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Pulmonary congestion is a hallmark feature of heart failure and is a major reason for hospital admissions in this patient population. Heart failure patients often demonstrate restrictive and obstructive pulmonary function abnormalities; however, the mechanisms of these functional declines remain controversial. It has been suggested that the bronchial circulation may play an important role in the development of these pulmonary abnormalities and in the symptoms associated with pulmonary congestion.
Congestion may occur in the bronchial circulation from either a marked increase in flow or an increase in blood volume but with a reduction in flow due to high cardiac filling pressures and/or high pulmonary vascular pressures (a stasis like condition). Either may lead to thickened bronchial mucosal and submucosal tissues and reduced airway compliance resulting in airway obstruction and restriction and a lack of airway distensibility. These structural changes may contribute to “cardiac asthma” and dyspnea, characteristic features common in HF patients. Thus the bronchial circulation may be a potential target for therapeutic interventions.
The aim of this paper is to review factors governing the control of the bronchial circulation, how bronchial vascular conductance may change with HF and to pose arguments, both supporting and in opposition to the bronchial circulation contributing to congestion and altered pulmonary function in HF. We ultimately hypothesize that the engorgement of the bronchial circulatory bed may play a role in pulmonary function abnormalities that occur in HF patients and contribute to symptoms such as orthopnea and exertional dyspnea.
Heart failure (HF) is a disorder that ultimately influences a number of organ systems, including the pulmonary system. The heart and lungs are not only linked hemodynamically, mechanically, and neurally, but they are also linked humorally. Biochemical intermediates (e.g., hormones, peptides) that affect one system may be produced by and could serve to influence the other of these two organ system (e.g., ANP, BNP, Angiotensin II). A prominent component of HF includes pulmonary congestion, which is more severely pronounced in states of decompensation [1–3]. The manifestation of pulmonary congestion is typically thought to include excessive fluid accumulation in the interstitial space as well as within capillary blood vessels of the lungs. Chronic remodeling of these capillaries, reactive pulmonary vascular constriction, and/or alterations in vascular permeability may also serve to influence symptoms of congestion in chronic HF patients .
Less well recognized, the lungs contain a second vascular system known as the bronchial circulation that primarily serves as the nutrient supply to various structures of the lungs (pleura, intrapulmonary nerves, vaso vasorum of the greater vessels, etc) [5, 6]. Experimental evidence demonstrates that other functions of this circulation include providing a type of “rescue” flow to ischemic areas of the lung [7, 8], maintaining lung and pleural fluid and protein balances , and also to aid in the conditioning of inspired air [10, 11].
Of particular interest is the fact that the bronchial circulation also supplies blood flow to the tissues of the bronchial mucosa of the airways [12, 13]. The bronchial mucosa is highly vascularized with interconnected vascular networks around (peribronchial) and within (mucosal) each bronchiole. Of these networks, the mucosal vascular plexus is located relatively close to the epithelial surface of the airways, where it is estimated that the mucosal capillaries primarily lie within 100µm of the airway lumen and engorgement of this vascular bed may cause airway edema [14, 15]. Arguments favoring a role of the bronchial circulation in HF related pulmonary congestion additionally suggest that bronchovascular engorgement has the potential to significantly impact airway function [16, 17].
In addition to the unique location of the bronchial circulation, closely adjacent to displaceable air space, the flow characteristics of this bed are also quite distinctive. In humans, blood flow for the bronchial circulation originates in the systemic vascular system, specifically from branches of the descending aorta, with subsequent divisions following distally with increasing generations of the airway tree. A large percentage of the post capillary vessels anastomose with venous structures of the pulmonary circulation. It is estimated that greater than 65% of the total flow through this circulation returns to the left side of the heart through these anastomoses to recombine with the general systemic circulation [18–20]. Thus flow through this vascular bed is considered a systemic to pulmonary shunt and may be influenced by systemic, cardiac and pulmonary vascular pressures.
Regulation of bronchial vascular tone is complex and under normal resting conditions is determined by a balance of α-adrenoreceptor and cholinergic autonomic vasoconstrictor mechanisms as well as by nitric oxide (NO) dependent vasodilator mechanisms . Under normal conditions the bronchial circulation is under efferent autonomic control such that the circulation is vasoconstricted [22, 23]. These conditions result in low capillary hydrostatic pressures that in turn facilitate the transfer of excess interstitial fluid from the mucosa back into the vasculature. Interestingly, the bronchial circulation does not seem to be under arterial baroreflex control at rest and thus resting tonic activity from arterial baroreceptors does not drive the baseline autonomic vasoconstriction .
