmonary vessels due to marked negative swings in pleural pressure may account in part for the elevated right ventricular afterload during exercise in patients with COPD.162, 185

Right Ventricular Hemodynamics in Cystic Fibrosis Cystic fibrosis is another disease in which right ventricular dysfunction develops as a consequence of pulmonary abnormalities. A substantial number of these patients die from cardiac complications. 35 , 50, 63, 64, 81, 101, 147, 163, 175, 203, 204, 215, 221, 228 In fact, in one study cor pulmonale was demonstrated in over 70 per cent of children dying of cystic fibrosis,50 Overt right heart failure occurs late in the clinical course of cystic fibrosis, and once it develops, the mean survival is between 3 and 8 months regardless of therapy .175,228 In a cardiac catheterization study of 34 patients with cystic fibrosis, Siassi et al. noted that a p a02 tension ::;50 mm Hg, arterial carbon dioxide tension 2:45 mm Hg, a FE VI < 1 liter, and a severely depressed Schwachman clinical score were associated with a markedly elevated mean pulmonary artery pressure (2:38 mm Hg). These correlations are not surprising in view of the pathophysiology of cystic fibrosis which involves alveolar hypoventilation resulting from mucous obstruction of airways, recurrent infection, and progressive multilobar bronchiectasis. Resultant chronic hypoxia causes pulmonary artery

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hypertension, right ventricular enlargement, and right ventricular failure.35, 63. 64. 174.204.228 Unfortunately right ventricular enlargement is difficult to identify noninvasively in cystic fibrosis prior to overt cardiopulmonary decompensation. Similar to experience in chronic bronchitis and emphysema, the electrocardiogram has not proved to be a sensitive technique for determining right ventricular enlargement in cystic fibrosis. 147. 174.221 Echocardiography has been applied to patients with COPD,t0' 50. 120. 122. 147. 178. 189. 202. 205 particularly those with cystic fibrosis, and mild increases in right ventricular wall thickness and cavitary diameter have been demonstrated. However, measurements of right ventricular dimensions with M-mode echocardiography, particularly in patients with obstructive lung diseases such as cystic fibrosis, are technically difficult and frequently unreliable 29, 74, 139, 147 because of marked respiratory variation and lung hyperinflation. However, in patients with adequate examinations, especially children and young adults with cystic fibrosis, potentially important clinical information has been obtained,189, 202, 205 Rosenthal et a1. 202 studied 96 patients with cystic fibrosis, and 50 (52 per cent) had echocardiograms technically suitable for measurement of right ventricular diastolic dimensions. Weak but significant correlations were demonstrated between right ventricular dimensions

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Figure 12. Incidence of ventricular performance abnormalities at rest or during exercise in 30 patients with chronic obstructive pulmonary disease (COPD). The shaded bars refer to right ventricular (RV) performance, while the open bars refer to left ventricular (LV) performance. Note that the predominant hemodynamic abnormality involves right ventricular function, especially during exercise. Abnormal left ventricular performance was relatively common. (From Berger, H. J., and Matthay, R. A.: Amer. J. Cardio!., in press. Reproduced with permission.)

and forced vital capacity, FE V!> and clinical severity of the disease assessed by the Schwachmen score. However, these dimensions were of limited clinical value in assessment of cardiac function. Hirschfeld et al. 119, 120, 196 used pulmonic and aortic valve echo grams to measure right and left ventricular systolic time intervals in children with cystic fibrosis. Patients with clinically evident Ilight heart failure demonstrated elevated right ventricular pre-ejection period to ejection time ratios compared to those without right heart failure. There was a good correlation between this ratio and forced vital capacity, residual volume and Schwachman clinical score. In general, right ventricular systolic time intervals determined by echocardiography also correlate well with pulmonary artery pressures measured at cardiac catheterization and with right ventricular wall thickness measured at postmortem examination. However, because of pulmonary hyperinflation, technically adequate studies are obtained only in approximately two thirds of the patients. 50, 89, 119, 120,202 Radionuclide angiocardiography has been utilized recently to evaluate right heart performance noninvasively in cystic fibrosis. 5 0,163 In 22 young adults with cystic fibrosis evaluated in our laboratory using the first-pass technique (Fig. 13),163 the magnitude of right ventricular dysfunction was related to disease severity assessed by the Schwachman clinical score, P a02, and FEV1 • Four patients without cor pulmonale who had an abnormal basal RVEF developed acute respiratory failure and right-sided heart failure within 6 to 12 months of the initial study. Yet, none of the 13 with normal baseline

