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.

CO2 pulse and acid-base status during increasing work rate exercise in health and disease.

The CO2 pulse (VCO2/heart rate), analogous to the O2 pulse (VO2/heart rate), was calculated during cardiopulmonary exercise testing and evaluated in normal and diseased states. Our aim was to define its application in its release in excess of that from VCO2/heart rate in the presence of impaired cardiovascular and lung function. In the current study, forty-five patients were divided into six physiological states: normal, exercise-induced myocardial ischemia, chronic heart failure, pulmonary vasculopathy, chronic obstructive pulmonary disease, and interstitial lung disease. We subtracted the O2 pulse from the CO2 pulse to determine the exhaled CO2 that could be attributed to CO2 pulse of buffering of lactic acid. The difference between the CO2 pulse and O2 pulse (VCO2/heart rate-VO2/heart rate) includes CO2 generated from HCO3(-) buffering of lactic acid. The accumulated CO2 per body mass was found to be significantly correlated with the corresponding [HCO3(-)] decrease (R(2)=0.72; P<0.0001). In summary, the increase in CO2 pulse over the O2 pulse accounted for the anaerobically-generated excess-CO2 in each of the physiological states and correlated with the decreases in the arterial Bicarbonate concentration.

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.

Clinical significance of a spiral phenomenon in the plot of CO2 output versus O2 uptake during exercise in cardiac patients.

A spiral phenomenon is sometimes noted in the plots of CO2 output (VCO2) against O2 uptake (VO2) measured during cardiopulmonary exercise testing (CPX) in patients with heart failure with oscillatory breathing. However, few data are available that elucidate the clinical significance of this phenomenon. Our group studied the prevalence of this phenomenon and its relation to cardiac and cardiopulmonary function. Of 2,263 cardiac patients who underwent CPX, 126 patients with a clear pattern of oscillatory breathing were identified. Cardiopulmonary indexes were compared between patients who showed the spiral phenomenon (n = 49) and those who did not (n = 77). The amplitudes of VO2 and VCO2 oscillations were greater and the phase difference between VO2 and VCO2 oscillations was longer in the patients with the spiral phenomenon than in those without it. Patients with the spiral phenomenon also had a lower left ventricular ejection fraction (43.4 ± 21.4% vs 57.1 ± 16.8%, p <0.001) and a higher level of brain natriuretic peptide (637.2 ± 698.3 vs 228.3 ± 351.4 pg/ml, p = 0.002). The peak VO2 was lower (14.5 ± 5.6 vs 18.1 ± 6.3, p = 0.002), the slope of the increase in ventilation versus VCO2 was higher (39.8 ± 9.5 vs 33.6 ± 6.8, p <0.001), and end-tidal PCO2 both at rest and at peak exercise was lower in the patients with the spiral phenomenon than in those without it. In conclusion, the spiral phenomenon in the VCO2-versus-VO2 plot arising from the phase difference between VCO2 and VO2 oscillations reflects more advanced cardiopulmonary dysfunction in cardiac patients with oscillatory breathing.

Better parameters of ventilation-CO2output relationship predict death in CHF patients.

OBJECTIVE: Measures of ventilation-CO2output relationship have been shown to be more prognostic than peak O2uptake in assessing life expectancy in patients with chronic heart failure (CHF). Because both the ratios (VE/Vco2) and slopes (VE-vs-Vco2) of ventilation-co2 output of differing durations can be used, we aim to ascertain which measurements best predicted CHF life expectancy. METHODS: Two hundred and seventy-one CHF patients with NYHA class II-IV underwent incremental cardiopulmonary exercise testing (CPET) and were followed-up for a median duration of 479 days. Four different linear regression VE-vs- Vco2 slopes were calculated from warm-up exercise onset to: 180 s, anaerobic threshold (AT), ventilatory compensation point (VCP); and peak exercise. Five VE/Vco2 ratios were calculated for the following durations: rest (120 s), warm-up (30 s), AT (60 s), lowest value (90 s), and peak exercise (30 s). Death or heart transplant were considered end-points. Multiple statistical analyses were performed. RESULTS: CHF patients had high lowest VE/Vco2 (41.0 ± 9.2, 141 ± 30%pred), high VE/Vco2 at AT (42.5 ± 10.4, 145 ± 35%pred), and high VE-vs-Vco2 slope to VCP (37.6 ± 12.1, 126 ± 41%pred). The best predictor of death was a higher lowest VE/Vco2 (≥ 42, ≥ 141%pred), whereas the VE-vs-Vco2slope to VCP was less variable than other slopes. For death prognosis in 6 months, %pred values were superior: for longer times, absolute values were superior. CONCLUSION: The increased lowest VE/Vco2 ratio easily identifiable and simply measured during exercise, is the best measurement to assess the ventilation-co2output relationship in prognosticating death in CHF patients.

