The Role of Gas Exchange Variables in Cardiopulmonary Exercise Testing for Risk Stratification and Management of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is common in the developed world and results in significant morbidity and mortality. Accurate risk assessment methods and prognostic variables are therefore needed to guide clinical decision making for medical therapy and surgical interventions with the ultimate goal of decreasing risk and improving health outcomes. The purpose of this review is to examine the role of cardiopulmonary exercise testing (CPET) and its most commonly used ventilatory gas exchange variables for the purpose of risk stratification and management of HFrEF. We evaluated five widely studied gas exchange variables from CPET in HFrEF patients based on nine previously used systematic criteria for biomarkers. This paper provides clinicians with a comprehensive and critical overview, class recommendations and evidence levels. Although some CPET variables met more criteria than others, evidence supporting the clinical assessment of variables beyond peak V̇O2 is well-established. A multi-variable approach also including the V̇E-V̇CO2 slope and EOV is therefore recommended.

Exercise responses in patients with chronically high creatine kinase levels.

INTRODUCTION: Elevated serum creatine kinase (CK) is often taken to reflect muscle disease, but many individuals have elevated CK without a specific diagnosis. How elevated CK reflects muscle metabolism during exercise is not known. METHODS: Participants (46 men, 48 women) underwent incremental exercise testing to assess aerobic performance, cardiovascular response, and ventilatory response. Serum lactate, ammonia, and CK were measured at rest, 4 minutes into exercise, and 2 minutes into recovery. RESULTS: High-CK and control subjects demonstrated similar aerobic capacities and cardiovascular responses to incremental exercise. Those with CK ≥ 300 U/L exhibited significantly higher lactate and ammonia levels after maximal exercise, together with increased ventilatory responses, whereas those with CK ≥200 U/L but ≤ 300 U/L did not. CONCLUSIONS: We recommend measurement of lactate and ammonia profiles during a maximal incremental exercise protocol to help identify patients who warrant muscle biopsy to rule out myopathy. Muscle Nerve 56: 264-270, 2017.

Reverse fiber type disproportion: A distinct metabolic myopathy.

INTRODUCTION: In this investigation we characterized the physiological and metabolic responses to incremental exercise in 13 subjects with a predominance of type II fibers on muscle biopsy. METHODS: Subjects underwent incremental exercise testing with measures of maximum oxygen uptake ( V˙O2 max), maximum heart rate (fc max), chronotropic index (fc / V˙O2 slope), maximum ventilation ( V˙emax), blood lactate, ammonia, and creatine kinase (CK) levels. Muscle fiber type was determined by myosin ATPase histochemistry. RESULTS: Muscle biopsies showed more type II fibers (75%) in subjects compared with normal individuals (P < 0.01). Subjects exhibited normal V˙O2 max and end-exercise lactate, whereas ammonia and CK levels at maximum exercise were significantly higher. CONCLUSIONS: Subjects with type II muscle fiber predominance exhibited exaggerated increases in ammonia and elevated CK levels during exercise. Predominance of type II fibers on muscle biopsy is the opposite finding of congenital fiber type disproportion; we suggest these patients be referred to as having "reverse fiber type disproportion." Muscle Nerve 54: 86-93, 2016.

Responses to exercise in systemic sclerosis-associated interstitial lung disease.

