State of the Art Airway Obstruction and Bronchial Hyperresponsiveness in Left Ventricular Failure and Mitral Stenosis 1 , 2

PHILLIP D. SNASHALL and K. FAN CHUNG Contents Introduction "Cardiac Asthma": A Semantic Ambiguity Airways Obstruction in Left Ventricular Failure, Mitral Stenosis, and Extracellular Volume Overload Pathologic observations Clinical studies Acute heart failure Chronic heart failure and mitral stenosis Narrowing of small airways Renal failure with volume overload Animal studies Mechanisms of Airway Obstruction Intraluminal edema liquid Airway wall vascular engorgement and edema Anatomy and physiology of the bronchial circulation and lymphatics Mechanisms of wall thickening Bronchoconstriction Humoral mechanisms Neural mechanisms Vagal reflex constriction Vagal afferents Bronchodilator influences in left ventricular failure Peribronchial and extrabronchial factors Airway compression by peribronchial edema Lung volume and elastic recoil Peribronchial fibrosis Bronchial hyperresponsiveness Studies in mitral stenosis and left ventricular failure Effect of bronchial mucosal thickening Sodium balance and bronchial responsiveness Significance of bronchial hyperresponsiveness Nocturnal attacks of left ventricular failure Diagnosis and management Summary Introduction

Clinical conditions characterized by airway obstruction and those by pulmonary vascular congestion and edema usually form distinct and easily recognizable synAM REV RESPIR DIS 1991; 144:945-956

dromes. Sometimes, however, clinical features overlap and the patient presents with both heart failure and airway obstruction. There is now a substantial body of evidence that cardiac disease can precipitate airway narrowing. This report reviews the evidence and also discusses experimental work dealing with the mechanisms of this cardiac-airway interaction. "Cardiac Asthma": A Semantic Ambiguity

The term "cardiac asthma" was coined by Hope in 1835 (1), and Osler (2) and McKenzie (3) gave vivid accounts of wheezing during episodes of cardiac failure. Osler, in 1897, described cardiac asthma as follows: "The patient goes to bed feeling quite well and, in the early hours awakes in an attack which, in its abruptness of onset and general features, resembles asthma. There is usually a sensation of praecordial distress, a feeling of constriction, and oppression.... Two other features about this form of attack will attract your attention, the evident effort in the breathing and the presence of a wheezing in the bronchial tubes and of moist rales at the bases of the lungs. The patient may spring from the bed and throw open the window in his terrible air hunger. . . . Death may occur in the attack." Today, this presentation would usually be termed "paroxysmal nocturnal dyspnea" (PND) or "acute left ventricular failure" (LVF),and, in line with this, standard texts (4-6) describe cardiac asthma and PND as synonymous. Because wheeziness is often part of these attacks, and since the Greek word aotiua merely means "to breathe with open mouth" or "to gasp," this usage is perhaps justified. However, there is limited evidence that airway obstruction, as compared with wheeziness is usually an important feature of these attacks, and therefore some

(7, 8) confine the term cardiac asthma to cases with prominent clinical features of airway obstruction. Moreover, with time the word asthma has acquired a far more specific meaning than in the original Greek. It refers to "a condition characterised by widespread narrowing of intrapulmonary airways which may be relieved spontaneously or as the result of treatment" (9), a definition that specifically excludes bronchial narrowing due to cardiovascular disease. The American Thoracic Society's definition includes increased responsiveness ofthe bronchi to a wide variety of stimuli (10). Bronchial hyperresponsivenessto cholinergic agents (but not to a wide variety of other agonists) has also been demonstrated in cardiac failure (11) but may not always be present (12),and its relationship to the development of airways narrowing in LVFis not clear. Bronchial hyperresponsivenessis also found in patients with other respiratory conditions as well as in some normal people (13). The term cardiac asthma is best avoided, despite important points of similarity in the bronchial obstruction observed in asthma and in cardiac failure. They share a common pattern of presentation, often occurring at night. Neurogenic bronchoconstriction, bronchial hyperresponsiveness, and mucosal swelling may be common mechanisms for bronchial narrowing in these conditions. (Received in original form March 27, 1991 and in revised form July 3, 1991) 1 From the Department of Medicine, Charing Cross and Westminster Medical School, and the Department of Thoracic Medicine, National Heart and Lung Institute, RoyalBrompton National Heart and Lung Hospital, London, United Kingdom. 2 Correspondence and requests for reprints should be addressed to Dr. K. F. Chung, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.

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Airways Obstruction in LVF, Mitral Stenosis, and Extracellular Volume Overload

