Does recovery from submaximal exercise predict response to cardiac resynchronisation therapy?

BACKGROUND: Exercise parameters are not routinely incorporated in decision making for cardiac resynchronisation therapy (CRT). Submaximal exercise parameters better reflect daily functional capacity of heart failure patients than parameters measured at maximal exertion, and may therefore better predict response to CRT. We compared various exercise parameters, and sought to establish which best predict CRT response. METHODS: In 31 patients with chronic heart failure (61% male; age 68±7 years), submaximal and maximal cycling testing was performed before and 3 months after CRT. Submaximal oxygen onset (τVO2 onset) and recovery kinetics (τVO2 recovery), peak oxygen uptake (VO2 peak) and oxygen uptake efficiency slope (OUES) where measured. Response was defined as ≥15% relative reduction in end-systolic volume. RESULTS: After controlling for age, New York Heart Association and VO2 peak, fast submaximal VO2 kinetics were significantly associated with response to CRT, measured either during onset or recovery of submaximal exercise (area under the curve, AUC=0.719 for both; p<0.05). By contrast, VO2 peak (AUC=0.632; p=0.199) and OUES (AUC=0.577; p=0.469) were not associated with response. Among patients with fast onset and recovery kinetics, below 60 s, a significantly higher percentage of responders was observed (91% and 92% vs 43% and 40%, respectively). CONCLUSIONS: Impaired VO2 kinetics may serve as an objective marker of submaximal exercise capacity that is age-independently associated with non-response following CRT, whereas maximal exercise parameters are not. Assessment of VO2 kinetics is feasible and easy to perform, but larger studies should confirm their clinical utility.

The utility of the oxygen pulse recovery as a marker of the cardiac output response to exercise in patients with chronic heart failure.

PURPOSE: The cardiac output (CO) response to exercise is a useful marker to grade the prognosis and severity of chronic heart failure (CHF). The recovery of the oxygen pulse (OP) is a non-invasive parameter, which is related to exercise capacity in cardiac patients. However, the relation between OP recovery and the central haemodynamic response to exercise remains to be determined. We hypothesized that an impaired OP recovery is associated with a reduced CO response to exercise in CHF patients. METHODS: Sixty one CHF patients performed cardiopulmonary exercise test with simultaneous measurement of CO. Impaired OP recovery was defined as an overshoot during the first minute of recovery or OP at 1-min recovery as a percentage of peak OP (OPRR ). RESULTS: An OP overshoot was observed in 9% (n = 5) of patients. In these patients, peak CO and VO2 were significantly lower (peak CO 7.9 ± 0.8 versus 11.2 ± 4.3 L/min and peak VO2 14.1 ± 4.7 versus 19.6 ± 5.8 ml min-1  kg-1 ). Mean relative recovery of OP was 78 ± 20%. Slow OP recovery (negative OPRR ) was seen in 13% (n = 8). Peak CO and VO2 were significantly lower in the negative OPRR group (11 ± 4 versus 8 ± 0.7 L/min and 19.7 ± 5.9 versus 14.6 ± 3.7 ml kg min-1 ). There was a significant relation between OPRR and stroke volume (SV) RR (r = .57), as well as between OPRR and a-v O2 diff RR (rs  = .4). CONCLUSION: An impaired OP recovery is associated with a reduced CO response to exercise and worse functional status. Therefore, the OP recovery can be used to grade the severity of CHF.

High intensity interval training after cardiac resynchronization therapy: An explorative randomized controlled trial.

