A possible role for systemic hypoxia in the reactive component of pulmonary hypertension in heart failure.

BACKGROUND: The mechanisms underlying the reactive component of pulmonary hypertension (PH) in heart failure (HF) are unclear. We examined whether resting systemic oxygen levels are related to pulmonary hemodynamics in HF. METHODS AND RESULTS: Thirty-nine HF patients underwent right heart catheterization. Subsequently, patients were classified as having: 1) no PH (n = 12); 2) passive PH (n = 10); or 3) reactive PH (n = 17). Blood was drawn from the radial and pulmonary arteries for the determination of PaO(2), SaO(2), PvO(2), SvO(2), and vasoactive neurohormones. PaO(2) and PvO(2) were lower in reactive PH versus no PH and passive PH patients (65.3 ± 8.6 vs 78.3 ± 11.4 mm Hg and 74.5 ± 14.0 mm Hg; 29.2 ± 4.1 vs 36.2 ± 2.8 mm Hg and 33.4 ± 2.3 mm Hg; P < .05). SaO(2) and SvO(2) were lower in reactive PH versus no PH patients (93 ± 3% vs 96 ± 3%; 51 ± 11% vs 68 ± 4%; P < .05), but not different versus passive PH patients. The transpulmonary pressure gradient (TPG) was inversely related to PaO(2), PvO(2), SaO(2), and SvO(2) in the reactive PH patients only (r ≤ -0.557; P < .05). Similarly, plasma endothelin-1 correlated with PaO(2), PvO(2), SvO(2) (r ≤ -0.495), and TPG (r = 0.662; P < .05) in reactive PH patients only. CONCLUSIONS: Systemic hypoxia may play a role in the reactive component of PH in HF, potentially via a hypoxia-induced increase in endothelial release of the vasoconstrictor endothelin-1.

A pulmonary hypertension gas exchange severity (PH-GXS) score to assist with the assessment and monitoring of pulmonary arterial hypertension.

Submaximal exercise gas analysis may be a useful method to assess and track pulmonary arterial hypertension (PAH) severity. The aim of the present study was to develop an algorithm, using exercise gas exchange data, to assess and monitor PAH severity. Forty patients with PAH participated in the study, completing a range of clinical tests and a novel submaximal exercise step test, which lasted 6 minutes and incorporated rest (2 minutes), exercise (3 minutes), and recovery (1 minute) ventilatory gas analysis. Using gas exchange data, including breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse, a pulmonary hypertension gas exchange severity (PH-GXS) score was developed. Patients were retested after about 6 months. There was significant separation between healthy controls and patients with moderate PAH (World Health Organization [WHO] class I/II) and those with more severe PAH (WHO class III/IV) for breathing efficiency, end-tidal carbon dioxide, oxygen saturation, and oxygen pulse. The PH-GXS score was significantly correlated with WHO class (r = 0.51), 6-minute walking distance (r = -0.59), right ventricular systolic pressure (r = 0.49), log N-terminal pro-B-type natriuretic peptide (r = 0.54), and pulmonary vascular resistance (r = 0.71). The PH-GXS score remained unchanged in 22 patients retested (1.50 ± 0.92 vs 1.48 ± 0.94), as did WHO class (2.3 ± 0.8 vs 2.3 ± 0.8) and 6-minute walking distance (455 ± 120 vs 456 ± 103 m). Small individual changes were observed in the PH-GXS score, with 8 patients improving and 8 deteriorating. In conclusion, the PH-GXS score differentiated between patients with PAH and was correlated with traditional clinical measures. The PH-GXS score was unchanged in our cohort after 6 months, consistent with traditional clinical metrics, but individual differences were evident. A PH-GXS score may be a useful way to track patient responses to therapy.

The usefulness of submaximal exercise gas exchange to define pulmonary arterial hypertension.