Pathologic Observations In his classic monograph, Hope (1) describes postmortem findings in cases of fatal heart failure in which airways were narrowed by mucosal swelling and edema. An early bronchoscopic study of patients with LVF made similar observations (14). Modern reports of this phenomenon are few, and it is omitted from most lung pathology texts. Spencer (15) refers to congestion of the mucosa of the main bronchi in chronic LVF and mitral stenosis, but according to Moolten (16) such postmortem features are caused by terminal acute infective bronchitis, to which such patients may be prone. Regardless of the sparseness of this evidence, airway wall thickening by bronchial congestion and edema is being proposed as an important cause of airway narrowing and hyperresponsiveness in heart failure (17). Clinical Studies Airway obstruction may be temporally associated with raised pulmonary vascular pressures, without obvious pulmonary edema (II, 18),with pulmonary edema in the presence of raised pulmonary vascular pressures (12, 18-21),and with pulmonary edema after resolution of pulmonary vascular hypertension (21). Airway obstruction may develop acutely (22-24) or be present chronically (20, 25, 26). Acute heartjailure. Plotz (27) was the first to demonstrate reversible airway obstruction in acute LVE Light and George (21) found decreased expiratory flow rates in acute heart failure that resolved with diuretic treatment. In LVF associated with acute myocardial infarction there was increased pulmonary resistance (22) and decreased FEV (23). These improved as clinical signs of cardiac failure resolved (22, 23). Airway obstruction correlated with a fall in FVC and with the development of frequency dependence of resistance (22). Patients with cardiogenic pulmonary edema had a 2-fold increase in pulmonary resistance, which improved during recovery (20). Pepine and Wiener (24) electrically paced patients with myocardial ischemia until they developed angina, at which point left ventricular and diastolic pressures increased sharply and specific airways conductance decreased by 40070. Glyceryl trinitrate promptly reversed these changes. The rapid onset and recovery suggest that airways may

narrow before the development of pulmonary edema. Chronic heartfailure and mitral stenosis. Chronic heart failure is also associated with airway narrowing. Cosby and colleagues (25) found an obstructive ventilatory pattern in patients bedridden with chronic congestive heart failure due to hypertensive and rheumatic heart disease. A total of 80% of patients with severe mitral stenosis have a history of bouts of wheezing and cough (28), and in such patients airway resistance is on the average four times higher than in mild disease (26). Overall, in mitral stenosis airway resistance is approximately doubled (29, 30). Maximal expiratory flows are reduced at all lung volumes, suggesting both large and small airways are narrowed. The degree of narrowing is related to the severity of valve disease (29,30). Narrowing of small airways. In LVF and mitral stenosis, airway narrowing is particularly liable to occur in small bronchioles. Petermann and coworkers (31), in a miscellaneous group of 60 patients with LVF, found that expiratory flow rates at low lung volumes were reduced, suggesting small airway narrowing (32). Airway resistance was normal and did not change with treatment of heart failure, whereas tests of small airway function returned to normal. Wilhelmsen and Varnauskas (33) measured "upstream airway resistance," which was found to be increased in normal subjects given rapid infusions of dextran intravenously. Small airway narrowing also may be evidenced by high airway closing volumes following myocardial infarction (34, 35), in pulmonary vascular congestion and edema (36), and also in valvular disorders of the left heart (37). Renal failure with volume overload. Many of the clinical features of congestive heart failure including raised pulmonary vascular pressures and pulmonary edema may be present in patients with severe salt and water retention resulting from renal failure, albeit usually without cardiac disease. On dialysis, the expansion of extracellular fluid volume may be rapidly relieved. Several studies have examined airway function under these circumstances, but without consistency of results. Before dialysis, maximum expiratory flow rates either are modestly below their predicted values (38, 39) or are normal (40), and with dialysis these rates may rise (39, 40) or may not change (38). Airway conductance is not affected by dialysis (38, 39). Several studies have shown elevated closing volumes in

terminal renal failure, which werereduced by hemodialysis (38, 40-42).

Animal Studies Narrowing of large and small airways has been observed in acute experiments in dogs. Brief elevation of left atrial pressure caused a prompt elevation of lung resistance (18,43,44) before edema could have formed. Large airway narrowing in the presence of measured pulmonary edema but at normal vascular pressures has also been shown (45, 46) (figure I). In these latter studies, the degree of airway narrowing was not a function of the degree of edema, but in other studies airway resistance increased in the presence of severe edema (47). Hogg and colleagues (48) partitioned airway resistance into central and peripheral components and found that brief elevations of left atrial pressure to 15 mm Hg caused an immediate increase in peripheral resistance that fell equally promptly when pressure was lowered. More sustained elevation of pressure led to an increase in peripheral resistance that was much slower to resolve. Central airway resistance changed little in these experiments. Similar observations were made by Ishii and coworkers (49). Mechanisms of Airway Obstruction

Several mechanisms, acting at different sites in the bronchial wall, may explain airway narrowing in LVF(figure 2). Within the bronchial lumen accumulation of edema and foam may directly obstruct airflow, in addition to increasing surface tension and hence promoting constriction. Bronchial wall thickening by edema and increased vascular volume may encroach on the lumen. Outside the bronchial wall there may be competition for space in bronchovascular sheaths due to edema and vascular distension, a reduction of radial distending forces secondary to reduction of lung volume, and peribronchial fibrosis. In addition, airways may be narrowed by smooth muscle contraction induced by reflex and nonreflex mechanisms. The presence of increased bronchial responsiveness may increase the likelihood of bronchoconstriction after trivial bronchoconstrictor stimuli.

Intraluminal Edema Liquid Patients with acute LVFexpectorate pink frothy sputum, which is edema fluid welling up from the lung parenchyma. It is stained pink with blood oozing from alveolar microhemorrhages (50). Frothi-

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face tension are to amplify the luminal narrowing produced by smooth muscle shortening. The relevance of these findings to larger animals and to LVF is as yet unclear.

