Altered breathing syndrome in heart failure: newer insights and treatment options.

In patients with heart failure (HF), altered breathing patterns, including periodic breathing, Cheyne-Stokes breathing, and oscillatory ventilation, are seen in several situations. Since all forms of altered breathing cause similar detrimental effects on clinical outcomes, they may be considered collectively as an "altered breathing syndrome." Altered breathing syndrome should be recognized as a comorbid condition of HF and as a potential therapeutic target. In this review, we discuss mechanisms and therapeutic options of altered breathing while sleeping, while awake at rest, and during exercise.

Relation between oscillatory breathing and cardiopulmonary function during exercise in cardiac patients.

BACKGROUND: Oscillatory breathing, alternating between hyperpnea and hypopnea, has been recognized in cardiac patients, especially in those with heart failure. We evaluated whether the cycle length and amplitude of oscillatory breathing correlate with impaired cardiopulmonary function during exercise. METHODS AND RESULTS: We analyzed respiratory gas data during cardiopulmonary exercise testing (CPX) in 17 cardiac patients (68 ± 12 years) who showed clear oscillatory ventilation during CPX. The cycle length (time from peak to peak) and the amplitude (difference between peak and nadir) for both oscillating ventilation (VE) and oscillating O(2) uptake (VO(2)) were calculated from several consecutive oscillations noted at rest, and compared with indices of CPX. Oscillating VO(2) preceded oscillating VE in 16 of the 17 patients. Peak VO(2) (10.3 ± 3.1 ml min(-1)kg(-1)) correlated significantly negatively with the cycle length of the VE oscillation (r=-0.60, P=0.010), and of the VO(2) oscillation (r=-0.61, P=0.008), and the difference in time between the peak of oscillating VE and the corresponding peak of VO(2) (r=-0.58, P=0.012). Similarly, the slope of the increase in VE to the increase in CO(2) output (45.6 ± 11.5) correlated significantly positively with the cycle length of the VE and VO(2) oscillations (r=0.68, P=0.002; r=0.67, P=0.003, respectively). CONCLUSIONS: The cycle length of oscillatory breathing is closely related to impaired cardiac reserve during exercise in cardiac patients.

Abnormal end-tidal PO(2) and PCO(2) at the anaerobic threshold correlate well with impaired exercise gas exchange in patients with left ventricular dysfunction.

BACKGROUND: The aim of the present study was to compare the end-tidal O(2) pressure (PETO(2)) to end-tidal CO(2) pressure (PETCO(2)) in cardiac patients during rest and during 2 states of exercise: at anaerobic threshold (AT) and at peak. The purpose was to see which metabolic state, PETO(2) or PETCO(2), best correlated with exercise limitation. METHODS AND RESULTS: Thirty-eight patients with left ventricular (LV) ejection fraction <40% underwent cardiopulmonary exercise testing (CPX). PETO(2) and PETCO(2) were measured during CPX, along with peak O(2) uptake (VO(2)), AT, slope of the increase in ventilation (VE) relative to the increase in CO(2) output (VCO(2)) (VE vs. VCO(2) slope), and the ratio of the increase in VO(2) to the increase in work rate (ΔVO(2)/ΔWR). Both PETO(2) and PETCO(2) measured at AT were best correlated with peakVO(2), AT, ΔVO(2)/ΔWR and VE vs. VCO(2) slope. PETO(2) at AT correlated with reduced peak VO(2) (r=-0.60), reduced AT (r=-0.52), reduced ΔVO(2)/ΔWR (r=-0.55) and increased VE vs. VCO(2) slope (r=0.74). PETCO(2) at AT correlated with reduced peak VO(2) (r=0.67), reduced AT (r=0.61), reduced ΔVO(2)/ΔWR (r=0.58) and increased VE vs. VCO(2) slope (r=-0.80). CONCLUSIONS: PETCO(2) and PETO(2) at AT correlated with peak VO(2), AT and ΔVO(2)/ΔWR, but best correlated with increased VE vs. VCO(2) slope. PETO(2) and PETCO(2) at AT can be used as a prime index of impaired cardiopulmonary function during exercise in patients with LV failure.

Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension.