BACKGROUND: CRT leads to improvement in exercise capacity, cardiac function and mortality in selected CHF patients. Exercise capacity improves even greater when combining CRT with moderate-intensity exercise training (ET). However, high-intensity interval training (HIT) as additional therapy to CRT has not yet been established. Given the complementary physiological effects of HIT, we hypothesized that HIT after CRT may have additional effects on exercise capacity. METHODS: 24 CHF patients, NYHA class II/III and accepted for CRT underwent an echocardiogram, QoL questionnaire and CPET with cardiac output (CO) measurements before implantation, at 3 and 6 months. After 3 months, patients were randomized to usual care (UC) or HIT, consisting of 36 sessions at 85-95% of peak V̇O2. RESULTS: Peak V̇O2 increased after CRT (17±5.3 to 18.7±6.2 ml/kg/min, p < 0.05); after HIT there was a non-significant increase of 1.4 ml/kg/min (p = 0.12). Peak workload increased after CRT (109±45 to 118±44 W, p = 0.001). An additional significant within- and between group increase after HIT was found in the intervention group (128±42 to 148±48 W, versus 110±50 to 110±50, respectively, p = 0.03). Peak CO did not change significantly after CRT or HIT. V̇O2 recovery kinetics speeded by 27% after CRT (p = 0.04), no further improvement after HIT was observed. LVEF increased 25% after CRT (p = 0.0001), no additional increase was seen after HIT. CONCLUSION: This study demonstrates that HIT provides additional improvement of exercise capacity without a concomitant change in peak V̇O2 or CO suggesting that the additional effect of HIT is mainly mediated by an improvement of anaerobic performance.

Aerobic Interval Training Impacts Muscle and Brain Oxygenation Responses to Incremental Exercise.

The purpose of the present study was to assess the effects of aerobic interval training on muscle and brain oxygenation to incremental ramp exercise. Eleven physically active subjects performed a 6-week interval training period, proceeded and followed by an incremental ramp exercise to exhaustion (25 W min-1). Throughout the tests pulmonary gas exchange and muscle (Vastus Lateralis) and brain (prefrontal cortex) oxygenation [concentration of deoxygenated and oxygenated hemoglobin, HHb and O2Hb, and tissue oxygenation index (TOI)] were continuously recorded. Following the training intervention V . ⁢ O 2 peak had increased with 7.8 ± 5.0% (P < 0.001). The slope of the decrease in muscle TOI had decreased (P = 0.017) 16.6 ± 6.4% and the amplitude of muscle HHb and totHb had increased (P < 0.001) 40.4 ± 15.8 and 125.3 ± 43.1%, respectively. The amplitude of brain O2Hb and totHb had increased (P < 0.05) 40.1 ± 18.7 and 26.8 ± 13.6%, respectively. The training intervention shifted breakpoints in muscle HHb, totHb and TOI, and brain O2Hb, HHb, totHb and TOI to a higher absolute work rate and V . ⁢ O 2 (P < 0.05). The relative (in %) change in V . ⁢ O 2 peak was significantly correlated to relative (in %) change slope of muscle TOI (r = 0.69, P = 0.011) and amplitude of muscle HHb (r = 0.72, P = 0.003) and totHb (r = 0.52, P = 0.021), but not to changes in brain oxygenation. These results indicate that interval training affects both muscle and brain oxygenation, coinciding with an increase in aerobic fitness (i.e., V . ⁢ O 2 peak). The relation between the change in V . ⁢ O 2 peak and muscle but not brain oxygenation suggests that brain oxygenation per se is not a primary factor limiting exercise tolerance during incremental exercise.

Skeletal muscle fiber characteristics in patients with chronic heart failure: impact of disease severity and relation with muscle oxygenation during exercise.