Ventilatory regulation of arterial H(+) (pH) during exercise.

We hypothesized that exercise ventilation and arterial H(+) ([H(+)]a) are mutually interactive, [H(+)]a stimulating V(E) and V(E) regulating [H(+)]a increase. Fifty-five patients were studied, 10 normal and 45 with cardio-respiratory disorders. Each patient underwent cardiopulmonary exercise testing with simultaneous serial arterial blood gas and pH measurements. Subsequently, they were classified into one of 7 clinical groups: (1) normal, (2) exercise-induced hypoxemia (PaO2<50mmHg), (3) exercise-induced myocardial ischemia, (4) heart failure, (5) COPD, (6) interstitial lung disease, and (7) pulmonary vasculopathy. The average resting pHa was 7.42 or 7.43 for each group. At anaerobic (lactic acidosis) threshold (AT), [H(+)]a increased due to PaCO2 increase (+2mmHg), primarily. At peak exercise, [H(+)]a increased further due to arterial HCO3(-) decrease. In summary, [H(+)]a appears to be closely regulated at rest to AT and further to peak exercise by CO2 elimination from the venous return. No evidence was observed for over-ventilation of CO2, causing the arterial blood to become more alkaline during exercise in the patient groups studied.

Parameters of oxygen uptake and carbon dioxide output ventilatory efficiency during exercise are index of circulatory function in normal subjects / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe oxygen uptake efficiency plateau (OUEP, i.e.highest V˙O2/V˙E) and carbon dioxide output efficiency (lowest V˙E/V˙CO2) parameter changes during exercise in normal subjects.</p><p><b>METHODS</b>Five healthy volunteers performed the symptom limited maximal cardiopulmonary exercise test (CPET) at Harbor-UCLA Medical Center. V˙O2/V˙E and V˙E/V˙CO2 were determined by both arterial and central venous catheters. After blood gas analysis of arterial and venous sampling at the last 30 seconds of every exercise stage and every minute of incremental loading, the continuous parameter changes of hemodynamics, pulmonary ventilation were monitored and oxygen uptake ventilatory efficiency (V˙O2/V˙E and V˙E/V˙CO2) was calculated.</p><p><b>RESULTS</b>During CPET, as the loading gradually increased, cardiac output, heart rate, mixed venous oxygen saturation, arteriovenous oxygen difference, minute ventilation, minute alveolar ventilation, tidal volume, alveolar ventilation and pulmonary ventilation perfusion ratio increased near-linearly (P < 0.05-0.01, vs.resting); arterial oxygen concentration maintained at a high level without significant change (P > 0.05); stroke volume, respiratory rate, arterial partial pressure of carbon dioxide, arterial blood hydrogen ion concentration and dead space ventilation ratio significantly changed none-linearly (compare resting state P < 0.05-0.01).OUE during exercise increased from 30.9 ± 3.3 at resting state to the highest plateau 46.0 ± 4.7 (P < 0.05 vs.resting state), then, declined gradually after anaerobic threshold (P < 0.05-0.01, vs.OUEP) and reached 36.6 ± 4.4 at peak exercise. The V˙E/V˙CO2 during exercise decreased from the resting state (39.2 ± 6.5) to the minimum value (24.2 ± 2.4) after AT for a few minutes (P > 0.05 vs.earlier stage), then gradually increased after the ventilatory compensation point (P < 0.05 vs.earlier stage) and reached to 25.9 ± 2.7 at peak exercise.</p><p><b>CONCLUSIONS</b>Cardiac and lung function as well as metabolism change during CPET is synchronous.In the absence of pulmonary limit, appearing before and after anaerobic threshold, OUEP and lowest V˙E/V˙CO2 could be used as reliable parameters representing the circulatory function.</p>

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.

Context mediates antimicrobial efficacy of kinocidin congener peptide RP-1.

