Effect of Acute β-blocker Withholding on Ventilatory Efficiency in Patients With Advanced Chronic Heart Failure

doi:10.1016/j.cardfail.2010.02.006

Journal of Cardiac Failure

Volume 16, Issue 7, July 2010, Pages 548-555

https://doi.org/10.1016/j.cardfail.2010.02.006 Get rights and content

Abstract

Background

This is the first study to examine the effect of acute (24-hour) β-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure (CHF) during maximal incremental treadmill cardiopulmonary exercise test.

Methods and Results

Seventeen CHF patients were studied either 3 hours after administration of β-blocker (BB_ON) or 27 hours after the last β-blocker ingestion (BB_OFF). The ventilatory efficiency was measured via the slope of the linear relationship between ventilation (V′_E) and carbon dioxide production (V′CO₂) (ie, V′_E/V′CO₂ slope). Measurements were also made at rest, anaerobic threshold (AT), maximal end-tidal pressure for carbon dioxide (P_ETCO_2max), respiratory compensation point (RC), and peak exercise. Compared with BB_ON, the V′_E/V′CO₂ slope was significantly increased during BB_OFF (30.8 ± 7.4 vs. 29.1 ± 5.4, P = .04). At peak exercise, oxygen uptake (V′O₂, 16.0 ± 2.7 vs. 15.6 ± 2.8 mL·kg·min) and V′CO₂ (1458 ± 459 vs. 1414 ± 429 mL/min) were not different between the 2 conditions, whereas V′_E was higher during BB_OFF (49.5 ± 10.7 vs. 46.1 ± 9.6 L/min, P = .04). No differences were noted at AT and RC in V′O₂, V′CO₂, V′_E, V′_E/V′O₂, and V′_E/V′CO₂ ratios during the 2 conditions. At P_ETCO_2max, used to noninvasively estimate the CO₂ set point, V′_E was higher (33.9 ± 7.6 vs. 31.7 ± 7.3 L/min, P = .002) and P_ETCO₂ was lower (37.4 ± 4.8 vs. 38.5 ± 4.0 mm Hg, P = .03), whereas V′CO₂ was unchanged (1079 ± 340 vs. 1050 ± 322 mL/min) during BB_OFF.

Conclusion

Acute β-blocker withholding resulted in decreased ventilatory efficiency mostly from an increase of V′CO₂-independent regulation of V′_E and less likely from a change in ventilation/perfusion mismatching.

Section snippets

Subjects

All patients with advanced systolic CHF, in New York Heart Association Class II-IV, on stable medical therapy including β-blockers for at least 3 months referred for cardiopulmonary exercise tolerance testing (CPET) were screened for participation in the study from March 2008 through December 2008. Patients with atrial fibrillation, inability to exercise, hospital admission for heart failure, or acute coronary syndrome in the past 90 days or with symptoms of myocardial ischemia were excluded.

Results

Subjects' characteristics are summarized in Table 1.

Discussion

The main findings of this study are as follows. 1) Acute β-blocker withholding worsened ventilatory efficiency in CHF patients during exercise; 2) acute β-blocker withholding did not modify the ventilation/perfusion mismatching during exercise; 3) acute β-blocker withholding was associated with an increase of reflex regulation of V′_E (V′CO₂-independent); and 4) correlative analysis did not show an association between change in peak HR and change in peak V′_E or in V′_E/V′CO₂ slope.

Based on Weber

Limitations

The number of patients of the present study is limited; therefore, we must be very circumspect in any generalization of our findings to the larger CHF population. The lack of measurement of central hemodynamics and PaCO₂ during exercise precludes a definitive assessment of the effect of acute (24-hour) β-blocker withholding on ventilation/perfusion mismatching and on regulation of CO₂ set point during exercise. Our use of unpublished data to evaluate a unified mechanism is somewhat unusual.

Conclusion

The current study extends previous studies on the physiological mechanisms of β-blocker efficacy by exploring the interaction between the ventilatory efficiency and ventilation/perfusion mismatching and regulation of CO₂ set point during exercise. Our results suggest that both acute and chronic β-blocker withholding produce decreased ventilatory efficiency, mostly from an increase of V′CO₂-independent regulation of V′_E and less likely from a change in ventilation/perfusion mismatching. Further

Disclosures

None.