Skeletal muscle function in patients with heart failure and reduced ejection fraction (HFrEF) greatly determines exercise capacity. However, reports on skeletal muscle fiber dimensions, fiber capillarization, and their physiological importance are inconsistent. Twenty-five moderately impaired patients with HFrEF and 25 healthy control (HC) subjects underwent muscle biopsy sampling. Type I and type II muscle fiber characteristics were determined by immunohistochemistry. In patients with HFrEF, enzymatic oxidative capacity was assessed, and pulmonary oxygen uptake (V̇o2) and skeletal muscle oxygenation during maximal and moderate-intensity exercise were measured using near-infrared spectroscopy. While muscle fiber cross-sectional area (CSA) was not different between patients with HFrEF and HC, the percentage of type I fibers was higher in HC (46 ± 15 vs. 37 ± 12%, respectively, P = 0.041). Fiber type distribution and CSA were not different between patients in New York Heart Association (NYHA) class II and III. Type I muscle fiber capillarization was higher in HFrEF compared with HC[capillary-to-fiber perimeter exchange (CFPE) index: 5.70 ± 0.92 vs. 5.05 ± 0.82, respectively, P = 0.027]. Patients in NYHA class III had slower V̇o2 and muscle deoxygenation kinetics during onset of exercise and lower muscle oxidative capacity than those in class II (P < 0.05). Also, fiber capillarization was lower but not compared with HC. Higher CFPE index was related to faster deoxygenation (rspearman = -0.682, P = 0.001), however, not to muscle oxidative capacity (r = -0.282, P = 0.216). Type I muscle fiber capillarization is higher in HFrEF compared with HC but not in patients with greater exercise impairment. Greater capillarization may positively affect V̇o2 kinetics by enhancing muscle oxygen diffusion.NEW & NOTEWORTHY The skeletal myopathy of chronic heart failure (HF) includes a greater percentage of fatigable type II fibers and, for less impaired patients, greater skeletal muscle fiber capillarization. Near-infrared spectroscopy measurements of skeletal muscle oxygenation indicate that greater capillarization may compensate for reduced blood flow in mild HF by enhancing the diffusive capacity of skeletal muscle. This thereby augments and speeds oxygen extraction during contractions, which is translated into faster pulmonary oxygen uptake kinetics.

The influence of adipose tissue on spatially resolved near-infrared spectroscopy derived skeletal muscle oxygenation: the extent of the problem.

OBJECTIVE: Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO2) are useful for the assessment of skeletal muscle perfusion and function during exercise, however, they are influenced by overlying skin and adipose tissue. This study explored the extent and nature of the influence of adipose tissue thickness (ATT) on StO2. APPROACH: NIR spatially resolved spectroscopy (SRS) derived oxygenation was measured on vastus lateralis in 56 patients with chronic heart failure (CHF) and 20 healthy control (HC) subjects during rest and moderate intensity exercise with simultaneous assessment of oxygen uptake kinetics (τ [Formula: see text]). In vitro measurements were performed on a flow cell with a blood mixture with full oxygen saturation (100%), which was gradually decreased to 0% by adding sodium metabisulfite. Experiments were repeated with 2 mm increments of porcine fat layer between the NIRS device and flow cell up to 14 mm. MAIN RESULTS: Lower ATT, higher τ [Formula: see text], and CHF were independently associated with lower in vivo StO2 in multiple regression analysis, whereas age and gender showed no independent relationship. With greater ATT, in vitro StO2 was reduced from 100% to 74% for fully oxygenated blood and increased from 0% to 68% for deoxygenated blood. SIGNIFICANCE: This study shows that ATT independently confounds NIR-SRS derived StO2 by overestimating actual skeletal muscle oxygenation and by decreasing its sensitivity for deoxygenation. Because physiological properties (e.g. presence of disease and slowing of τ [Formula: see text]) also influence NIR-SRS, a correction based on optical properties is needed to interpret calculated values as absolute StO2.

Oxygen delivery is not a limiting factor during post-exercise recovery in healthy young adults.

