Clin Physiol Funct Imaging (2016) 36, pp92–98
doi: 10.1111/cpf.12197
Relationship between non-invasive haemodynamic responses and cardiopulmonary exercise testing in patients with coronary artery disease via Cristina Rossi Caruso2, Renata Goncßalves Mendes2, Daniela Bassi Milena Pelosi Rizk Sperling1,2, Fla 2 2 e Carlos Bonjorno Jr1, Aparecida Maria Catai2, Ross Arena3 and Audrey Dutra , Vivian Maria Arakelian , Jos 1,2 Borghi-Silva Programa de Pos-graduacß~ao Interunidades Bioengenharia (EESC/FMRP/IQSC), Universidade de S~ao Paulo, USP, 2Laboratorio de Fisioterapia Cardiopulmonar, Universidade Federal de S~ao Carlos, UFSCar, S~ao Carlos, SP, Brasil and 3Department of Physical Therapy and Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL, USA 1
Summary Correspondence Audrey Borghi-Silva, Cardiopulmonary Physiotherapy Laboratory, Department of Physical Therapy, Federal University of S~ao Carlos (UFSCar), Rod. Washington Luis, Km: 235 CEP:13.565-905, S~ao Carlos, SP, Brazil E-mail: [email protected]
Accepted for publication Received 14 May 2014; accepted 11 September 2014
Key words cardiac disease; cardiac output; cardiopulmonary exercise testing; impedance cardiography; oxygen uptake; oxygen uptake efficiency slope; stroke volume
Background Non-invasive assessment of haemodynamic function by impedance cardiography (IC) constitutes an interesting approach to monitor cardiac function in patients with coronary artery disease (CAD). However, such measurements are most often performed at rest, whereas symptoms are also possible during exertion, particularly at higher intensities. In addition, the association between IC during exertion and cardiopulmonary exercise testing (CPX) is not well understood in these patients, which was the aim of this study. Methods Nineteen men (age = 62 6 years) with CAD [left ventricular ejection fraction (LVEF) = 61 10%] underwent a CPX using an incremental protocol on a cycle ergometer, with simultaneous measurement of IC. Cardiac output (CO), stroke volume (SV), cardiac index (CI), peak oxygen consumption (VO2), the oxygen uptake efficiency slope (OUES), circulatory power and ventilatory power were determined. Results Pearson product-moment correlation analysis revealed peak VO2 (r = 046) was significantly related to CO. Peak oxygen pulse (052) was associated with SV. OUES was associated with resting SV (047) and with peak SV (r = 052). Conclusion These findings suggest that IC indices are associated with certain, but not all, established CPX measures in patients with stable CAD.
Introduction Evaluation of metabolic, ventilatory and haemodynamic measures during a maximal aerobic exercise test portends important diagnostic and prognostic information (Gibbons et al., 1997; Neder & Nery, 2002; ATS/ACCP, 2003; Guazzi et al., 2012). This approach is referred to as cardiopulmonary exercise testing (CPX), which is the gold standard for non-invasively assessing the integrated response of the physiological systems responsible for determining an individual’s unique response to an exercise stimulus (Zeballos & Weisman, 1994). Cardiopulmonary exercise testing provides particularly valuable information in a number of patient populations, including those diagnosed with coronary artery disease (CAD) (Ramos et al., 2013). It is well known that CAD oftentimes leads to lower peak oxygen consumption (VO2) and exercise tolerance compared to apparently healthy individuals, and the 92
magnitude of this reduction varies with the severity of CAD (Guazzi et al., 2012). Diminished systolic function limits maximum cardiac output (CO), which impairs O2 delivery and thus utilization in skeletal muscle, and, in this way, peak VO2 may serve as a surrogate reflection of cardiac function (Fletcher et al., 2013). In addition, during maximal effort, the arteriovenous O2 difference is relatively constant; thus, oxygen pulse [VO2/heart rate (HR)] may be considered an estimate of stroke volume. Additional approaches to haemodynamic measurements, as a complement or alternative to established CPX variables, may provide value during information regarding cardiac function during aerobic exercise (Arena et al., 2009), particularly in patients with myocardial ischaemia. However, thermodilution, considered a gold standard, is a difficult undertaking, given it is invasive, time-consuming, expensive, carries an inherent risk (Garcia et al., 2011), and is difficult to measure accurately
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al. 93
