Clin Res Cardiol DOI 10.1007/s00392-014-0784-1
ORIGINAL PAPER
Cheyne-Stokes respiration in heart failure: friend or foe? Hemodynamic effects of hyperventilation in heart failure patients and healthy volunteers Olaf Oldenburg • Jens Spießho¨fer • Henrik Fox Thomas Bitter • Dieter Horstkotte
•
Received: 11 April 2014 / Accepted: 24 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective In patients with heart failure (HF), CheyneStokes respiration (CSR) is characterized by chronic hyperventilation (HV) with low arterial partial pressure of carbon dioxide (pCO2). It is still unclear whether this HV represents a compensatory response to HF or an independent comorbidity. This study investigated the hemodynamic effects of HV in HF patients and volunteers. Methods A total of 15 volunteers [13 male, 25 ± 4 years, brain natriuretic peptide (BNP) \49 pg/mL, left ventricular rejection fraction (LVEF) [55 %) and 20 HF patients with reduced LVEF (15 male, 67.7 ± 12 years, NYHA class 2.6 ± 0.6, BNP 790 ± 818 pg/mL, LVEF 32.4 ± 7.3 %) were enrolled. Hemodynamics was monitored noninvasively in volunteers (TaskForce Monitor, CNSystems) and invasively in HF patients. Results During HV, the transcutaneous CO2 pressure in volunteers decreased from 38.7 ± 2.5 to 28.6 ± 3.3 mmHg (p \ 0.001) and pCO2 in HF patients decreased from 33.6 ± 3.7 to 22.2 ± 3.2 mmHg (p \ 0.001). There was a significant increase in cardiac output (CO) in both volunteers (6.2 ± 1.3–7.5 ± 1.3 L/min, p \ 0.001) and HF patients (4.4 ± 1.3–5.0 ± 1.3 L/min), mainly as a result of an increase in heart rate (67.4 ± 7.6–82.8 ± 10.9/ min, p \ 0.001; and 77.2 ± 17.7–86.2 ± 22.4/min, p \ 0.001, respectively); stroke volume (SV) was unchanged in volunteers (93.7 ± 19.6–93.8 ± 21.4 mL) O. Oldenburg and J. Spießho¨fer contributed equally. O. Oldenburg (&) J. Spießho¨fer H. Fox T. Bitter D. Horstkotte Department of Cardiology, Heart and Diabetes Center NRW, University Hospital, Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany e-mail: [email protected]; [email protected]
and only slightly increased in HF patients (64.4 ± 28.7–68.5 ± 23.2 mL). Conclusions CSR with associated HV may be a compensatory mechanism in patients with a failing heart. This compensatory mechanism includes an increase in heart rate, which might be deleterious in the long run. Keywords Hyperventilation Heart failure Hemodynamics Cheyne-Stokes respiration
Introduction Sleep-disordered breathing (SDB) and central sleep apnea (CSA) with Cheyne-Stokes respiration (CSR) are highly prevalent comorbidities in patients with heart failure (HF) [1, 2]. In contrast to obstructive sleep apnea (OSA), CSA with CSR is characterized by chronic hyperventilation (HV) and low carbon dioxide (pCO2) levels [3–5]. While the pathophysiology of this hyperventilation remains complex and is not wellunderstood, markedly augmented respiratory drive is a key element in the typical crescendo ventilation pattern which then causes a further fall in pCO2 below the apneic threshold [6, 7]. Current debate focuses on whether HV in HF patients represents a compensatory response of the failing heart or an independent risk factor [8, 9]. Recent studies in HF patients have shown that CSR has an independent prognostic impact on mortality [10–12]. Although the physiologic effects of HV and hypocapnia in healthy volunteers are known [13], the hemodynamic effects of HV and resulting hypocapnia in HF patients in general, and in those treated according to current guidelines in particular, are unknown. This study investigates the hemodynamic effects of voluntary HV in healthy volunteers and in patients with HF.