PURPOSE: It is still equivocal whether oxygen uptake recovery kinetics are limited by oxygen delivery and can be improved by supplementary oxygen. The present study aimed to investigate whether measurements of muscle and pulmonary oxygen uptake kinetics can be used to assess oxygen delivery limitations in healthy subjects. METHODS: Sixteen healthy young adults performed three sub-maximal exercise tests (6 min at 40% Wmax) under hypoxic (14%O2), normoxic (21%O2) and hyperoxic (35%O2) conditions on separate days in randomized order. Both Pulmonary VO2 and near infra red spectroscopy (NIRS) based Tissue Saturation Index (TSI) offset kinetics were calculated using mono-exponential curve fitting models. RESULTS: Time constant τ of VO2 offset kinetics under hypoxic (44.9 ± 7.3s) conditions were significantly larger than τ of the offset kinetics under normoxia (37.9 ± 8.2s, p = 0.02) and hyperoxia (37±6s, p = 0.04). TSI mean response time (MRT) of the offset kinetics under hypoxic conditions (25.5 ± 13s) was significantly slower than under normoxic (15 ± 7.7, p = 0.007) and hyperoxic (13 ± 7.3, p = 0.008) conditions. CONCLUSION: The present study shows that there was no improvement in the oxygen uptake and muscle oxygenation recovery kinetics in healthy subjects under hyperoxic conditions.Slower TSI and VO2 recovery kinetics under hypoxic conditions indicate that both NIRS and spiro-ergometry are appropriate non-invasive measurement tools to assess the physiological response of a healthy individual to hypoxic exercise.

Test-retest reliability of skeletal muscle oxygenation measurements during submaximal cycling exercise in patients with chronic heart failure.

The potential purpose of near-infrared spectroscopy (NIRS) as a clinical application in patients with chronic heart failure (CHF) is the identification of limitations in O2 delivery or utilization during exercise. The objective of this study was to evaluate absolute and relative test-retest reliability of skeletal muscle oxygenation measurements in patients with CHF. Thirty patients with systolic heart failure (left ventricular ejection fraction 31 ± 8%) performed 6-min constant-load cycling tests at 80% of the anaerobic threshold (AT) with tissue saturation index (TSI) measurement at the vastus lateralis. Tests were repeated after 10 ± 5 days to evaluate reliability. Absolute reliability was assessed with limits of agreement (LoA, expressed as bias ± random error) and coefficients of variation (CV) for absolute values (LoA range: 0·4 ± 6·2% to 0·6 ± 7·9%; CV range: 4·7-7·1%), amplitudes (LoA range -0·5 ± 5·8% to -0·7 ± 6·8%; CV range: 26·2-42·1%), onset and recovery kinetics (mean response times; LoA 0·4 ± 9·5 s, CV 23·5% and LoA -5·8 ± 50·8 s, CV 67·4% respectively) and overshoot characteristics (CV range 45·7-208·6%). Relative reliability was assessed with intraclass correlation coefficients for absolute values (range 0·74-0·90), amplitudes (range 0·85-0·92), onset and recovery kinetics (0·53 and 0·51, respectively) and overshoot characteristics (range 0·17-0·74). In conclusion, absolute reliability of absolute values and onset kinetics seems acceptable for serial within-subject comparison, and as such, for evaluation of treatment effects. Absolute reliability of amplitudes and recovery kinetics is considered unsatisfactory. Relative reliability of absolute values and amplitudes is sufficient for purposes of physiological distinction between patients with CHF. Despite lower relative reliability, kinetics may still be useful for clinical application.

Limitations of skeletal muscle oxygen delivery and utilization during moderate-intensity exercise in moderately impaired patients with chronic heart failure.