during incremental exercise (Warburton et al., 1999; Jong et al., 2009; Pugsley & Lerner, 2010). On the other hand, non-invasive methods for quantifying CO, such as impedance cardiography (IC), have recently been refined, and several such methods have undergone validation for use during dynamic exercise (Lang et al., 2007; Balady et al., 2010; Cattadori et al., 2011) in patients with pulmonary arterial hypertension (Ferreira et al., 2012), chronic heart failure (Fukuda et al., 2012; Myers et al., 2013) and in CAD patients when compared with invasive methods at rest (Treister et al., 2005) and during exercise (Scherhag et al., 2005). Non-invasive determinants of haemodynamic responses by techniques such as IC may prove to be a valuable surrogate. However, IC responses during exertion and its relationship to established CPX variables in patients with CAD require further exploration. Therefore, the objective of this study was to evaluate the relationship between non-invasive haemodynamic responses via IC and key CPX variables in clinically stable patients with CAD. We hypothesize that there is a significant relationship between key IC and CPX variables in subjects diagnosed with CAD.
Methods Study design and population This was an observational clinical research study involving 19 males with clinically stable CAD (sample of convenience) participating in an outpatient cardiac rehabilitation programme. Inclusion criteria consisted of (i) being at least 12 months post an acute event (i.e. myocardial infarction) or 12 months after a surgical or percutaneous revascularization procedure and (ii) being clinically stable on a stable pharmacologic regimen. Over a 1-year period, 42 patients assessed for eligibility, 26 were recruited, five did not meet the inclusion criteria and one was excluded for having inadequate response of BP during CPX. Also one subject had a poor-quality IC signal and was excluded. Among the remaining patients, 19 patients were included in the final analyses. The study was approved by the University Ethics Committee for Human Research (no. 1331-11). All study objectives and experimental procedures and risks were described in detail, and all subjects completed written informed consent before initiation of the study. Experimental procedures All patients were evaluated in the afternoon in order to respect the different responses due to circadian influence. The experiments were carried out in a climate-controlled room (21– 24°C) with a relative air humidity of 40–60%. Each patient was instructed to avoid caffeinated and alcoholic beverages and any other stimulants the night before and day of data collection. Patients were also instructed not to perform activities requiring moderate to heavy physical exertion the day before CPX.
Lastly, patients were instructed to avoid heavy meals 2 h before the test. Immediately before data collection, subjects were interviewed and examined to confirm their state of good health and the occurrence of a normal night’s sleep, and to confirm that HR and systemic blood pressure (BP) were within normal range. The patients were oriented not to speak unnecessarily during the evaluation to avoid interfering with the capture of the electrocardiograph signal, and to communicate any abnormal symptoms before, during and after the application of the protocol. Clinical examination was performed by a physician (cardiologist) before study initiation. This examination consisted of anamnesis and resting 12-lead electrocardiography. Blood analysis was used to determine haemoglobin, triglycerides, total cholesterol and fractions such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), fasting glucose and uric acid. A transthoracic echocardiogram was also performed for all subjects. Cardiopulmonary exercise testing A symptom-limited incremental exercise test was performed on a cycle ergometer (Recumbent Corival of MedGraphics – St. Paul MN, USA) with the collection of gas exchange and ventilatory variables using a calibrated computer-based exercise system (Metabolic analyzer System Greenhouse telemetry module for field studies Oxycon-Mobile, Jaeger, Hoechberg, Germany). An IC device (Physioflow model PF05 Lab1; Manatec Biomedical, Macheren, France) was used to determine stroke volume (SV, ml), cardiac output (CO, l min 1), cardiac index (CI, l min 1 m 2) and HR at rest and during exercise beatto-beat. This device and its method of application have been widely described in the literature (Bernstein, 1986; Charloux et al., 2000; Borghi-Silva et al., 2008). The exercise test consisted of: (i) 5 min of rest; (ii) 4 min with real ‘zero’ workload, obtained by means of a system which moves the ergometer freewheel at 60 revolutions per minute (rpm); (iii) the incremental phase; (iv) 1-min active recovery period; and (v) 5 min passive recovery period. The workload (W) was continuously increased in a linear ‘ramp’ pattern of 15 W min 1 (Neder & Nery, 2002), so that the incremental exercise testing duration was between eight and 12 min (Buchfuhrer et al., 1983). The test finished when subjects reached physical exhaustion or abnormal test responses warranted test termination (Neder & Nery, 2002). The test was continuously monitored by a 12-lead electrocardiogram (WinCardio USB, Micromed Biotechnology, Brasilia, Brazil). Blood pressure and perceived exertion (Borg scale) were obtained at 3-min intervals. Symptoms were assessed by means of the 10-point Borg Scale Rating (Guazzi et al., 2012). Ventilatory and metabolic measurements The following data were obtained breath-by-breath: VO2 (ml min 1 and ml kg 1 min 1) standard temperature and
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
94 Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al.
pressure, containing no water vapour (STPD); carbon dioxide production (VCO2, ml min 1 STPD); and minute ventilation (VE, l min 1 at body temperature and ambient pressure, saturated with water vapour (BTPS). The partial pressure of endtidal CO2 (PETCO2) was also collected at rest and during exercise. Calibration of volumes and gases (O2 and CO2) was carefully performed before each test. Peak VO2 was defined as the highest value during the last 15 s of exercise (Guazzi et al., 2012). Peak respiratory exchange ratio (RER) was the 15-s averaged VCO2 divided by VO2. The O2 pulse was determined by dividing peak VO2 (ml min 1) by maximal HR (ml beat 1). The VO2 at Ventilatory Threshold (VT) was measured by the V-slope method (Beaver et al., 1986). Resting PETCO2 was expressed as a 1-min resting averaged value. Fifteen-second averaged PETCO2 at VT and peak was also determined. Fifteen-second averaged VE and VCO2 data, obtained from the initiation of exercise to peak, were input into spreadsheet software (Microsoft Excel; Microsoft Corp., Bellevue, WA, USA) to calculate the VE/ VCO2 slope via least squares linear regression (y = mx + b, m = slope). The oxygen uptake efficiency slope (OUES) was calculated using the log-transformation (base 10) of VE on the x-axis and VO2 in the y-axis; both variables logVE and VO2 used to calculate the OUES were in l min 1. Circulatory power was defined as the product of peak VO2 and peak systolic BP (SBP). Ventilatory power was defined as peak SBP divided by the VE/VCO2 slope. Haemodynamic/cardiovascular measurements: impedance cardiography Before each test, verification of the correct signal quality was performed by visualizing the electrocardiogram (ECG) tracing and its first derivative (dECG/dt) and the impedance waveform (DZ) with its first derivative (dZ/dt) (Charloux et al., 2000). Two pairs of electrodes, one transmitting and the other receiving, were applied above one another so as not to overlap at the supraclavicular fossa at the left base of the neck and at the midpoint of the thoracic region of the spine. An additional pair of electrodes was used to monitor a single lateral ECG lead (V1/V6 positions). Haemodynamic variables were determined continuously at rest and during exercise (beat-bybeat), and peak values were considered as a mean of the last 30 s (Woltjer et al., 1997). Statistic analysis The sample size for the current study was estimated considering correlation analyses between ventilatory/metabolic and haemodynamic measures. To reach an 80% chance of detecting a moderate association (r ≥ 06) at an a level of 005, the power calculation indicated a sample of 16 patients (Browner et al., 2003). The data distribution was verified by the Shapiro–Wilk test, and when the normality had been confirmed, the data were
expressed as mean and SD. The paired Student t-test was used to compare measurements between rest and peak exercise. Pearson’s product-moment correlation coefficient was used to examine the relationship between CPX and IC. The magnitude of the correlations was determined considering the following classification scheme for r -values: ≤035 low or weak; 036 ≤ 067 moderate; ≥068 strong or high; ≥09 very high; and perfect: 1 (Taylor, 1990). The probability of occurrence of type 1 error was established at 5% for all tests (a = 005). The statistical analysis was carried out using Sigma Plot for Windows version 11.0 (Sigma Plot, San Jose, CA, USA).