A possibility for control of the tonic efferent activity present in the bronchial circulation is input from cardiac afferents [16, 25]. Studies in animals have suggested that both spinal and vagal afferents regulate bronchovascular conductance. Blockade of cardiac afferents in canines by an injection of procaine intrapericardially produced a rise in flow measured at the feed bronchial artery . Pharmacologic stimulation of vagal and spinal afferents was also used to determine if and how these specific afferent signals exert neurologic control on the bronchial circulation . Again in the canine model, nicotine was used as a vagal stimulus, and bradykinin was used as a spinal afferent stimulus, and these drugs were injected at separate times into the pericardium. Stimulation of vagal and spinal afferents produced a dilatation and constriction, respectively in the feeding bronchial artery suggesting a regulatory role for both afferent neurological pathways in the bronchovasculature.
Although it is currently unknown how HF directly affects flow in the bronchial circulation, there are numerous physiological changes that occur in HF pathologies that are likely to impact this circulatory bed. These include 1) left heart stretch which has been shown through reflex mechanisms to increase bronchial conductance , 2) a rise in left atrial pressure and pulmonary vascular pressures that may cause a reduction in flow from the bronchial vascular bed, through an increased resistance to forward flow, leading to fluid stasis and possible vascular distension due to an increased volume [15, 27], 3) a rise in circulating inflammatory mediators may cause further increases in conductance in the bronchial circulation [28, 29], 4) the release of other vasoactive substances (e.g., atrial natriuretic peptide, ANP, brain natriuretic peptide, BNP, bradykinin, angiotensin II) that influence vascular tone and overall fluid handling [30, 31] (Figure 1). Furthermore, the chronic hyperventilation (cooling) and hypocapnia (low CO2) associated with HF may further alter flow in this vascular bed [32–34].
However it remains controversial as to how much swelling may actually occur in the bronchial circulation and the extent as to which this swelling can influence airway diameter and subsequently lung function.
A previous study by Cabanes, et al (1992) examined patients with a history of HF and exertional dyspnea and had them exercise both maximally and also at a constant submaximal load . Subjects were treated with either a placebo or with inhaled methoxamine, a specific α1-agonist known to constrict the bronchial blood vessels. Surprisingly exercise tolerance was markedly increased with methoxamine. The authors suggested that constriction of the bronchial circulation may have served to reduce congestion, thus reducing dyspnea and improving exercise tolerance .
In a subsequent study, Cabanes and colleagues observed that 1) the markedly increased airway hyper responsiveness to methacholine (a known bronchial vessel dilator) common in HF could be abolished with methoxamine and 2) that this protective effect could be blocked by phentolamine (an α-adrenergic antagonist). The most likely explanation of the preventive influence of methoxamine was that it opposed the vasodilatation of the bronchial vessels induced by methacholine .
Rapid saline infusion has also been used to induce a thoracic fluid volume overload and changes in pulmonary function, structure, and lung fluid handling were observed . This specific physiologic challenge allows investigators to isolate only the physiologic state of fluid overload that is commonly seen in HF patients, but to do so without many of the confounding factors that are typically associated with the disease.
Work by Pellegrino et al (2003) using this technique examined lung mechanics in healthy adults before and after acute intravenous rapid saline loading and suggested that the bronchial circulation may causatively be involved in the restrictive and obstructive changes that subsequently developed . Consistent with these findings, work by King et al (2002) examined airway wall thickness, where the bronchial circulation resides, in response to acute intravenous fluid loading . These authors found evidence for a widening of airway wall and a decreased airway lumen diameter suggesting that some impingement of the airway wall into the lumen space . Additional studies have examined larger airways including the trachea. Although the trachea is fed by a different feed artery than that of the bronchial vessels, this airway also demonstrated that rapid intravenous fluid loading caused impingement upon the lumen, even with its relatively large cartilaginous composition [39, 40].
Despite the observation of significant increases in wall thickness by certain investigators, the potential for swelling of this nature within airway walls is thought to either 1) only minimally influence the lumen diameter of an airway, and 2) may be unlikely to occur in the absence of a purposefully induced fluid challenge. The argument can also be made that structural changes pre- and post- fluid loading may be dependent on airway size and airway wall composition. As the amount of cartilage within the airway wall declines with smaller airway diameters (higher generations), increasingly smaller caliber airways may be less likely to retain their structural patency and be more sensitive to shifts in thoracic fluid. However, many of the smaller, less cartilaginous airways of the lungs are beyond the spatial resolution of X-Ray CT scanning techniques available for live animal and human studies. Changes in these smaller airways may not be adequately represented in studies attempting to examine changes in airway wall structure. Therefore, it is likely that the structural differences observed in the larger airways in these studies are not only occurring further down the airway tree, beyond the current measurement resolution, but may also significantly impact pulmonary mechanics and function under a less intense fluid load. In addition, in these smaller airways, small changes in luminal diameter markedly affect the internal flow resistance of an individual vessel. Assessment of what occurs in these smaller, more distal airways is important to the understanding of how changes in thoracic fluid volume and in the bronchial circulation influence airway and pulmonary function.
