Alveolar gas diffusion abnormalities in heart failure

In heart failure (HF), development of pressure or volume overload of the lung microcirculation elicits a series of structural adaptations, whose functional correlate is an increased resistance to gas transfer across the alveolar-capillary membrane. Acutely, hydrostatic mechanical injury causes endothelial and alveolar cell breaks, impairment of the cellular pathways involved in fluid filtration and reabsorption, and resistance to gas transfer. This process, which is reminiscent of the so-called alveolar-capillary stress failure, is generally reversible. When the alveolar membrane is chronically challenged, tissue alterations are sustained and a typical remodeling process may take place that is characterized by fixed extracellular matrix collagen proliferation and reexpression of fetal genes. Remodeling leads to a persistent reduction in alveolar-capillary membrane conductance and lung diffusion capacity. Changes in gas transfer not only reflect the underlying lung tissue damage but also bring independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities. They are not responsive to fluid withdrawal by ultrafiltration and tend to be refractory even to heart transplantation. Some drugs can be effective that modulate lung remodeling (eg, angiotensin-converting enzyme inhibitors, whose impact on the natural course of cardiac remodeling is well known) or that increase nitric oxide availability and nitric oxide-mediated pulmonary vasodilation (eg, type 5 phosphodiesterase inhibitors). This review focuses on the current knowledge of these topics.     

Augmented ventilatory response to exercise in pulmonary hypertension

The ventilatory response to submaximal exercise, defined as the slope of minute ventilation over carbon dioxide production (VE/VCO2), was determined in 12 normal subjects, ten patients with pulmonary hypertension before and after heart-lung transplantation, and eight patients following heart transplantation. Patients with pulmonary hypertension show an augmented ventilatory response compared to normal subjects (pulmonary hypertension [mean, 57.7 +/- 6.8 (SE) ml/ml VCO2; normal subjects, 22.3 +/- 1.4 ml/ml VCO2; p less than 0.001]). Following heart-lung transplantation, VE/VCO2 slope fell to 24.7 +/- 1.6 ml/ml VCO2, a value which is not significantly different than the value in normal subjects. Patients after heart transplantation show a mean slope value of 25.3 +/- 1.3 ml/ml VCO2, which is not significantly different than the normal value or the value found after heart-lung transplantation. The augmented ventilatory response to exercise did not correlate with the usual chemical modulators of ventilation (arterial pH, arterial carbon dioxide tension, or arterial oxygen tension). These results suggest the following: the existence of a neural system in patients with pulmonary hypertension which results in an augmentation of ventilatory drive in response to exercise; the augmented ventilatory response reflects excessive neural activity of pulmonary afferents during exercise; narrow regulation of the ventilatory response to exercise in normal subjects which is preserved in the denervated lung, indicating that pulmonary afferents are not critical to ventilatory control during exercise in the normal subject; and the possible use of measurements of the ventilatory response to exercise as a noninvasive screening test for pulmonary hypertension.     

Syndrome X and hyperventilation.

The cardiorespiratory responses to exercise and forced hyperventilation were measured in 17 unselected patients with syndrome X (angina, positive exercise test, normal coronary arteriogram, no other cardiovascular disease) and compared with those in 15 healthy subjects. Forced hyperventilation produced hypocapnia and metabolic alkalosis but no chest pain or electrocardiographic change. Patients with syndrome X showed reduced maximum oxygen consumption with an increased respiratory exchange ratio at peak exercise, confirming that exercise was limited by skeletal muscle perfusion--and thus that the increase in cardiac output with exercise is limited in syndrome X as in heart failure. Arterial carbon dioxide tension (PCO2) homoeostasis during exercise was normal but the ventilatory cost of carbon dioxide excretion was increased in syndrome X (as in heart failure). End tidal PCO2 measurements correlated only poorly with arterial PCO2 in individual patients with syndrome X, providing a possible explanation for previous reports, based on end tidal PCO2 of inappropriate hyperventilation. Patients with syndrome X did not show inappropriate hyperventilation but they did show hyperventilation that was appropriate to maintain normal arterial PCO2 in the face of reduced cardiac reserve.     