Results Clinical characteristics of the patients and CPX responses are summarized in Tables 1 and 2. All patients had normal left ventricular systolic function (and mild left ventricle diastolic dysfunction in 474% of study population) by echocardiography. The majority of patients had hypertension, a history of smoking and a family history of CAD. Myocardial infarction was the predominant clinical diagnosis, and all patients were NYHA class I. Medical treatment included antiplatelets, betablockers, ACE inhibitors and hypoglycaemic agents. Mean CPX values indicate this cohort had a well-preserved functional capacity, good ventilatory efficiency and put forth a maximal effort during the exercise test. Figure 1 lists the correlation analysis between key CPX and CI variables. There were several statistically significant moderate associations including (i) VO2 at VT and CO; (ii) peak VO2 and CO; (iii) OUES and SV (resting and peak); (iv) O2 pulse and SV (resting and peak); (v) circulatory power and peak CO; and (vi) ventilatory power with resting CO.
Discussion In the present study, we examined the relationship between CPX and IC responses at rest and during exercise, in consecutive outpatients with clinically stable CAD and preserved systolic function. At best, we found moderate associations among certain CPX and IC variables. Specifically, peak VO2 or variables that included VO2 in its calculation (i.e. VO2 at VT, the O2 pulse, the OUES, cardiac power) were moderately correlated with a number of IC measures, primarily during exercise. To our knowledge, this is the first study to evaluate the relationship between non-invasive haemodynamic and ventilatory/metabolic measurements during exercise in outpatients with clinically stable CAD. Whereas the dose of betablock was optimized for patients, we believe that the ventilatory, metabolic and haemodynamic responses were appropriate to exercise intensity for all patients. However, even though a smaller magnitude of heart rate for beta blocked, we believe that the association between the variables CPX and IC was maintained, regardless of the magnitude of the population response.
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al. 95
Table 1
Table 2 Cardiopulmonary exercise testing and impedance cardiography responses.
Baseline characteristics of study population. CAD (n = 19)
Demographic/anthropometric data Age, years Height, m Body mass, kg BMI, kg m 2 Transthoracic echocardiography LVEF, % LV diastolic diameter, cm LV diastolic volume, ml Septal thickness, cm Posterior wall thickness, cm Doppler at the echocardiography LV diastolic functiona Normal Mild Risk Factors, n (%) Diabetes Hypertension History of smoking Family history of CAD Functional Class (NYHA): I Clinical Diagnosis, n (%) Myocardial infarction Coronary artery bypass grafting Medications, n (%) Antiplatelets drugs (aspirin) Beta-blockers ACE inhibitors Hypoglycaemics
62 166 738 267
6 010 99 01
61 53 142 09 09
10 06 40 02 01
10 (526) 9 (474) 4 12 12 18 19
(211) (632) (632) (947) (100%)
14 (737) 8 (421) 19 14 6 4
(100) (737) (316) (211)
CAD, coronary artery disease; BMI, body mass index; LVEF, left ventricular eject fraction; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme. Data are presented as mean SD and number (percentage) of subjects. a Recommendations for Echocardiography (American Society of Echocardiography and European Association of Echocardiography).