Fig. 1. Tantalum bronchograms of the right lung in a dog supported in a headup position. Panel A shows the control bronchogram and Panel S the bronchogram after mild pulmonary edema induced by extracellular volume overload, with pulmonary capillary wedge pressure allowed to return to baseline levels. A mean airway narrowing of 11% is shown on Panel S, an effect accounted for by a combination of vagally mediated constriction and lung volume loss (46).

ness of edema liquid is due to protein and surfactant. Edema foam, particularly in small airways, may completely obstruct airflow, as was directly observed in isolated lungs (51). In animal experiments, marked increases of airway resistance with severe edema have been attributed to airway foam (47, 49). Areas of lung depleted of surfactant become unstable and indistensible with consequent atelectasis (52). The quantitative importance of luminal edema has been examined by Yager and coworkers (53) in guinea-pig bronchi (externalrelaxeddiameter < 1.25 mm). Under normal circumstances, the mucosa of these bronchi is thrown into longitudinal folds. Bronchoconstriction exaggerates this folding. Between folds,

there are narrow ("-'10 urn across) interstices that are normally air-filled, but become liquid-filled with airway inflammation under the influence of capillarity. Filling of interstices induced by lyso-PAF reduced the luminal cross-sectional area by as much as 30010 in small bronchi (relaxed external diameter < 0.5 mm) that were considerably preconstricted. With interstices filled, a newair-fluid interface of circular cross section forms at the tips of the mucosal folds. Because edema liquid may have a higher surface tension than normal airway lining liquid, this combined with the shortened radius of curvature may lead to significant bronchial constriction in these very small preconstricted bronchi. Interestingly, the effects of interstitial filling and of sur-

Airway Wall Vascular Engorgement and Edema Early observations (1, 14)that in LVFmajor airways are narrowed by mucosal swellinghave neither been confirmed nor refuted. However, studies of the anatomy and physiology of the bronchial circulation and lymphatics have given insight into how bronchial wall thickness may increase in heart failure. Anatomy andphysiology ofthe bronchial circulation and lymphatics. Branches of the bronchial artery ramify in a vascular plexus on the adventitial surface of the trachea and bronchi, and penetrate the glandular and muscular layers to form a second very dense plexus in the bronchial mucosa. Both plexuses extend the length of the bronchial tree to the terminal bronchiole, where they fuse (54). Prominent in these plexuses are thinwalled veins, which throughout their length anastomose to alveolar capillaries and small branches of the pulmonary vein (55). Venous drainage from the trachea and major bronchi is largely into the systemic venous system via the azygos vein on the right and the superior hemiazygos and superior intercostal veins on the left (56, 57). From intrapulmonary bronchi and bronchioles, bronchial blood drains into the pulmonary circuit, mainly into pulmonary capillaries and veins, but also into branches of the pulmonary artery (58). Lymphatic drainage of bronchi is into pulmonary lymphatics running in the peribronchial connective tissue sheath. Drainage from bronchi is promoted by the movement of bronchi during the act of breathing (59). Pulmonary lymphatic vessels join lymph vessels draining into the central veins (56). Histologically, the vascularity of the bronchial wall and, in particular, the mucosa is very high (59). Consequently, the available surface area for microvascular exchange is high (60, 61). Microvascular exchange is further promoted by high blood flow rates. In conscious sheep, total bronchial arterial flowis 1.7 ± 0.3% of cardiac output (62). In humans, bronchopulmonary anastomotic flow during cardiopulmonary bypass was 3.2 ± 4.2% of pump flow (63). This represents bronchial arterial flow, albeit under abnormal circumstances and in some cases with

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Bronchoconstriction Left ventricular failure and mitral stenosis

Fig. 2. Potential mechanisms of airway narrowing in left ventricular failure and mitral stenosis. Bold lines between boxes indicate linkages for which there is convincing evidence; for interrupted lines evidence is either inadequate or conflicting. + = positive influence; - = negative influence. I I

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abnormal lungs. Most of the bronchial flow is to the airway mucosa, where it supplies water and heat for the airconditioning function of the mucosa. In sheep, tracheal mucosal blood flow ranged from 50 to 240 ml/min/lOO g (62), which is comparable to perfusion rates of heart muscle or brain (64). Mechanisms of wall thickening. In heart failure, the bronchial circulation may promote thickening of the bronchial wall by an increase in vascular volume and by edema formation. Venous outflow pressure is a major factor determining these outcomes. With isolated failure of the left ventricle or in early mitral stenosis, pulmonary vascular pressures may rise while central venous pressure remains normal. Under these circumstances, bronchial venous outflow pressure in intrapulmonary bronchi increases, but this may be moderated by the extensive anastomoses with the systemic venous drainage pathways in central bronchi (54). Usually, however, right heart failure complicates the early course of LVF (65), and with the consequent rise of central venous pressure all bronchial veins and lymphatics are exposed to raised outflow pressure. In chronic mitral stenosis, bronchial mucosal veins may become grossly distended to a degree that correlates with pulmonary artery wedge pressure (66), suggesting that bronchial veins are engorged by increased bronchopulmonary

anastomotic flow. Whether these veins encroach on the airway lumen is not known. Although there is not enough experimental evidence to substantiate the importance of these mechanisms in heart failure, studies of the effect of vasoactive drugs on the bronchial circulation demonstrate their potential for causing airway narrowing. Laitinen and colleagues (67) showed acute increases in canine tracheal wall thickness produced by direct injection of drugs and mediators into the tracheal arterial supply. Vasodilators increased thickness, but a given degree of vasodilatation was not associated with a predictable increase in thickness. Bradykinin, histamine, and methacholine were particularly effective at increasing thickness but substance P, vasoactive intestinal peptide, and prostaglandins F 2U and E were less so, despite being powerful vasodilators (68, 69). The observed increases in thickness (of the order of 25070) would have caused approximately a 1% reduction in tracheal luminal diameter. With longer exposure to vasodilators and raised venous pressure more substantial bronchial edema may form, particularly after histamine (70) and substance P (71). Thickening of mucosa and submucosa is likely to have a larger effect on the luminal caliber in small airways, where wall thickness is greater in proportion to luminal caliber.