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Elevated exercise ventilation in mild COPD is not linked to enhanced central chemosensitivity
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As in previous studies, PETCO2 was consistently reduced at rest and exercise in mild COPD (Ofir et al., 2008; Elbehairy et al., 2015a). Further, the maximal PETCO2 value obtained during CPET, which is considered a non-invasive index of the CO2 set point (Laveneziana et al., 2010; Weatherald et al., 2020), was consistently lower in patients. If the higher ventilatory output in COPD principally reflects a compensation by the intact respiratory controller for high physiological dead space, then PETCO2 should not be lower at rest and throughout exercise than in healthy controls.
The purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇_E/V̇CO₂) response during exercise in mild chronic obstructive pulmonary disease (COPD).
Twenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇_EB), the central chemoreflex ventilatory recruitment threshold for CO₂ (VRTCO₂), and central chemoreflex sensitivity (V̇_ES) were assessed using the modified Duffin’s CO₂ rebreathing method. Resting arterialized blood gas data were also obtained.
At standardized exercise intensities, absolute V̇_E and V̇_E/V̇CO₂ were consistently elevated and the end-tidal partial pressure of CO₂ was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇_E, VRTCO₂, or V̇_ES (all p > 0.05).
These data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity.
Gas Exchange and Ventilatory Efficiency During Exercise in Pulmonary Vascular Diseases
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Our results suggest that an altered CO2 setpoint could play an important role. Indeed, maximal exercise performance was most highly related to the maximal PETCO2 value between the AT and RCP, an indicator of the CO2 setpoint,15–17 in the overall population and in hypocapnic patients, but not normocapnic patients. The normocapnic patients still had reduced peak exercise capacity but likely are limited by other mechanisms than impaired gas exchange or ventilatory inefficiency.
Ventilatory inefficiency (high V′_E/V′CO₂) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO₂ suggests increased chemosensitivity or an altered PaCO₂ set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO₂ set-point, exercise capacity, hemodynamics and V′_E/V′CO₂.
Pulmonary arterial hypertension (n = 34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO₂: hypocapnic (PaCO₂ ≤34 mmHg) or normocapnic (PaCO₂ 35–45 mmHg). The PaCO₂ set-point was estimated by the maximal value of end-tidal PCO₂ (maximal P_ETCO₂) between the anaerobic threshold and respiratory compensation point.
The hypocapnic group (n = 39) had lower resting cardiac index (3.1 ±0.8 vs. 3.7 ±0.7 L/min/m², p < 0.01), lower peak V′O₂ (15.8 ± 3.5 vs. 20.7 ± 4.3 mL/kg/min, p < 0.01), and higher V′_E/V′CO₂ slope (60.6 ± 17.6 vs. 38.2 ± 8.0, p < 0.01). At peak exercise, hypocapic patients had lower PaO₂, higher V_D/V_T and higher P_(a-ET)CO₂. Maximal P_ETCO₂ (r = 0.59) and V_D/V_T (r = −0.59) were more related to cardiac index than PaO₂ or PaCO₂ at rest or peak exercise. Maximal P_ETCO₂ was the strongest correlate of V′_E/V′CO₂ slope (r = −0.86), peak V′O₂ (r = 0.64) and peak work rate (r = 0.49).
Resting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO₂ set-point. Maximal P_ETCO₂ may be a useful non-invasive marker of PaCO₂ setpoint and disease severity even with submaximal effort.
La ineficiencia ventilatoria (V’_E/V’CO₂ alta) y la hipocapnia en reposo son comunes en la enfermedad vascular pulmonar y se asocian con un mal pronóstico. La PaCO₂ baja en reposo sugiere una mayor quimiosensibilidad o una alteración en el ajuste fisiológico de la PaCO₂. Nuestro objetivo fue determinar las relaciones entre las variables de intercambio de gases que reflejan el ajuste de la PaCO₂ durante el ejercicio, la capacidad de ejercicio, la hemodinámica y la V’_E/V’CO₂.
Se realizaron mediciones de gases en sangre arterial durante las pruebas de ejercicio cardiopulmonar a pacientes con hipertensión arterial pulmonar (n = 34), hipertensión pulmonar tromboembólica crónica (HPTEC, n = 19) y enfermedad venooclusiva pulmonar (EVOP, n = 6). Los pacientes se agruparon de acuerdo con su PaCO₂ en reposo: hipocapnia (PaCO₂ ≤34 mmHg) o normocapnia (PaCO₂ 35–45 mmHg). El ajuste de la PaCO₂ se estimó mediante el valor máximo de PCO₂ exhalado (P_ETCO₂ máximo) entre el umbral anaeróbico y el punto de compensación respiratoria.