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right heart perfonnance decompensated during a 1.5 year follow-up. Thus, radio nuclide angiocardiography may prove useful in identifYing patients with cystic fibrosis who are at high risk for overt cardiopulmonary failure.

THE LEFT VENTRICLE IN COPD The subject ofleft ventricular performance in chronic obstructive pulmonary disease is both complicated and controversial.ll, 13, 66, 84, 85, 88, 98, 131, 134, 173 While it is clear that left ventricular dysfunction does occur, controversy exists about whether fight ventricular pathology produces the left ventricular disease, or whether the latter results from independent causes. 165 It has been postulated that several factors may contribute to left ventricular failure in COPD, including hypoxia, acidosis, coronary artery or valvular heart disease, systemic hypertension, bulging of the interventricular septum into the left ventricular cavity and alterations in intrathroacic pressuresY' 15,40,84,85, 128, 131, 198, 199,201,226 Regardless of etiology, when left ventricular failure occurs, it may severely aggravate cor pulmonale by increasing the pulmonary blood volume and promoting the accumulation of extravascular water. Consequently, pul-

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monary compliance is reduced and airway resistance is increased, thereby augmenting the work of breathing and disturbing gas exchange. ss The latter abnormality may lead to further augmentation in pulmonary artery pressure and right ventricular afterload.

Left Ventricular Perfonnance in Chronic Bronchitis and Emphysema

In several studies of patients with chronic bronchitis and emphysema, left ventricular hypertrophy has been noted at postmortem examination. 15. 66. 93.142.166.176.193.217.223 Rao et al. l93 and Baum et al. 15 reported increased left ventricular filling pressures at cardiac catheterization as evidence of left ventricl.).lar dysfunction in patients with COPD. Moreover, several investigators have suggested that hypertrophy and failure of the right ventricle can lead to disorders in left ventricular performance. 13. 15.134.193 Animal studies have shown that (1) right ventricular failure following banding of the pulmonary artery leads to similar morphological and biochemical changes in both cardiac chambers and to reduced contractility of the left ventricle,39. 43. 49 (2) in both isolated hearts and intact animals alterations in right ventricular compliance or dimensions also change the mechanical properties of the left ventricle,132. 143. 229 and (3) cattle with severe pulmonary hypertension at high altitude have increased left ventricular end-diastolic pressures. 1l4. 165 However, as FiShman85 has emphasized, the relevance of the animal studies to cor pulmonale in man is tenuous. 58. 84. 97. 226. 241. 249 Most recent studies utilizing cardiac catheterization and/or non-invasive techniques have demonstrated preserved left ventricular performance and a normal-sized left ventricle in patients with chronic bronchitis and emphysema, in the absence of other associated cardiac abnormalities.16. 34. 41. 52. 58. 97. 110. 131. 134. 138. 158. 160. 162. 226. 238. 249 It is possible that occult abnormalities in left ventricular performance in COPD can be demonstrated by acutely augmenting left ventricular afterload. Accordingly, in patients with chronic bronchitis and emphysema, Jezek and Schrijen 128 increased systemic arterial pressures and left ventricular afterload with an angiotensin infusion and showed that left ventricular function was almost always normal in patients with COPD who had not been in cardiac failure. On the other hand, a majority of patients with decompensated obstructive airway disease showed abnormal left ventricular function when afterload was increased. Baum et al. 15 noted elevated left ventricular enddiastolic pressures following an angiotensin infusion in patients with chronic bronchitis and emphysema. However, angiotensin has been shown to have a negative inotropic effect26. 96 and this may accout for at least some of the left ventricular dysfunction reported in these two studies. 128. 151 The effects of a methoxamine-induced increase in left ventricular afterload were evaluated by right heart catheterization and radionuclide angiocardiography in a group of stable patients with chronic bronchitis and emphysema. 160 Methoxamine is a pressor agent with little direct effect on myocardial contractility. Resting basal left ventricular performance, assessed by measurements of ejection fraction, stroke volume index and pulmonary capillary wedge pressure, was normal and did not deteriorate with methoxamine. Williams and associates 248 also reported a normal left ventricular response to a methoxamine-induced increase in afterload in patients with COPD.

