Standards for the use of cardiopulmonary exercise testing for the functional evaluation of cardiac patients: a report from the Exercise Physiology Section of the European Association for Cardiovascular Prevention and Rehabilitation

Abstract

Cardiopulmonary exercise testing (CPET) is a methodology that has profoundly affected the approach to patients' functional evaluation, linking performance and physiological parameters to the underlying metabolic substratum and providing highly reproducible exercise capacity descriptors. This study provides professionals with an up-to-date review of the rationale sustaining the use of CPET for functional evaluation of cardiac patients in both the clinical and research settings, describing parameters obtainable either from ramp incremental or step constant-power CPET and illustrating the wealth of information obtainable through an experienced use of this powerful tool. The choice of parameters to be measured will depend on the specific goals of functional evaluation in the individual patient, namely, exercise tolerance assessment, training prescription, treatment efficacy evaluation, and/or investigation of exercise-induced adaptations of the oxygen transport/utilization system. The full potentialities of CPET in the clinical and research setting still remain largely underused and strong efforts are recommended to promote a more widespread use of CPET in the functional evaluation of cardiac patients.

Keywords

anaerobic threshold cardiac disease cardiopulmonary exercise testing critcal power functional evaluation oxygen consumption ventilation

Introduction

Cardiopulmonary exercise testing (CPET) is a methodology that has profoundly changed the approach to patients' functional evaluation, linking performance and physiological parameters to the underlying metabolic substratum and providing highly reproducible exercise capacity descriptors, for example, peak oxygen uptake (peakVO₂) [1–3]. Moreover, CPET has dramatically increased the mass of information obtainable from a relatively simple and inexpensive procedure such as exercise testing, furnishing an all-round vision of the systems involvedinbothO₂ transport from air to mitochondria and its utilization, and making it possible to identify the link(s) limiting the exercise capacity in the individual patient. However, during the last 20 years, the use of CPET for prognostic purposes [mainly in chronic heart failure (CHF) patients] has overshadowed its application for the functional evaluation of cardiac patients, indeed its original one. This report aims to provide professionals with an up-to-date review of the rationale sustaining the use of CPET for the functional evaluation of cardiac patients in both clinical and research settings (Table 1), describing parameters obtainable either from ramp incremental or step constant-power CPET, as specified in the respective paragraphs.

Table 1

Aims of cardiac patients functional evaluation

Reproducible assessment of patient's exercise capacity

Prescription of endurance training intensity

Evaluation of response to endurance training

Evaluation of response to therapeutic interventions (drugs, ventricular resynchronization, etc.) affecting exercise capacity

Evaluation of the O₂ transport and utilization system efficiency (ventilatory, hemodynamic, and metabolic components)

Finally, as treatment of the use of CPET for differentiation of cardiac versus pulmonary causes of dyspnea and/or impaired exercise capacity is not a specific goal of this report, readers interested in this topic are referred to previously published reviews [4], as are those interested in the use of CPET for prognostic stratification of patients with cardiac disease (in particular, CHF) [5].

Use of cardiopulmonary exercise testing for the evaluation of O₂ transport and utilization efficiency

Ventilatory anaerobic threshold

During incremental exercise, an energy requirement is reached above which blood lactate concentration increases at a progressively steeper rate [6]. This is because of anaerobic glycolysis activation, that occurs as the oxygen supply rate is not rapid enough to reoxidize cytosolic NADH + H⁺ [7]. Almost all of the H⁺ generated in the cell from lactic acid (La) dissociation is buffered by bicarbonate according to the following reaction:

H^{+} {La}^{-} + {HCO}_{3}^{-} \Leftrightarrow H_{2} O + {CO}_{2} + {La}^{-}

Such a production of CO₂, in excess of that produced by aerobic metabolism (excess CO₂), makes the CO₂ production (VCO₂) versus VO₂ relationship become steeper. This has been labeled ‘anaerobic threshold’ or also ‘aerobic threshold’ or ‘first lactate turn point’, with some terminology disagreement in the scientific literature [8], and is a reliable index of aerobic fitness used for training prescription in both normal individuals and cardiac patients, especially for sustainable submaximal work [9, 10]. Interindividual variance, exercise protocol (e.g. fast versus slow work rate increments, step versus ramp protocols) [11], blood sampling source (e.g. venous, capillary, arterial, arterialized) [12], and type of exercise (e.g. running, swimming, cycling, rowing, etc.) [13] can all affect blood lactate kinetics.

By measuring gas exchange modifications induced by metabolic changes at the mouth, the ‘ventilatory anaerobic threshold’ (VAT) can be determined analyzing the slope of the VCO₂ versus VO₂ (plotted on equal scales) relationship during ramp incremental exercise (V-slope method) [14], where VAT is the point of transition of the VCO₂ versus VO₂ slope from less than 1 (activation of aerobic metabolism alone) to greater than 1 (anaerobic plus aerobic metabolism) (Fig. 1, upper panel). Moreover, the excess CO₂ produced above VAT increases ventilatory drive, which keeps the ventilation (VE) versus VCO₂ relationship linear and the end-tidal CO₂ pressure (P_ETCO₂) value constant (i.e. the individual does not hyperventilate with respect to the volume of CO₂ metabolically produced). However, an inversion of the VE versus VO₂ relationship behavior (increase versus initial decrease, i.e. hyperventilation with respect to O₂) is observed above VAT; this makes both the VE versus VO₂ ratio and end-tidal O₂ pressure increase, in the presence of a still decreasing or constant VE/VCO₂ and P_ETCO₂. VAT is thus also identifiable with the nadir of the VE versus VO₂ relationship and with the point where end-tidal O₂ pressure begins to increase [2] (Fig. 1, lower panel). In the final phase of exercise, hyper-ventilation does occur also with respect to CO₂ (respiratory compensation point), making VE/VCO₂ increase and P_ETCO₂ decrease [15] (Fig. 1, lower panel). VAT is usually expressed as a VO₂ value relative to predicted maximal oxygen uptake (VO_2max), the lower limit of normality being 40% of predicted VO_2max [16]. In the vast majority of healthy individuals, VAT occurs at approximately 40-60% of VO_2max (Table 2); in trained endurance athletes, VAT can reach intensities as high as 80% of their VO_2max [23].

All cardiac diseases affecting the O₂ transport chain (typically CHF) can determine a pathologic VAT (i.e. < 40% predicted VO_2max) [24], as can deconditioning following bed rest for cardiac events, even in the presence of normal left ventricular systolic function [25]. However, when expressed relative to measured peakVO₂ (and not to predicted VO_2max), VAT will still occur at approximately 40-60% of peakVO₂ in most cardiac patients, with a trend toward higher percentages of peakVO₂ in patients with CHF [7, 16, 24, 26]. Notably, VAT may be not detectable in a variable percentage of patients [27], and especially in those with CHF because of exercise oscillatory VE and/or shortness of exercise time.

Maximal oxygen uptake

VO_2max is a parameter which describes the maximal amount of energy obtainable by aerobic metabolism per unit of time (aerobic power). VO₂ is defined by the Fick equation:

{VO}_{2} = CO \times C (a - v) O_{2}

where CO is cardiac output and C(a-v)O₂ is the arteriovenous O₂ content difference. In healthy individuals, VO_2max is mostly limited by CO rather than by peripheral factors [28], its value, however, being influenced by several parameters, such as arterial O₂ content, fractional distribution of CO to exercising muscles, and muscle ability to extract O₂; recent data also indicate a possible role of a central nervous system governor [29]. VO_2max attainment is evidenced by failure of VO₂ to increase despite increasing work rate [30]. However, flattening of the VO₂ versus power relationship is not seen often in routine clinical practice, and therefore a more realistic goal is to assess peakVO₂ rather than VO_2max. PeakVO₂ is defined as the highest VO₂, averaged over a 20 to 30-s period, achieved at presumed maximal effort during an incremental exercise test, and may or may not be equal to VO_2max, even if available evidence suggests that these two concepts are substantially analogous [31]. In any case, peakVO₂ describes patients' exercise tolerance far more reliably than exercise duration or peak power [32]. Achievement of truly maximal effort (and thus of reliable VO_2max values) can be assumed in the presence of one or more of the following criteria [33]:

(1)

Failure of VO₂ and/or heart rate to increase with further increases in work rate.

(2)

Peak respiratory exchange ratio (VCO₂/VO₂) ≥ 1.10-1.15.

(3)

Postexercise blood lactate concentration ≥ 8mmol/dl.

(4)

Rating of perceived exertion ≥ 8 (on the 10-point Borg scale).