Syndrome X and hyperventilation

The cardiorespiratory responses to exercise and forced hyperventilation were measured in 17 unselected patients with syndrome X (angina, positive exercise test, normal coronary arteriogram, no other cardiovascular disease) and compared with those in 15 healthy subjects. Forced hyperventilation produced hypocapnia and metabolic alkalosis but no chest pain or electrocardiographic change. Patients with syndrome X showed reduced maximum oxygen consumption with an increased respiratory exchange ratio at peak exercise, confirming that exercise was limited by skeletal muscle perfusion--and thus that the increase in cardiac output with exercise is limited in syndrome X as in heart failure. Arterial carbon dioxide tension (PCO2) homoeostasis during exercise was normal but the ventilatory cost of carbon dioxide excretion was increased in syndrome X (as in heart failure). End tidal PCO2 measurements correlated only poorly with arterial PCO2 in individual patients with syndrome X, providing a possible explanation for previous reports, based on end tidal PCO2 of inappropriate hyperventilation. Patients with syndrome X did not show inappropriate hyperventilation but they did show hyperventilation that was appropriate to maintain normal arterial PCO2 in the face of reduced cardiac reserve.     

Right ventricular hemodynamics and lung function following amrinone injection

Amrinone is a positive inotropic agent which has been widely used for treatment of left heart failure. As this drug has a relaxing effect on smooth muscle cells, we considered that hemodynamics and ventilatory mechanics could be simultaneously improved in patients with right heart failure caused by obstructive lung disease. Swan-Ganz catheters were used in 11 patients. Following injection of 1.5 mg/kg Amrinone, cardiac output increased from 6.1 to 6.9 l/min (p less than 0.05). Stroke volume showed only a slight increase; pulmonary vascular resistance was reduced from 407 to 308 dynes . s . cm-5 (p less than 0.01). Body plethysmographic examination revealed a decrease of specific airway resistance from 33 to 24 cm H2O . s (p less than 0.01). Conclusion: In patients with right heart failure due to obstructive lung disease Amrinone application can result in an improvement in both hemodynamics and ventilatory mechanics.     

Carvedilol reduces exercise-induced hyperventilation: A benefit in normoxia and a problem with hypoxia

AIMS: To evaluate whether carvedilol influences exercise hyperventilation and the ventilatory response to hypoxia in heart failure (HF). METHODS AND RESULTS: Fifteen HF patients participated to this double blind, randomised, placebo controlled, cross-over study. Patients were evaluated by quality of life questionnaire, echocardiography, pulmonary function and cardiopulmonary exercise tests (ramp and constant workload) both in normoxia (FiO2 = 21%) and hypoxia (FiO2 = 16%, equivalent to a simulated altitude of 2000 m). Carvedilol improved clinical condition and reduced left ventricle size, but had no effect on lung mechanics. In normoxia during exercise, ventilation was lower, V(CO2) unchanged and PaCO2 (constant workload) or PetCO2 (ramp) higher with carvedilol, exercise capacity was unchanged (peak workload 92+/-22 and 90+/-22W for placebo and carvedilol, respectively). Abnormal V(E)/V(CO2) slope was reduced by carvedilol. Hypoxia increased ventilation but less with carvedilol; exercise capacity decreased to 87+/-21W (placebo) and to 80+/-11 W (carvedilol, p < 0.01). With hypoxia, carvedilol decreased V(E)/V(CO2) slope. At constant workload exercise with hypoxia, PaO2 decreased to 69+/-6 mm Hg (placebo) and to 64+/-5 (carvedilol, p < 0.01). CONCLUSION: Carvedilol reduced hyperventilation possibly by reducing peripheral chemoreflex sensitivity as suggested by PaCO2 increase with normoxia and PaO2 decrease with hypoxia without V(CO2) and V(D)/V(T) changes. Lessening hyperventilation is beneficial when breathing normally, but detrimental when hyperventilation is needed for exercise at high altitude.     

The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology.