BACKGROUND AND OBJECTIVE: Increased pulmonary arterial pressure (PAP) usually coexists with impaired lung function in IPF. Data on the effect of pulmonary hypertension (PH) on cardiopulmonary responses during exercise in IPF patients is very limited. We sought to investigate the impact of PH on exercise capacity and the correlation between systolic PAP (sPAP) and pulmonary function testing, as well as cardiopulmonary exercise parameters, in patients with IPF and PH. METHODS: Eighty-one consecutive patients with IPF, who were evaluated over a 6-year period, were retrospectively studied. Patients underwent pulmonary function testing, Doppler echocardiography and maximal cardiopulmonary exercise testing. PH was defined as sPAP > 35 mm Hg. RESULTS: PH was diagnosed in 57% of the patients. Categorization of patients according to severity of PH indicated a significant reduction in maximum work rate, peak O(2) uptake, anaerobic threshold and peak O(2) pulse in those with sPAP > 50 mm Hg. In IPF patients with PH, estimated sPAP correlated with peak O(2) uptake, anaerobic threshold, peak O(2) pulse and end-tidal CO(2) at anaerobic threshold, while the strongest correlation was between sPAP and ventilatory equivalent for CO(2) at anaerobic threshold (r = 0.611, P < 0.001). There were no differences in pulmonary function or exercise parameters indicative of lung volume reduction, across the patient categories, and none of these parameters correlated with sPAP. CONCLUSIONS: PH has a negative impact on exercise capacity in IPF patients. In IPF patients with PH, resting sPAP correlated with exercise parameters indicative of gas exchange and circulatory impairment, but not with defective lung mechanics.

Paradoxical potentiation of exercise hyperpnea in congestive heart failure contradicts Sherrington chemoreflex model and supports a respiratory optimization model.

Congestive heart failure (CHF) patients suffer decreased exercise tolerance, yet they demonstrate an augmented ventilatory response to exercise such that P(aCO2) remains normal (isocapnic) from rest to maximal exercise in the face of increased pulmonary dead space (Fig. 1). On the other hand, the effect of a large external dead space is hypercapnic instead of isocapnic. This discrepancy suggests that external dead space and pulmonary dead space may exert distinct influences on control of breathing. These paradoxical clinical phenomena are at variance with the conventional chemoreflex model (Johnson 2001), but appear to be consistent with the predictions of the optimization model (Poon 2001; Poon, Tin et al. 2007).

Alveolar membrane conductance decreases as BNP increases during exercise in heart failure. Rationale for BNP in the evaluation of dyspnea.

BACKGROUND: In left ventricular failure (LVF) patients, brain natriuretic peptide (BNP), lung diffusion for carbon monoxide (DLCO), and alveolar-membrane conductance (DM) correlate with LVF severity and prognosis. The reduction of DLCO and DM during exercise reflects pulmonary edema formation. METHODS AND RESULTS: To evaluate, in LVF patients, the correlation between BNP and lung diffusion parameters at rest and during exercise, we studied 17 severe LVF patients, 13 moderate, and 10 normals measuring BNP and lung diffusion parameters before, at the end, and 1 hour after a 10-minute high-intensity constant-workload exercise. At rest, a significant correlation exists between BNP and lung diffusion parameters. Resting BNP, DLCO, and DM correlate with peak oxygen consumption (P < .0001 for all analyses). With exercise, BNP increase is significant (severe LVF 180 +/- 49 pg/mL, moderate 68 +/- 58, normals 18 +/- 12); differently, only in severe LVF, with exercise, DLCO (-1.1 +/- 0.7 mL/mm Hg/min, P < .0001) and DM (-6.4 +/- 2.8, P < .0006) decrease. One hour after exercise, only in severe LVF, BNP is still higher than at rest, while DLCO, DM, and DM/Vc are lower. Significant correlations are observed between BNP and DM changes during exercise and recovery (P < .0001) in severe LVF. CONCLUSIONS: In severe LVF, BNP changes during exercise correlate with simultaneous reductions in DM, suggesting that BNP increase and pulmonary edema formation could be related.

A sex-specific relationship between capillary density and anaerobic threshold.