INTRODUCTION: Pulmonary complications in systemic sclerosis (SSc) significantly increase morbidity and mortality. Our aim was to determine the factors limiting exercise capacity in SSc patients with and without interstitial lung disease (ILD), and to identify and quantify abnormalities during exercise that might assist in clinical assessment of this complication. METHODS: Fifteen patients with SSc and ILD (SSc-ILD) were compared with 10 patients with SSc without ILD and 9 age- and sex-matched normal volunteers. Subjects performed symptom-limited incremental treadmill exercise with online measurement of respiratory gas exchange, arterial blood gas sampling and measurement of neurohormones in venous blood. RESULTS: Patients with SSc-ILD had lower exercise capacity than SSc patients without ILD or normal subjects (peak oxygen consumption (PV̇O2 ) (17.1 [4.2] vs. 22.0 [4.7] and 23.0 [5.4] ml kg-1 min-1 , respectively, mean [SD], p < 0.01 ANOVA), but PV̇O2 did not correlate with static pulmonary function measurements. Ventilatory equivalent for CO2 (V̇E/V̇CO2 ; nadir) was higher in SSc-ILD patients than the other two groups (36.6 [8.0] vs. 29.9 [4.4] and 30.0 [2.5], p < 0.005) as were peak exercise dead-space tidal volume ratio (0.44 [0.06] vs. 0.26 [0.09] and 0.26 [0.05], p < 0.001) and peak exercise alveolar-arterial difference (28.9 [16.9] vs. 18.8 [14.0] and 11.5 [6.9] mmHg, p < 0.05). Atrial natriuretic peptide was elevated in both SSc patient groups. CONCLUSIONS: SSc-ILD results in lower exercise capacity than SSc without ILD, and abnormalities of gas exchange are seen. The possible use of cardiopulmonary exercise testing to identify disease and quantify impairment in SSc-ILD merits further study.

Cardiopulmonary Exercise Testing and Metabolic Myopathies.

Skeletal muscle requires a large increase in its ATP production to meet the energy needs of exercise. Normally, most of this increase in ATP is supplied by the aerobic process of oxidative phosphorylation. The main defects in muscle metabolism that interfere with production of ATP are (1) disorders of glycogenolysis and glycolysis, which prevent both carbohydrate entering the tricarboxylic acid cycle and the production of lactic acid; (2) mitochondrial myopathies where the defect is usually within the electron transport chain, reducing the rate of oxidative phosphorylation; and (3) disorders of lipid metabolism. Gas exchange measurements derived from exhaled gas analysis during cardiopulmonary exercise testing can identify defects in muscle metabolism because [Formula: see text]o2 and [Formula: see text]co2 are abnormal at the level of the muscle. Cardiopulmonary exercise testing may thus suggest a likely diagnosis and guide additional investigation. Defects in glycogenolysis and glycolysis are identified by a low peak [Formula: see text]o2 and absence of excess [Formula: see text]co2 from buffering of lactic acid by bicarbonate. Defects in the electron transport chain also result in low peak [Formula: see text]o2, but because there is an overreliance on anaerobic processes, lactic acid accumulation and excess carbon dioxide from buffering occur early during exercise. Defects in lipid metabolism result in only minor abnormalities during cardiopulmonary exercise testing. In defects of glycogenolysis and glycolysis and in mitochondrial myopathies, other features may include an exaggerated cardiovascular response to exercise, a low oxygen-pulse, and excessive ammonia release.

Structural and Functional Lung Impairment in Adult Survivors of Bronchopulmonary Dysplasia.

RATIONALE: As more preterm infants recover from severe bronchopulmonary dysplasia (BPD), it is critical to understand the clinical consequences of this condition on the lung health of adult survivors. OBJECTIVES: To assess structural and functional lung parameters in young adult BPD survivors and preterm and term control subjects. METHODS: Young adult survivors of BPD (mean age, 24 yr) underwent spirometry, lung volume assessment, transfer factor, lung clearance index, and fractional exhaled nitric oxide measurements, together with high-resolution chest computed tomography and cardiopulmonary exercise testing. MEASUREMENTS AND MAIN RESULTS: Twenty-five adult BPD survivors (mean ± SD gestational age, 26.8 ± 2.3 wk; birth weight, 866 ± 255 g), 24 adult prematurely born non-BPD control subjects (gestational age, 30.6 ± 1.9 wk; birth weight, 1,234 ± 207 g), and 25 adult term-birth control subjects (gestational age, 38.5 ± 0.9 wk; birth weight, 3,569 ± 2,979 g) were studied. Subjects with BPD were more likely to be wakened by cough (odds ratio, 9.7; 95% confidence interval, 1.8-52.6; P < 0.01) or wheeze and breathlessness (odds ratio, 12.2; 95% confidence interval; 1.3-112; P < 0.05) than term control subjects after adjusting for sex and current smoking. Preterm subjects had greater airway obstruction than term subjects. Subjects with BPD had significantly lower values for FEV1 and forced expiratory flow, midexpiratory phase (percent predicted and z-scores), than term control subjects (both P < 0.001). Although non-BPD subjects also had lower spirometric values than term control subjects, none of the differences reached statistical significance. More subjects with BPD (25%) had fixed airflow obstruction than non-BPD (12.5%) and term (0%) subjects (P = 0.004). Both BPD and non-BPD subjects had significantly greater impairment in gas transfer (Kco percent predicted) than term subjects (both P < 0.05). Eighteen (37%) preterm participants were classified as small for gestational age (birth weight below the 10th percentile for gestational age). These subjects had significantly greater impairment in FEV1 (percent predicted values and z-scores) than those born appropriate for gestational age. BPD survivors had significantly more severe radiographic structural lung impairment than non-BPD subjects. Both preterm groups had impaired exercise capacity compared with term control subjects. There was a trend for greater limitation and leg discomfort in BPD survivors. CONCLUSIONS: Adult preterm birth survivors, especially those who developed BPD, continue to experience respiratory symptoms and exhibit clinically important levels of pulmonary impairment.