OBJECTIVE: To assess the exercise limitation of patients with chronic heart failure (CHF) and its relation to possible pulmonary and ventilatory abnormalities. SETTING: A tertiary referral centre for cardiology. METHODS: The metabolic gas exchange responses to maximum incremental treadmill exercise were assessed in 55 patients with CHF (mean (SD) age 57.9 (13.0) years; 5 female, 50 male) and 24 controls (age 53.0 (11.1) years; 4 female, 20 male). Ventilatory response was calculated as the slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope). RESULTS: Oxygen consumption (VO2) was the same at each stage in each group. Ventilation (VE) was higher in patients at each stage. Patients had a lower peak VO2 and a steeper VE/VCO2 slope than controls. Dead space ventilation as a fraction of tidal volume (VD/VT) was higher in patients at peak exercise, but dead space per breath was greater in controls at peak exercise (0.74 (0.29) v 0.57 (0.17) litres/breath; P = 0.002). End tidal CO2 was lower in patients at all stages, and correlated with peak VO2 (r = 0.58, P < 0.001). Alveolar oxygen tension was higher in patients at each stage than in controls. CONCLUSIONS: Patients with CHF have an increased ventilatory response at all stages of exercise. Although this is accompanied by an increase in VD/VT, there is hyperventilation relative to blood gases. It is more likely that the excessive ventilation is not due to a primary pulmonary pathology, but rather, the increase in dead space is likely to be a response to increased ventilation.     

Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy

Thirty-one subjects with chronic congestive heart failure (CHF) were separated into 3 groups according to ventilatory patterns during graded exercise: Group 1--oscillators (n = 6); group 2-intermediate oscillators (n = 14); and group 3--nonoscillators (n = 11). Group 1 patients showed cyclic fluctuations in minute ventilation (change of 30 to 40 liters/min) and arterial PO2 (change of 38.0 +/- 4.1 mm Hg) and PCO2 (change of 11 +/- 2.8 mm Hg). The nadir in arterial PO2 occurred at times when wasted ventilatory effort was maximal. The amplitude of ventilatory oscillations in group 1 patients increased in the transition from rest to light exercise and damped with heavy exercise. There was no evidence of alveolar hypoventilation at the nadirs of minute ventilation; arterial PCO2 was always 40 mm Hg or less. Substantial hyperventilation (ventilatory equivalent for CO2 twice normal) occurred with maximal minute ventilation in group 1 patients. Oscillatory hyperventilation correlated with severity of CHF. Maximal oxygen uptake was significantly lower in group 1 (11.7 +/- 1.1 ml/kg/min) than group 3 (17.9 +/- 1.8 ml/kg/min) (p less than 0.05). Oscillatory hyperventilation during exercise may accompany severe CHF and compounds the inadequate delivery of oxygen by the failing heart.     

Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation.

The exercise capacity and cardiopulmonary response to progressive dynamic exercise of eight healthy recipients of heart-lung transplants were compared with those of matched recipients of orthotopic cardiac transplants and normal controls. In both transplant groups the maximum workloads were lower than that in the normal group. The transplant recipients had higher pre-exercise heart rates and lower maximum heart rates than the normal controls. Ventilation during submaximal exercise was similar in the heart transplant group and the controls. The heart-lung group had an increased ventilatory response associated with lower end tidal carbon dioxide concentrations. Exercise capacity after combined heart-lung transplantation is similar to that after cardiac transplantation. Transplant recipients have an abnormal heart rate response during exercise related to cardiac denervation. The altered ventilatory response in heart-lung recipients may be the result of pulmonary denervation.     

Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation

The exercise capacity and cardiopulmonary response to progressive dynamic exercise of eight healthy recipients of heart-lung transplants were compared with those of matched recipients of orthotopic cardiac transplants and normal controls. In both transplant groups the maximum workloads were lower than that in the normal group. The transplant recipients had higher pre-exercise heart rates and lower maximum heart rates than the normal controls. Ventilation during submaximal exercise was similar in the heart transplant group and the controls. The heart-lung group had an increased ventilatory response associated with lower end tidal carbon dioxide concentrations. Exercise capacity after combined heart-lung transplantation is similar to that after cardiac transplantation. Transplant recipients have an abnormal heart rate response during exercise related to cardiac denervation. The altered ventilatory response in heart-lung recipients may be the result of pulmonary denervation.     