Although both capillary density and peak oxygen consumption (Vo(2)) improve with exercise training, it is difficult to find a relationship between these two measures. It has been suggested that peak Vo(2) may be more related to central hemodynamics than to the oxidative potential of skeletal muscle, which may account for this observation. We hypothesized that change in a measure of submaximal performance, anaerobic threshold, might be related to change in skeletal muscle capillary density, a marker of oxidative potential in muscle, with training. Due to baseline differences among these variables, we also hypothesized that relationships might be sex specific. A group of 21 subjects completed an inactive control period, whereas 28 subjects (17 men and 11 women) participated in a 6-mo high-intensity exercise program. All subjects were sedentary, overweight, and dyslipidemic. Potential relationships were assessed between change in capillary density with both change in Vo(2) at peak and at anaerobic threshold with exercise training. All variables and relationships were assessed for sex-specific effects. Change in peak Vo(2) was not related to change in capillary density after exercise training in either sex. Men had a positive correlation between change in Vo(2) at anaerobic threshold and change in capillary density with exercise training (r = 0.635; P < 0.01), whereas women had an inverse relationship (r = -0.636; P < 0.05) between the change in these variables. These findings suggest that, although enhanced capillary density is associated with training-induced improvements in submaximal performance in men, this relationship is different in women.

Oxygen uptake kinetics during and after exercise are useful markers of coronary artery disease in patients with exercise electrocardiography suggesting myocardial ischemia.

BACKGROUND: The aim of the current study was to determine if the slowed exercise oxygen uptake (VO(2)) kinetics, which is developed by myocardial ischemia, would be accompanied by delayed recovery VO(2) kinetics in patients with coronary artery disease (CAD). METHODS AND RESULTS: Thirty-seven patients with significant ST depression during treadmill exercise underwent cardiopulmonary exercise testing with cycle ergometer. Measurements performed are the ratios of change in increase in oxygen (O(2)) uptake relative to increase in work rate (DeltaVO(2)/DeltaWR) across anaerobic threshold (AT) and 1 mm ST depression point (ST-dep), the time constants of VO(2) during recovery (T(1/2) VO(2)), stress radio-isotope scintigraphy and coronary angiography. Patients were divided into CAD positive (CAD+) and CAD negative (CAD-) groups, based on coronary angiography. In CAD+, DeltaVO(2)/DeltaWR decreased above AT and ST-dep, in contrast to CAD- patients. The T(1/2) VO(2) in CAD+ (103.1 +/-13.0 s) was greater than that of CAD- (76.5 +/-8.7 s) and showed negative correlations to the ratios of DeltaVO(2)/DeltaWR across AT and ST-dep. These parameters improved in the patients who underwent coronary bypass surgery. CONCLUSIONS: Exercise and recovery VO(2) kinetics were slowed when myocardial ischemia was provoked by exercise. Measurement of exercise and recovery VO(2) kinetics improve the accuracy of the exercise electrocardiogram diagnosis of CAD.

Effect of biventricular pacing on the exercise pathophysiology of heart failure.

BACKGROUND: Biventricular pacing (BVP) is used for cardiac resynchronization therapy in wide-QRS-complex heart failure. We sought to quantify the effect of BVP on the exercise pathophysiology of heart failure patients. METHODS: Using cardiopulmonary exercise testing, we analyzed exercise data for a multicenter study sponsored by St. Jude Medical. Patients had pacemaker electrodes implanted in both ventricles in the standard manner and were randomized by St. Jude before exercise testing. Exercise measurements included peak oxygen uptake (Vo(2)), peak O(2) pulse, anaerobic threshold (AT), and ventilatory equivalent for CO(2) (reflecting change in peak exercise cardiac output, stroke volume, maximal sustainable exercise capacity, and ventilation-perfusion mismatching, respectively) at baseline and at a 6-month follow-up. The studies included progressively and uniformly increasing work rate to maximum tolerance. The investigators were blinded both to sponsor-controlled randomization and pacemaker status. There were 239 paired 6-month studies, as follows: 47 studies served as the control with the pacemaker off (ie, the BVP-OFF group); and 192 patients received pacing (ie, the BVP-ON group). RESULTS: The BVP-ON group significantly improved in all exercise parameters in contrast to the control group (p < 0.0001). When baseline measurements for the BVP-ON group were ranked in quintiles, only patients in the three functionally worst quintiles improved significantly at 6 months (peak Vo(2) < 11.6 mL/min/kg, AT < 7.6 mL/min/kg, peak O(2) pulse < 12.0 mL/beat, and minute ventilation/Vco(2) ratio at AT > 38.1) [p < 0.01 to < 0.0001]. CONCLUSION: BVP benefited aerobic function and ventilation-perfusion mismatching most in those patients with the greatest physiologic impairment.