BACKGROUND: The 6-minute walk test is widely used to characterize activity tolerance and response to therapy in pulmonary arterial hypertension (PAH) but provides little information about cardiopulmonary pathophysiology. The aim of the present study was to determine whether measures of pulmonary gas exchange during relatively light exercise could differentiate between PAH patients and healthy individuals and also stratify disease severity. METHODS: The study comprised 40 PAH patients and 25 matched controls. Each completed a sub-maximal exercise test, consisting of 2 minutes of rest, 3 minutes of exercise, and 1 minute of recovery. Ventilation, pulmonary gas exchange, arterial oxygen saturation (Sao(2)), and heart rate were measured throughout using a simplified gas analysis system. RESULTS: A number of gas exchange variables differentiated PAH patients and controls. End-tidal CO(2) (P(ET)co(2)) and Sao(2) were lower in PAH vs controls (31 ± 7 vs 39 ± 3 mm Hg and 89% ± 5% vs 95% ± 2%, respectively, p < 0.05). Breathing efficiency (V(E)/Vco(2) ratio) was poorer in PAH vs controls (42 ± 10 vs 33 ± 5, p < 0.05). In addition, P(ET)co(2) and V(E)/Vco(2) discriminated between different severities of PAH. CONCLUSIONS: Gas exchange variables obtained during light sub-maximal exercise differentiated PAH patients from healthy controls and also between different severities of PAH. Sub-maximal exercise gas exchange may be a useful end point measure in a PAH population.

Submaximal exercise gas exchange is an important prognostic tool to predict adverse outcomes in heart failure.

AIMS: Traditionally, VO(2peak) has been used to determine prognosis in heart failure; however, this measure has limitations. Hence, other exercise and gas exchange parameters measured submaximally, e.g. breathing efficiency (V(E)/VCO(2)), end-tidal CO(2) (P(ET)CO(2)), oxygen uptake efficiency slope (OUES), and circulatory power [ systolic blood pressure (SBP)], have been investigated. The aim of this study was to investigate the prognostic relevance of submaximal exercise gas exchange in heart failure patients. Method and results One hundred and thirty-two consecutive heart failure patients (mean age 56 ± 12 years, ejection fraction 29 ± 11%) performed peak treadmill testing. Gas exchange and haemodynamic variables were measured continuously. Gas exchange data obtained from the first 2 min of exercise and at a respiratory exchange ratio (RER) of 0.9 were the measurements of interest. Over a median follow-up period of 62.4 (range 0-114) months, there were 44 endpoints (death or transplant). Univariate analysis demonstrated submaximal predictors of survival, which included V(E)/VCO(2) slope and ratio, P(ET)CO(2), OUES, and circulatory power (P ≤ 0.01). When these and additional submaximal variables were included together in the multivariable analysis, the strongest submaximal exercise predictive model (C-statistic 0.75) comprised data from the first stage of exercise (V(E) and circulatory power) and at an RER of 0.9 (V(E)/VCO(2) ratio). The inclusion of VO(2 peak) and demographic data, with submaximal data (V(E)/VCO(2) ratio at an RER = 0.9), increased the predictiveness of the model (C-statistic 0.78). CONCLUSION: Submaximal exercise measures provide useful prognostic information for predicting survival in heart failure. This form of testing is logistically easier, cheaper, and safer for patients compared with maximal exercise.

The usefulness of submaximal exercise gas exchange in pulmonary arterial hypertension: a case series.