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Methods Study participants Healthy volunteers (medical students aged [18 years with no history of any cardiac disease, normal electro- and echocardiogram findings, and without any medication) and consecutive HF patients [New York Heart Association (NYHA) class CII; left ventricular ejection fraction (LVEF) B45 %] were eligible for inclusion in this study. The study protocol was approved by the local ethics committee, and all patients and volunteers gave written informed consent to participate in the trial. The study was carried out in accordance with the Declaration of Helsinki. Study protocol Both volunteers and HF patients were advised to hyperventilate using deep breaths and a breathing frequency of [20/min until intolerable symptoms of HV occurred. To verify and quantify HV and hypocapnia, transcutaneous carbon dioxide pressure (PtcCO2) was monitored in volunteers (V-StatsTM3.00, SenTec AG, Therwil, Switzerland) and blood gas analysis using aortic blood samples was undertaken in HF patients. Hemodynamic measurements Hemodynamics were measured at baseline and at the end of the HV period using non-invasive methods in volunteers (Task Force Monitor, CNSystems, Graz, Austria) and invasive methods, including combined right and left heart catheterization, in HF patients (who all had independent indications for catheterization). Non-invasive continuous hemodynamic monitoring using the TaskForceÒ device has been described previously [14] and included calibrated beat-to-beat blood pressure and transthoracic impedance measurements, allowing estimation of cardiac stroke volume (SV) and systemic vascular resistance (SVR). This system has shown good validity, especially by analyzing intra-individual changes in hemodynamics and stroke volume in particular [15–17]. In addition, BP variability (BPV; sampling rate of 100 Hz) and HR variability (HRV; sampling rate of 1,000 Hz) were assessed. Based on these recordings, sympathetic nervous activity was analyzed using the lowfrequency component of diastolic BPV (0.04–0.15 Hz; LFnudBP), while parasympathetic nervous activity was analysed using the high-frequency component of HRV (0.15–0.4 Hz; HFnuRRI), respectively [18–20]. Invasive hemodynamic measurements were performed using a standard Swan-Ganz catheter for right heart catheterization as well as a pig-tail catheter for aortic and/or
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left ventricular measurements, including mean right atrial (RAP) pressure, right ventricular end-diastolic pressure (RVEDP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), mean aortic pressure (MAP) and, in some cases, left ventricular enddiastolic pressure (LVEDP). Cardiac output (CO) was determined using standard thermodilution method as described previously [21]. Pulmonary vascular resistance (PVR) and SVR were calculated using measured hemodynamic data. Statistical analysis All data are expressed as mean ± standard deviation (SD). A paired t test was used to compare the hemodynamic effects of hyperventilation with baseline. Mann–Whitney Rank Sum test was used if data did not have a normal distribution. Pearson correlation was employed to correlate hyperventilation induced percent changes in PtcCO2 with corresponding percent changes in hemodynamic parameters. A p value of B0.05 was considered to be statistically significant. Results A total of 15 healthy volunteers and 20 consecutive HF patients were enrolled. Demographic and clinical data for all subjects are summarized in Table 1. In volunteers, PtcCO2 fell from 39 ± 3 mmHg to 29 ± 3 mmHg (p \ 0.001) within 3 ± 1 min of voluntary HV (Fig. 1). HF patients terminated voluntary HV after all Table 1 Subject demographic data and clinical characteristics at baseline Healthy volunteers (n = 15)
Heart failure patients (n = 20)
Male, n (%)
13 (87)
15 (75)
Age, years (mean ± SD)
25 ± 4
67 ± 12
NYHA class (mean ± SD)
–
2.6 ± 0.6
LVEF, % (mean ± SD)
Normala
32 ± 7
BNP, pg/mL (mean ± SD)
\10
790 ± 818
Medication, n (%) ACEI/ARB
–
20 (100)
b-Blocker
–
18 (90)
Diuretics
–
12 (60)
Aldosterone antagonists
–
13 (65)
ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, BNP brain natriuretic peptide, LVEF left ventricular ejection fraction, NYHA New York Heart Association, SD standard deviation a
Normal LVEF was defined as [55 %
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Fig. 1 Acute hemodynamic effects of voluntary hypertentilation in healthy volunteers (left bars) and heart failure patients (right bars). Hyperventilation leads to a significant increase in heart rate in healthy volunteers and heart failure patients, accompanied by an increase in
cardiac output and a decrease in systemic vascular resistance. No significant changes were observed regarding a change in stroke volume
hemodynamic measurements had been taken (after 5.5 ± 2 min). During this period, aortal blood pH increased from 7.439 ± 0.025 to 7.562 ± 0.062, oxygen pressure (pO2) from 78.6 ± 11.5 to 113.1 ± 17 mmHg, and oxygen saturation from 95.9 ± 1.9 to 98.9 ± 1.0 %, while pCO2 decreased from 33.6 ± 3.7 to 22.2 ± 3.2 mmHg (p \ 0.001 vs baseline for all comparisons). HV was associated with an increase in CO in both volunteers and HF patients (Table 2). This increase was mainly a result of an increase in heart rate. Despite of a decrease in vascular resistance, SV during HV was unchanged in volunteers, whereas there was a trend towards a slight increase of SV in HF patients.