The extent and speed of transient skeletal muscle deoxygenation during exercise onset in patients with chronic heart failure (CHF) are related to impairments of local O2 delivery and utilization. This study examined the physiological background of submaximal exercise performance in 19 moderately impaired patients with CHF (Weber class A, B, and C) compared with 19 matched healthy control (HC) subjects by measuring skeletal muscle oxygenation (SmO2) changes during cycling exercise. All subjects performed two subsequent moderate-intensity 6-min exercise tests (bouts 1 and 2) with measurements of pulmonary oxygen uptake kinetics and SmO2 using near-infrared spatially resolved spectroscopy at the vastus lateralis for determination of absolute oxygenation values, amplitudes, kinetics (mean response time for onset), and deoxygenation overshoot characteristics. In CHF, deoxygenation kinetics were slower compared with HC (21.3 ± 5.3 s vs. 16.7 ± 4.4 s, P < 0.05, respectively). After priming exercise (i.e., during bout 2), deoxygenation kinetics were accelerated in CHF to values no longer different from HC (16.9 ± 4.6 s vs. 15.4 ± 4.2 s, P = 0.35). However, priming did not speed deoxygenation kinetics in CHF subjects with a deoxygenation overshoot, whereas it did reduce the incidence of the overshoot in this specific group (P < 0.05). These results provide evidence for heterogeneity with respect to limitations of O2 delivery and utilization during moderate-intensity exercise in patients with CHF, with slowed deoxygenation kinetics indicating a predominant O2 utilization impairment and the presence of a deoxygenation overshoot, with a reduction after priming in a subgroup, indicating an initial O2 delivery to utilization mismatch.

Effects of high-intensity interval training on central haemodynamics and skeletal muscle oxygenation during exercise in patients with chronic heart failure.

Background High-intensity interval training (HIT) improves exercise capacity in patients with chronic heart failure (CHF). Moreover, HIT was associated with improved resting cardiac function. However, the extent to which these improvements actually contribute to training-induced changes in exercise capacity remains to be elucidated. Therefore, we evaluated the effects of HIT on exercising central haemodynamics and skeletal muscle oxygenation. Methods Twenty-six CHF patients were randomised to a 12-week 4 × 4 minute HIT program at 85-95% of peak VO2 or usual care. Patients performed maximal and submaximal cardiopulmonary exercise testing with simultaneous assessment of cardiac output and skeletal muscle oxygenation by near infrared spectroscopy, using the amplitude of the tissue saturation index (TSIamp). Results Peak workload increased by 11% after HIT ( p between group = 0.01) with a non-significant increase in peak VO2 (+7%, p between group = 0.19). Cardiac reserve increased by 37% after HIT ( p within group = 0.03, p between group = 0.08); this increase was not related to improvements in peak workload. Oxygen uptake recovery kinetics after submaximal exercise were accelerated by 20% ( p between group = 0.02); this improvement was related to a decrease in TSIamp ( r = 0.71, p = 0.03), but not to changes in cardiac output kinetics. Conclusion HIT induced improvements in maximal exercise capacity and exercising haemodynamics at peak exercise. Improvements in recovery after submaximal exercise were associated with attenuated skeletal muscle deoxygenation during submaximal exercise, but not with changes in cardiac output kinetics, suggesting that the effect of HIT on submaximal exercise capacity is mediated by improved microvascular oxygen delivery-to-utilisation matching.

The relation between cardiac output kinetics and skeletal muscle oxygenation during moderate exercise in moderately impaired patients with chronic heart failure.

Oxygen uptake (V̇o2) kinetics are prolonged in patients with chronic heart failure (CHF). This may be caused by impaired oxygen delivery or skeletal muscle derangements. We investigated whether impaired cardiac output (Q̇) kinetics limit skeletal muscle oxygen delivery relative to the metabolic demands at submaximal exercise in CHF patients by evaluating the relation between Q̇ kinetics and skeletal muscle deoxygenation. Forty-three CHF patients, NYHA II-III, performed a constant-load exercise test at 80% of the ventilatory aerobic threshold (VAT) to assess V̇o2 kinetics (τV̇o2). Q̇ kinetics (τQ̇) were assessed by a radial artery pulse contour analysis method. Skeletal muscle deoxygenation was assessed by near infrared spectroscopy at the m. vastus lateralis, using the minimal value of the tissue saturation index during onset of exercise (TSImin). Patients were categorized in slow and normal Q̇ responders relative to metabolic demands (τQ̇/V̇o2 ≥1 and τQ̇/V̇o2 <1, respectively), τQ̇ (62 ± 29 s), and τV̇o2 (60 ± 21 s) were significantly related (r = 0.66, P = 0.001). There was a significant correlation between τQ̇ and TSImin in the slow Q̇ responders [rs= -0.57, P = 0.005, n = 22 (51%)]. In conclusion, in moderately impaired CHF patients with relatively slow Q̇ kinetics, central hemodynamics may limit skeletal muscle oxygenation during moderate-intensity exercise.