Normal values of VO_2max depend on age and sex, and are influenced by body size, level of physical activity, and genetic endowment [34]. VO_2max is measured in liters or milliliters of O₂ per minute, or in milliliters of O₂ per kilogram of body weight per minute. The highest values of VO_2max are reported in endurance athletes (94 ml/kg per min) [35]. VO_2max declines on average by 10% per decade after the age of 30, because of decreasing maximal heart rate, stroke volume, blood flow to skeletal muscle, and skeletal muscle aerobic potential with age [36]. VO_2max is also 10 to 20% greater in males than in females of comparable age [37], because of higher hemoglobin (Hb) concentration and greater muscle mass and stroke volume in males. Several formulae based on age and body dimensions are available for VO_2max prediction in sedentary men and women, the most detailed recommendation being provided by Wasserman et al. [16] (Table 2).

Many cardiovascular diseases can affect VO_2max/peakVO₂. Namely, all pathologies impairing CO response to exercise will determine some degree of reduction of peakVO₂ with respect to predicted VO_2max. For example, in patients with CHF peakVO₂ is classically reduced with respect to age-matched and sex-matched normal individuals [24], but is also lower than normal in patients with preserved left ventricular function entering a rehabilitation program after recent cardiac surgery [38], because of bed rest-induced deconditioning. When possible, determination of peakVO₂ in patients referred for cardiac rehabilitation is a cornerstone for rational exercise prescription and evaluation of training efficacy [39, 40].

Table 2

Normal values


Parameters	Normal values			Formulae

VO₂ at VAT (ml/min) [16]	> 40% predicted VO_2max, 40-60% peakVO₂			−
Critical power (W) [17]	65-70% of peak power, 25-30% of ΔVAT-peak power			−
VO_2max (ml/min) [16]	Age (years)	M a	F a	Sedentary men b
	20	3246 (43.3)	1996 (33.3)	[50.72-(0.372 × age)] × weight
	30	2967 (39.6)	1821 (30.3)	Sedentary women b
	40	2688 (35.8)	1646 (27.4)	[22.78-(0.17 × age)] × (weight + 43)
	50	2409 (32.1)	1471 (24.5)
	60	2130 (28.4)	1296 (21.6)
	70	1851 (24.7)	1121 (18.7)
	80	1572 (21.0)	945 (15.7)
VO₂ on-kinetics mean response time (s) [18]	30-44	34-43		Sedentary men
	45-59	44-53		(0.67 × age)+ 13.9
	60-80	54-67
VO₂ off-kinetics T_1/2 (s) [19]		60 ± 20 c		−
O₂ uptake efficiency slope [(ml/min)/(l/min)] [20]		M d	F d	Sedentary men d
	50-59	2647-2407	1773-1630	1.320-(26.7 × age) + (1.394 × BSA)
	60-69	2380-2140	1615-1472	Sedentary women d
	70-80	2113-1846	1457-1300	1.175-(15.8 × age) + (841 × BSA)
VE versus VCO₂ slope [21]		M	F
	20-39	23.4-25.7	26.8-28.3	Sedentary men
	40-59	25.8-28.1	28.4-29.9	(0.12 × age)+ 21
	60-80	28.2-30.6	30.0-31.6	Sedentary women (0.08 × age)+25.2
Peak cardiac output (l/min) [22]		−		5 × peakVO₂ + 3 e
Peak circulatory power (mmHg × ml/kg per min)		M f	M f
	20-39	8600-7000	6660-5600	−
	40-59	7050-5680	5480-4400
	60-80	5630-4200	4320-3140

BSA, body surface area; F, females; M, males; peakVO₂, peak oxygen consumption; T_1/2, time necessary for VO₂ to decrease by 50% from its peak effort value; VAT, ventilatory anaerobic threshold; VO_2max, maximal oxygen uptake.

Values are calculated for men of 75 kg and women of 60 kg weight, values in brackets are ml/kg per min.

Formula for normal weight individuals, Ref. [16] also reports formulae for underweight and overweight individuals.

Value for VO₂ off-kinetics after incremental exercise.

Values are calculated for men of 1.9 m² BSA and women of 1.65 m² BSA.

PeakVO₂ in liters/minute for 20-50 year old males.

Values are calculated for VO_2max reported above and peak systolic blood pressure of 200 mmHg.

Critical power

Critical power represents the highest power sustainable in conditions of both VO₂ and lactate steady state [17], overlapping, as such, the concept of maximal lactate steady state, that is, the highest power sustainable in conditions of stable blood lactate concentration [41]. As aerobic exercise is usually performed in steady-state conditions, the critical power is a crucial (though quite neglected) marker of the upper limit of sustainable aerobic training intensity [42], situated between VATand peakVO₂ powers as assessed during ramp incremental CPET.

From a mathematical standpoint, critical power corresponds to the power asymptote of the hyperbolic relationship linking power and duration of the constant-power exercise [17]. The determination of critical power requires the performance of four to five constant-power exercise tests in the above-VAT threshold effort intensity domains (see section ‘VO₂ on-kinetics’), with relative intensities ranging between 70 and 120% of peak power reached during an incremental ramp exercise test [17]; the critical power is then obtained by fitting a rectangular hyperbola on the obtained power versus duration points (Fig. 2). Such a procedure is of course not feasible in the routine clinical setting; however, the existence of a very close correlation between critical power and power at respiratory compensation point during ramp incremental CPET has been described [43]. If these data were confirmed, a single and easy-to-perform test, CPET, would provide operators with all the parameters describing O₂ transport and utilization system efficiency, that is, anaerobic threshold, critical power, and peakVO2.

Critical power has been evaluated by several authors in sedentary young normal individuals, revealing repeatable values around 65-70% of peak power (or 25-30% of ΔVAT — peakVO₂ power) (Table 2) at incremental exercise testing, with a steady-state VO₂ mean value corresponding to 70-80% of peakVO₂ [17, 42]. Elderly individuals show critical power values similar to those of young individuals when expressed relative to peak power, but with higher relative steady-state VO₂ values (approximately 80-90% of peakVO₂), demonstrating a broadening of the high-intensity domain of effort, probably aimed at preservation of habitual activities performance in steady-state, nonfatiguing metabolic conditions [44]. Notably, similar to the other O₂ transport and utilization system efficiency descriptors, critical power is also increased by aerobic training [45].

No data are currently available on critical power in cardiac patients. However, there is information suggesting that CHF patients can perform their habitual activities at absolute and relative intensities higher than the individual VAT [46]. This underlines the need for studies addressing critical power in this population.

VO₂ on-kinetics

During constant-power exercise below the anaerobic threshold (moderate-intensity effort domain), three phases of VO₂ on-kinetics are classically described in human physiology [47–49]: phase I, during which the VO₂ increase would rely mostly on pulmonary blood flow (i.e. CO) increment in the presence of an unchanging C(a-v)O₂; phase II, characterized by a monoexponential VO₂ increase mainly reflecting skeletal muscle VO₂ consumption, as described by C(a-v)O₂ widening; and phase III, that is, steady-state attainment (Fig. 3). As VO₂ does not reach instantaneously its steady-state value at step exercise onset, during phase I and phase II an O₂ deficit accumulates, defined as the cumulative difference between steady-state VO₂ level and VO₂ levels throughout the whole on-response (Fig. 3); the O₂ deficit will be larger the greater the recourse to anaerobic energy sources (alactic and lactic) and body O₂ stores before steady-state attainment [49, 50]. Above anaerobic threshold and up to critical power (high-intensity effort domain), it is still possible to reach a VO₂ steady state for constant-power efforts (see section ‘Critical power’), even if in this intensity domain an additional, delayedonset VO₂ component (‘slow component’) adds to the expected steady-state VO₂ value according to the below-VAT VO₂ versus power relationship [49, 51, 52]. The latter can be determined either by performing multiple constant-power exercise tests at different below-VAT powers and then fitting a linear relationship on the obtained VO₂ versus power points, or with an incremental ramp CPET, by fitting a linear function to the breath-by-breath below-VAT VO₂ versus power data, excluding from the fitting window the initial nonincreasing or poorly increasing VO₂ period [53, 54]; the VO₂ versus power slope values obtained with the above two methods have been shown to be superimposable [54]. Beyond critical power (very high-intensity effort domain), a steady state is no longer attainable, and the VO₂ slow component makes VO₂ increase inexorably up to VO_2max [49, 51, 52].

The presence of the VO₂ slow component introduces some methodological caveats about VO₂ on-response evaluation in the high-intensity and very-high-intensity domains [51, 52]; for this reason, VO₂ on-kinetics is more easily assessed during moderate-intensity effort, and can thus be evaluated also in individuals unable to exercise maximally. In this context, phase I is described in terms of its amplitude and duration, whereas the monoexponential VO₂ increase during phase II through its time constant (i.e. the time needed to reach 63% of the steady-state value), fitted on the VO₂ data starting from the phase I to phase II transition [49] (Fig. 3).