El grupo hipocápnico (n = 39) tenía un índice cardíaco en reposo más bajo (3,1 ± 0,8 vs. 3,7 ± 0,7 L/min/m², p< 0,01), un pico de V’O₂ más bajo (15,8 ± 3,5 vs 20,7 ± 4,3 mL/kg/min, p< 0,01), y mayor pendiente de V’_E/V’CO₂ (60,6 ± 17,6 vs. 38,2 ± 8,0, p< 0,01). En el punto de ejercicio máximo, los pacientes hipocápnicos tenían una PaO₂ más baja, un V_D/V_T más alto y una P_(a-ET) CO₂ más alta. La P_ETCO₂ máxima (r = 0,59) y la V_D/V_T (r = -0,59) estaban más relacionadas con el índice cardíaco que la PaO₂ o la PaCO₂ en reposo o en el punto de máximo esfuerzo. La P_ETCO₂ máxima fue la que mayor correlación tuvo con la pendiente V’_E/V’CO₂ (r = -0,86), la V’O₂ máxima (r = 0.64) y la tasa de esfuerzo máximo (r = 0,49).
La hipocapnia en reposo se asocia a una peor función cardíaca, una mayor ineficiencia ventilatoria y una capacidad disminuída de ejercicio. Esto podría explicarse por una quimiosensibilidad elevada y un ajuste fisiológico más bajo de la PaCO₂. La P_ETCO₂ máxima puede ser un marcador no invasivo útil del ajuste de PaCO₂ y la gravedad de la enfermedad incluso con un esfuerzo submáximo.
Ventilatory efficiency and breathing pattern in world-class cyclists: A three-year observational study
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Citation Excerpt :
During incremental effort, the slope of the linear relationship between VE and VCO2 (VE/VCO2 slope or DeltaCO2) is the most widely used method to evaluate ventilatory efficiency (Arena et al., 2007b; Brown et al., 2013; Schneider and Berwick, 1998; Sun et al., 2002; Ukkonen et al., 2008). The VE/VCO2 slope has been commonly used in patients suffering from congestive heart failure (Arena et al., 2007a,b; Ingle et al., 2007; Laveneziana et al., 2010; Robertson, 2011) as well as in healthy subjects (Sun et al., 2002). It is well established that the values of the VE/VCO2 slope vary from 19 to 32 in healthy subjects (Sun et al., 2002), with values exceeding 34 considered abnormal (Arena et al., 2007a,b) or indicative of the inefficiency of the respiratory system (Brown et al., 2013).
The purpose of this three-year observational study was to analyze the ventilatory efficiency and breathing pattern in world-class professional cyclists. Twelve athletes (22.61 ± 3.8 years; 177.38 ± 5.5 cm; 68.96 ± 5.5 kg and VO_2max 75.51 ± 3.3mL kg⁻¹ min⁻¹) were analyzed retrospectively. For each subject, respiratory and performance variables were recorded during incremental spiroergometry: oxygen uptake (VO₂), carbon dioxide output (VCO₂), pulmonary ventilation (VE), tidal volume (Vt), breathing frequency (f_R), driving (Vt/Ti), timing (Ti/Ttot), peak power output (PPO) and maximum oxygen uptake (VO_2max). Ventilatory efficiency (VE/VCO₂ slope) was calculated from the beginning of exercise testing to the second ventilatory threshold (VT₂). The VE/VCO₂ slope was unaffected during the study period (24.63 ± 3.07; 23.61 ± 2:79; 24:89 ± 2:61) with a low effect size (ES = 0.04). The PPO improved significantly in the third year (365 ± 33.74; 386.36 ± 32.33; 415.00 ± 24.15) (p < 0.05). The breathing pattern variables, Vt/Ti and Ti/Ttot, did not change significantly over the three year period (ES = 0.00; ES = 0.03 respectively). These findings suggest that changes in cycling performance in world-class professional cyclists do not modify breathing variables related to the control of ventilatory efficiency.
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: Pierantonio Laveneziana, MD, pulmonologist, was supported by a Grant from Fondazione Don C. Gnocchi (Department of Pulmonary Rehabilitation), Florence, Italy.

: The results of this study were presented, in part, at the European Respiratory Society (ERS) Annual Congress (Vienna, September 2009).

: See page 554 for disclosure information.

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Clinical InvestigationEffect of Acute β-blocker Withholding on Ventilatory Efficiency in Patients With Advanced Chronic Heart Failure

Abstract

Background

Methods and Results

Conclusion

Section snippets

Subjects

Results

Discussion

Limitations

Conclusion

Disclosures

Am Heart J

Int J Cardiol

Am Heart J

Chest

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology

Heart

Impairment of ventilatory efficiency in heart failure: prognostic impact

Circulation

Comparison of the effects of carvedilol and metoprolol on exercise ventilatory efficiency in patients with congestive heart failure

Circ J

The effects of alpha and beta blockade on ventilatory responses to exercise in chronic heart failure

Heart

Long-term β-blockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol

Circulation

Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart

Circulation

In vivo demonstration of cardiac beta 2-adrenoreceptor sensitization by beta 1-antagonist treatment

Circ Res

Clinical Investigation
Effect of Acute β-blocker Withholding on Ventilatory Efficiency in Patients With Advanced Chronic Heart Failure