Spirometric criteria for airway obstruction: Use percentage of FEV1/FVC ratio below the fifth percentile, not < 70%.

BACKGROUND: Current authoritative spirometry guidelines use conflicting percentage of FEV1/FVC ratios (FEV1/FVC%) to define airway obstruction. The American Thoracic Society/European Respiratory Society Task Force characterizes obstruction as a FEV1/FVC% below the statistically defined fifth percentile of normal. However, many recent publications continue to use the Global Initiative for Chronic Obstructive Lung Disease (GOLD) primary criterion that defines obstruction as a FEV1/FVC% < 70%. Data from the Third National Health and Nutrition Examination Survey (NHANES-III) should identify and quantify differences, help resolve this conflict, and reduce inappropriate medical and public health decisions resulting from misidentification. METHODS: Using these two guidelines, individual values of FEV1/FVC% were compared by decades in 5,906 healthy never-smoking adults and 3,497 current-smokers of black (African American), Hispanic (Latin), or white ethnicities aged 20.0 to 79.9 years. RESULTS: In the never-smoking population, the lower limits of normal used in other reference equations fit reasonably well the NHANES-III statistically defined fifth percentile guidelines. But nearly one half of young adults with FEV1/FVC% below the NHANES-III fifth percentile of normal were misidentified as normal because their FEV1/FVC% was > 70% (abnormals misidentified as normal). Approximately one fifth of older adults with observed FEV1/FVC% above the NHANES-III fifth percentile had FEV1/FVC% ratios < 70% (normals misidentified as abnormal). CONCLUSIONS: The GOLD guidelines misidentify nearly one half of abnormal younger adults as normal and misidentify approximately one fifth of normal older adults as abnormal.

Mixed-expired and end-tidal CO2 distinguish between ventilation and perfusion defects during exercise testing in patients with lung and heart diseases.

BACKGROUND: Mismatching of ventilation to perfusion is found in patients with COPD, left ventricular failure (LVF), and pulmonary vascular diseases. Such mismatching may be due to ventilation or perfusion defects or both. Our primary hypothesis was that pressures of mixed-expired CO2 pressure (Peco(2)), end-tidal Pco(2) pressure (Petco(2)), and their ratios would differ between groups during exercise testing, depending on whether the ventilation/perfusion (V/Q) abnormality was dominantly caused by airways or perfusion defects. METHODS: We administered incremental cycle ergometry tests to 25 normal subjects and three groups of 25 patients, each group with uncomplicated COPD, LVF, or primary pulmonary arterial hypertension (PAH). We compared Peco(2), Petco(2), and their ratios at rest, unloaded pedaling, anaerobic threshold, and peak exercise. RESULTS: Although each patient group had mean peak O(2) uptake of approximately 50% of predicted normal, the levels and patterns of change for each group for Peco(2), Petco(2), and their ratios were surprisingly distinctive. As hypothesized, the COPD group always had markedly lower Peco(2)/Petco(2) ratios than all other groups (p < 0.001). In addition, patients with LVF had slightly lower Peco(2)/Petco(2) ratios at heavy exercise than normal subjects (p < 0.05). At all times, except for COPD group Petco(2) at peak exercise, each group had significantly lower Petco(2) and Peco(2) than normal subjects (p < 0.001). In patients with PAH, the Petco(2) decline with exercise was distinctive. CONCLUSIONS: The levels and changes in Peco(2), Petco(2), and their ratios during cardiopulmonary exercise testing are distinctive and explained by the differing pathophysiologies of V/Q mismatching in these disorders.

Effect of sildenafil on ventilatory efficiency and exercise tolerance in pulmonary hypertension.