heart rate with little or no effect on SV. Thus, hyperventilation as seen in CSR might be a compensatory, but possibly deleterious, mechanism of the failing heart. CSR is characterized by typical episodes of a crescendo and decrescendo in respiratory tidal volume alternating with central apnea or hypopnea [22]. The net effect is hyperventilation with hypocapnia [2, 5]. While the effects of HV and hypocapnia in healthy volunteers have been studied previously [13, 23], hemodynamic changes during HV in patients with HF, both overall and in those receiving therapy based on current treatment guidelines have not been clearly defined. Our results show that hemodynamic changes induced by HV are comparable in volunteers and HF patients: hyperventilation was associated with a significant increase in CO, mainly based on an increase in heart rate, even in HF patients receiving b-blocking agents. In accordance with the physiologic studies of Burnum et al. [24, 25], this study documented an increase in HR and CO during HV in healthy volunteers, with a parallel
Discussion HV in healthy volunteers and in patients with HF is associated with an increase in CO, largely due to an increase in
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Clin Res Cardiol Table 2 Hemodynamic effects of hyperventilation in healthy volunteers and heart failure patients Baseline
Hyperventilation
p value
Healthy volunteers Heart rate, min-1
\0.001
67 ± 8
83 ± 11
Systolic BP, mmHg
136 ± 15
127 ± 16
0.007
Diastolic BP, mmHg
82 ± 10
75 ± 10
\0.001
Stroke volume, mL
94 ± 20
94 ± 21
0.984
Cardiac output, L/min
6.2 ± 1.3
7.8 ± 1.9
\0.001
1,334 ± 313 47.1 ± 8.2
1,026 ± 222 45.6 ± 8.2
\0.001 0.523
52.9 ± 14.0
36.0 ± 16.7
0.003
1.5 ± 0.2
1.0 ± 0.3
0.002
SVR, dyne sec cm-5 LFnudBP, % HFnuRRI, % LFnudBP (%)/ HFnuRRI (%) Heart failure patients Heart rate, min-1
75.4 ± 16.7
84.8 ± 21.3
0.001
MAP, mmHg
87.5 ± 14.4
88.5 ± 13.6
0.654
Stroke volume, mL
64.4 ± 28.7
68.5 ± 23.2
0.241 0.002
Cardiac output, L/min
4.4 ± 1.3
5.0 ± 1.3
PVR, dyne sec cm-5
172 ± 68
119 ± 82
0.027
SVR, dyne sec cm-5
1,536 ± 316
1,353 ± 430
0.003
8.0 ± 6.3 8.1 ± 5.2
7.5 ± 6.8 7.8 ± 5.4
0.558 0.813
RAP mean, mmHg RVEDP, mmHg PAP mean, mmHg
25.7 ± 9.4
22.8 ± 11.3
0.104
PCWP, mmHg
16.8 ± 10.1
16.5 ± 10.1
0.826
LVEDP, mmHg (n = 7)
23.9 ± 9.0
21.4 ± 5.5
0.294
Values are mean ± standard deviation BP blood pressure, HFnuRRI high-frequency component of heart rate variability, LFnudBP low-frequency component of diastolic blood pressure variability, LVEDP left ventricular end-diastolic pressure, MAP mean aortic pressure, PA pulmonary artery, PCWP pulmonary capillary wedge pressure, PVR peripheral vascular resistance, RA right atrial, SVR systemic vascular resistance
decrease in BP and SVR. The exact physiology underlying these changes is still a topic of debate: HV leads to a decrease in pCO2 and increase in pH which might have a direct or an indirect centrally mediated vasodilatory effect [24–26]. In addition, the effect of HV might be time dependent, with a slight fall in BP within the first seconds [27], a return to baseline values within the first few minutes [27], and an increase with ongoing HV [23]. Analyzing the balance between sympathetic nerve activity (SNA; LFnudBP) and parasympathetic nervous activity (PNA; HFnuRRI) in this cohort of healthy volunteers suggest that the decrease in SVR recorded is based on a net shift towards vagal tone. This, in turn, could have contributed to the increase in heart rate, leading to increased CO. Obviously; it was primarily the significant increase in heart rate that contributed to the elevated CO in the volunteers, rather than a direct effect on SV.