Clinical evidence for smooth muscle contraction in LVF comes from the immediate effect of bronchodilator drugs. Plotz (27) rapidly relieved the airway obstruction of acute LVF with subcutaneous adrenalin. Similarly, Sharp and coworkers (72) improved airway obstruction with aminophylline. In acute myocardial infarction complicated by LVF, airway resistance was increased but returned to baseline after inhalation of a mixture of a I3r sympathomimetic agonist (fenoter01) and a cholinergic antagonist (ipratropium bromide) (73). However, Light and George (21) reported little bronchodilator effect of a 132-agonistin 28 obstructed patients with acute heart failure. Raised closing airway volumes in left heart disease decreased after inhalation of albuterol or atropine (37). Humoral mechanisms. Evidence for a direct contribution of bronchoconstrictor mediators to airway narrowing in LVF is slim, in contrast to the situation in bronchial asthma (74). There are 3- to lO-fold elevations of circulating vasodilator prostaglandin 12and E 2 metabolites in patients with severe chronic heart failure (75). Both prostaglandins may cause bronchodilatation or afford protection against bronchoconstrictor influences, although they may paradoxically cause bronchoconstriction, probably through reflex mechanisms (76, 77). Elevated plasma levels of immunoreactive atrial natriuretic factor (ANF), released from the atria of the heart, have been reported in patients with congestive cardiac failure (78). When infused into asthmatic subjects ANF decreases bronchial responsiveness to histamine (79). Studies are needed to measure airway concentrations of various bronchoconstrictor mediators by examining bronchoalveolar lavage fluid or edema foam. In addition to acting on bronchial smooth muscle, mediators may also have powerful effects on the bronchial vasculature, as discussed previously. Bronchial blood flow may be reduced in LVF by falls in arterial pressure and rises in venous pressure contributing to a net reduction of driving pressure (80). This may reduce the clearance of vasoactive mediators (81).

Neural mechanisms-Vagalreflex constriction. The possibility of reflex bronchoconstriction in LVF has been addressed by a number of acute studies in anesthetized dogs in which pulmonary vascular hypertension and edema have been produced either by left atrial balloons or by rapid fluid loading. Different

AlffNAY OBSTRUCTION AND BHR IN LVF AND MITRAL STENOSIS

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conclusions have been reached, probably sion in others. These investigators sug- tivity increased by 5- to 6-fold at the end largely because of the use of different ex- gested that increased tension was the re- of the infusion of fluid, when calculated perimental preparations and anesthetics. flex effect of C-fiber activation, where- pulmonary microvascular pressure was Noble and colleagues (47) and Kikuchi as relaxation was a reflex dependent on 37em H 2 0 and lung water was increased and coworkers (82) used pentobarbital sensitization of slowly adapting stretch by a mean of 50%. By bleeding, pulmobut failed to find evidence for reflexbron- receptors by edema (83, 84). Thus, the nary microvascular pressure was rapidly choconstriction after elevating pulmo- reflex bronchoconstrictor effect of dis- reduced to normal and the activity of pulnary vascular pressure, whereas Jones tending both atrium and vessels may be monary C-fibers decreased, but not to and coworkers (43), using closed-chested, less than that of atrial distension alone normal. Bronchial C-fibers only rechloralose anesthetized dogs found a due to the opposing effects of these two mained active in very edematous dogs in prompt rise of total lung resistance and mechanisms. However, these experi- which cuffs of edema were seen around airway closing volume when left atrial ments, and those of Ishii and colleagues the bronchi. These findings demonstrate pressure was raised to 15 mm Hg, an ef- (49) suggest that acute vascular conges- that bronchial and pulmonary C-fibers fect that depended upon intact vagi. In tion may also increase airway resistance are sensitiveto both vascular pressure and a similar preparation, there was narrow- mechanically in some way. edema, but that bronchial fibers are less ing of airways (2- to 15-mm diameter), Neural mechanisms-Vagal afferents. sensitive to edema than pulmonary fivisualized radiographically by tantalum Pulmonary edema stimulates unmyeli- bers. As might be expected, pulmonary bronchography, after induction of pul- nated C-fiber nerve endings in lung pa- vascular C-fibers are also stimulated by monary edema by volume overload (46). renchyma (J or juxtacapillary endings) embolism (88) and this may also result By initially cooling and subsequently cut- (85, 86), and in bronchi (87). In addition, in bronchoconstriction (89). Paintal (85, ting the vagi, the tonic bronchoconstric- stretching of the pulmonary vasculature 90) suggested that C-fiber endings functor effect of the vagus was found to be stimulates similar fibers in vascular walls tion as stretch receptors that respond to approximately 100070 greater in the pres- independent of the development of ede- an increase in volume or pressure in the ence of edema (at normal pulmonary vas- ma (86).Roberts and coworkers (87)mea- interstitial spaces in which they are cular pressures) than under baseline con- sured the firing frequency of pulmonary located. ditions, but with considerable variation and bronchial C-fibers in dogs with volStimulation of C-fibers by capsaicin between dogs. On average, extravascular ume overload pulmonary edema (figure results in reflex bronchoconstriction (91, lung water was approximately doubled, 3). Pulmonary and bronchial C-fiber ac- 92) and cough (93). Although this reflex but postmortem histologic examination of the frozen inflated lungs showed normal bronchial wall thickness despite A -r.....,...,t-H.......Jr-+-+++-t-H--+-+-++..J,-J,-.J~-+.....{,...J.- ECG peribronchial cuffing. It is likely that narrowing was due to increased afferent IIII 11111' • •M--SAPSR - - -...• • •IlI*------Il• vagal discharge, probably reflexly stimulated (46). ---------------t--------+----Pulm. C Ishii and colleagues (49) obtained different results in open-chested, chloom _-ralose anesthetized dogs. They found that the increase in airway resistance after elevating left atrial pressures was only J J J J--------.-J J rr r r r r B r partly influenced by vagotomy. They partitioned resistance into central (airways > 2 mm diameter) and peripheral (airways < 2 mm diameter) and produced II I III III I I 111111 11111 Jill III I III II IIII I 1 111111 edema by elevating left atrial pressure. Central resistance increased initially but this was little influenced by vagotomy, whereas a substantial rise of peripheral resistance that occurred when pressure r was first elevated was abolished by vagotomy. Lloyd (44), using pentobarbital1.11111 anesthetized dogs on cardiopulmonary bypass, also found that the initial rise of I II 11111 1111 III JIIII III 11111 1111. II II Pulm. C airway resistance that occurred with distension of the left atrium and pulmonary vessels was unaffected by vagotomy. However, in a similar preparation, isolated distension of the left atrium caused I sec an increase in tension in trachealis musFig. 3. Increases in impulse activity of a pulmonary C-fiber (Pulm. C) and a slowly adapting pulmonary stretch cle, abolished by vagotomy. Distension recepror (SAPSR) in an anesthetized mechanioally-ventilated dog after volume overload. PenelA: Control. Penel of the pulmonary vasculature alone B: Pulmonary microvascular pressure raised from to.4 to 34.2 cm H after infusion. PenelC: Reduction of pulmo20 caused a vagally dependent increase in nary microvascular pressure to 9 cm H20 after bleeding. Interstitial edema was present on morphological examinatension in some dogs and decreased ten- tion of the lungs. ECG, electrocardiogram; PT, tracheal pressure. Reproduced with permission from reference (fl.