VO₂ on-kinetics in the moderate-intensity effort domain becomes more prolonged with age (Table 2), as demonstrated by increasing values of both its mean response time (i.e. the time constant of the whole VO₂ on-response, involving both phase I and phase II, fitted on the VO₂ data from time = 0 of the exercise phase, see Fig. 3) [18] and phase II time constant [55], which is because of modifications of the O₂ transport and utilization system during the aging process described in the section ‘Maximal oxygen uptake’. Moreover, aerobic training affects the VO₂ on-kinetics similarly to the other descriptors of aerobic performance efficiency by shortening both the mean response time and the phase II time constant [56], that is, making the system adapt more rapidly to changes of loading conditions.

Cardiac disease can affect VO₂ on-kinetics in the moderate-intensity effort domain mainly by reducing O₂ delivery to exercising skeletal muscles. This is evidenced by a prolonged mean response time in patients with coronary artery disease and lone atrial fibrillation with respect to normal individuals [57, 58], and is confirmed by the finding of improved VO₂ on-kinetics after percutaneous transluminal coronary angioplasty [59]. A significant prolongation of mean response time is also observed in patients with CHF [60], whose pathophysiology affects several steps of the O₂ transport/utilization system (see section ‘Patients with chronic heart failure’), whereas a shortening of mean response time is observed in these patients after left ventricular assist device implantation [61].

VO₂ off-kinetics

During the resting recovery phase after constant-power moderate-intensity exercise, the O₂ debt contracted during the O₂ deficit accumulation is paid by a VO₂ in excess of the resting level (Fig. 3) [7, 62]; the same phenomenon is observed during recovery from an incremental exercise test. Such an O₂ uptake is necessary for the rephosphorylation of creatine in skeletal muscles and, later, conversion of lactate to pyruvate and other mechanisms [63, 64]. VO₂ during recovery fits an exponential function, and can be described by the time constant of the VO₂ off-response or its T_1/2, that is, the time necessary for VO₂ to decrease by 50% from its peak effort value [19]. The more efficient the O₂ delivery to, and O₂ utilization by, exercising skeletal muscles, the faster this time is; hence, it is shorter in athletes and longer in deconditioned patients [65].

After an incremental ramp exercise test, the average T_1/2 value in normal individuals ranges between 60 and 90 s (Table 2), and would seem to become more prolonged with advancing age, although no conclusive data are available on age-induced VO₂ off-kinetics modifications [19, 66, 67]. T_1/2 is largely independent of exercise intensity, at least as long as it remains greater that 75% of the maximum [19]; this can be particularly interesting in individuals who stop exercising before peak effort because of symptoms, poor motivation, or fear and in whom peakVO₂ is underestimated. Thus, a low peakVO₂ in the presence of normal VO₂ recovery kinetics suggests submaximal effort; conversely, a long T_1/2 reinforces the value of a low peakVO₂.

All pathologies affecting the O₂ transport chain from ambient air to exercising skeletal muscle are expected to influence the postexercise VO₂ behavior. Indeed, several authors have shown that the kinetics of VO₂ recovery both after the constant-power and the incremental exercise testing are slowed in patients with congenital heart disease and CHF [19, 66–69]; data for post-myocardial infarction patients are less clear [70, 71].

Use of cardiopulmonary exercise testing for the evaluation of ventilation efficiency and control

VO₂ versus ventilation relationship: the oxygen uptake efficiency slope

The oxygen uptake efficiency slope (OUES) represents the rate of increase of VO₂ in response to a given VE during incremental exercise, indicating how effectively oxygen is extracted and taken into the body [72]. OUES is mainly influenced by the onset of lactic acidosis (which depends on the distribution of blood to the working muscles), muscle mass, oxygen extraction and utilization, and the physiologic pulmonary dead space (which in turn is affected by lung perfusion and structural integrity), thus incorporating cardiovascular, musculoskeletal, and respiratory function into a single index.

OUES is determined from the linear relation of VO₂ (y-axis) versus the logarithm of VE (x-axis) during exercise, that is, VO₂ = a log₁₀ VE + b, where ‘a’ is the OUES and ‘b’ is the intercept [72] (Fig. 4, upper panel). The logarithmic transformation of VE is aimed at linearizing the otherwise curvilinear relation of VO₂ versus VE, thus making the OUES theoretically independent of the patient-achieved effort level. Several studies have tested this hypothesis [20, 72–79], showing either equal or slightly higher or lower submaximal versus maximal OUES values, which thus outweigh the substantially larger differences in peakVO₂ measurements observed in the case of premature termination of the exercise test. The feasibility and repeatability of OUES determination is superior to that of VAT [20, 73–76, 79–81], and is easily calculated by a simple mathematical formula, thus improving intraobserver and interobserver measurement variability and objectivity [82]. In healthy individuals, OUES has been investigated in children [72] and adults [20, 74, 77]. Age-adjusted OUES values can be predicted using the sex-specific equations by Hollenberg and Tager [20] (Table 2).

In patients with coronary artery disease, OUES is significantly reduced [75, 79, 81]. However, patients who have undergone percutaneous transluminal coronary angioplasty with or without prior myocardial infarction have significantly higher OUES values compared with patients after coronary artery bypass grafting [79]. This may be explained by a higher disease severity, preoperative and postoperative deconditioning, and the impact of chest surgery on lung perfusion and structural integrity in the latter group. Furthermore, OUES is impaired in coronary artery disease patients with atrial fibrillation as compared with those in normal sinus rhythm [79]; this is likely because of the impact of decreased oxygen delivery on the working muscles in patients with atrial fibrillation, owing to lower stroke volume and CO response during exercise [83]. In CHF, the OUES is reduced in proportion to disease severity [20, 75, 76, 81] (see section ‘Patients with chronic heart failure’ and Fig. 4, upper panel).

Physical training has been shown to increase OUES in both coronary artery disease and CHF patients [79, 81], suggesting that, after training, a given oxygen uptake is achieved with a lower ventilatory cost. This OUES increase may be because of a reduced metabolic acidosis and/or ventilatory response at submaximal effort intensities. The training-induced changes of OUES parallel those of peakVO₂ [79, 81], showing that OUES is sensitive to improvements in exercise tolerance. OUES would therefore seem to be clinically useful to monitor changes in exercise performance and effects of physical training, particularly in patients who can only perform submaximal exercise.

Ventilation versus VCO₂ relationship: the VE versus VCO₂ slope

Despite a manifold increase in VCO₂ and VO₂ during incremental exercise, the ventilatory control mechanisms normally keep arterial CO₂ tension (PaCO₂) and pH remarkably constant over a wide range of metabolic rates. The slope of the relationship between VE and VCO₂ describes the ventilatory efficiency during effort, showing the amount of air that must be ventilated to eliminate 1 l of CO₂ (Fig. 4, lower panel). The basic information given by the VE versus VCO₂ slope is incorporated in the modified alveolar equation [84]:

VE = 863 \times VCO / {PaCO}_{2} \times (1 - V_{D} / V_{T})

where V _D and V _T are volume of pulmonary dead space and tidal volume, respectively.

If PaCO₂ is driven down by a high ventilatory drive from peripheral chemoreceptors and/or V _D/V _T is high, the VE versus VCO₂ slope increases; a low V _T with respect to a normal anatomic dead space and/or an abnormally high physiological dead space are potential sources of high V _D/V _T [85]. Another proposed cause of increased ventilatory drive during exercise is effort-induced muscle metaboreflex (ergoreflex) overactivation [86]. Notably, during incremental exercise VE and VCO₂ are linearly related until VE increases disproportionately to VCO₂ (respiratory compensation point, see section ‘Ventilatory anaerobic threshold’). There is still controversy about whether the VE versus VCO₂ slope should be calculated across the overall exercise data or only up to the respiratory compensation point; although its assessment until this point is the logical one from a physiological standpoint, calculation over the whole exercise period seems to increase the VE versus VCO₂ slope prognostic value in CHF patients [87].

Normal values of the VE versus VCO₂ slope range between 20 and 30, with an intercept on the VE axis of some 4-5 l/min because of a reduction of V _D/V _T ratio after the start of exercise and/or early exercise hyperventilation. The VE versus VCO₂ slope is affected by age, showing increasing values with increasing age [21] (Table 2). A higher than normal VE versus VCO₂ slope may be of undeterminable origin (primary hyperventilation) or because of hypoxia or respiratory or cardiac diseases that can stimulate VE (secondary hyperventilation). Conversely, a downward displacement of the VE versus VCO₂ slope occurs when the PaCO₂ set point is raised, that is, in primary alveolar hypoventilation syndrome (impaired ventilatory chemoreflex function).