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However, in the failing heart CO and SV in particular are highly dependent on cardiac pre- and afterload [28]. In the HF patients studied, HV did not appear to have a significant impact on either right or left ventricular preload. In contrast, both right- (PVR) and left (SVR) ventricular afterload decreased significantly, and there was no significant change in either pulmonary artery or MAPs. It should be assumed that an increase in MAP would have a significant impact on SV [28]. In this study, only a trend towards an increase in SV was documented in HF patients exclusively, while changes in heart rate from baseline during HV were highly significant in heart failure patients and healthy volunteers. The results of this study do not allow the mechanisms for the observed hemodynamic changes in patients with HF to be determined, but a similar pathophysiology as discussed in healthy volunteers might be conceivable. Recently, Yumino et al. [29] investigated the effects of obstructive and central respiratory events (apneas and hypopneas) in a cohort of HF patients with SDB. While obstructive events were accompanied by a decrease in SV and CO, central hypopneas and apneas were associated with no or little change in these parameters. The authors also claimed a more pronounced increase in heart rate during obstructive compared with central respiratory events [29]. While these results and the method of hemodynamic monitoring used have been a topic of debate [8], the main difference compared with the current study is that Yumino et al. investigated hemodynamic effects during the sleep-related respiratory event (apnea or hypopnea), while this study investigated the net effect of HV. In this context, it would be interesting to analyze hemodynamics during the ventilatory phase after apneas or hypopneas. This study provides further insights into the physiology of hemodynamic changes during HV. The immediate effects of HV in heart failure patients were an increase in heart rate and a decrease in cardiac afterload resulting in an increase in cardiac output. Thus, this immediate effect of HV can be interpreted as a ‘‘cardioprotective’’ compensatory mechanism of the failing heart. Heart failure with resulting pulmonary congestion [21, 30] might trigger CSR, which is characterized by respiratory instability and chronic hyperventilation, to maintain cardiac output. In contrast, we documented a significant increase in heart rate, even in patients receiving b-blockers. This might be detrimental on the long-run and might at least explain in part the negative effect of CSR on survival in HF patients [10– 12, 31–33]. Indeed, an increased heart rate in HF patients has been shown to be related to an impaired prognosis [31– 36]. Based on results of this study it is possible that interventions to reduce CSR in patients with HF may have beneficial effects. One such intervention is adaptive
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servoventilation (ASV) therapy, which was especially designed to target chronic hyperventilation during CSR in HF. Preliminary small-scale studies have shown that ASV has positive effects on quality of life, respiratory stability, cardiac function and survival [4, 10, 37, 38]. In addition, a multicenter randomized controlled trial is underway to better characterize these potential benefits [39].
Limitations The present study investigates the hemodynamic effects of voluntary hyperventilation in healthy volunteers and heart failure patients. Hyperventilation represents a key element of respiratory instability in heart failure patients, resulting in nocturnal or even daytime CSR and/or excessive or oscillatory ventilation (EOV) during exercise, all accompanied by an impaired prognosis in heart failure [40, 41]. However, we performed a physiology experiment and investigated only short-term hemodynamic effects. Therefore, this study provides some new hints and generates some new hypothesis rather than giving final answer why CSR and hyperventilation might be detrimental in heart failure. Acknowledgments English language medical writing assistance was provided by Nicola Ryan, independent medical writer, on behalf of ResMed. Conflict of interest
There are no conflicts of interest to declare.