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is partly dependent on an intact vagus nerve, it is possible that local axon reflexes may also be triggered by the activation of C-fiber nerve endings, causing release of sensory neuropeptides, such as substance P, as has been suggested in asthma (94). Substance P may in turn cause histamine release from mast cells as has been demonstrated in skin (95). Neuropeptides could further contribute to airway narrowing by augmenting both pulmonary and airway edema (71, 96), but whether C-fiber activation by edema or congestion leads to substance P release is not known. Sustained increases in the activity of rapidly adapting receptors (RAR) in large airwayshas been reported with minor levels of pulmonary venous congestion (mean left atrial pressure increase by 10mm Hg) in dogs, with smaller increases seen in the activities of slowly adapting stretch receptors and bronchial C-fiber receptors (97). Type J receptor activity was not affected. In a similar preparation, an increase in tracheal tone as measured by an isometric force-displacement method was abolished by cooling the vagi bilaterally at 8 to 9° C (98), which would preferentially inhibit myelinated fibers that carry afferent impulses from RAR. These findings imply that the major afferent pathway for the reflex increase in tracheal tone is from the RAR. RAR may be located in close proximity to bronchial venules and may be stimulated by increases in fluid fluxes occurring with venous congestion (99). In summary, a complex picture has emerged of the vagal reflex bronchomotor effects in LVE Elevation of pulmonary vascular pressures stimulates bronchial and lung C-fibers and bronchial RAR. Pulmonary edema stimulates lung C-fibers and peribronchial edema stimulates bronchial C-fibers. These forms of afferent stimulation cause reflex narrowing of large and small airways. Stimulation of slowly adapting receptors may cause reflex bronchial relaxation while atrial distension causes airway contraction. These findings have been obtained predominantly from studies in dogs. Bronchodilator Influences in LVF The evidence for bronchoconstriction in LVF must be seen in the context of abnormalities of autonomic control, which would tend to cause bronchodilatation. Thus, in patients with low ejection fractions (New York Heart Association [NYHA] grades II to IV), Porter and colleagues (100) showed reciprocally

SNASHALL AND FAN CHUNG

related elevations of sympathetic and depressions of parasympathetic activity. These abnormalities included rises in plasma epinephrine and norepinephrine concentrations by 6- and 4-fold, respectively, and a decrease in cardiac vagal activity. Other studies have shown that elevations of plasma catecholamines depend on the severity of cardiac failure (101). Chronic elevation of plasma catecholamines may lead to the down-regulation of bronchial beta receptors. However, the situation at night may be different. During rapid eye movement sleep changes in autonomic balance are seen, with a decrease in sympathetic and increase in parasympathetic activity (102, 103). Whether similar changes occur in heart failure is not known, but such a reversal of the prevailing autonomic balance may lead to severebronchoconstriction, as has been proposed for nocturnal attacks of bronchial asthma. Peribronchial and Extrabronchial Factors Intrapulmonary airways lie within the bronchovascular connective tissue sheath accompanied by branches of the pulmonary artery and pulmonary lymphatics. Lung parenchyma is attached to the outer aspect of this sheath and by its recoil pressure tends to dilate the bronchovascular compartment. In pulmonary edema, liquid drains from the parenchyma into the bronchovascular compartment and accumulates there as cuffs of edema, initially around pulmonary arteries and veins, but with more severe edema also around bronchi (104). Thus, theoretically, bronchi may be narrowed (1) by a loss of lung elastic recoil pressure, generally caused by a loss of lung volume, and (2) by "competition for space" in bronchovascular sheaths by vascular distension or edema.