Characterization of exercise limitations by evaluating individual cardiac output patterns: a prospective cohort study in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) suffer from exercise intolerance due to impaired central hemodynamics and subsequent alterations in peripheral skeletal muscle function and structure. The relative contribution of central versus peripheral factors in the reduced exercise capacity is still subject of debate. The main purpose was to investigate heterogeneity in the nature of exercise intolerance by evaluating individual cardiac output (Q) patterns. The secondary purpose was to evaluate whether patient and disease characteristics were associated with a central hemodynamic exercise limitation. METHODS: Sixty-four stable CHF patients performed a symptom limited incremental exercise test with respiratory gas analysis and simultaneous assessment of Q, using a radial artery pulse contour analysis method. A central hemodynamic exercise limitation was defined as a plateau or decline in Q from 90 to 100 % of exercise duration. RESULTS: Data from 61 patients were analyzed. A central hemodynamic exercise limitation was observed in 21 patients (34 %). In these patients, a higher occurrence of a plateau/decrease in oxygen uptake (VO2) (52 % vs 23 %, p = 0.02), stroke volume (SV) (100 % vs. 75 %, p = 0.01) and chronotropic incompetence (31 % vs. 2.5 %, p = 0.01) was observed, while presence of a left bundle branch block (LBBB) occurred significantly less (19 % vs 48 %, p = 0.03) There was no difference in disease characteristics such as etiology, duration, NYHA class, mitral regurgitation or ischemia. CONCLUSIONS: The study revealed considerable heterogeneity in the nature of exercise limitations between moderately impaired CHF patients. In one third of the study population a plateau or decrease in Q towards peak exercise was demonstrated, which is indicative of a central hemodynamic exercise limitation. A central hemodynamic exercise limitation was associated with an impairment to augment stroke volume and heart rate.

Causes of nonlinearity of the oxygen uptake efficiency slope: a prospective study in patients with chronic heart failure.

BACKGROUND: The oxygen uptake efficiency slope (OUES) is an exercise parameter with strong prognostic value in the heart failure population. Yet, the optimal determination method of OUES remains unclear. The purpose of the present study was to investigate the influence of the ventilatory anaerobic threshold (VAT) and occurrence of a plateau in oxygen uptake (VO2) on determination of OUES from submaximal exercise data in patients with chronic heart failure (CHF). METHODS AND RESULTS: Ninety-eight CHF patients (New York Heart Association class II-III) were included. All patients performed a symptom-limited exercise test with gas exchange analysis on a cycle ergometer. VAT was determined by the V-slope method and OUES was derived via least-squares linear regression using 100% (OUES100), 90% (OUES90), and 75% (OUES75) of exercise duration, and, in addition, by using only the first 50% of data points preceding VAT (OUES½VAT), all data preceding VAT (OUESVAT), and only data following VAT (OUESpostVAT). Whereas OUESVAT (1720 ± 430 ml/min/log(l/min)), OUES75 (1811 ± 476 ml/min/log(l/min)), and OUESpostVAT (1742 ± 564 ml/min/log(l/min)) were not significantly different from OUES100 (1767 ± 542 ml/min/log(l/min)), OUES½VAT (1500 ± 314 ml/min/log(l/min)) was significantly lower than all other values (p < 0.01). When a VO2 plateau was present, OUES100 was lower than OUES90 (p < 0.05). CONCLUSIONS: The study results indicate that OUES values should be interpreted with caution when CHF patients do not reach the ventilatory anaerobic threshold or when a VO2 plateau is present.