The relationship between VO2 and CO is important given the influence of cardiac function on the Fick equation (Fletcher et al., 2013), and it is generally assumed that VO2 increases linearly with CO. In the present study, VO2 moderately increased in a linear tendency in relation to CO (r = 046; P
doi: 10.1111/cpf.12197
Relationship between non-invasive haemodynamic responses and cardiopulmonary exercise testing in patients with coronary artery disease via Cristina Rossi Caruso2, Renata Goncßalves Mendes2, Daniela Bassi Milena Pelosi Rizk Sperling1,2, Fla 2 2 e Carlos Bonjorno Jr1, Aparecida Maria Catai2, Ross Arena3 and Audrey Dutra , Vivian Maria Arakelian , Jos 1,2 Borghi-Silva Programa de Pos-graduacß~ao Interunidades Bioengenharia (EESC/FMRP/IQSC), Universidade de S~ao Paulo, USP, 2Laboratorio de Fisioterapia Cardiopulmonar, Universidade Federal de S~ao Carlos, UFSCar, S~ao Carlos, SP, Brasil and 3Department of Physical Therapy and Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL, USA 1
Summary Correspondence Audrey Borghi-Silva, Cardiopulmonary Physiotherapy Laboratory, Department of Physical Therapy, Federal University of S~ao Carlos (UFSCar), Rod. Washington Luis, Km: 235 CEP:13.565-905, S~ao Carlos, SP, Brazil E-mail: [email protected]
Accepted for publication Received 14 May 2014; accepted 11 September 2014
Key words cardiac disease; cardiac output; cardiopulmonary exercise testing; impedance cardiography; oxygen uptake; oxygen uptake efficiency slope; stroke volume
Background Non-invasive assessment of haemodynamic function by impedance cardiography (IC) constitutes an interesting approach to monitor cardiac function in patients with coronary artery disease (CAD). However, such measurements are most often performed at rest, whereas symptoms are also possible during exertion, particularly at higher intensities. In addition, the association between IC during exertion and cardiopulmonary exercise testing (CPX) is not well understood in these patients, which was the aim of this study. Methods Nineteen men (age = 62 6 years) with CAD [left ventricular ejection fraction (LVEF) = 61 10%] underwent a CPX using an incremental protocol on a cycle ergometer, with simultaneous measurement of IC. Cardiac output (CO), stroke volume (SV), cardiac index (CI), peak oxygen consumption (VO2), the oxygen uptake efficiency slope (OUES), circulatory power and ventilatory power were determined. Results Pearson product-moment correlation analysis revealed peak VO2 (r = 046) was significantly related to CO. Peak oxygen pulse (052) was associated with SV. OUES was associated with resting SV (047) and with peak SV (r = 052). Conclusion These findings suggest that IC indices are associated with certain, but not all, established CPX measures in patients with stable CAD.
Introduction Evaluation of metabolic, ventilatory and haemodynamic measures during a maximal aerobic exercise test portends important diagnostic and prognostic information (Gibbons et al., 1997; Neder & Nery, 2002; ATS/ACCP, 2003; Guazzi et al., 2012). This approach is referred to as cardiopulmonary exercise testing (CPX), which is the gold standard for non-invasively assessing the integrated response of the physiological systems responsible for determining an individual’s unique response to an exercise stimulus (Zeballos & Weisman, 1994). Cardiopulmonary exercise testing provides particularly valuable information in a number of patient populations, including those diagnosed with coronary artery disease (CAD) (Ramos et al., 2013). It is well known that CAD oftentimes leads to lower peak oxygen consumption (VO2) and exercise tolerance compared to apparently healthy individuals, and the 92
magnitude of this reduction varies with the severity of CAD (Guazzi et al., 2012). Diminished systolic function limits maximum cardiac output (CO), which impairs O2 delivery and thus utilization in skeletal muscle, and, in this way, peak VO2 may serve as a surrogate reflection of cardiac function (Fletcher et al., 2013). In addition, during maximal effort, the arteriovenous O2 difference is relatively constant; thus, oxygen pulse [VO2/heart rate (HR)] may be considered an estimate of stroke volume. Additional approaches to haemodynamic measurements, as a complement or alternative to established CPX variables, may provide value during information regarding cardiac function during aerobic exercise (Arena et al., 2009), particularly in patients with myocardial ischaemia. However, thermodilution, considered a gold standard, is a difficult undertaking, given it is invasive, time-consuming, expensive, carries an inherent risk (Garcia et al., 2011), and is difficult to measure accurately