BACKGROUND: The pulmonary vasculopathy in pulmonary arterial hypertension (PAH) results in increased resistance to pulmonary blood flow, limiting the cardiac output required for the increased O(2) demands of exercise. AIMS: We sought to determine the physiologic basis for clinical improvement in PAH patients receiving sildenafil, hypothesizing that the key mechanisms of improvement are improved blood flow and ventilatory efficiency, leading to improved exercise capacity and O(2) pulse over time. METHODS: We studied 28 PAH patients with (n=14) and without (n=14) sildenafil treatment. All received warfarin and diuretic therapy, and 13/14 sildenafil-treated patients were already receiving specific PAH drugs. Cardiopulmonary exercise testing was performed before and after sildenafil. RESULTS: Peak VO2 , peak O(2) pulse, V E/CO2 and PETCO2, were 0.84+/-0.1 L/min, 6.1+/-0.7 mL beat(- 1), 49+/-2 and 26+/-1.5 mm Hg, and improved after adding sildenafil to 0.91+/-0.1 L/min, 6.8+/-0.8 mL beat(- 1), 43+/-2, and 30+/-1.9, respectively, whereas control patients worsened (p=0.012, 0.008, 0.008 and 0.0002, treated vs. controls, respectively). CONCLUSIONS: Sildenafil improves PETCO2, V E/V CO(2), peak O2 pulse and peak VO2 during exercise compared to controls. A prospective, placebo-controlled study is needed to validate these findings.

Mechanisms That Modulate Peripheral Oxygen Delivery during Exercise in Heart Failure.

Oxygen uptake ([Formula: see text]o2) measured at the mouth, which is equal to the cardiac output (CO) times the arterial-venous oxygen content difference [C(a-v)O2], increases more than 10- to 20-fold in normal subjects during exercise. To achieve this substantial increase in oxygen uptake [[Formula: see text]o2 = CO × C(a-v)O2] both CO and the arterial-venous difference must simultaneously increase. Although this occurs in normal subjects, patients with heart failure cannot achieve significant increases in cardiac output and must rely primarily on changes in the arterial-venous difference to increase [Formula: see text]o2 during exercise. Inadequate oxygen delivery to the tissue during exercise in heart failure results in tissue anaerobiosis, lactic acid accumulation, and reduction in exercise tolerance. H+ is an important regulatory and feedback mechanism to facilitate additional oxygen delivery to the tissue (Bohr effect) and further aerobic production of ATP when tissue anaerobic metabolism increases the production of lactate (anaerobic threshold). This H+ production in the muscle capillary promotes the continued unloading of oxygen (oxyhemoglobin desaturation) while maintaining the muscle capillary Po2 (Fick principle) at a sufficient level to facilitate aerobic metabolism and overcome the diffusion barriers from capillary to mitochondria ("critical capillary Po2," 15-20 mm Hg). This mechanism is especially important during exercise in heart failure where cardiac output increase is severely constrained. Several compensatory mechanisms facilitate peripheral oxygen delivery during exercise in both normal persons and patients with heart failure.

Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension.

In a clinical trial of 178 patients with pulmonary arterial hypertension, treatment improved the 6-minute walk (6MW) distance but not the peak VO2. To clarify this discrepancy, we examined the exercise data from all study sites. Patients received either the endothelin receptor antagonist sitaxsentan or placebo and underwent serial 6MW and cardiopulmonary exercise testing (CPET). In 518 pairs of body weight-adjusted and unadjusted 6MW and CPET data, the correlation between 6MW and peak VO2 was 0.48. In the 4 sites with the highest overall correlation at baseline (r = 0.62 compared with 0.46 for the other 19 sites, p = 0.04), the correlations at baseline (0.66) and at week 12 (0.65) were similar (p = 0.90). However, the correlation increased significantly from baseline (0.34) to week 12 (0.54, p = 0.0005) for the other 19 sites. The correlations between weight-adjusted 6MW distance and peak VO2 for all centers (0.76) were significantly higher than the unadjusted correlations (0.48, p < 0.0001). Improvement in the correlations over time between the 6MW and CPET data at less-experienced sites was most consistent with improved technical skill with increasing experience. Weight adjustment of the 6MW improved its correlation with peak VO2. In conclusion, in future multicenter trials, CPET expertise should be validated at all sites before subject enrollment.

Discriminating measures and normal values for expiratory obstruction.