In patients with coronary artery disease (previous myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and significant chronic coronary stenosis), the VE versus VCO₂ slope has been shown to be higher the lower the peakVO₂ is [88]. This could be because of a marked sympathetic overactivity and neurohormonal imbalance in these patients, causing an exaggerated ventilatory response to exercise and/or to exercise-induced ischemia, causing a mismatch between CO response to exercise and increasing work rate and a consequent metabolic acidosis. The VE versus VCO₂ slope has been found to be increased also in patients with congenital heart disease, probably because of an altered V _D/V _T ratio in this population [89, 90]. Finally, a high VE versus VCO₂ slope is frequently observed in CHF patients (Fig. 4, lower panel) and is associated with the severity of disease [91–93] (see section ‘Patients with chronic heart failure’).

Exercise oscillatory ventilation

Periodic breathing oscillations of VO₂, VCO₂, and VE may be present in humans during spontaneous breathing while awake (both at rest and during exercise) and during sleep, and their presence is usually associated with an underlying pathological condition [94]. Exercise-induced oscillatory ventilation (EOV) is a slow, prominent, consistent (rather than random) fluctuation of VE during incremental exercise that may be evanescent or transient and has several distinct patterns. It has been observed throughout the entire exercise protocol, or only during early or peak exercise [95–98]. The origin of these oscillations is unclear, and several mechanisms have been proposed, which may be conveniently grouped into ventilatory (i.e. instability in the feedback ventilatory control system) and hemodynamic (i.e. pulmonary blood flow fluctuations) [99].

EOV has been defined in different ways. Kremser et al.'s [95] definition relies on the presence of cyclic fluctuations in VE lasting longer than 66% of the exercise protocol, with an amplitude of more than 15% of the average value at rest, and increasing in the transition from rest to light exercise and diminishing during heavy exercise (Fig. 5). Leite et al.'s [100] description is based on the following criteria: (i) three or more regular oscillations (i.e. clearly distinguishable from inherent data noise); (ii) regularity, so-defined when the standard deviation of three consecutive cycle lengths (time between two consecutive nadirs) is within 20% of the average; and (iii) minimal average amplitude of VE oscillation equals to 5 l (peak value minus the average of two in-between consecutive nadirs). Notably, the detection of VAT is often masked by the presence of EOV [97].

Among cardiac patients, EOV during exercise testing has been specifically detected in those with CHF (see section ‘Patients with chronic heart failure), and associated with cyclic changes in arterial O₂ and CO₂ tensions; the magnitude of EOV during exercise is correlated with the severity of heart failure [99].

Use of cardiopulmonary exercise testing for the evaluation of central hemodynamics

VO₂ and cardiac output

As already shown in the section ‘Maximal oxygen uptake’, VO₂ is the product of CO times C(a-v)O₂. In the systemic circulation, O₂ content increases during incremental exercise above VAT because of an increase in Hb, which is mainly because of the oncotic effect of increased intracellular lactate concentration [101, 102]. In the pulmonary artery, O₂ content diminishes progressively throughout the entire exercise; below anaerobic threshold, this is because of a reduction of arterial O₂ tension (PaO₂) and above anaerobic threshold of both a shift in the oxyhemoglobin dissociation curve (Bohr effect) and a reduction of PaO₂ [103]. As a consequence, C(a-v)O₂ increases linearly with progression of work rate, and its value is relatively fixed at anaerobic threshold and peak effort in normal individuals, which makes C(a-v)O₂ at a given relative intensity of effort predictable, and CO indirectly assessable according to the Fick equation, when the corresponding absolute VO₂ value is known [104, 105]. Alternatively, stroke volume at peak exercise can be estimated through the oxygen pulse, which is VO₂/heart rate, that is, stroke volume multiplied by C(a-v)O₂; assuming normal values of arterial O₂ content and C(a-v)O₂ at peak effort, peak stroke volume in milliliter can then be calculated as (peak oxygen pulse/15) × 100, where oxygen pulse is in milliliters per beat [30]; however, this estimation must be used with caution in nonperfectly normal and motivated individuals.

Few data are available as to normal CO values during effort. A frequently used formula based on the cardiac index versus VO₂ relationship during incremental exercise [106] has been adapted for CO estimation by converting cardiac index into CO values [22] (Table 2). This formula estimates the lower limit of normality for CO increase at a given VO₂ (i.e. energy expenditure) value in young to middle-aged healthy males.

In CHF patients, C(a-v)O₂ has a lower variability at VAT than at peak exercise, allowing more reliable CO estimates at such exercise intensity [107]. Indeed, estimated CO at VAT has been shown to independently predict multivessel coronary artery disease and the combined end point of cardiac death, reinfarction, and clinically driven revascularization in patients with recent acute myocardial infarction and reduced left ventricular ejection fraction [108]. However, rather than CO estimation during exercise, its direct noninvasive determination by means of CO₂ rebreathing or inert gas methods [109] together with VO₂ measurement might be a major advance in the evaluation of cardiac patients, allowing to calculate the C(a-v)O₂ and to build the CO/C(a-v)O₂/VO₂ plot (Fig. 6) [110]. This plot helps to discriminate between exercise limitation because of altered left ventricle pump function or other causes, mainly muscle deconditioning; indeed, for corresponding VO₂ values, in the former case CO increase is limited in the presence of a maximal widening of the C(a-v)O₂, whereas in the latter CO increase is greater with a lesser widening of the C(a-v)O₂. This can be useful in CHF patients, in whom both a normal and reduced CO response during effort has been described in the presence of a reduced peakVO₂ [22, 111, 112]. Moreover, the role of anemia in functional capacity impairment can be precisely calculated as well [113]. As each Hb gram carries 1.34 ml of O₂, and as at peak exercise Hb desaturation is approximately 70%, each gram of Hb delivers to the muscle about 1 ml of O₂. In normal conditions, Hb is 15 g/dl, and, if peak CO (dl/min) is known, one can easily estimate the amount of missing VO₂ owing to anemia at peak effort. For example, if peak CO is 7.0 l/min, that is, 70 dl/min, and Hb is 10 g/dl, the amount of VO₂ lacking because of anemia is 15 (normal Hb) − 10 (observed Hb) × 70 = 350 ml/min. Such a calculation is possible only if patients are normoxic, have no cardiac shunt, and the exercise is performed at sea level. This information can be very useful when planning a training intervention in the cardiac rehabilitation setting.

Circulatory power

Cardiac power, the product of CO and central aortic (or mean arterial) pressure, is one of the most powerful indices of cardiac systolic function [114–116]. This is because the heart and proximal vascular system are closely coupled and for two similar CO responses to exercise or to any stress, the ability — as opposed to inability — to sustain an optimal pressure testifies to a higher efficiency of the cardiac pump. Indeed, it has been shown that an impaired blood pressure response during exercise is associated with cardiac dysfunction and poor outcome [117]. For cardiac pumping capability determination during effort, cardiac power can be assessed noninvasively by using the CO₂ rebreathing or inert gas methods to measure CO [118–121]. The ‘circulatory power’ is a cardiac power surrogate obtainable from CPET, calculated as peakVO₂ multiplied by peak systolic blood pressure [122]. As such, circulatory power represents the triple product of CO times; C(a-v)O₂ (from the Fick equation) times; systolic blood pressure. For circulatory power to closely estimate cardiac power, there should not be a great difference in C(a-v)O₂ at peak exercise in either normal individuals or cardiac patients, which is usually the case [104, 105, 123–125]. Moreover, systolic blood pressure and mean arterial pressure should increase in parallel during exercise. In any case, given the inconsistency of diastolic blood pressure manual recording during exercise, systolic blood pressure measurement is more reliable than mean blood pressure in a noninvasive laboratory setting. Finally, unlike invasive assessment of cardiac power, never possible at truly peak exercise, circulatory power can be easily assessed at maximal effort during incremental exercise testing.

The normal values of peak circulatory power have not been extensively assessed and, like peakVO₂, depend on age, sex, body mass, and training level. Considering 25-40 ml/kg per min as normal values for peakVO₂ and 150-220 mmHg for peak systolic blood pressure, normal values of peak circulatory power between 3500 and 8800 mmHg times; ml/kg/min are obtained (Table 2), the highest being found in athletes and in hypertensive patients with preserved systolic function. Patients with CHF generally have values less than 3000 mmHgx ml/kg per min, and values less than 1800 mmHg times; ml/kg per min seem to be associated with a very-high short-term risk requiring aggressive treatment, such as in the case of heart transplantation. Circulatory power can also be calculated expressing peakVO₂ as a percentage of predicted VO_2max [126].