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Exercise may reveal latent left ventricular performance abnormalities in COPD. Khaja and Parker134 found a normal left ventricular enddiastolic pressure at rest and during exercise in COPD patients. Two recent studies evaluated the left ventricular ejection fraction (LVEF) response to submaximal, relatively steady state upright bicycle exercise in patients with chronic bronchitis and emphysema. 162, 181 Matthay et aI.t62 reported an abnormal LVEF at rest «55 per cent) in only 4 of 30 patients, and abnormal left ventricular exercise reserve in only 6 of 30 patients (Figures 10, 11, 12). In a similar study, Olvey et aJ.181 found a normal resting LVEF in all 18 of their patients. However, the left ventricular exercise response was abnormal in 9. The authors attributed the failure to increase L VEF during exercise to the low level of exercise achieved due to pulmonary symptoms. 181 Latent coronary artery disease also may have accounted for a subnormal increase in LVEF. Acute respiratory decompensation is another important stress that may cause left ventricular dysfunction in COPD.70, 144,226 Such episodes are associated frequently with profound arterial hypoxemia, respiratory acidosis, and marked alterations in intrathoracic pressures. Steele et al. 226 measured LVEF at rest in patients with acutely decompensated COPD. Of 92 patients, 26 (28 per cent) had an abnormal resting LVEF. However, only 13 of 92 patients (14 per cent) had evidence ofleft ventricular dysfunction without known concomitant coronary artery disease or hypertension.

Left Ventricular Performance in Cystic Fibrosis With few exceptions,14, 50, 147, 182 left ventricular structure and function have been found normal in patients with cystic fibrosis. In our laboratory, L VEF was determined at rest in 22 ambulatory young adults with cystic fibrosis, and all had normal resting LVEF (Fig. 13).163 However, Chipps et al. 50 demonstrated abnormalities in LVEF at rest in 4 of 18 patients (22 per cent) with cystic fibrosis. Eight patients with normal LVEF at rest underwent assessment of left ventricular performance during peak supine exercise, and 3 exhibited an abnormal left ventricular response to exercise. Overall, there was evidence of left ventricular performance abnormalities in approximately one third of the patients studied by Chipps and colleagues. 5o

Effects of Alterations in Intrathoracic Pressure on Left Ventricular Performance in COPD Almost every study of cardiac performance in COPD includes patients who have abnormal left ventricular function, at rest and/or exercise, even in the absence of concomitant systemic hypertension or coronary artery disease. Several studies 40 , 100, 185, 198, 199, 200, 201, 21L 232 have provided data that may explain some of these cases of left ventricular dysfunction. Large changes in intrathoracic pressures, which occur frequently in patients with COPD, can decrease left ventricular performance. Marked negative swings in pleural pressure occurring during inspiration in COPD cause an increase in pulmonary artery pressure and right ventricular afterload and an increase in venous return to the right heart. The right ventricle distends because of the increased venous return and increased right heart afterload. This distention causes the left ventricle to be effectively stiffer, raising left ventricular end-diastolic pressure, decreasing pulmonary venous return and hence left ventricular stroke volume. 199, 201, 240 This phenomenon interacts with an effective increase

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in left ventricular afterload, also created by the fall in pleural pressure during inspiration, further raising left ventricular end-diastolic pressure and decreasing left ventricular stroke volume. 201 Buda and colleagues 40 demonstrated that the net effect of this fall in pleural pressure may be an increase in the left ventricular end-systolic volume and a decrease in LVEF; thus, left ventricular performance is impaired. If these effects are added to hypoxia, hypercapnia, and acidosis, particularly in acutely decompensated patients with obstructive airway disease, there may be substantial effect on the left ventricle.