Airway compression by peribronchial edema. In pentobarbital-anesthetized dogs, elevation of the left atrial pressure caused a rapid rise of peripheral airway resistance that declined promptly when vascular pressures were lowered (14). More prolonged pressure elevation led to increases of resistance that only declined slowly after restoration of normal pressures, and it was argued that bronchi had narrowed due to "competition for space between arteries and small airways" and that the more chronic changes were caused by interstitial and alveolar edema. However, in similar experiments in chloralose-anesthetized dogs the initial rise of peripheral resistance with elevation ofthe left atrial pressurewasprevented by vagotomy, suggestinga reflexrather than mechanical explanation (44). The concept of small airway narrowing by interstitial edema was undermined by the morphometric analysisof Michel and coworkers (105). They produced pulmonary edema in dogs, and after rapidly freezing the inflated lungs measured dimensions of bronchioles and respiratory bronchioles. These structures were not narrowed by edema, which is strange because with edema interstitial pressure rises (106, 107) and airway transmural pressure falls (108). It would seem that edema cuffs encroach on alveoli rather than on airways (105). Lung volume and elastic recoil. Bronchial caliber is a function of lung inflation. Over a wide range of lung volume, airway diameter varies with one-third root oflung volume (109). In two studies of pulmonary edema (45,46), airway narrowing was found to be a function of the edema-induced lung volume loss, but the degree of narrowing was much greater than the previously described relationship would suggest (figure 4). A reduction in lung volume is often seen in pul-

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AIRWAY OBSTRUCTION ANO BHR IN LVF AND MITRAL STENOSIS

monary edema in humans (110, 111). One important reason for a loss of lung volume in volume overloaded dogs could be the accumulation of liquid beneath the diaphragm (45). A similar situation may prevail clinically in left ventricular failure, and particularly in conditions in which extracellular fluid volumes are greatly increased. Further loss of volume occurs due to atelectasis caused by alveolar flooding (52). Peribronchial fibrosis. Peribronchial fibrosis has been described in chronic heart failure and mitral stenosis (15, 16). Chronic pulmonary edema may lead to alveolar interstitial fibrosis and there is a tendency for the fibrous tissue to extend to surround small bronchi and bronchioles and to narrow them (15, 16). Peribronchial fibrosis would seem to offer a plausible explanation for the clinical features of airway narrowing in mitral stenosis.

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were more functionally severethan those studied by Cabanes and associates (11) (NYHA grade IV in 11). All had radiographic evidence of pulmonary edema, which was severe in five patients. In contrast, Eichacker and coworkers (12) found hyper responsiveness to methacholine in only two of nine patients with severeleft ventricular disease (NYHA grade IV; mean pulmonary wedge pressure = 27 mm Hg), and Seibert and colleagues (114) failed to show hyperresponsiveness in either of two patients recovering from LVFassociated with bronchospasm. Normal responsiveness was found in volumeoverloaded patients with terminal renal failure, and no change in responsiveness was detected after dialysis (39). A proportion of patients in these studies had low expiratory flow rates at the time of study, more severe in the NYHA grade IV patients (12, 19) than in less dyspneic grade III patients (11). However, hyperresponsiveness was more common in the latter group, and in none ofthe studies was there a relationship between the index of bronchial narrowing and responsiveness. In one study, diuretic treatment produced a 30/0 fall in body weight and partial clearing of pulmonary edema (assessed radiographically), but responsiveness remained the same whereas airway obstruction improved a little (19). In another study, responsiveness measured several days after recovery from

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acute heart failure was no different from that measured during the acute attack (114). This suggests that responsiveness is not merely a function of pulmonary edema or of raised pulmonary vascular pressures. Indeed, at cardiac catheterization Sasaki and colleagues found no relationship between cardiac pressures and responsiveness (113).

Effect of Bronchial Mucosal Thickening Evidence for bronchial mucosal and submucosal thickening as the basis for bronchial hyperresponsiveness in LVF was presented by Cabanes and coworkers (11). They inhibited methacholine bronchoconstriction by pretreatment with an a-adrenergic vasoconstrictor agent, methoxamine. This is surprising because methoxamine is itself a bronchoconstrictor (115) and might be expected to enhance the bronchoconstriction of methacholine. The suggestion is that methacholine narrowed bronchi partly by causing bronchial wall engorgement and edema. This may be more likely to occur in LVF because of high bronchial venous pressures. However,there was no evidencefor wall thickening before methacholine inhalation and the administration of methoxamine did not improve baseline FEV 1 despite presumably causing bronchial vasoconstriction (11). Inhalation of albuterol reversed approximately 50070 of the FEV 1 fall induced by methacholine, demonstrating that some smooth muscle spasm was also involved, and it may be suggested that wall thickening may amplify the effect of spasm to produce a more rapid fall in FEV r- However, their methacholine dose-response relationships do not appear to be steepened as would be expected from such a mechanism. Moreover, the virtual abolition ofmethacholine response after methoxamine suggests that this drug is also preventing bronchial smooth muscle contraction. An alternative explanation is that bronchial vascular engorgement due to the combined effects of methacholine and raised venous outflow pressure stimulated C-fibers in the bronchial wall, leading to reflex bronchoconstriction. By decreasing engorgement methoxamine would decrease C-fiber activity and inhibit the response. That such a reflex mechanism could be involved was demonstrated by the experiments of Kikuchi and colleagues (82) in pentobarbitalanesthetized dogs. Brief elevations of left atrial pressure caused no change in lung resistance, but after giving histamine by aerosol raising left atrial pressure caused