Circulatory power is an interesting parameter for the functional evaluation of cardiac patients as it summarizes heart rate, stroke volume, blood pressure, and C(a-v)O₂ responses to exercise (all of which can be altered in several cardiac pathophysiological conditions, in particular CHF), although it does not allow to distinguish between them as to relative responsibility for the exercise capacity impairment. Vasodilators and β-blockers may alter peakVO₂ and systolic blood pressure in opposite ways, but the final interaction between drug therapy and circulatory power has not been thoroughly evaluated yet [127].

Use of cardiopulmonary exercise testing for the evaluation of exercise relative intensity

The VO₂ reserve (VO₂R) is the difference between resting and peakVO₂, and, as it describes the O₂ used during exercise in addition to basal consumption, is considered a direct measure of the exercise load or energy expenditure [128, 129]. As a consequence, the percentage of VO₂R (%VO₂R) is now considered the gold standard for estimation, prescription, and monitoring of exercise relative intensity [130], even if limited by possible poor correspondence to exercise intensity as defined by physiological descriptors of effort intensity domains (i.e. VATand critical power, see section ‘VO₂ on-kinetics) [131].

Similar to VO₂R, heart rate reserve (HRR) is defined as the difference between basal and peak heart rate. In healthy sedentary (on both cycle ergometry and treadmill exercise) and in obese adults, the percentage of HRR (%HRR) has been found to be substantially equivalent to %VO₂R, and not to the percentage of VO_2max (%VO_2max) [128, 129, 132]. Indeed, %HRR has been found to be equivalent to %VO_2max in children and adolescents [133]; in contrast, in adults there is a discrepancy between %HRR and %VO_2max, which decreases with increasing exercise intensity and seems to be inversely related to individuals fitness [128, 129]. The equivalence between %HRR and %VO₂R has been observed also in elite endurance athletes [134]; notably, particularly in trained individuals, there seems to be a better prediction of %VO₂R from %HRR for running than for arm exercise [135]. Moreover, in patients with type 2 diabetes, %HRR was found to be an excellent descriptor of %VO₂R regardless of the presence of autonomic neuropathy [136]. This finding is consistent with those in patients with previous myocardial infarction both on and off β-blocking therapy [137], in whom an incremental ergometric test without respiratory gas analysis would thus be sufficient for exercise relative intensity assessment. However, in patients with CHF (independently of β -blocking therapy), a considerable uncertainty in prediction of %VO₂R on the basis of %HRR has been observed [138]; carrying out a CPET in individual CHF patient thus seems advisable for exercise relative intensity determination and to avoid training stimulus inadequacy or excessive exercise-related risk.

Regarding minimal aerobic training stimulus intensity, analysis of available studies supports the use of 45%VO₂R as a minimal effective intensity threshold for fit individuals (peakVO₂ > 40 ml/kg per min) and 30%VO₂R for those with a peakVO₂ less than 40 ml/kg per min [139]. Moreover, guidelines recommend a minimal intensity of 40%VO₂R to elicit improvements in aerobic fitness of less fit individuals, 50%VO₂R for the physically active, and up to 85%VO₂R for highly fit individuals [140].

In patients with coronary artery disease, 45%VO₂R is the minimum intensity recommended for improving aerobic fitness [39]; such a relative intensity is higher than that suggested for less fit normal individuals, as most cardiac patients do not reach their maximal effort and thus intensity prescription is based on peakVO₂ and not VO_2max. In any case, in agreement with the lower fitness-lower training stimulus intensity principle [141], relative intensities as low as 23%VO₂R [142], and probably even lower [143], have proved to be effective in CHF patients. From such a low-to-moderate intensity domain, aerobic training stimulus relative intensity can be increased according to individual needs in the high-intensity domain, up to the physiologic limit of aerobic steady-state performance, that is, critical power (see section ‘Critical power). Once exercise-related risk has been thoroughly assessed, such a training intensity can safely be prescribed also in cardiac patients, both with stable coronary artery disease and preserved left ventricular systolic function or CHF [144, 145].

The reported increase in peakVO₂ after a period of aerobic training in normal individuals ranges between 10 and 25%, whereas in cardiac patients it has been found to vary between 7 and 54%, with comparable increases described for VO₂ at VAT [146, 147]. However, a great discrepancy exists between different studies as to training-induced peakVO₂ and VO₂ at VAT changes, probably because of differences in study populations, individuals or patients baseline exercise capacity, and training stimulus intensity and duration. Physiological and performance parameters obtainable from CPET, and useful for aerobic training prescription and monitoring, are summarized in Table 3.

Table 3

Cardiopulmonary exercise testing physiological and performance parameters useful for aerobic exercise training prescription and monitoring


	Physiological	Performance

Intensity
Absolute	VO₂ at VAT	Power at VAT
	HR at VAT
	VO₂ at critical power	Critical power
	HR at critical power
	PeakVO₂	Peak power
	HR at peakVO₂
Relative	%VO₂R at VAT
	%HRR at VAT
	%VO₂R at critical power
	%HRR at critical power

%HRR, percentage of heart rate reserve; %VO₂R, percentage of VO₂ reserve; HR, heart rate; VAT, ventilatory anaerobic threshold; VO₂, oxygen uptake.

Use of cardiopulmonary exercise testing for the functional evaluation of specific populations

Patients with exercise-induced ischemia

CPET can be useful to detect exercise-induced myocardial ischemia, especially among patients with resting ECG abnormalities. Narrowing of the great epicardial coronary arteries does not let adequate blood flow to the myocardium during effort, which increases the myocardial O₂ need by increasing heart rate, blood pressure, and contractility. Exercise-induced myocardial ischemia is followed by decreased contractility and development of new regional wall-motion abnormalities; these, in turn, can result in decreasing stroke volume and CO and, consequently, reduced oxygen delivery to the periphery above the ischemic threshold. Indeed, patients with exercise-induced silent or symptomatic ischemia have been found to have lower peakVO₂ and oxygen pulse compared with nonischemic controls [148]. Moreover, symptomatic patients had significantly lower values of the same parameters and a higher reduction of left ventricular ejection fraction at peak effort compared with the silent ischemia group [148]. In another study [149], patients with exercise-induced ischemia presented peakVO₂ and oxygen pulse values similar to those of patients with normal perfusion; however, patients with extensive transient perfusion defects had a lower peak oxygen pulse than those with lower exercise-induced ischemia. Decreased VAT VO₂ has also been consistently shown to be related to the presence [148–152] and the extent [153] of myocardial ischemia.

The ischemia-induced reduction in stroke volume can also decrease the VO₂ versus power rise [154] and increase to some extent O₂ deficit values, which in turn could slow the VO₂ off-kinetics. Based on the above considerations, CPET has also been used for myocardial ischemia diagnostic purposes. Belardinelli et al. [155] showed that CPET improves significantly the diagnostic accuracy of standard ECG stress test for detecting exercise-induced myocardial ischemia, demonstrating a flattening of both VO₂ versus power slope and oxygen pulse increase as a consequence of worsening myocardial contraction during ischemia (Fig. 7). Bussotti et al. [150] also demonstrated a significant flattening of VO₂ versus power slope above anaerobic threshold in patients with exercise-induced silent ST-segment depression and presence of great coronary artery narrowing, as compared with patients with ST-segment depression but without coronary artery stenosis. In addition, the presence of a ‘hump’ morphology (i.e. a transient convex bulge at approximately 1 min of the VO₂ off-kinetics) has been shown to identify exercise-induced ischemia with 57% sensitivity and 97% specificity among patients with anterior Q-wave myocardial infarction [156]; such phenomenon could be because of a paradoxical increase of stroke volume after cessation of effort. Therefore, most pathophysiological factors linked to exercise-induced ischemia can be reliably measured by CPET, which should be used extensively for myocardial perfusion evaluation in patients with coronary artery disease, especially in the presence of an uninterpretable ECG during effort. In any case, it must be considered that a significant overlap of data exists among patients with and without ischemia; as a consequence, information derived from CPET should be integrated with other clinical and instrumental descriptors of exercise-induced myocardial ischemia. Changes of CPET parameters induced by myocardial ischemia are summarized in Table 4.