EFFECTS OF THERAPEUTIC INTERVENTION ON CARDIOVASCULAR PERFORMANCE IN COPD Because cor pulmonale is a consequence of pulmonary artery hypertension, the major goal of therapy is to decrease the workload of the right ventricle by decreasing pulmonary artery pressure. S5 ,88 Little permanent relief can be expected when anatomic lesions, such as healed multiple pulmonary emboli or diffuse pulmonary fibrosis, are the basis for the pulmonary hypertension. 85 However, disorders in which pulmonary vasoconstriction is of primary importance are much more amenable to therapy. In chronic bronchitis, emphysema and cystic fibrosis, ventilation-perfusion ratios are distorted acutely and/or chronically, leading to marked hypoxemia and pulmonary vasoconstriction. TheI;apeutic intervention may reduce pulmonary artery distending pressures by reversing vasoconstriction. The following forms of therapy aimed at improving cardiovascular function in COPD will be reviewed: oxygen, diuretics, digitalis, theophylline, beta-adrenergic agents, and vasodilators.

Oxygen Oxygen therapy in patients with cor pulmonale has been shown to (1) reduce pulmonary artery pressure and pulmonary vascular resistance, (2) augment right ventricular ejection fraction at rest and during exercise, and (3) reduce hematocrit. 5, 6, 36, 42, 55, 91, 137, 145, 186, 224, 225,'237 In acute respiratory failure, supplemental oxygen results in prompt and often dramatic improvement in pulmonary hemodynamics. 41 , 247 In patients with progressive right ventricular enlargement or recurrent heart failure from cor pulmonale associated with severe hypoxemia (P a02 < 50 mm Hg) and severe pulmonary hypertension, marked improvement usually occurs if oxygen is administered for 15 or more hours per day.42, 165, 224 While there is usually a small, acute response of pulmonary artery pressures to oxygen therapy in these patients, substantial falls in pressure and pulmonary vascular resistance require about 4 to 6 weeks of this therapy. 5,7,27 The ideal number of hours per day of oxygen therapy is currently under study.90,180 Preliminary results of a study by the Nocturnal Oxygen Therapy Trial group (NOTT) revealed that continuous oxygen therapy was associated with a lower mortality than nocturnal oxygen therapy in patients with hypoxemic chronic obstructive lung disease. 18o Another study recently completed in the United Kingdom suggests that 15 hours of oxygen administration per day augments survival in COPD patients with cor pulmonale compared with those who do not receive oxygen therapy.90 Olvey and colleagues 181 evaluated the acute effects of low-flow oxygen

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adminstration on right ventricular performance in patients with COPD. Mean RVEF at rest was unchanged by low-flow oxygen. However, the ejection fraction response during exercise was improved markedly by oxygen therapy. Ellis et a1. 69 studied the chronic effects of oxygen therapy in 38 patients with severe airway obstruction and scalar electrocardiographic evidence of right ventricular hypertrophy; 29 (76 per cent) had a history of decompensated cor pulmonale. After 6 months of oxygen therapy, there was a significant decrease in pulmonary artery pressure and pulmonary arteriolar resistance index, a decrease in hematocrit, and a significant increase in right ventricular performance assessed by ejection fraction measurements.

Diuretics Excess fluid in the lung compromises pulmonary gas exchange and augments pulmonary vascular resistance. 27, 99,115,179 A prompt initial diuresis will lower pulmonary artery pressure through a decrease in the total blood volume. 99 Additional benefit may be realized from a transient increase in peripheral blood pooling, which is an extrarenal effect of loop diuretics such as furosemide. 62 This is similar to the venodilator effect of nitroglycerin. Diuretics must be given with caution to patients with COPD and decompensated cor pulmonale because of the threat of excessive volume depletion and a resulting decrease in cardiac output. Bed rest and modest salt restriction alone may relieve significant water accumulation in circumstances of less urgency. Moreover, overzealous administration of powerful diuretics can lead to hypokalemic metabolic alkalosis, which diminishes the effect of carbon dioxide on the respiratory centers and lessens the ventilatory drive. If the diuretics deplete potassium and chloride, renal excretion of bicarbonate is compromised. For these reasons, careful monitoring of serum electrolytes following administration of diuretic or during periods of salt and water restriction is mandatory when managing patients with decompensated obstructive airway disease.