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ORIGINAL PAPER
Cheyne-Stokes respiration in heart failure: friend or foe? Hemodynamic effects of hyperventilation in heart failure patients and healthy volunteers Olaf Oldenburg • Jens Spießho¨fer • Henrik Fox Thomas Bitter • Dieter Horstkotte
•
Received: 11 April 2014 / Accepted: 24 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Objective In patients with heart failure (HF), CheyneStokes respiration (CSR) is characterized by chronic hyperventilation (HV) with low arterial partial pressure of carbon dioxide (pCO2). It is still unclear whether this HV represents a compensatory response to HF or an independent comorbidity. This study investigated the hemodynamic effects of HV in HF patients and volunteers. Methods A total of 15 volunteers [13 male, 25 ± 4 years, brain natriuretic peptide (BNP) \49 pg/mL, left ventricular rejection fraction (LVEF) [55 %) and 20 HF patients with reduced LVEF (15 male, 67.7 ± 12 years, NYHA class 2.6 ± 0.6, BNP 790 ± 818 pg/mL, LVEF 32.4 ± 7.3 %) were enrolled. Hemodynamics was monitored noninvasively in volunteers (TaskForce Monitor, CNSystems) and invasively in HF patients. Results During HV, the transcutaneous CO2 pressure in volunteers decreased from 38.7 ± 2.5 to 28.6 ± 3.3 mmHg (p \ 0.001) and pCO2 in HF patients decreased from 33.6 ± 3.7 to 22.2 ± 3.2 mmHg (p \ 0.001). There was a significant increase in cardiac output (CO) in both volunteers (6.2 ± 1.3–7.5 ± 1.3 L/min, p \ 0.001) and HF patients (4.4 ± 1.3–5.0 ± 1.3 L/min), mainly as a result of an increase in heart rate (67.4 ± 7.6–82.8 ± 10.9/ min, p \ 0.001; and 77.2 ± 17.7–86.2 ± 22.4/min, p \ 0.001, respectively); stroke volume (SV) was unchanged in volunteers (93.7 ± 19.6–93.8 ± 21.4 mL) O. Oldenburg and J. Spießho¨fer contributed equally. O. Oldenburg (&) J. Spießho¨fer H. Fox T. Bitter D. Horstkotte Department of Cardiology, Heart and Diabetes Center NRW, University Hospital, Ruhr University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany e-mail: [email protected]; [email protected]
and only slightly increased in HF patients (64.4 ± 28.7–68.5 ± 23.2 mL). Conclusions CSR with associated HV may be a compensatory mechanism in patients with a failing heart. This compensatory mechanism includes an increase in heart rate, which might be deleterious in the long run. Keywords Hyperventilation Heart failure Hemodynamics Cheyne-Stokes respiration
Introduction Sleep-disordered breathing (SDB) and central sleep apnea (CSA) with Cheyne-Stokes respiration (CSR) are highly prevalent comorbidities in patients with heart failure (HF) [1, 2]. In contrast to obstructive sleep apnea (OSA), CSA with CSR is characterized by chronic hyperventilation (HV) and low carbon dioxide (pCO2) levels [3–5]. While the pathophysiology of this hyperventilation remains complex and is not wellunderstood, markedly augmented respiratory drive is a key element in the typical crescendo ventilation pattern which then causes a further fall in pCO2 below the apneic threshold [6, 7]. Current debate focuses on whether HV in HF patients represents a compensatory response of the failing heart or an independent risk factor [8, 9]. Recent studies in HF patients have shown that CSR has an independent prognostic impact on mortality [10–12]. Although the physiologic effects of HV and hypocapnia in healthy volunteers are known [13], the hemodynamic effects of HV and resulting hypocapnia in HF patients in general, and in those treated according to current guidelines in particular, are unknown. This study investigates the hemodynamic effects of voluntary HV in healthy volunteers and in patients with HF.