Table 4

Cardiopulmonary exercise testing parameters in special populations


	Exercise-induced ischemia	Recent coronary or valvular surgery	Recent or previous heart transplantation	Chronic heart failure

VO₂ at VAT	N or ↓ a	N or ↓	↓	↓or ↓↓
Critical power	?	?	?	?
Peak VO₂	↓	N or ↓	↓	↓or ↓↓
VO₂ on-kinetics mean response time	N or ↓ a	N or ↓?	↓	↓or ↓↓
VO₂ off-kinetics T_1/2	N or ↓ b	N or ↓?	↓	↓or ↓↓
O₂ uptake efficiency slope	N?	N or ↓?	↓	↓or ↓↓
VE versus VCO₂ slope	N?	N or ↑?	↑	↑ or ↑↑
Exertional oscillatory ventilation	Absent	?	Absent?	May be present c
Peak cardiac output		N or ↓?	↓	↓or ↓↓
Peak circulatory power	↓?	N or ↓?	↓?	↓ or ↓↓

?, not enough data available; ↓, reduced or shortened; ↓↓, severely reduced or shortened; ↑, increased or prolonged; ↑↑, markedly increased or prolonged; N, normal; VAT, ventilatory anaerobic threshold; VCO₂, CO₂ production; VE, ventilation; VO₂, oxygen uptake;

Depending on exercise level with respect to ischemic threshold.

Possible ‘hump’ phenomenon.

Usually detectable in 10-12% of patients.

Patients with recent coronary and valvular surgery

After recent coronary and/or valvular surgery, exercise testing is performed mostly to evaluate exercise tolerance, prescribe individualized training programs, look for residual ischemia and/or exercise-induced arrhythmias, and evaluate prognosis (mostly after coronary artery bypass grafting) [157–160]. Moreover, exercise testing and aerobic training have been recently confirmed to be safe early after heart valve surgery and coronary artery bypass grafting [161]. CPET adds to conventional ergometry the possibility of measuring more precisely patients exercise capacity and providing a sound physiological basis for exercise training prescription, in a population of patients with sometimes significantly impaired exercise performance. Indeed, early after cardiac surgery many factors can contribute to a drop of the exercise capacity with respect to the preoperative level: ventilatory impairment (from atelectasia, pleural effusion, and/or phrenic nerve injury), congestive heart failure, reduction of ribs and sternal mobility, anemia, sinus tachycardia, atrial fibrillation (in about 40% of patients), transient postoperative left ventricular dysfunction, and global fatigue [160, 162]. Indeed, among patients entering a rehabilitation program after a recent acute cardiac event those with recent coronary artery bypass graft have been found to have the lowest peakVO₂ [38].

Exercise tolerance may be even more impaired after heart valve surgery, as physiological hemodynamic conditions are not fully restored by valve replacement or repair. All prostheses are more or less stenotic, and this may result in a hemodynamically significant stenosis during exercise, mostly after mitral valve replacement but probably also in the presence of prosthesis/patient size mismatch after aortic valve replacement [163]. Moreover, heart rate is often higher than after coronary artery bypass grafting (because of absence of systematic β-blocking therapy and/or higher incidence of atrial fibrillation) and no formula allows the calculation of the heart rate at the anaerobic threshold, which is often used as a target during the training sessions. Le Tourneau et al. [164] investigated the functional effects of surgical correction of mitral regurgitation by mitral valve replacement or repair in the absence of cardiac rehabilitation. Patients underwent CPET before and 216 ± 80 days after surgery (i.e. after healing of all transient postoperative complications); surprisingly, mitral regurgitation correction did not lead to an overall improvement of peakVO₂ in either the valve repair or replacement group; these results were confirmed by Kim et al. [165]. In contrast, a recent study in early postmitral valve repair patients [166] showed that a CPET performed 21 ± 10 days after surgery allowed to prescribe an exercise aerobic training driven by the measured heart rate at VAT; after completion of the training period, peakVO₂, peak power, peak oxygen pulse, and chronotropic reserve improved significantly. These results confirmed those of Douard et al. [167], who observed a significant increase of peakVO₂ after a 3-month aerobic training period driven by CPET results in patients having undergone mitral balloon valvuloplasty for mitral stenosis. In summary, early after coronary and especially valvular heart surgery, the spontaneous exercise capacity improvement is weak and CPET allows the prescription of an efficient training program focused on the patient s physiological limitations. Changes in CPET parameters induced by recent coronary and valvular surgery are summarized in Table 4.

Patients with chronic heart failure

A reduced ability to perform aerobic exercise is the hallmark of the CHF pathophysiologic feature [24], related to changes in both peripheral (skeletal muscle, endothelium, regional blood flow, and reflex cardiopulmonary control systems) and central (lung, heart, and Hb content of arterial blood) links of the O₂ transport chain from ambient air to the skeletal muscle [168–170]. These changes promote a vicious cycle of deterioration involving catabolic drive and reflex neurohormonal over-activation [170, 171], which may lead to disease progression and functional deterioration. As a consequence, in CHF patients peakVO₂ is typically reduced with respect to age-matched normal individuals when computed either in absolute (l/min) or weighted terms (ml/kg per min), or as percent of predicted VO_2max, and its reduction is proportional to the severity of the syndrome [24, 172]. Together with peakVO₂, also all the other descriptors of O₂ transport and utilization system efficiency are altered. For example, a reduction in the values of VO₂ at VAT, a parameter derived from submaximal work rate and therefore independent of patient motivation, has been classically described [26]. However, in the most advanced stages of the syndrome a clear VAT is often not identifiable, particularly in the presence of EOV. Consistent with the above findings, also a reduction in the VO₂ versus power slope and a prolongation of both VO₂ on-kinetics and off-kinetics in moderate-intensity constant-power effort and of VO₂ off-kinetics after incremental exercise have been described [19, 60] and, in addition to VAT, provide useful submaximal descriptors of O₂ transport/utilization system efficiency. Patients with CHF and permanent atrial fibrillation show peakVO₂ values even lower than those of CHF patients in sinus rhythm, but with VAT occurring at a higher percentage of peakVO₂ [173].

CPET also reveals an increased VE at comparable absolute submaximal levels of effort in CHF patients with respect to age-matched normal individuals [91]. As a consequence, the VE versus VCO₂ slope is usually increased [174, 175] (Fig. 4, lower panel), testifying to a reduced ventilatory efficiency, which may be improved by aerobic training [174]. Such ventilatory inefficiency is further evidenced by a decrease of the OUES with respect to age-matched normal individuals [20, 76, 81] (Fig. 4, upper panel). Among the causes of the increased ventilatory response to exercise, a reduced oxygen-diffusing capacity because of an impairment of alveolar-arterial oxygen transfer has been suggested [176], although O₂ transfer is preserved and arterial O₂ desaturation during exercise is rare in otherwise uncomplicated CHF [177]. An increase in dead space VE can be advocated because of a mismatching of VE relative to pulmonary perfusion of the high alveolar VE versus low alveolar perfusion type [91]. Another likely mechanism explaining the excessive exercise VE of CHF patients is an exaggerated ergoreflex response originating in the exercising skeletal muscles during effort [174], in the context of a generalized myopathy with early acidotic response: this may explain also the sympathetic hyper-responsiveness present in this syndrome [175]. In addition, EOV has been described in a variable percentage (20-60%) of CHF patients (Fig. 5), associated with poor exercise capacity and severe prognosis [177, 178]. It has been attributed to the interaction of altered hemodynamic and neurohormonal regulatory factors [177, 179], even if recent data seem to depict an even more complex pathophysiologic feature [180].

CPETcan also be used to monitor the effects of cardiac resynchronization therapy by biventricular pacing on CHF exercise pathophysiology [181], also when upgrading from right ventricular to biventricular pacing [182]. Moreover, CPET has been used for the functional evaluation of CHF patients after left ventricular assist device implantation, demonstrating a significant short-term peakVO₂ improvement [183, 184]. Finally, CPET can describe both functional impairment and prognosis of patients with diastolic heart failure [185]. Changes in CPET parameters induced by CHF are summarized in Table 4.

Patients with recent or previous heart transplantation

Despite a successful replacement of the failing heart and a recovery of cardiac function, most heart transplant (HTx) recipients experience a persistent impairment in maximal exercise capacity. Indices of maximal and submaximal aerobic exercise capacity (peakVO₂ and VO₂ at VAT) improve significantly during the first 2 years after HTx, remaining, however, around 60-70% of the age-related and sex-related reference values [186, 187].