Ventilatory and gas exchange responses during heavy constant work-rate exercise.

PURPOSE: At constant work-rates below the gas exchange threshold (VO(2 theta)), VO(2) normally achieves steady-state values within 3 min, whereas at heavier work-rates, VO(2) may continue to rise. The VO(2) response to heavy exercise can be described by a three-exponential model with the slow phase usually commencing 2-3 min after the onset of exercise. The aim of our study was to estimate precisely the VO(2), VCO(2), VE and f(C) required for above-VO(2 theta) exercise from the relationship of the specific variable to work-rate below VO(2 theta) and to compare this with the actual value achieved. METHODS: Nine cyclists performed five constant work-rates of 8 min duration, four below VO(2 theta) (40, 80, 120, 160 W) and one midway between VO(2 theta) and VO(2max) (295 +/- 34 W). The VO(2), VCO(2), VE and f(C) were averaged for the final 2 min of each below-VO(2 theta) test and were found to be linear with respect to work-rate (average r2 >0.95). Variables for the above-VO(2 theta) work-rate were predicted by extrapolation and compared with the actual measured values at the end of the exercise bout. RESULTS: VO(2) exceeded the predicted value by 0.48 +/- 0.21 L x min(-1) (12.4 +/- 5.1%), VCO(2) by 0.78 +/- 0.26 L x min(-1) (23.2 +/- 7.2%), VE by 40.3 +/- 16.3 L x min(-1) (51.0 +/- 23.1%), and f(C) by 12.2 +/- 12.5 beats x min(-1) (8.8 +/- 9.3%), all P < 0.0001 except f(C) P < 0.02, paired t-test. The point at which VO(2) during above-VO(2 theta) exercise exceeded the predicted value (145.7 +/- 64.9 s) agreed with the point at which the slow component of VO(2) began, as determined by nonlinear regression analysis (131.5 +/- 44.3 s, P = NS, ANOVA). CONCLUSION: There is an excessive metabolic response to heavy exercise over and above that predicted by extrapolation from light-moderate exercise and this excess VO(2) approximates on average to the slow phase of a three-compartment exponential model.

Pulmonary capillary haemangiomatosis - An unusual cause of hypoxia.

We describe the case of a 58-year-old man who presented with progressive dyspnoea on exertion and severe exertional hypoxia. There was a paucity of radiological findings, mild pulmonary hypertension, and no demonstrable anatomical shunt. Post mortem examination of lung tissue suggested a diagnosis of pulmonary capillary haemangiomatosis. The case is unusual in displaying few radiological findings. We postulate that the severe hypoxia was due to shunting through the abnormal capillary proliferations.

The utility of cardiopulmonary exercise testing in difficult asthma.