Exercise dyspnea in patients with COPD

Dyspnea, a symptom limiting exercise capacity in patients with COPD, is associated with central perception of an overall increase in central respiratory motor output directed preferentially to the rib cage muscles. On the other hand, disparity between respiratory motor output, mechanical and ventilatory response of the system is also thought to play an important role on the increased perception of exercise in these patients. Both inspiratory and expiratory muscles and operational lung volumes are important contributors to exercise dyspnea. However, the potential link between dyspnea, abnormal mechanics of breathing and impaired exercise performance via the circulation rather than a malfunctioning ventilatory pump per se should not be disregarded. Change in arterial blood gas content may affect dyspnea via direct or indirect effects. An increase in carbon dioxide arterial tension seems to be the most important stimulus overriding all other inputs from dyspnea in hypercapnic COPD patients. Hypoxia may act indirectly by increasing ventilation and indirectly independent of changes in ventilation. A greater treatment effect is often achieved after the addition of pulmonary rehabilitation with pharmacological treatment.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure.

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.     

Effects of exercise training on abnormal ventilatory responses to exercise in patients with chronic heart failure

Patients with chronic heart failure frequently report shortness of breath during daily activities as their primary symptom. In recent years, many efforts have been made by researchers to explain the mechanisms that underlie the characteristic heightened ventilatory response to activity in patients with chronic heart failure. The degree to which the ventilatory response to exercise is heightened parallels the severity of the disease, and measuring the ventilatory gas exchange response to exercise can help quantify the patient's response to therapy. Prior to the 1990s, patients with chronic heart failure were generally discouraged from participating in programs of exercise training. However, in the last decade, studies have demonstrated that exercise training is quite safe for these patients, and a multitude of benefits have been reported. Among the benefits of training are improvements in the abnormal ventilatory response to exercise. Although many mechanisms could potentially explain this response, it appears most likely that this improvement after training is due to a reduction in lactate accumulation and an attenuation of the heightened muscle receptor reflex response that occurs in chronic heart failure. This article reviews the mechanisms of dyspnea in chronic heart failure, along with recent studies assessing the effects of training on abnormal ventilatory responses to exercise in these patients. (c)2000 by CHF, Inc.     

Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis

BACKGROUND: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO(2). AIMS: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO(2) during exercise in heart failure. METHOD AND RESULTS: We studied 18 patients with chronic heart failure. We measured VE/VCO(2) slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO(2) slope nor arterial pCO(2) were related to arterial lactate concentrations at peak exercise (r = -0.16, p = 0.65 and r = -0.15, p = 0.6). During early recovery, patients with a high VE/VCO(2) slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r = 0.57, p < 0.05 and r = 0.84, p < 0.0001) and yet their arterial pCO(2) rose rather than fell (r = 0.79, p < 0.001). The rise in arterial pCO(2) correlated with the increase in arterial hydrogen concentration (r = 0.78, p < 0.001) and with arterial pCO(2) at peak exercise (r = -0.76, p < 0.001). CONCLUSIONS: In heart failure VE/VCO(2) slope and low arterial pCO(2) at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.     