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Methods Study participants Healthy volunteers (medical students aged [18 years with no history of any cardiac disease, normal electro- and echocardiogram findings, and without any medication) and consecutive HF patients [New York Heart Association (NYHA) class CII; left ventricular ejection fraction (LVEF) B45 %] were eligible for inclusion in this study. The study protocol was approved by the local ethics committee, and all patients and volunteers gave written informed consent to participate in the trial. The study was carried out in accordance with the Declaration of Helsinki. Study protocol Both volunteers and HF patients were advised to hyperventilate using deep breaths and a breathing frequency of [20/min until intolerable symptoms of HV occurred. To verify and quantify HV and hypocapnia, transcutaneous carbon dioxide pressure (PtcCO2) was monitored in volunteers (V-StatsTM3.00, SenTec AG, Therwil, Switzerland) and blood gas analysis using aortic blood samples was undertaken in HF patients. Hemodynamic measurements Hemodynamics were measured at baseline and at the end of the HV period using non-invasive methods in volunteers (Task Force Monitor, CNSystems, Graz, Austria) and invasive methods, including combined right and left heart catheterization, in HF patients (who all had independent indications for catheterization). Non-invasive continuous hemodynamic monitoring using the TaskForceÒ device has been described previously [14] and included calibrated beat-to-beat blood pressure and transthoracic impedance measurements, allowing estimation of cardiac stroke volume (SV) and systemic vascular resistance (SVR). This system has shown good validity, especially by analyzing intra-individual changes in hemodynamics and stroke volume in particular [15–17]. In addition, BP variability (BPV; sampling rate of 100 Hz) and HR variability (HRV; sampling rate of 1,000 Hz) were assessed. Based on these recordings, sympathetic nervous activity was analyzed using the lowfrequency component of diastolic BPV (0.04–0.15 Hz; LFnudBP), while parasympathetic nervous activity was analysed using the high-frequency component of HRV (0.15–0.4 Hz; HFnuRRI), respectively [18–20]. Invasive hemodynamic measurements were performed using a standard Swan-Ganz catheter for right heart catheterization as well as a pig-tail catheter for aortic and/or
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left ventricular measurements, including mean right atrial (RAP) pressure, right ventricular end-diastolic pressure (RVEDP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), mean aortic pressure (MAP) and, in some cases, left ventricular enddiastolic pressure (LVEDP). Cardiac output (CO) was determined using standard thermodilution method as described previously [21]. Pulmonary vascular resistance (PVR) and SVR were calculated using measured hemodynamic data. Statistical analysis All data are expressed as mean ± standard deviation (SD). A paired t test was used to compare the hemodynamic effects of hyperventilation with baseline. Mann–Whitney Rank Sum test was used if data did not have a normal distribution. Pearson correlation was employed to correlate hyperventilation induced percent changes in PtcCO2 with corresponding percent changes in hemodynamic parameters. A p value of B0.05 was considered to be statistically significant. Results A total of 15 healthy volunteers and 20 consecutive HF patients were enrolled. Demographic and clinical data for all subjects are summarized in Table 1. In volunteers, PtcCO2 fell from 39 ± 3 mmHg to 29 ± 3 mmHg (p \ 0.001) within 3 ± 1 min of voluntary HV (Fig. 1). HF patients terminated voluntary HV after all Table 1 Subject demographic data and clinical characteristics at baseline Healthy volunteers (n = 15)
Heart failure patients (n = 20)
Male, n (%)
13 (87)
15 (75)
Age, years (mean ± SD)
25 ± 4
67 ± 12
NYHA class (mean ± SD)
–
2.6 ± 0.6
LVEF, % (mean ± SD)
Normala
32 ± 7
BNP, pg/mL (mean ± SD)
\10
790 ± 818
Medication, n (%) ACEI/ARB
–
20 (100)
b-Blocker
–
18 (90)
Diuretics
–
12 (60)
Aldosterone antagonists
–
13 (65)
ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, BNP brain natriuretic peptide, LVEF left ventricular ejection fraction, NYHA New York Heart Association, SD standard deviation a
Normal LVEF was defined as [55 %
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Fig. 1 Acute hemodynamic effects of voluntary hypertentilation in healthy volunteers (left bars) and heart failure patients (right bars). Hyperventilation leads to a significant increase in heart rate in healthy volunteers and heart failure patients, accompanied by an increase in
cardiac output and a decrease in systemic vascular resistance. No significant changes were observed regarding a change in stroke volume
hemodynamic measurements had been taken (after 5.5 ± 2 min). During this period, aortal blood pH increased from 7.439 ± 0.025 to 7.562 ± 0.062, oxygen pressure (pO2) from 78.6 ± 11.5 to 113.1 ± 17 mmHg, and oxygen saturation from 95.9 ± 1.9 to 98.9 ± 1.0 %, while pCO2 decreased from 33.6 ± 3.7 to 22.2 ± 3.2 mmHg (p \ 0.001 vs baseline for all comparisons). HV was associated with an increase in CO in both volunteers and HF patients (Table 2). This increase was mainly a result of an increase in heart rate. Despite of a decrease in vascular resistance, SV during HV was unchanged in volunteers, whereas there was a trend towards a slight increase of SV in HF patients.