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al. 93
during incremental exercise (Warburton et al., 1999; Jong et al., 2009; Pugsley & Lerner, 2010). On the other hand, non-invasive methods for quantifying CO, such as impedance cardiography (IC), have recently been refined, and several such methods have undergone validation for use during dynamic exercise (Lang et al., 2007; Balady et al., 2010; Cattadori et al., 2011) in patients with pulmonary arterial hypertension (Ferreira et al., 2012), chronic heart failure (Fukuda et al., 2012; Myers et al., 2013) and in CAD patients when compared with invasive methods at rest (Treister et al., 2005) and during exercise (Scherhag et al., 2005). Non-invasive determinants of haemodynamic responses by techniques such as IC may prove to be a valuable surrogate. However, IC responses during exertion and its relationship to established CPX variables in patients with CAD require further exploration. Therefore, the objective of this study was to evaluate the relationship between non-invasive haemodynamic responses via IC and key CPX variables in clinically stable patients with CAD. We hypothesize that there is a significant relationship between key IC and CPX variables in subjects diagnosed with CAD.
Methods Study design and population This was an observational clinical research study involving 19 males with clinically stable CAD (sample of convenience) participating in an outpatient cardiac rehabilitation programme. Inclusion criteria consisted of (i) being at least 12 months post an acute event (i.e. myocardial infarction) or 12 months after a surgical or percutaneous revascularization procedure and (ii) being clinically stable on a stable pharmacologic regimen. Over a 1-year period, 42 patients assessed for eligibility, 26 were recruited, five did not meet the inclusion criteria and one was excluded for having inadequate response of BP during CPX. Also one subject had a poor-quality IC signal and was excluded. Among the remaining patients, 19 patients were included in the final analyses. The study was approved by the University Ethics Committee for Human Research (no. 1331-11). All study objectives and experimental procedures and risks were described in detail, and all subjects completed written informed consent before initiation of the study. Experimental procedures All patients were evaluated in the afternoon in order to respect the different responses due to circadian influence. The experiments were carried out in a climate-controlled room (21– 24°C) with a relative air humidity of 40–60%. Each patient was instructed to avoid caffeinated and alcoholic beverages and any other stimulants the night before and day of data collection. Patients were also instructed not to perform activities requiring moderate to heavy physical exertion the day before CPX.
Lastly, patients were instructed to avoid heavy meals 2 h before the test. Immediately before data collection, subjects were interviewed and examined to confirm their state of good health and the occurrence of a normal night’s sleep, and to confirm that HR and systemic blood pressure (BP) were within normal range. The patients were oriented not to speak unnecessarily during the evaluation to avoid interfering with the capture of the electrocardiograph signal, and to communicate any abnormal symptoms before, during and after the application of the protocol. Clinical examination was performed by a physician (cardiologist) before study initiation. This examination consisted of anamnesis and resting 12-lead electrocardiography. Blood analysis was used to determine haemoglobin, triglycerides, total cholesterol and fractions such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), fasting glucose and uric acid. A transthoracic echocardiogram was also performed for all subjects. Cardiopulmonary exercise testing A symptom-limited incremental exercise test was performed on a cycle ergometer (Recumbent Corival of MedGraphics – St. Paul MN, USA) with the collection of gas exchange and ventilatory variables using a calibrated computer-based exercise system (Metabolic analyzer System Greenhouse telemetry module for field studies Oxycon-Mobile, Jaeger, Hoechberg, Germany). An IC device (Physioflow model PF05 Lab1; Manatec Biomedical, Macheren, France) was used to determine stroke volume (SV, ml), cardiac output (CO, l min 1), cardiac index (CI, l min 1 m 2) and HR at rest and during exercise beatto-beat. This device and its method of application have been widely described in the literature (Bernstein, 1986; Charloux et al., 2000; Borghi-Silva et al., 