Previous studies by Csete et al , Mariassy et al , and Baier et al  support the role for either an increase in bronchial vascular conductance or bronchial vascular congestion (with mucosal edema) influencing airway function. Csete  observed that vasodilator drugs like nitroglycerin administered locally through a bronchoscope in conscious ewes resulted in a dose dependent increase in mean airflow resistance, presumably due to vascular congestion. Mariassy  quantified the subepithelial microvascular volume and its relation to the airway lumen by fixing the lungs of sheep and studied them under conditions of pharmacological vasodilatation, pulmonary hypertension, and under control conditions. Pulmonary hypertension increased microvascular volume fraction in the bronchioles while pulmonary hypertension with vasodilation increased microvascular volume in both the bronchioles and trachea. Both conditions resulted in a fall in airway cross sectional area in the 1-mm bronchioles. Baier and colleagues  examined the impact of hypervolemia and/or elevated left atrial pressure on tracheal mucosal fluid and airway resistance in dogs. Baier observed that under both interventions mucosal edema and vascular congestion occurred and in particular noted a rise in pulmonary resistance with dextran induced hypervolemia. Collectively, these studies in large animals suggest that bronchiole vascular dilators, fluid loading or high cardiac pressures will influence airway function and/or structure. It is speculated that changes occur through mucosal edema, bronchiole vascular engorgement, or from compression of the entire airway from expanded parenchymal structures in the lung (Figure 2).
Because of the invasive nature of traditional methods of measuring the flow of the bronchial circulation, studies on the role of the bronchial circulation in HF in human subjects have been limited. Only one study has examined directly how bronchial blood flow is altered in an HF patient population . This study examined bronchial blood flow in subjects undergoing procedures requiring total cardiopulmonary bypass . Patients were divided into 3 groups: those with HF (EF<40%) for less than 2 months (acute HF), patients with conditions and a history of HF (EF#x0003C;40%) lasting longer than 6 months (chronic HF), those undergoing surgical procedures with no conditions or history of HF (non-HF, EF#x0003E;60%). Because it is estimated that >65% of the bronchial circulation is a shunt from the systemic to the pulmonary circulation, the volume of blood returning to the left side of the heart during bypass is representative of this shunt and thus the majority of the blood flowing through the bronchial circulation. Results from this study showed significantly higher bronchial shunt blood flow (Qbrs–p) in patients with chronic HF (89 ± 18 ml/min) when compared to the acute HF patients and non-HF patients (27 ± 3 and 22 ± 2 ml/min, respectively). Although these data were obtained in non-physiologic conditions and also in the absence of any pulmonary circulatory pressure that would serve to restrain forward flow, the authors concluded that the observed elevated flow in those with chronic HF imply differences in the vascular resistance of the conduit bronchial vessels. The authors further suggest that the elevated shunt flow displayed by the chronic HF patient group may indicate the presence of either dilated, larger, and/or more numerous intrapulmonary bronchial blood vessels.
At present, there are no studies that have been carried out specifically examining the bronchial circulation in relatively stable, awake, and ambulatory HF patients and further work is needed to determine the role of the bronchial circulation in the HF pathology.
There are many physiologic changes associated with HF and the manner in which they collectively affect bronchial blood flow has not been fully elucidated in humans. Although there is evidence in the literature supporting the idea that engorgement of the bronchial circulation occurs in HF and subsequently contributes to declines in pulmonary function and symptoms of pulmonary congestion, there also stands a line of reasoning to suggest that this circulation may not be dilated in HF and/or that there is inadequate local interstitial edema and swelling in the tissue space surrounding the airways to significantly affect function in patients who are relatively stable.
One argument counter to the theory of vascular engorgement of the bronchial circulation in HF is centered on sympathetic activity. It has been shown that patients with HF have significantly increased sympathetic nervous outflow accompanied by increased circulating catecholamine levels, in part due to norepinephrine spillover from stimulated sympathetic nerve terminals . Increases in sympathetic activity and catecholamines would serve as agonists to the α-adrenergic receptors known to mediate constriction in the vasculature surrounding the bronchi and bronchioles. In the presence of high sympathetic activity and circulating catecholamines, it may is less likely for the bronchial circulation to be engorged in the HF population and thereby may not be a significant contributor to symptoms of pulmonary congestion and/or pulmonary function abnormalities.