INTRODUCTION: Submaximal exercise gas exchange may be a useful tool to track responses to therapy in pulmonary arterial hypertension (PAH) patients. METHODS: Three patients diagnosed with idiopathic PAH, on differing therapies, were included. Standard clinical tests (echocardiography; 6 minute walk) were performed pre and 3-5 months after treatment. Gas exchange was measured during 3 minutes of step exercise at both time points. RESULTS: Gas exchange variables, end tidal CO(2) (P(ET)CO(2)) and the ratio of ventilation to CO(2) production (V(E)/VCO(2)), during submaximal exercise were able to track patient responses to therapy over a 3-5 month period. Two patients demonstrated positive improvements, with an increased P(ET)CO(2) and decreased V(E)/VCO(2) during light exercise, in response to an altered therapeutic regime. The third patient had a worsening of gas exchange (decreased P(ET)CO(2) and increased V(E)/VCO(2)) following no changes in the medical regime from the baseline visit. CONCLUSION: Gas exchange variables measured during light submaximal exercise, such as P(ET)CO(2) and V(E)/VCO(2), may be able to better detect small changes in functional status following treatment and could, therefore, be a useful tool to track disease severity in PAH patients. Further study is required to determine the clinical usefulness of these gas exchange variables.

Causes of breathing inefficiency during exercise in heart failure.

BACKGROUND: Patients with heart failure (HF) develop abnormal pulmonary gas exchange; specifically, they have abnormal ventilation relative to metabolic demand (ventilatory efficiency/minute ventilation in relation to carbon dioxide production [V(E)/VCO2]) during exercise. The purpose of this investigation was to examine the factors that underlie the abnormal breathing efficiency in this population. METHODS AND RESULTS: Fourteen controls and 33 moderate-severe HF patients, ages 52 ± 12 and 54 ± 8 years, respectively, performed submaximal exercise (∼65% of maximum) on a cycle ergometer. Gas exchange and blood gas measurements were made at rest and during exercise. Submaximal exercise data were used to quantify the influence of hyperventilation (PaCO2) and dead space ventilation (V(D)) on V(E)/VCO2. The V(E)/VCO2 relationship was lower in controls (30 ± 4) than HF (45 ± 9, P < .01). This was the result of hyperventilation (lower PaCO2) and higher V(D)/V(T) that contributed 40% and 47%, respectively, to the increased V(E)/VCO2 (P < .01). The elevated V(D)/V(T) in the HF patients was the result of a tachypneic breathing pattern (lower V(T), 1086 ± 366 versus 2003 ± 504 mL, P < .01) in the presence of a normal V(D) (11.5 ± 4.0 versus 11.9 ± 5.7 L/min, P = .095). CONCLUSIONS: The abnormal ventilation in relation to metabolic demand in HF patients during exercise was due primarily to alterations in breathing pattern (reduced V(T)) and excessive hyperventilation.

Maximizing patient benefit from cardiac resynchronization therapy with the addition of structured exercise training: a randomized controlled study.

OBJECTIVES: We evaluated the benefits of additional exercise training after cardiac resynchronization therapy (CRT). BACKGROUND: Cardiac resynchronization therapy results in improved morbidity and mortality in appropriate patients. We hypothesized that a structured exercise training program in addition to CRT would maximize the improvements in exercise capacity, symptoms, and quality of life (QOL). METHODS: Fifty patients referred for CRT were recruited. Patients were assessed before and 3 and 6 months after CRT. Functional class and QOL scores were recorded, and exercise tests were performed with hemodynamic measurements. Peak lower limb skeletal muscle torque was measured during extension, and echocardiography was undertaken at each visit. At 3 months, patients were randomized with a simple sealed envelope method to exercise training (n = 25) or control group (n = 25). The exercise group underwent an exercise program consisting of 3 visits/week for 3 months. Paired sample t tests were used to look for in-group differences and independent sample t tests for between-group differences. RESULTS: Three months after CRT there were significant improvements in all functional, exercise hemodynamic, and echocardiographic measures. After randomization the exercise group showed further significant improvements in functional, exercise hemodynamic, and QOL measures compared with the control group. There were also significant in-group improvements in peak skeletal muscle function and ejection fraction that did not reach statistical significance on intergroup analysis. CONCLUSIONS: Exercise training leads to further improvements in exercise capacity, hemodynamic measures, and QOL in addition to the improvements seen after CRT. Therefore, exercise training allows maximal benefit to be attained after CRT.