2008). The exercise test consisted of: (i) 5 min of rest; (ii) 4 min with real ‘zero’ workload, obtained by means of a system which moves the ergometer freewheel at 60 revolutions per minute (rpm); (iii) the incremental phase; (iv) 1-min active recovery period; and (v) 5 min passive recovery period. The workload (W) was continuously increased in a linear ‘ramp’ pattern of 15 W min 1 (Neder & Nery, 2002), so that the incremental exercise testing duration was between eight and 12 min (Buchfuhrer et al., 1983). The test finished when subjects reached physical exhaustion or abnormal test responses warranted test termination (Neder & Nery, 2002). The test was continuously monitored by a 12-lead electrocardiogram (WinCardio USB, Micromed Biotechnology, Brasilia, Brazil). Blood pressure and perceived exertion (Borg scale) were obtained at 3-min intervals. Symptoms were assessed by means of the 10-point Borg Scale Rating (Guazzi et al., 2012). Ventilatory and metabolic measurements The following data were obtained breath-by-breath: VO2 (ml min 1 and ml kg 1 min 1) standard temperature and
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
94 Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al.
pressure, containing no water vapour (STPD); carbon dioxide production (VCO2, ml min 1 STPD); and minute ventilation (VE, l min 1 at body temperature and ambient pressure, saturated with water vapour (BTPS). The partial pressure of endtidal CO2 (PETCO2) was also collected at rest and during exercise. Calibration of volumes and gases (O2 and CO2) was carefully performed before each test. Peak VO2 was defined as the highest value during the last 15 s of exercise (Guazzi et al., 2012). Peak respiratory exchange ratio (RER) was the 15-s averaged VCO2 divided by VO2. The O2 pulse was determined by dividing peak VO2 (ml min 1) by maximal HR (ml beat 1). The VO2 at Ventilatory Threshold (VT) was measured by the V-slope method (Beaver et al., 1986). Resting PETCO2 was expressed as a 1-min resting averaged value. Fifteen-second averaged PETCO2 at VT and peak was also determined. Fifteen-second averaged VE and VCO2 data, obtained from the initiation of exercise to peak, were input into spreadsheet software (Microsoft Excel; Microsoft Corp., Bellevue, WA, USA) to calculate the VE/ VCO2 slope via least squares linear regression (y = mx + b, m = slope). The oxygen uptake efficiency slope (OUES) was calculated using the log-transformation (base 10) of VE on the x-axis and VO2 in the y-axis; both variables logVE and VO2 used to calculate the OUES were in l min 1. Circulatory power was defined as the product of peak VO2 and peak systolic BP (SBP). Ventilatory power was defined as peak SBP divided by the VE/VCO2 slope. Haemodynamic/cardiovascular measurements: impedance cardiography Before each test, verification of the correct signal quality was performed by visualizing the electrocardiogram (ECG) tracing and its first derivative (dECG/dt) and the impedance waveform (DZ) with its first derivative (dZ/dt) (Charloux et al., 2000). Two pairs of electrodes, one transmitting and the other receiving, were applied above one another so as not to overlap at the supraclavicular fossa at the left base of the neck and at the midpoint of the thoracic region of the spine. An additional pair of electrodes was used to monitor a single lateral ECG lead (V1/V6 positions). Haemodynamic variables were determined continuously at rest and during exercise (beat-bybeat), and peak values were considered as a mean of the last 30 s (Woltjer et al., 1997). Statistic analysis The sample size for the current study was estimated considering correlation analyses between ventilatory/metabolic and haemodynamic measures. To reach an 80% chance of detecting a moderate association (r ≥ 06) at an a level of 005, the power calculation indicated a sample of 16 patients (Browner et al., 2003). The data distribution was verified by the Shapiro–Wilk test, and when the normality had been confirmed, the data were
expressed as mean and SD. The paired Student t-test was used to compare measurements between rest and peak exercise. Pearson’s product-moment correlation coefficient was used to examine the relationship between CPX and IC. The magnitude of the correlations was determined considering the following classification scheme for r -values: ≤035 low or weak; 036 ≤ 067 moderate; ≥068 strong or high; ≥09 very high; and perfect: 1 (Taylor, 1990). The probability of occurrence of type 1 error was established at 5% for all tests (a = 005). The statistical analysis was carried out using Sigma Plot for Windows version 11.0 (Sigma Plot, San Jose, CA, USA).