Several mechanisms, both central and peripheral, may account for this finding. First, surgical-induced cardiac denervation results in a decreased peak heart rate, a delayed heart rate response, and a decreased HRR during incremental exercise (i.e. chronotropic incompetence), which persist for many years after HTx [186]. It has been proposed that the observed chronotropic incompetence, together with cyclosporin-induced diastolic dysfunction, is the major cause of exercise intolerance in HTx recipients; however, recent data obtained in paced and physically trained HTx patients question this hypothesis [188–190]. Second, because of irreversible pretransplant damage of the alveolar-capillary membrane, chronic administration of immunosuppressive drugs, and cytomegalovirus infection, pulmonary diffusion capacity is impaired in most HTx recipients; it is still under debate whether an impaired pulmonary diffusion capacity is a major factor in the limitation of the exercise capacity after HTx [191]. Third, blood flow and oxygen distribution to the skeletal muscles are impaired after HTx. Several authors have demonstrated a decreased capillary density and vascular dysfunction with persistent endothelial dysfunction in the skeletal muscle of HTx patients [192]. It has been shown that improvements in the exercise capacity after exercise training in HTx are highly correlated with improvements in skeletal muscle endothelial function and not to alterations in cardiac or pulmonary function, implying a major role of endothelial function in the observed exercise capacity impairment [193]. Moreover, during the progression of CHF a specific myopathy develops, which persists after HTx and is even worsened by the administration of corticosteroids and cyclosporin, inducing muscle atrophy and a further decrease in oxidative capacity; these detrimental changes result in an inefficient muscle metabolism and a decreased muscle strength [194]. As for endothelial dysfunction, these muscular adaptations can be reversed by exercise training and correlate closely with the observed improvements in exercise capacity [195]. Owing to these muscular metabolic changes, both on-kinetics and off-kinetics of VO₂ during constant-power moderate-intensity exercise are delayed in HTx patients [196, 197].

Finally, ventilatory efficiency (expressed both as OUES and VE versus VCO₂ slope) improves during the first years after HTx, remaining, however, impaired and reaching values comparable with those observed in moderate CHF. The increased ventilatory response to exercise may be caused by sustained increases in peripheral chemoreceptor sensitivity and increased muscle metaboreflex activity in response to locally produced metabolites during effort [197, 198]. Changes of CPET parameters induced by HTx are summarized in Table 4.

Conclusion

CPET is a methodology now widely available throughout the world and supported by an impressive body of scientific evidence in several different clinical fields. This study emphasizes the opportunities that CPET offers for the functional evaluation of cardiac patients, illustrating the wealth of information obtainable through an experienced use of this powerful tool. The choice of parameters to measure will depend on the specific goals of the functional evaluation in the individual patient, namely, exercise tolerance assessment, training prescription, treatment efficacy evaluation, investigation of exercise-induced adaptations of the O₂ transport/utilization system (whether of single links or the whole system), etc. However, the full potentialities of CPET in the clinical and research setting still remain largely underused because of inertia of the cardiologic world in the face of a demanding methodology from the cultural standpoint. Strong efforts are needed to promote a more widespread use of CPET in the functional evaluation of cardiac patients.

Footnotes

Acknowledgements

The authors are grateful to Rosemary Allpress for her careful revision of the English manuscript. There are no conflicts of interest.

References

Wasserman

Hansen

Sue

Stringer

Whipp

BJ.

Principles of exercise testing and interpretation: including pathophysiology and clinical applications. Philadelphia: Lippincott Williams & Wilkins; 2005.

2 Task Force

ERS

Palange

Ward

Carlsen

Casaburi

Gallagher

Gosselink

. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007; 29:185–209.

3 Arena

Myers

Williams

Gulati

Kligfield

Balady

.; American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Nursing. Assessment of functional capacity in clinical and research settings. A Scientific Statement From the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing. Circulation 2007; 116:329–343.

Gay

Weisman

Flaherty

Martinez

FJ.

Cardiopulmonary exercise testing in unexplained dyspnea. In: Weisman

Zeballos

, editors. Clinical exercise testing. Basel: Karger; 2002. pp. 81–88.

5 Task Force of the Italian Working Group on Cardiac Rehabilitation and Prevention (Gruppo Italiano di Cardiologia Riabilitativa e Prevenzione, GICR); Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology. Statement on cardiopulmonary exercise testing in chronic heart failure due to left ventricular dysfunction: recommendations for performance and interpretation Part III: Interpretation of cardiopulmonary exercise testing in chronic heart failure and future applications. Eur J Cardiovasc Prev Rehabil 2006; 13:485–494.

Hill

Long

CNH

Lupton

Muscular exercise, lactic acid and the supply and utilization of oxygen. Proc R Soc Lond 1924; 96:438–475.

Wasserman

Hansen

Sue

Stringer

Whipp

BJ.

Physiology of exercise. In: Wasserman

Hansen

Sue

Stringer

Whipp

, editors. Principles of exercise testing and interpretation: including pathophysiologyand clinical applications. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 10–65.

8 Binder

Wonisch

Corra

Cohen-Solal

Vanhees

Saner

. Methodological approach to the 1st and 2nd lactate threshold in incremental cardiopulmonary exercise testing. Eur J Cardiovasc Prev Rehabil 2008; 15:726–734.

Meyer

Lucía

Earnest

Kindermann

A conceptual framework for performance diagnosis and training prescription from submaximal gas exchange parameters-theory and application. Int J Sports Med 2005; 26 (Suppl 1):S38–S48.

10.

Goodman

McKenzie

Taunton

Walters

MB.

Ventilatory threshold and training heart rate in exercising cardiac patients. Can J Sport Sci 1988; 13:220–224.

11.

McLellan

TM.

Ventilatory and plasma lactate response with different exercise protocols: a comparison of methods. Int J Sports Med 1985; 6:30–35.

12.

Yeh

Gardner

Adams

Yanowitz

Crapo

RO.

Anaerobic threshold: problems of determination and validation. J Appl Physiol 1983; 55:1178–1186.

13.

Davis

Vodak

Wilmore

Vodak

Kurtz

Anaerobic threshold and maximal aerobic power for three modes of exercise. J Appl Physiol 1976; 41:544–550.

14.

Beaver

Wasserman

Whipp

BJ.

A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986; 60:2020–2027.

15.

Meyer

Faude

Scharhag

Urhausen

Kindermann

Is lactic acidosis a cause of exercise induced hyperventilation at the respiratory compensation point? Br J Sports Med 2004; 38:622–625.

16.

Wasserman

Hansen

Sue

Stringer

Whipp

BJ.

Normal values. In: Wasserman

Hansen

Sue

Stringer

Whipp

, editors. Principles of exercise testing and interpretation: including pathophysiology and clinical applications. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 160–182.

17.

Hill

DW.

The critical power concept. Sports Med 1993; 16:237–254.

18.

Babcock

Paterson

Cunningham

Dickinson

JR.

Exercise on-transient gas exchange kinetics are slowed as a function of age. Med Sci Sports Exerc 1994; 26:440–446.

19.

Cohen-Solal

Laperche

Morvan

Geneves

Caveziel

Gourgon

Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy. Circulation 1995; 91:2924–2932.

20.

Hollenberg

Tager

IB.

Oxygen uptake efficiency slope: an index of exercise performance and cardiopulmonary reserve requiring only submaximal exercise. J Am Coll Cardiol 2000; 36:194–201.

21.

Neder

Nery

Peres

Whipp

BJ.

Reference values for dynamic responses to incremental cycle ergometry in males and females aged 20 to 80. Am J Respir Crit Care Med 2001; 164:1481–1486.

22.

22 Chomsky

Lang

Rayos

Shyr

Yeoh

Pierson

III . Haemodynamic exercise testing. A valuable tool in the selection of cardiac transplantation candidates. Circulation 1996; 94:3176–3183.

23.

Joyner

Coyle

EF.

Endurance exercise performance: the physiology of champions. J Physiol 2008; 586:35–44.

24.

Solal

Chabernaud

Gourgon

Comparison of oxygen uptake during bicycle exercise in patients with chronic heart failure and in normal subjects. J Am Coll Cardiol 1990; 16:80–85.

25.

25 Capelli

Antonutto

Kenfack

Cautero

Lador

Moia

. Factors determining the time course of VO2(max) decay during bedrest: implications for VO2(max) limitation. Eur JAppl Physiol 2006; 98:152–160.

26.

Metra

Raddino

Dei Cas

Visioli

Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure. Am J Cardiol 1990; 65:1127–1133.

27.

Cohen-Solal

Aupetit

Gueret

Kolsky

Zannad

Can anaerobic threshold be used as an end-point for therapeutic trials in heart failure? Lessons from a multicentre randomized placebo-controlled trial. The VO2 French Study Group. Eur Heart J 1994; 15:236–241.

28.

Saltin

Calbet

JA.

Point: in health and in a normoxic environment, VO2max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol 2006; 100:744–745.

29.

Noakes

TD.

Testing for maximum oxygen consumption has produced a brainless model of human exercise performance. Br J Sports Med 2008; 42:551–555.

30.

Wasserman

Hansen

Sue

Stringer

Whipp

BJ.