OBJECTIVES: To develop mean and 95% confidence limits for the lower limit of normal (LLN) values for forced expiratory volume in 3 s (FEV3)/FVC ratio for Latin, black, and white adults; to ascertain comparative variability of the FEV1/FVC ratio, the FEV3/FVC ratio, and forced expiratory flow, midexpiratory phase (FEF(25-75)) in never-smoking adults; to evaluate their utility in measuring the effect of smoking on airflow limitation; and to develop and use the fraction of the FVC that had not been expired during the first 3 s of the FVC (1 - FEV3/FVC) to identify the growing fraction of long-time-constant lung units. DESIGN: Analysis of the Third National Health and Nutrition Examination Survey (NHANES III) database of never-smokers and current smokers. PARTICIPANTS: A total of 5,938 adult never-smokers and 3,570 current smokers from NHANES III with spirometric data meeting American Thoracic Society standards. MEASUREMENTS AND RESULTS: After establishing new databases for never-smokers and current smokers, we quantified the mean and LLN values of FEV3/FVC in never-smokers, and identified spirometric abnormalities in current smokers. When associated with older age, FEV3/FVC decreases and 1 - FEV3/FVC increases as FEV1/FVC decreases. On average, using these measurements, the condition of current smokers worsened about 20 years faster than that of never-smokers by middle age. If < 80% of the mean predicted FEF(25-75) was used to identify abnormality, over one quarter of all never-smokers would have been falsely identified as being abnormal. Using 95% confidence limits, 42% of 683 smokers with reduced FEV1/FVC and/or FEV3/FVC would have been judged as normal by FEF(25-75). CONCLUSIONS: FEV1/FVC, FEV3/FVC, and 1 - FEV3/FVC characterize expiratory obstruction well. In contrast, FEF(25-75) measurements can be misleading and can cause an unacceptably large number of probable false-negative results and probable false-positive results.

Exercise-induced pulmonary edema in heart failure.

BACKGROUND: In heart failure (HF) patients, exercise may increase pulmonary capillary hydrostatic pressure and thereby generate pulmonary edema. If pulmonary edema developed, alveolar-capillary membrane conductance (Dm), measured immediately after exercise, would decrease. To test this hypothesis, we measured Dm before and at 2 and 60 minutes after exercise. METHODS AND RESULTS: We studied 10 HF patients with exercise-induced periodic breathing, 10 with peak o2 < or =15 mL x min(-1) x kg(-1) (severe HF), 10 with o2=15 to 20 mL x min(-1) x kg(-1) (moderate HF), and 10 normal subjects (control). Using the Roughton-Forster technique, we measured carbon monoxide diffusion capacity (DLco) and its components, capillary blood volume (Vc) and Dm, at rest and 2 and 60 minutes after exercise. At rest, DLco and Dm were lowest in periodic breathing and highest in control subjects. Dm decreased in periodic breathing, severe HF, and moderate HF (-7.83+/-3.98, -5.57+/-2.03, and -3.85+/-3.53 mL x min(-1) x mm Hg(-1), respectively; P<0.01) at 2 minutes after exercise but not in control subjects. Vc increased in all groups at 2 minutes and remained elevated at 60 minutes only in periodic breathing. Dm/Vc was decreased in periodic breathing, severe HF, and moderate HF at 2 minutes but not in control subjects. Dm and Dm/Vc remained low at 60 minutes only in periodic breathing. CONCLUSIONS: Dm decreases after exercise in HF patients but not in control subjects, which suggests a decrease in conductance across the alveolar-capillary barrier, as with pulmonary edema. The reductions were most marked in HF patients with periodic breathing and less reduced in less severe HF.

Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension.

BACKGROUND: Because of high pulmonary vascular resistance in patients with primary pulmonary hypertension (PPH), right atrial pressure may exceed left atrial pressure during exercise, resulting in a right-to-left shunt via a patent foramen ovale (PFO). This shunting would disturb arterial PCO2 and H+ homeostasis if the pulmonary blood were not simultaneously hyperventilated to compensate for the high CO2 and H+ in the shunted blood. This article first hypothesizes and then describes unique changes in gas exchange when right-to-left exercise-induced shunting (EIS) occurs. METHODS AND RESULTS: Retrospectively, the cardiopulmonary exercise tests of 71 PPH patients were studied. Criteria postulated to document hyperventilation of the pulmonary blood flow due to a right-to-left EIS were (1) an abrupt and sustained increase in end-tidal O2 with a simultaneous sustained decrease in end-tidal CO2; (2) an abrupt and sustained increase in the respiratory exchange ratio; and (3) usually, an associated decline in pulse oximetry saturation. Each patient was evaluated for a PFO with resting echocardiography. The investigators interpreting the gas exchange evidence of EIS were blinded to the echocardiographic readings. Forty-five percent of the patients had demonstrable EIS by gas exchange criteria. Almost all were also positive for a PFO by echocardiography. Using the resting echocardiograph as the reference, the sensitivity, specificity, positive and negative predictive values, and accuracy were all between 90% to 96%. CONCLUSIONS: Exercise-induced right-to-left shunting can be detected by noninvasive, cardiopulmonary exercise testing in patients with PPH.