Exercise-induced changes in exhaled nitric oxide in heart failure

BACKGROUND: In heart failure abnormalities of pulmonary function are frequently observed as shown by hyperpnea, reduced lung compliance, reduced alveolar-capillary gas diffusion, positive methacholine challenge and, during exercise, early expiratory flow limitation. Nitric oxide (NO) might be related to all the above abnormalities. AIMS: We evaluated whether a correlation between exhaled NO (eNO) and lung function exists at rest and during exercise in heart failure. METHODS: We studied 33 chronic heart failure patients and 11 healthy subjects with: (a) standard pulmonary function, (b) lung diffusion for carbon monoxide (DLco) including its subcomponents, capillary volume and membrane resistance and eNO both at rest and during light exercise, (c) maximal cycloergometer cardiopulmonary exercise test. RESULTS: Forced expiratory volume in 1 s (FEV(1)) was reduced in heart failure patients (83+/-17% of predicted), as was DLco (75+/-18% of predicted) due to reduced membrane resistance (32.6+/-10.3 ml mmHg(-1) min(-1) vs. 39.9+/-6.9 in patients vs. controls, P<0.02). Exhaled NO was lower in patients vs. controls (9.7+/-5.4 ppm vs. 14.4+/-6.4, P<0.05) and was, during exercise, constant in patients and reduced in controls. No significant correlation was found between eNO and lung function. Vice-versa eNO changes during exercise were correlated with peak exercise oxygen consumption (r=0.560, P<0.001). CONCLUSIONS: The hypothesis of a link between eNO and lung function in heart failure was not proved. The correlation between eNO changes during exercise and peak V(O(2)) might be due to hemoglobin oxygenation, which binds NO to hemoglobin.     

Ventilatory mechanisms of exercise intolerance in chronic heart failure.

Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 +/- 6 ml/kg/min) than among patients with CHF (17.7 +/- 4 ml/kg/min; p less than 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p less than 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (r = -0.73, p less than 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VD/VT, lower tidal volume, and higher respiratory rate compared with normal subjects (p less than 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance.     

The resistive and elastic work of breathing during exercise in patients with chronic heart failure

Patients with heart failure (HF) display numerous derangements in ventilatory function, which together serve to increase the work of breathing (W(b)) during exercise. However, the extent to which the resistive and elastic properties of the respiratory system contribute to the higher W(b) in these patients is unknown. We quantified the resistive and elastic W(b) in patients with stable HF (n = 9; New York Heart Association functional class I-II) and healthy control subjects (n = 9) at standardised levels of minute ventilation (V'(E)) during graded exercise. Dynamic lung compliance was systematically lower for a given level of V'(E) in HF patients than controls (p<0.05). HF patients displayed slightly higher levels of inspiratory elastic W(b) with greater amounts of ventilatory constraint and resistive W(b) than control subjects during exercise (p<0.05). Our data indicates that the higher W(b) in HF patients is primarily due to a greater resistive, rather than elastic, load to breathing. The greater resistive W(b) in these patients probably reflects an increased hysteresivity of the airways and lung tissues. The marginally higher inspiratory elastic W(b) observed in HF patients appears related to a combined decrease in the compliances of the lungs and chest wall. The clinical and physiological implications of our findings are discussed.     

Lung function with carvedilol and bisoprolol in chronic heart failure: Is β selectivity relevant?

BACKGROUND: Carvedilol is a beta-blocker with similar affinity for beta1- and beta2 receptors, while bisoprolol has higher beta1 affinity. The respiratory system is characterized by beta2-receptor prevalence. Airway beta receptors regulate bronchial tone and alveolar beta receptors regulate alveolar fluid re-absorption which influences gas diffusion. AIMS: To compare the effects of carvedilol and bisoprolol on lung function in patients with chronic heart failure (CHF). METHODS AND RESULTS: We performed a double-blind, cross-over study in 53 CHF patients. After 2 months of full dose treatment with either carvedilol or bisoprolol, we assessed lung function by salbutamol challenge, carbon monoxide lung diffusion (DLCO), including membrane conductance (DM), and gas exchange during exercise. FEV1 and FVC were similar; after salbutamol FEV1 was higher with bisoprolol (p<0.04). DLco was 82+/-21% of predicted with carvedilol and 90+/-20% with bisoprolol (p<0.01) due to DM changes. Peak VO2 was 17.8+/-4.5 mL/min/kg on bisoprolol and 17.0+/-4.6 on carvedilol, (p<0.05) with no differences in bronchial tone (same expiratory time) throughout exercise. Differences were greater in the 22 subjects with DLCO<80%. CONCLUSION: Carvedilol and bisoprolol have different effects on DLCO and response to salbutamol. DLCO differences, being DM related, are due to changes in active membrane transport which is under alveolar beta2-receptor control. Peak VO2 was slightly higher with bisoprolol particularly in CHF patients with reduced DLCO.