bronchial narrowing, an effect that was abolished by vagotomy. This suggests synergy between histamine and raised vascular pressures acting via the vagus. As discussed previously, thickening of bronchial walls may cause hyperresponsiveness as well as bronchial narrowing (116-118). This is a consequence of geometry. When bronchial smooth muscle contracts, the radius of curvature of the mucosal tissue inside the muscle ring decreases, and inevitably its thickness increases. The thickening of the mucosa means that the lumen narrows more rapidly than the muscle ring. The thicker the mucosa before contraction, the larger the difference betweennarrowing of the muscle ring and narrowing of the bronchial lumen, and where the mucosa is very thick or the lumen partly occluded by secretions, then the effect of smooth muscle contraction may be greatly amplified and even occlude the lumen. The quantitative importance of this mechanism was mathematically explored by Moreno and coworkers (117). When the ratio of cross-sectional area of bronchial tissue within the muscle ring to total cross-sectional area within the ring is less than 10070, as would seem to be the case in the trachea and main bronchi (67), the mechanism is unimportant over a realistic range of smooth muscle contraction. However, for the 30 to 45070 range of ratios that they quote for human bronchi it could be important when contraction of smooth muscle narrows external diameter by more than 20070. We assume, however, that ratios as high as this can only apply in small bronchi and bronchioles or for larger bronchi with a marked degree of edema or hyperemia. Wall thickening has only a modest effect on resting airway resistance, but the effect of contraction is magnified, i.e., the luminal narrowing produced by a given degree of smooth muscle contraction is increased and the dose-response relationship of the bronchial response is steepened. This may also occur if bronchial smooth muscleis hypertrophied. As mentioned previously,the patients studied by Cabanes and coworkers (11) did not show such steepening, but rather a shift to the left of the dose-response curve, as is the case in bronchial asthma (119). Smoke inhalation in guinea pigs (118)caused airway edema and bronchial hyperresponsivenessto histamine. The dose-response curve was steepened. However, this effect was blocked by atropine pretreatment, suggesting increased muscle strength rather than increased mucosal thickness. More extensive morphomet-

ric data on the effect of mucosal thickening on bronchial narrowing and responsiveness is needed in order to assess precisely the importance of these mechanisms.

Sodium Balance and Bronchial Responsiveness LVF is usually associated with salt and water retention. From the bronchial asthma literature a complex picture is emerging on the role of salt in determining bronchial responsiveness. In some subjects, increasing sodium intake increases bronchial responsiveness to histamine (120-122) and it has been suggested that the high salt Western diet is responsible for the emergence of asthma in communities in the developing world (123). It is conceivable that a higher salt intake has this effect by increasing the osmolarity of airway lining liquid. When osmolarity is increased in asthmatic subjects either by drying (on exerciseor with dry air hyperventilation) or by inhalation of hypertonic saline,bronchoconstriction may ensue (124-126). Inhaled frusemide prevents bronchoconstriction induced by hypertonic saline in patients with asthma (127), probably by inhibiting sodium and chloride transport into airway lining liquid (128, 129). It is possible that LVF enhances sodium and chloride movement into the airway lumen and this may in some way promote hyperresponsiveness. However, the effect of frusemide on bronchial responsiveness in patients with congestive cardiac failure is not known. Significance of Bronchial

Hyperresponsiveness The significance of bronchial hyperresponsiveness in the development of airway obstruction in LVF and mitral stenosis is far from clear. All human studies to date have used cholinergic agonists for provocation; whether histamine and other inflammatory mediators would be as effective is unknown. If hyperresponsiveness in LVFand mitral stenosis is as "nonspecific"(with regard to bronchoconstrictor stimuli) as it is in asthma, then stimuli such as exercise or breathing cold air or pollutants may provoke airway narrowing. Nocturnal Attacks of LVF

Attacks of both bronchial asthma and LVF tend to occur at night. In asthma the reasons for this are far from clear. Diurnal variation of airway obstruction in bronchial asthma is closely entrained to the sleep-wakefulness cycleand can on-