Digitalis The use of digitalis and its derivatives in patients with cor pulmonale remains controversia1. 24, 69, 75, 76, 125, 129, 157,235,243 In a recent review, Green and Smith reached the conclusion that there is no definitive evidence supporting the use of cardiac glycosides in patients with cor pulmonale unless there is coexistent left ventricular failure or a supraventricular tachyarrhythmia for which digitalis is the drug of choice. 102 In general, digitalis has been used in cor pulmonale patients with right ventricular failure and systemic venous congestion resulting from pressure overloading of the right ventricle. In this setting, digitalis is utilized for its presumed inotropic effects on the right ventricle. Ferrer et al,75 were the first to show significant changes in hemodynamic variables with acute digitalization. With intravenous digitalis, right ventricular end-diastolic pressure dropped toward normal; however, systolic pulmonary artery pressure and cardiac output increased further. Similar findings have been reported by others.125, 129 Most investigators also have found a slight but consistent rise in pulmonary vascular resistance with acute digitalization. 102 , 129, 149 Any en-' hancement of elevated pulmonary vascular resistance, together with in-

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creased cardiac output, will increase the pressure work of the right ventricle. 102 Ellis et al. 69 failed to demonstrate improvement in right ventricular performance, assessed by ejection fraction, following acute intravenous administration of ouabain in adults with severe obstructive airway disease and cor pulmonale. Jezek and Schrijen 129 evaluated the effects of intravenous digitalis (deslanoside) at rest and during exercise in patients with chronic bronchitis. In the patients at rest without right heart failure, deslanoside induced a slight reduction in cardiac output, right ventricular end-diastolic and pulmonary capillary wedge pressures, and an increase in systemic and pulmonary vascular resistances. The effects of deslanoside were more positive in patients at rest with right heart failure. An increase in cardiac output, stroke volume, right und left ventricular stroke work and stroke power, and a more pronounced decrease of right ventricular end-diastolic and pulmonary artery wedge pressures were observed, with no changes in vascular resistances. However, these investigators failed to find a significant improvement in cardiac performance after deslanoside during exercise in patients with chronic bronchitis. These studies by Ellis et al. 69 and Jezek and Schrijen 129 were limited to an evaluation of the acute effects of digitalis. In a preliminary study, Mathur et al. evaluated the chronic effects of digitalis on ejection fraction in 14 patients with cor pulmonale. 157 Eight weeks of digitalis therapy resulted in a significant improvement in both right and left ventricular ejection fraction in this group of patients. However, the overall improvement was due to the presence of four individual responders who demonstrated a significant increase in LVEF (from 43 to 56 per cent) and RVEF (from 30 to 37 per cent). In the remaining patients, there was no change in either left or right ventricular ejection fraction. Baseline L VEF was substantially lower in patients whose right ventricular ejection fraction responded to digitalis than in those who did not. These data tend to support the conclusion reached by Green and Smith 102 that digitalis may improve right ventricular function in obstructive airways disease only if there is concomitant left ventricular dysfunction. Further trials are needed to confirm the preliminary findings of Mathur et al. 157 and to evaluate whether chronic digitalis therapy has an additive effect with oxygen in improving right ventricular performance in patients with obstructive airways disease and cor pulmonale. In the meantime, current consensus favors digitalis for patients with COPD and coincident left heart failure, a supraventricular arrhythmia, or overt right ventricular failure that fails to respond to extensive application of other therapy to relieve pulmonary artery hypertension. 172