BACKGROUND: Unexplained persistent breathlessness in patients with difficult asthma despite multiple treatments is a common clinical problem. Cardiopulmonary exercise testing (CPX) may help identify the mechanism causing these symptoms, allowing appropriate management. METHODS: This was a retrospective analysis of patients attending a specialist-provided service for difficult asthma who proceeded to CPX as part of our evaluation protocol. Patient demographics, lung function, and use of health care and rescue medication were compared with those in patients with refractory asthma. Medication use 6 months following CPX was compared with treatment during CPX. RESULTS: Of 302 sequential referrals, 39 patients underwent CPX. A single explanatory feature was identified in 30 patients and two features in nine patients: hyperventilation (n = 14), exercise-induced bronchoconstriction (n = 8), submaximal test (n = 8), normal test (n = 8), ventilatory limitation (n = 7), deconditioning (n = 2), cardiac ischemia (n = 1). Compared with patients with refractory asthma, patients without "pulmonary limitation" on CPX were prescribed similar doses of inhaled corticosteroid (ICS) (median, 1,300 µg [interquartile range (IQR), 800-2,000 µg] vs 1,800 µg [IQR, 1,000-2,000 µg]) and rescue oral steroid courses in the previous year (median, 5 [1-6] vs 5 [1-6]). In this group 6 months post-CPX, ICS doses were reduced (median, 1,300 µg [IQR, 800-2,000 µg] to 800 µg [IQR, 400-1,000 µg]; P < .001) and additional medication treatment was withdrawn (n = 7). Patients with pulmonary limitation had unchanged ICS doses post CPX and additional therapies were introduced. CONCLUSIONS: In difficult asthma, CPX can confirm that persistent exertional breathlessness is due to asthma but can also identify other contributing factors. Patients with nonpulmonary limitation are prescribed inappropriately high doses of steroid therapy, and CPX can identify the primary mechanism of breathlessness, facilitating steroid reduction.

Changes in pulmonary vascular function after acute methionine loading in normal men.

Elevated blood levels of Hcy (homocysteine) are associated with endothelial dysfunction in the systemic and coronary arterial beds. We wished to know if similar changes could be detected in the pulmonary circulation, using non-invasive tests. We studied ten normal young men aged 23-31 years, in whom acute hyperhomocysteinaemia was induced by oral ingestion of methionine. Cardiopulmonary exercise testing [including measurement of exhaled breath NO (nitric oxide)] was performed on two occasions, with and without methionine loading. In addition, blood samples for vWf (von Willebrand factor) and factor VIIIc were taken as markers of endothelial function. After oral methionine, plasma Hcy increased from 11.8 +/- 3.1 to 31.2 +/- 10.3 micromol/l (values are means +/- S.D.; P < 0.0001), whereas there was no increase after placebo. After exercise there was an increase in V(NO) (NO production) and circulating plasma levels of vWf and factor VIIIc, but these were similar in the two tests. Exercise time, HR (heart rate) and BP (blood pressure) responses and P V(O2) (peak achieved O2 uptake) were also similar in the two tests. V(E) (expiratory minute ventilation)/ V(CO2) (CO2 production) was similar in the two groups at rest (methionine, 31.9 +/- 3.9; placebo, 30.5 +/- 3.9; P = 0.11), but increased during exercise after methionine (at peak, 32.2 +/- 4.6 compared with 29.9 +/- 2.8; P = 0.016). P(ETCO2) (end-tidal partial pressure of CO2) was also similar in the two groups at rest (35.1 +/- 2.9 compared with 36.8 +/- 3.2; P = 0.11), but decreased throughout the methionine test (peak 34.1 +/- 4.4 compared with 36.7 +/- 3.5; P = 0.006). V(E) vs V(CO2) slope also increased in the methionine test (25.2 +/- 2.4 compared with 22.8 +/- 2.3; P = 0.003). In conclusion, small, but consistent and significant, changes in respiratory gas exchange were seen after methionine loading, compatible with a V / Q (ventilation/perfusion) mismatch due to pulmonary vascular endothelial dysfunction.

Gas exchange responses to constant work-rate exercise in patients with glycogenosis type V and VII.

During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle's disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.