heart rate with little or no effect on SV. Thus, hyperventilation as seen in CSR might be a compensatory, but possibly deleterious, mechanism of the failing heart. CSR is characterized by typical episodes of a crescendo and decrescendo in respiratory tidal volume alternating with central apnea or hypopnea [22]. The net effect is hyperventilation with hypocapnia [2, 5]. While the effects of HV and hypocapnia in healthy volunteers have been studied previously [13, 23], hemodynamic changes during HV in patients with HF, both overall and in those receiving therapy based on current treatment guidelines have not been clearly defined. Our results show that hemodynamic changes induced by HV are comparable in volunteers and HF patients: hyperventilation was associated with a significant increase in CO, mainly based on an increase in heart rate, even in HF patients receiving b-blocking agents. In accordance with the physiologic studies of Burnum et al. [24, 25], this study documented an increase in HR and CO during HV in healthy volunteers, with a parallel
Discussion HV in healthy volunteers and in patients with HF is associated with an increase in CO, largely due to an increase in
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Clin Res Cardiol Table 2 Hemodynamic effects of hyperventilation in healthy volunteers and heart failure patients Baseline
Hyperventilation
p value
Healthy volunteers Heart rate, min-1
\0.001
67 ± 8
83 ± 11
Systolic BP, mmHg
136 ± 15
127 ± 16
0.007
Diastolic BP, mmHg
82 ± 10
75 ± 10
\0.001
Stroke volume, mL
94 ± 20
94 ± 21
0.984
Cardiac output, L/min
6.2 ± 1.3
7.8 ± 1.9
\0.001
1,334 ± 313 47.1 ± 8.2
1,026 ± 222 45.6 ± 8.2
\0.001 0.523
52.9 ± 14.0
36.0 ± 16.7
0.003
1.5 ± 0.2
1.0 ± 0.3
0.002
SVR, dyne sec cm-5 LFnudBP, % HFnuRRI, % LFnudBP (%)/ HFnuRRI (%) Heart failure patients Heart rate, min-1
75.4 ± 16.7
84.8 ± 21.3
0.001
MAP, mmHg
87.5 ± 14.4
88.5 ± 13.6
0.654
Stroke volume, mL
64.4 ± 28.7
68.5 ± 23.2
0.241 0.002
Cardiac output, L/min
4.4 ± 1.3
5.0 ± 1.3
PVR, dyne sec cm-5
172 ± 68
119 ± 82
0.027
SVR, dyne sec cm-5
1,536 ± 316
1,353 ± 430
0.003
8.0 ± 6.3 8.1 ± 5.2
7.5 ± 6.8 7.8 ± 5.4
0.558 0.813
RAP mean, mmHg RVEDP, mmHg PAP mean, mmHg
25.7 ± 9.4
22.8 ± 11.3
0.104
PCWP, mmHg
16.8 ± 10.1
16.5 ± 10.1
0.826
LVEDP, mmHg (n = 7)
23.9 ± 9.0
21.4 ± 5.5
0.294
Values are mean ± standard deviation BP blood pressure, HFnuRRI high-frequency component of heart rate variability, LFnudBP low-frequency component of diastolic blood pressure variability, LVEDP left ventricular end-diastolic pressure, MAP mean aortic pressure, PA pulmonary artery, PCWP pulmonary capillary wedge pressure, PVR peripheral vascular resistance, RA right atrial, SVR systemic vascular resistance
decrease in BP and SVR. The exact physiology underlying these changes is still a topic of debate: HV leads to a decrease in pCO2 and increase in pH which might have a direct or an indirect centrally mediated vasodilatory effect [24–26]. In addition, the effect of HV might be time dependent, with a slight fall in BP within the first seconds [27], a return to baseline values within the first few minutes [27], and an increase with ongoing HV [23]. Analyzing the balance between sympathetic nerve activity (SNA; LFnudBP) and parasympathetic nervous activity (PNA; HFnuRRI) in this cohort of healthy volunteers suggest that the decrease in SVR recorded is based on a net shift towards vagal tone. This, in turn, could have contributed to the increase in heart rate, leading to increased CO. Obviously; it was primarily the significant increase in heart rate that contributed to the elevated CO in the volunteers, rather than a direct effect on SV.