Structure-mechanism relationships are key determinants of host defense peptide efficacy. These relationships are influenced by anatomic, physiologic and microbiologic contexts. Structure-mechanism correlates were assessed for the synthetic peptide RP-1, modeled on microbicidal domains of platelet kinocidins. Antimicrobial efficacies and mechanisms of action against susceptible ((S)) or resistant ((R)) Salmonella typhimurium (ST), Staphylococcus aureus (SA), and Candida albicans (CA) strain pairs were studied at pH 7.5 and 5.5. Although RP-1 was active against all study organisms, it exhibited greater efficacy against bacteria at pH 7.5, but greater efficacy against CA at pH 5.5. RP-1 de-energized SA and CA, but caused hyperpolarization of ST in both pH conditions. However, RP-1 permeabilized ST(S) and CA strains at both pH, whereas permeabilization was modest for ST(R) or SA strain at either pH. Biochemical analysis, molecular modeling, and FTIR spectroscopy data revealed that RP-1 has indistinguishable net charge and backbone trajectories at pH 5.5 and 7.5. Yet, concordant with organism-specific efficacy, surface plasmon resonance, and FTIR, molecular dynamics revealed modest helical order increases but greater RP-1 avidity and penetration of bacterial than eukaryotic lipid systems, particularly at pH 7.5. The present findings suggest that pH- and target-cell lipid contexts influence selective antimicrobial efficacy and mechanisms of RP-1 action. These findings offer new insights into selective antimicrobial efficacy and context-specificity of antimicrobial peptides in host defense, and support design strategies for potent anti-infective peptides with minimal concomitant cytotoxicity.

Arterial H+ regulation during exercise in humans.

Resting arterial H+ concentration ([H+]a) is in the nanomolar range (40±2 nm/L) while its production is in the millimolar range/min, with little variation from subject to subject. To determine the precision with which [H(+)]a is regulated during exercise, [H+]a, PaCO2 and ventilation (V˙(E)) were measured during progressively increasing work rate exercise in 16 normal subjects. (V˙(E)) increased with [H+]a, the latter attributable to PaCO2 increase below the lactic acidosis threshold (LAT) (ΔV˙(E)/Δ[H+]a ≈ 15   L   min(-1)   nanomol(-1)). [H+]a and PaCO2 increased, simultaneously, as work rate was increased below LAT. PaCO2 reversed direction of change between LAT and ventilatory compensation point (VCP). Above LAT, [H+]a increase relative to (V˙(E)) increase was greater than below LAT. PaCO2 decreased above the LAT, while [H+]a continued to increase. Thus the exercise acidosis was converted from respiratory, below, to a metabolic, above the LAT. We conclude that [H+]a is increased and regulated over the full range of exercise, but with less sensitivity above the LAT.

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.

The utility of cardiopulmonary exercise testing in the assessment of suspected microvascular ischemia.

Evidence demonstrating the potential value of cardiopulmonary exercise testing (CPET) to accurately detect myocardial ischemia secondary to macro-vascular disease is beginning to emerge. Despite distinct mechanisms mediating ischemia in micro-vascular and macrovascular coronary artery disease (CAD), the net physiologic effect of exercise-induced left ventricular (LV) dysfunction is common to both. The abnormal physiologic response to CPET may, therefore, be similar in patients with macro- and micro-vascular ischemia. The following case report describes the CPET abnormalities in a patient with suspected microvascular CAD and the subsequent improvement in LV function following three weeks of medical therapy with the anti-ischemic drug ranolazine.

Developing pulmonary vasculopathy in systemic sclerosis, detected with non-invasive cardiopulmonary exercise testing.

BACKGROUND: Patients with systemic sclerosis (SSc) may develop exercise intolerance due to musculoskeletal involvement, restrictive lung disease, left ventricular dysfunction, or pulmonary vasculopathy (PV). The latter is particularly important since it may lead to lethal pulmonary arterial hypertension (PAH). We hypothesized that abnormalities during cardiopulmonary exercise testing (CPET) in patients with SSc can identify PV leading to overt PAH. METHODS: Thirty SSc patients from the Harbor-UCLA Rheumatology clinic, not clinically suspected of having significant pulmonary vascular disease, were referred for this prospective study. Resting pulmonary function and exercise gas exchange were assessed, including peakVO2, anaerobic threshold (AT), heart rate-VO2 relationship (O2-pulse), exercise breathing reserve and parameters of ventilation-perfusion mismatching, as evidenced by elevated ventilatory equivalent for CO2 (VE/VCO2) and reduced end-tidal pCO2 (PETCO2) at the AT. RESULTS: Gas exchange patterns were abnormal in 16 pts with specific cardiopulmonary disease physiology: Eleven patients had findings consistent with PV, while five had findings consistent with left-ventricular dysfunction (LVD). Although both groups had low peak VO2 and AT, a higher VE/VCO2 at AT and decreasing PETCO2 during early exercise distinguished PV from LVD. CONCLUSIONS: Previously undiagnosed exercise impairments due to LVD or PV were common in our SSc patients. Cardiopulmonary exercise testing may help to differentiate and detect these disorders early in patients with SSc.

The utility of cardiopulmonary exercise testing to detect and track early-stage ischemic heart disease.