Theophylline To the extent that reversible airway obstruction is a significant cause of abnormal pulmonary gas exchange in COPD, aerolized and systemically administered bronchodilators may be of great importance. Theophylline, a methylxanthine, provides benefits beyond the usual bronchodilatation, for this compound may produce favorable hemodynamic effects as well. Parker et al. 183 • 184 showed that the intravenous administration of aminophylline in patients with COPD and cor pulmonale significantly reduced mean pulmonary artery and right and left ventricular end-diastolic pressures. First-pass radionuclide techniques have been employed to assess the

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biventricular response to intravenous infusion of aminophylline and oral administration of a long-acting theophylline agent. 158. 161 Aminophylline significantly improved right and left ventricular ejection fractions in 15 adults with COPD in a compensated state (Fig. 14). This improvement in biventricular performance occurred in the presence of only minimal improvement in FE VI and forcd vital capacity. Furthermore, arterial oxygen tension did not change. In a parallel study of five normal control subjects, without evidence of cardiopulmonary disease, aminophylline infusion resulted in comparable increments in right and left ventricular ejection fraction without any change in ventilatory performance or arterial oxygen tension. 158 Preliminary studies with oral, long-acting theophylline (Theo-dur) have demonstrated that moderate improvement in biventricular performance can be obtained acutely and sustained during long-term follow-up.161 The two most likely mechanisms for the theophylline-induced improvement in right and left ventricular ejection fraction are a direct inotropic effect on myocardium and a decrease in biventricular afterload due to diminished pulmonic and systemic vascular resistances.

Vasodilators and Beta2 Agonists Vasodilators, \, 9. 45. 95. 104. 133. 167. 168.246 and beta-adrenergic stimulants l2 . 32. 57.187.188.206.219.234 have theoretical advantages for improving cardioRV EJECTION FRACTION

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vascular performance in patients with COPD and pulmonary hypertension. These agents may decrease right ventricular afterload (1) by a direct dilating effect on the pulmonary vasculature, (2) by recruitment of underperfused pulmonary vessels, or (3) by decreasing alveolar pressure. Using first-pass radionuclide angiocardiography and thermodilution pulmonary artery catheterization, the acute effects of the vasodilator, nitroglycerin, and the beta2-adrenergic agent, terbutaline, have been evaluated in patients with severe bronchitis and emphysema and right ventricular dysfunction. 37 ,38 Nitroglycerin decreased cardiac index and right ventricular enddiastolic volume index, but did not affect right ventricular afterload. 37 In addition, nitroglycerin caused a fall in arterial oxygen tension and systemic oxygen transport. These results and similar results of other studies 48 , \06,246 suggest that nitroglycerin may have deleterious effects in patients with COPD. In contrast, subcutaneous terbutaline, a presumed selective beta2 agonist, was found to improve both right and left ventricular ejection fraction while decreasing pulmonary and systemic vascular resistances. 38 Terbutaline also improved systemic oxygen transport. Teule and Majid234 administered terbutaline intravenously to patients with severe COPD and noted a significant decrease in mean pulmonary artery pressure and pulmonary vascular resistance and an increase in cardiac output and resting peak expiratory flow rate. Data from these two studies suggest that the beneficial therapeutic effect of terbutaline on systolic ventricular function is due predominantly to decreased biventricular afterload rather than positive inotropic effects on the myocardium. Thus, in addition to improving airway flow in obstructive pulmonary diseases, terbutaline may be useful in decreasing biventricular afterload, augmenting right and left ventricular performance, and improving oxygen delivery to tissue. Additional studies are required to assess the cardiovascular effects of oral and inhaled terbutaline and other beta-adrenergic agents utilized in patients with obstructive airways disease. A preliminary study by Klugman et al. 139 evaluated the hemodynamic effects of the calcium antagonist, nifedipine, in, patients with chronic pulmonary hypertension, including patients with COPD. Sublingual nifedipine decreased pulmonary and systemic vascular resistances. These effects were associated with an increase in cardiac index without a significant change in oxygen saturation. Thus, nifedipine appears to have an acute, positive hemodynamic effect in patients with COPD and pulmonary hypertension. Further studies are needed to evaluate the merits of this agent for chronic therapy.

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