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However, in the failing heart CO and SV in particular are highly dependent on cardiac pre- and afterload [28]. In the HF patients studied, HV did not appear to have a significant impact on either right or left ventricular preload. In contrast, both right- (PVR) and left (SVR) ventricular afterload decreased significantly, and there was no significant change in either pulmonary artery or MAPs. It should be assumed that an increase in MAP would have a significant impact on SV [28]. In this study, only a trend towards an increase in SV was documented in HF patients exclusively, while changes in heart rate from baseline during HV were highly significant in heart failure patients and healthy volunteers. The results of this study do not allow the mechanisms for the observed hemodynamic changes in patients with HF to be determined, but a similar pathophysiology as discussed in healthy volunteers might be conceivable. Recently, Yumino et al. [29] investigated the effects of obstructive and central respiratory events (apneas and hypopneas) in a cohort of HF patients with SDB. While obstructive events were accompanied by a decrease in SV and CO, central hypopneas and apneas were associated with no or little change in these parameters. The authors also claimed a more pronounced increase in heart rate during obstructive compared with central respiratory events [29]. While these results and the method of hemodynamic monitoring used have been a topic of debate [8], the main difference compared with the current study is that Yumino et al. investigated hemodynamic effects during the sleep-related respiratory event (apnea or hypopnea), while this study investigated the net effect of HV. In this context, it would be interesting to analyze hemodynamics during the ventilatory phase after apneas or hypopneas. This study provides further insights into the physiology of hemodynamic changes during HV. The immediate effects of HV in heart failure patients were an increase in heart rate and a decrease in cardiac afterload resulting in an increase in cardiac output. Thus, this immediate effect of HV can be interpreted as a ‘‘cardioprotective’’ compensatory mechanism of the failing heart. Heart failure with resulting pulmonary congestion [21, 30] might trigger CSR, which is characterized by respiratory instability and chronic hyperventilation, to maintain cardiac output. In contrast, we documented a significant increase in heart rate, even in patients receiving b-blockers. This might be detrimental on the long-run and might at least explain in part the negative effect of CSR on survival in HF patients [10– 12, 31–33]. Indeed, an increased heart rate in HF patients has been shown to be related to an impaired prognosis [31– 36]. Based on results of this study it is possible that interventions to reduce CSR in patients with HF may have beneficial effects. One such intervention is adaptive
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servoventilation (ASV) therapy, which was especially designed to target chronic hyperventilation during CSR in HF. Preliminary small-scale studies have shown that ASV has positive effects on quality of life, respiratory stability, cardiac function and survival [4, 10, 37, 38]. In addition, a multicenter randomized controlled trial is underway to better characterize these potential benefits [39].
Limitations The present study investigates the hemodynamic effects of voluntary hyperventilation in healthy volunteers and heart failure patients. Hyperventilation represents a key element of respiratory instability in heart failure patients, resulting in nocturnal or even daytime CSR and/or excessive or oscillatory ventilation (EOV) during exercise, all accompanied by an impaired prognosis in heart failure [40, 41]. However, we performed a physiology experiment and investigated only short-term hemodynamic effects. Therefore, this study provides some new hints and generates some new hypothesis rather than giving final answer why CSR and hyperventilation might be detrimental in heart failure. Acknowledgments English language medical writing assistance was provided by Nicola Ryan, independent medical writer, on behalf of ResMed. Conflict of interest
There are no conflicts of interest to declare.
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