Evidence demonstrating the potential value of noninvasive cardiopulmonary exercise testing (CPET) to accurately detect exercise-induced myocardial ischemia is emerging. This case-based concept report describes CPET abnormalities in an asymptomatic at-risk man with suspected early-stage ischemic heart disease. When CPET was repeated 1 year after baseline assessment, his cardiovascular function had worsened, and an anti-atherosclerotic regimen was initiated. When the patient was retested after 3.3 years, the diminished left ventricular function had reversed with pharmacotherapy directed at decreasing cardiovascular events in patients with coronary artery disease. Thus, in addition to identifying appropriate patients in need of escalating therapy for atherosclerosis, CPET was useful in monitoring progression and reversal of abnormalities of the coronary circulation in a safe and cost-effective manner without the use of radiation. Serial CPET parameters may be useful to track changes marking the progression and/or regression of the underlying global ischemic burden.

Usefulness of right-to-left shunting and poor exercise gas exchange for predicting prognosis in patients with pulmonary arterial hypertension.

We hypothesized that the longitudinal changes in peak oxygen uptake, ventilatory efficiency, and exercise-induced right-to-left shunting in patients with pulmonary arterial hypertension (PAH) would predict outcomes better than baseline measurements alone. Patients with PAH die prematurely. Identifying prognostic markers is critical for treating patients with PAH; however, longitudinal prognostic information of PAH is limited. We enrolled 103 patients with PAH into a long-term, prospective outcome study using serial cardiopulmonary exercise testing to measure the peak oxygen uptake, ventilatory efficiency (ratio of ventilation to carbon dioxide output at the anaerobic threshold), right-to-left shunting, and other factors in patients treated with optimal therapy. The patients were followed up for a mean of 4.7 years. During the study period, 20 patients died, and 3 underwent lung transplantation. The baseline peak oxygen uptake and ventilatory efficiency was 0.79 L/min and 49 (normal <34), respectively, reflecting severe disease. Poorer ventilatory efficiency and greater New York Heart Association classification were associated with poor outcome at baseline and at follow-up. On multivariate analysis, the persistence or development of an exercise-induced right-to-left shunt strongly predicted death or transplantation (p <0.0001), independent of the hemodynamics and all other exercise measures, including peak oxygen uptake and ventilatory efficiency. The absence of a shunt at baseline was associated with a 20% rate of nonsurvival, which decreased to 7% at follow-up. A poorer ventilatory efficiency appeared to be associated with a poor outcome in patients without a shunt. In conclusion, a persistent exercise-induced right-to-left shunt and poor ventilatory efficiency were highly predictive of poor outcomes in patients with pulmonary arterial hypertension.

Oscillatory breathing and exercise gas exchange abnormalities prognosticate early mortality and morbidity in heart failure.

OBJECTIVES: The goal of this study was to identify better predictors of early death in patients with chronic left ventricular heart failure (CHF). Potential predictors, derived from cardiopulmonary exercise testing, were compared with other commonly used cardiovascular measurements. BACKGROUND: The prediction of early death in patients with CHF remains challenging. METHODS: Five hundred eight patients with CHF due to systolic dysfunction underwent resting cardiovascular measurements, 6-min walking tests, and cardiopulmonary exercise testing. The peak oxygen uptake (.VO(2)), peak oxygen pulse, anaerobic threshold, ratio of ventilation to carbon dioxide output (.VE/.VCO(2)), slope of .VE versus .VCO(2), and presence or absence of a distinctive oscillatory breathing pattern (OB) were ascertained. Outcomes were 6-month mortality and morbidity, the latter a sum of cardiac hospitalizations and deaths. RESULTS: The single best predictor of mortality was an elevated lowest .VE/.VCO(2) (> or =155% predicted). Adding OB on the basis of stepwise regression (optimal 2-predictor model), the odds ratio for mortality increased from 9.4 to 38.9 (p < 0.001). The slope of .VE versus .VCO(2) slope, peak .VO(2), peak oxygen pulse, and anaerobic threshold combined with OB were also strong predictors. OB also increased the odds ratio 2- to 3-fold for each of these (p < 0.01). Kaplan-Meier survival curves and area under the receiver-operating characteristic curve confirmed that lowest .VE/.VCO(2) and OB were superior. For morbidity, elevated lowest .VE/.VCO(2) or lower peak .VO(2) with OB were the best predictors. No nonexercise measurements discriminated mortality and morbidity. CONCLUSIONS: Cardiopulmonary exercise testing parameters are powerful prognosticators of early mortality and morbidity in patients with CHF, especially the optimal 2-predictor model of a combination of elevated lowest .VE/.VCO(2) and OB.

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).