AIRWAY OBSTRUCTION AND BHR IN LVF AND MITRAL STENOSIS

ly be separated from it for short periods

les are not a sensitive indicator of pulmonary edema (135), and the radiographasthmatic and nonasthmatic subjects ic recognition of pulmonary vascular shows a circadian variation, reaching a congestion and mild edema requires skill peak during the early hours of the morn- and experience and is crucially dependent ing (131, 132) and there are variations of upon the technical quality of the chest plasma histamine and epinephrine (102), radiograph (136). With good technique which would favor bronchial narrowing. and an experienced eye the radiograph Whether these factors are relevant to LVF is, in fact, very sensitive (137-139), but is unclear. It seems likely, however, that the coexistence of airway obstruction in LVF, the horizontal body position is whether acute or chronic is likely to reof great importance in precipitating at- duce this sensitivity (140). tacks at night. Typically the patient has Cardiac failure precipitating airways gone to sleep propped up on several pil- obstruction must be distinguished from lows,but has then gradually slipped down failure with wheezing but without newly into a more horizontal position (6). With developed obstruction, and also from this, functional residual capacity falls failure presenting at the same time as (47), and airways narrow (108) and small bronchial asthma, but without precipitatairways in dependent zones may close al- ing or aggravating it. The use of a peak together, particularly if closing volume flow meter or portable spirometer at preis raised due to lung edema and vascular sentation will allow demonstration of an congestion (34-36,107). Approximately immediate bronchodilator response to 85% of total body blood volume is in nebulized anticholinergic agents or 132venules and veins (133), and in the up- adrenergic agonists, or to intravenousright position, much of this is in the de- ly administered aminophylline. More pendent vessels of the abdomen, pelvis, sophisticated tests of airway function and lower limbs. On lying down, some may demonstrate narrowing of small airblood will move centrally into the veins waysand elevation of closing volume, but ofthe thorax, heart, and lungs. In a nor- these will be of less practical value. Bronmal individual an additional volume of chial asthma and congestive heart failblood may be accommodated in the pul- ure may also present at the same time, monary vasculature with little change of both contributing to breathlessness. Both pressure, but where this vasculature is al- conditions may be precipitated by chest ready distended due to LVFor mitral ste- infection, thyrotoxicosis, or the use of nosis, pulmonary vascular pressure will 13-blockers. Administration of systemic tend to rise. Over a slightly longer time, corticosteroids for asthma may lead to posture-induced changes in distribution salt and water retention, and in this way of vascular pressures will lead to the redis- precipitate heart failure. Similarly, failtribution of interstitial fluid, which will ure may be precipitated by the extraordibe reabsorbed from the previously de- nary work of breathing in an asthma atpendent parts. Fluid reabsorption in- tack, with attendant tachycardia, hypoxcreases blood volume, as evidenced by ia, and demand for higher cardiac a reduction of hemoglobin and plasma output. protein concentrations that occur during In contrast to the extensive literature recumbency in both normal individuals on clinical observation and pathophysiand those with cardiac disease (134). Pul- ology, there has been little work on thermonary vascular pressures may therefore apy of the airways obstruction in LVE rise, and filtration into lung tissue will It is necessary to treat the underlying ciralso be promoted by a reduction in plas- culatory disorder with supplemental oxma protein osmotic pressure. If the rate ygen, loop diuretics, vasodilators, and of filtration into lung tissue exceeds the positive inotropic agents. Morphine rerate of maximal lymph drainage, pulmo- tains an important place in the therapy nary edema will gradually develop. of acute LVF, but should be avoided in asthmatic subjects in whom asthma may Diagnosis and Management be provoked through release of histamine Although cardiac failure can mimic some (141). Aminophylline is the only bronfeatures of bronchial asthma, it is impor- chodilator commonly recommended for tant that the underlying cardiac problem acute LVF, but it is unclear which of its is not overlooked or underplayed. The several pharmacologic actions is prinhistory of nocturnal breathless attacks cipally responsible for clinical benefit. Its may not allow a clear distinction between usefulness is marred by its low toxic-toPND and asthma: clinical signs of right therapeutic dose ratio and nausea, which ventricular failure may be absent; physi- may occur with low-therapeutic serum cal signs of basal late-inspiratory crack- concentrations. Toxiceffects of theophyl(130). Bronchial responsiveness in both

953 l~ne may beprecipitated when theophyllm~ IS administered to patients already taking a slow-release preparation (142)

particularly because the half-life of theophylline is prolonged in heart failure (143). The pragmatic question of whether it is beneficial to treat obstructed patients in LVF with inhaled bronchodilator drugs has been addressed by Rasche and colleagues (73). A mixture of ipratropium bromide and fenoterol relieved obstruction and breathlessness more promptly than by treatment solely directed to LVE Because there is strong evidence for reflex bronchoconstrictor effects, the use of anticholingergic agents such as ipratropium bromide is logical. Addition of a 132-agonist would seem to be safe and sensible for the relief of both airways obstruction and LVE In considering the need to treat, it is important to realize that although the typical patient with acute LVFis hyperventilating, with a low Pe02, approximately 10070 of such patients attending the emergency room have a raised Pe02 (144). This may be the consequence of a marked increase in the work of breathing (due to increased airway resistance and decreased compliance) and severe venous admixture. The use of bronchodilator treatment in this situation is yet to be tested. Summary Small and large airways narrow in LVF and the term cardiac asthma is often used. However, current usage of this term is inconsistent and its meaning is therefore ambiguous. The term is better avoided despite several emerging similarities with bronchial asthma. Airway narrowing may be precipitated by acute elevation of pulmonary or bronchial vascular pressures. This appears to be mainly due to reflex bronchoconstriction. The afferents of this reflex are C-fibers with their endings in the lung parenchyma, bronchi, and pulmonary blood vessels and RAR in the larger airways, and they run in the vagus nerves, as do the efferent bronchoconstrictor fibers. Chronic elevation of pulmonary vascular pressures, as in mitral stenosis, are also associated with airway narrowing. Pulmonaryedema (in the absence of vascular hypertension) also causes reflex bronchoconstriction. Bronchial responsiveness to bronchoconstrictor drugs is increased in LVF, partly, at least, due to reflex mechanisms. Bronchial mucosal swelling may also contribute. Narrowing by nonreflex mechanisms definitely occurs and there is direct evi-

SNASHALL AND

954

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