Additionally, the theory that local interstitial edema and tissue swelling in the airways, due to changes of flow and pressure in the bronchial circulation, contribute significantly to HF related functional declines should be closely examined. Functional adaptations, independent of the bronchial circulation, may also be affecting global pulmonary function. Specific adaptations include remodeling of the pulmonary tissue and/or increased lymph flow preventing bronchial mucosal edema until states of acute decompensation are reached.
The occurrence of pulmonary hypertension in HF has been argued as a contributor to engorgement in the bronchial circulation; however longstanding hypertension also serves to remodel the pulmonary vasculature inducing physiologic changes to global pulmonary function. The HF pathology tends to be progressive in nature and a gradual deterioration in health status over several years is thought to give rise to adaptive mechanisms that allow the lung to remain relatively dry despite conditions that would favor edema formation. Pulmonary vascular pressures can be markedly elevated in chronic HF patients, yet these patients can live and function somewhat normally despite the observed pulmonary hypertension. For example, chest X-Rays of HF patients may show clear, edema-free lungs even with wedge pressures exceeding 45 mmHg. There is evidence that with longstanding pulmonary hypertension, the pulmonary vasculature will undergo structural remodeling that allows for increased resistance to high vascular pressures and likely an increased resistance to the development of interstitial edema. Pathologic studies on patients with a mitral valve stenosis have allowed investigators to infer the relatively isolated effect of pulmonary hypertension on lung structure and function [44–47]. Histological examination of lung biopsies shows alveolar fibrosis as well as thickening of the capillary endothelial and alveolar epithelial basement membranes; these changes are thought to occur in response to chronically increased pulmonary vascular pressures [44–46]. Ultrafiltration studies by Agostoni and colleagues have suggested that similar remodeling of the lung also occurs in non ischemic HF patients [48–50]. Following ultrafiltration procedures, HF patients demonstrated improved pulmonary function related to mechanical properties of the lung; diffusion characteristics (abnormally low at baseline in HF patients) remained unaffected suggesting that there are also fluid-independent changes in the alveolar-capillary membrane . Structural remodeling that permits a constant state of fluid overload, in the absence of ultrafiltration treatment, may induce the observed pulmonary functional declines independent of any changes that may occur in the bronchial circulation.
Another adaptive mechanism potentially preventing gross mucosal edema and interstitial swelling occurs via the lymphatic system. The lymphatic system of the lung allows for steadily increased fluid clearance as HF disease state worsens .
The development of a soluble gas technique by Wanner and colleagues is promising in that its utilization allows for non-invasive and direct measurement of flow throughout the bronchial vasculature . This method evaluates the disappearance of an inhaled mixture containing the soluble gas dimethyl ether (DME) over time during a series of breath-holding maneuvers and can represent flow that occurs deeper within the lung reaching the smaller, more distal non-respiratory bronchiole structures. This method has also been validated with flow measurements using radioactive microspheres in experiments performed in sheep .
Although it also has its inherent limitations in that the measured flow reflects only the bronchial mucosal flow and not the flow from the bronchial artery into other structures of the lung, the greatest advantage is that it is non-invasive and likely measures bronchial blood flow in a large number of the airways. Investigations thus far using this technique have largely centered on the role of the bronchial circulation during induced airway inflammation and in the pathophysiology of asthma, however it would be a valuable tool to determine this circulation’s effect in other pathologies such as HF.
With HF there is altered reflex control of the bronchial circulation, including left atrial stretch that increases bronchial conductance. An increase in inflammatory mediators and other vasoactive peptides may further stimulate receptors that dilate the bronchial circulation. The network of vessels, forming a plexus near the airway wall may swell. A rise in pulmonary venous and left atrial pressure may inhibit forward flow resulting in a rise in bronchial blood volume. This may result in impingement of the luminal area of airways, a drop in lung compliance resulting in both the restrictive and obstructive changes associated with pulmonary function in the HF population. There may be further remodeling of the bronchial circulation that includes an increase in bronchial vessels, further influencing lung function. The stiffer lungs and mild obstruction subsequently lead to an increased work and cost of breathing and contribute to the symptoms of dyspnea.
The supine position would result in enhanced venous return, a rise in central blood volume, a rise in left heart pressures that would further enhance both a rise in bronchial conductance and an inhibition to forward flow, and would contribute to the symptoms of orthopnea (Figure 1).
There are now methods available that allow more careful assessment of the bronchial vascular bed non-invasively in humans. Recently developed soluble gas techniques combined with high resolution X-Ray CT scanning will allow for the assessment of the interplay between functional bronchial blood flow and its affects on airway structure and pulmonary function. These methods should be utilized to determine more definitively the potential role of the bronchial circulation in the congestive symptoms associated with HF.
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