Exercise anaerobic threshold and ventilatory efficiency identify heart failure patients for high risk of early death.

BACKGROUND: The maximal oxygen uptake (peak VO2) is used in risk stratification of patients with chronic heart failure (CHF). Peak VO2 might be lower than maximally possible if exercise is stopped early because of lack of patient motivation or premature cessation by the investigator. In contrast, the anaerobic threshold (VO2AT) and the ventilatory efficiency (VE versus VCO2 slope) are less subject to these influences. Thus, we compared these parameters with peak VO2 in identifying patients with CHF at increased risk for death within 6 months after evaluation. METHODS AND RESULTS: We performed cardiopulmonary exercise tests with gas exchange measurements in 223 consecutive patients with CHF (114 coronary artery disease, 92 dilated cardiomyopathy, 17 others) at the Herzzentrum Ludwigshafen between 1995 and 1998. We measured peak VO2, VO2AT and VE versus VCO2 slope. We selected peak VO2 of < or =14 mL/kg per minute, VO2AT of <11 mL/kg per minute, and VE versus VCO2 slope of >34 as threshold values for high risk of death. The median follow-up time was 644 days. Patients with peak VO2 of < or =14 mL/kg per minute had a >3-fold-increased risk (OR=3.4; CI, 1.3 to 9.1), with VO2AT <11 mL/min per kg or VE versus VCO2 slope >34 a 5-fold increased risk for early death (OR=5.3; CI, 1.5 to 19.0; OR=4.8; CI, 1.7 to 13.8, respectively). In patients with both VO2AT <11 mL/kg per minute and VE versus VCO2 slope >34, the risk of early death was 10-fold higher (OR=9.6; CI, 2.1 to 44.7). After correction for age, sex, left ventricular ejection fraction, and New York Heart Association class in a multivariate analysis, the combination of VO2AT <11 mL/kg per minute and VE versus VCO2 slope >34 was the best predictor of 6-month mortality (RR=5.1, P=0.001). CONCLUSIONS: VO2AT of <11 mL/kg per minute and slope of VE versus VCO2 >34, combined, better identified patients at high risk for early death from CHF than did peak VO2 and should therefore be considered when prioritizing patients for heart transplantation.

Pulmonary function in primary pulmonary hypertension.

OBJECTIVES: The study was done to ascertain the degree to which abnormalities in resting lung function correlate with the disease severity of patients with primary pulmonary hypertension (PPH). BACKGROUND: Patients with PPH are often difficult to diagnose until several years after the onset of symptoms. Despite the seriousness of the disorder, the diagnosis of PPH is often delayed because it is unsuspected and requires invasive measurements. Although PPH often causes abnormalities in resting lung function, these abnormalities have not been shown to be statistically significant when correlated with other measures of PPH severity. METHODS: Resting lung mechanics and diffusing capacity for carbon monoxide DL(CO) were assessed in 79 patients whose findings conformed to the classical diagnostic criteria of PPH and who had no evidence of secondary causes of pulmonary hypertension. These findings were correlated with severity of disease as assessed by cardiac catheterization, New York Heart Association (NYHA) class, and cardiopulmonary exercise testing. RESULTS: When PPH patients were first evaluated at our referral clinic, the DL(CO) and lung volumes were decreased in approximately three-quarters and one-half, respectively. The decreases in DL(CO), and to a lesser extent lung volumes, correlated significantly with decreases in peak oxygen uptake (reflecting maximum cardiac output), peak oxygen pulse (reflecting maximum stroke volume), and anaerobic threshold (reflecting sustainable exercise capacity) and higher NYHA class. CONCLUSIONS: Patients with PPH commonly have abnormalities in lung mechanics and DL(CO) levels that correlate significantly with disease severity. These measurements can be useful in evaluating patients with unexplained dyspnea and fatigue.

Beraprost therapy for pulmonary arterial hypertension.

OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available. METHODS: A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life. RESULTS: Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events. CONCLUSIONS: These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.