Results Clinical characteristics of the patients and CPX responses are summarized in Tables 1 and 2. All patients had normal left ventricular systolic function (and mild left ventricle diastolic dysfunction in 474% of study population) by echocardiography. The majority of patients had hypertension, a history of smoking and a family history of CAD. Myocardial infarction was the predominant clinical diagnosis, and all patients were NYHA class I. Medical treatment included antiplatelets, betablockers, ACE inhibitors and hypoglycaemic agents. Mean CPX values indicate this cohort had a well-preserved functional capacity, good ventilatory efficiency and put forth a maximal effort during the exercise test. Figure 1 lists the correlation analysis between key CPX and CI variables. There were several statistically significant moderate associations including (i) VO2 at VT and CO; (ii) peak VO2 and CO; (iii) OUES and SV (resting and peak); (iv) O2 pulse and SV (resting and peak); (v) circulatory power and peak CO; and (vi) ventilatory power with resting CO.
Discussion In the present study, we examined the relationship between CPX and IC responses at rest and during exercise, in consecutive outpatients with clinically stable CAD and preserved systolic function. At best, we found moderate associations among certain CPX and IC variables. Specifically, peak VO2 or variables that included VO2 in its calculation (i.e. VO2 at VT, the O2 pulse, the OUES, cardiac power) were moderately correlated with a number of IC measures, primarily during exercise. To our knowledge, this is the first study to evaluate the relationship between non-invasive haemodynamic and ventilatory/metabolic measurements during exercise in outpatients with clinically stable CAD. Whereas the dose of betablock was optimized for patients, we believe that the ventilatory, metabolic and haemodynamic responses were appropriate to exercise intensity for all patients. However, even though a smaller magnitude of heart rate for beta blocked, we believe that the association between the variables CPX and IC was maintained, regardless of the magnitude of the population response.
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd 36, 2, 92–98
Impedance cardiography during exercise testing in CAD, M. P. R. Sperling et al. 95
Table 1
Table 2 Cardiopulmonary exercise testing and impedance cardiography responses.
Baseline characteristics of study population. CAD (n = 19)
Demographic/anthropometric data Age, years Height, m Body mass, kg BMI, kg m 2 Transthoracic echocardiography LVEF, % LV diastolic diameter, cm LV diastolic volume, ml Septal thickness, cm Posterior wall thickness, cm Doppler at the echocardiography LV diastolic functiona Normal Mild Risk Factors, n (%) Diabetes Hypertension History of smoking Family history of CAD Functional Class (NYHA): I Clinical Diagnosis, n (%) Myocardial infarction Coronary artery bypass grafting Medications, n (%) Antiplatelets drugs (aspirin) Beta-blockers ACE inhibitors Hypoglycaemics
62 166 738 267
6 010 99 01
61 53 142 09 09
10 06 40 02 01
10 (526) 9 (474) 4 12 12 18 19
(211) (632) (632) (947) (100%)
14 (737) 8 (421) 19 14 6 4
(100) (737) (316) (211)
CAD, coronary artery disease; BMI, body mass index; LVEF, left ventricular eject fraction; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme. Data are presented as mean SD and number (percentage) of subjects. a Recommendations for Echocardiography (American Society of Echocardiography and European Association of Echocardiography).
The relationship between VO2 and CO is important given the influence of cardiac function on the Fick equation (Fletcher et al., 2013), and it is generally assumed that VO2 increases linearly with CO. In the present study, VO2 moderately increased in a linear tendency in relation to CO (r = 046; P