Measurements during integrative cardiopulmonary exercise testing. In: Wasserman

Hansen

Sue

Stringer

Whipp

, editors. Principles of exercise testing and interpretation: including pathophysiology and clinical applications. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 76–110.

31.

Day

Rossiter

Coats

Skasick

Whipp

BJ.

The maximally attainable VO2 during exercise in humans: the peak vs. maximum issue. J Appl Physiol 2003; 95:1901–1907.

32.

Myers

Applications of cardiopulmonary exercise testing in the management of cardiovascular and pulmonary disease. Int J Sports Med 2005; 26 (Suppl 1):S49–S55.

33.

Howley

Basset

Jr Welch

HG.

Criteria for maximal oxygen uptake: review and commentary. Med Sci Sports Exerc 1995; 27:1292–1301.

34.

34 Rivera

Pei

russe L

Simoneau

Gagnon

Dionne

Leon

. Linkage between a muscle-specific CK gene marker and VO2max in the HERITAGE family study. Med Sci Sports Exerc 1999; 31:698–701.

35.

2 Task Force

ERS

Palange

Ward

Carlsen

Casaburi

Gallagher

Gosselink

. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007; 29:185–209.

36.

Astrand

P-O

Rodahl

Physical training. In: Astrand

P-O

Rodahl

, editors. Textbook of work physiology. Physiological bases of exercise. New York: McGraw Hill Book Company; 1986. pp. 412–485.

37.

Betik

Hepple

RT.

Determinants of VO2max decline with aging: an integrated perspective. Appl Physiol Nutr Metab 2008; 33:130–140.

38.

Astrand

Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand 1960; 49 (Suppl 169):1–9.

39.

38 Ades

Savage

Brawner

Lyon

Ehrman

Bunn

. Aerobic capacity in patients entering cardiac rehabilitation. Circulation 2006; 113:2706–2712.

40.

Swain

Franklin

BA.

Is there a threshold intensity for aerobic training in cardiac patients? Med Sci Sports Exerc 2002; 34:1071–1075.

41.

Nieuwland

Berkhuysen

Van Veldhuisen

Rispens

Individual assessment of intensity-level for exercise training in patients with coronary artery disease is necessary. Int J Cardiol 2002; 84:15–20.

42.

Billat

Sirvent

Koralsztein

Mercier

The concept of maximal lactate steady state: a bridge between biochemistry, physiology and sport science. Sports Med 2003; 33:407–426.

43.

Poole

Ward

Gardner

Whipp

BJ.

Metabolic and respiratory profile of the upper limit for prolonged exercise in man. Ergonomics 1988; 31:1265–1279.

44.

Dekerle

Baron

Dupont

Vanvelcenaher

Pelayo

Maximal lactate steady state, respiratory compensation threshold and critical power. Eur J Appl Physiol 2003; 89:281–288.

45.

Neder

Jones

Nery

Whipp

BJ.

The effect of age on the power/duration relationship and the intensity-domain limits in sedentary men. Eur J Appl Physiol 2000; 82:326–332.

46.

Jenkins

Quigley

BM.

Endurance training enhances critical power. Med Sci Sports Exerc 1992; 24:1283–1289.

47.

Faggiano

D'Aloia

Gualeni

Lavatelli

Giordano

Assessment of oxygen uptake during the 6-minute walking test in patients with heart failure: preliminary experience with a portable device. Am Heart J 1997; 134:203–206.

48.

Linnarson

Dynamics of pulmonary gas exchange and heart rate changes at start and end of exercise. Acta Physiol Scand 1974; 415 (Suppl):1–68.

49.

Whipp

Ward

Physiological determinants of pulmonary gas exchange kinetics during exercise. Med Sci Sports Exerc 1990; 22:62–71.

50.

Whipp

Ward

Rossiter

HB.

Pulmonary O2 uptake during exercise: conflating muscular and cardiovascular responses. Med Sci Sports Exerc 2005; 37:1574–1585.

51.

Di Prampero

PE.

Energetics of muscular exercise. Rev Physiol Biochem Pharmacol 1981; 89:143–222.

52.

Gaesser

Poole

DC.

The slow component of oxygen uptake kinetics in humans. Exerc Sport Sci Rev 1996; 24:35–70.

53.

Whipp

BJ.

Domains of aerobic function and their limiting parameters. In: Steinacker

Ward

, editors. The physiology and pathophysiology of exercise tolerance. New York: Plenum Press; 1996. pp. 83–89.

54.

Hansen

Casaburi

Cooper

Wasserman

Oxygen uptake as related to work rate increment during cycle ergometer exercise. Eur J Appl Physiol 1988; 57:140–145.

55.

Whipp

Davis

Torres

Wasserman

A test to determine parameters of aerobic function during exercise. J Appl Physiol 1981; 50:217–221.

56.

DeLorey

Kowalchuk

Paterson

DH.

Effect of age on O2 uptake kinetics and the adaptation of muscle deoxygenation at the onset of moderate-intensity cycling exercise. J Appl Physiol 2004; 97:165–172.

57.

Jones

Koppo

Effects of training on VO2 kinetics and performance. In: Jones

Poole

, editors. Oxygen uptake kinetics in sport, exercise and medicine. London: Routledge; 2005. pp. 373–397.

58.

57 Koike

Yajima

Adachi

Shinizu

Kano

Sugimoto

. Evaluation of exercise capacity using submaximal exercise at a constant work rate in patients with cardiovascular disease. Circulation 1995; 91:1719–1724.

59.

Lok

Lau

CP.

Oxygen uptake kinetics and cardiopulmonary performance in lone atrial fibrillation and the effects of sotalol. Chest 1997; 111:934–940.

60.

59 Adachi

Koike

Niwa

Sato

Takamoto

Marumo

. Percutaneous transluminal coronary angioplasty improves oxygen uptake kinetics during the onset of exercise in patients with coronary artery disease. Chest 2000; 118:329–335.

61.

Sietsema

Ben-Dov

Zhang

Sullivan

Wasserman

Dynamics of oxygen uptake for submaximal exercise and recovery in patients with chronic heartfailure. Chest 1994; 105:1693–1700.

62.

61 Feldman

Khan

Slaughter

Sobieski

Graham

Eaheart

. Improvement in early oxygen uptake kinetics with left ventricular assist device support. ASAIO J 2008; 54:406–411.

63.

Meakins

Long

Oxygen consumption, oxygen debt and lactic acid in circulatory failure. J Clin Invest 1927; 4:273–293.

64.

Margaria

Edwards

Dill

The possible mechanisms of contracting and paying the oxygen debt and the role of lactic acid in muscular contraction. Am J Physiol 1933; 106:689–715.

65.

Harris

Edwards

Hultman

Nordesjo

Nylind

Sahlin

The time course of phosphoril-creatine resynthesis during recovery of the quadriceps muscle in man. Pflugers Arch 1976; 367:137–142.

66.

Hagberg

Hickson

Ehsani

Holloszy

JO.

Faster adjustment to and recovery from submaximal exercise in the trained state. J Appl Physiol 1980; 48:218–224.

67.

Degroote

Millaire

Decoulx

Nugue

Guimier

Ducloux

Kinetics of oxygen consumption during and after exercise in patients with dilated cardiomyopathy: new markers of exercise intolerance with clinical implications. J Am Coll Cardiol 1996; 28:168–175.

68.

67 Nanas

Nanas

Kassiotis

Nikolaou

Tsagalou

Sakellariou

. Early recovery of oxygen kinetics after submaximal exercise test predicts functional capacity in patients with chronic heart failure. Eur J Heart Fail 2001; 3:685–692.

69.

68 Giardini

Donti

Specchia

Coutsoumbas

Formigari

Prandstaller

. Recovery kinetics of oxygen uptake is prolonged in adults with an atrial septal defect and improves after transcatheter closure. Am Heart J 2004; 147:910–914.

70.

69 Giardini

Specchia

Coutsoumbas

Donti

Formigari

Fattori

. Impact of pulmonary regurgitation and right ventricular dysfunction on oxygen uptake recovery kinetics in repaired tetralogy of Fallot. Eur J Heart Fail 2006; 8:736–743.

71.

Sunagawa

Honda

Yoshii

Mizoguchi

Fukuda

Iwao

Estimation of exercise capacity from oxygen consumption in the recovery phase of submaximal exercise. Jpn Circ J 1986; 50:1309–1312.

72.

Shimizu

Koike

Koyama

Kobayashi

Marumo

Hiroe

Kinetics of pulmonary gas exchange during and while recovering from exercise in patients after anterior myocardial infarction. Jpn Circ J 1999; 63:459–466.

73.

72 Baba

Nagashima

Goto

Nagano

Yokota

Tauchi

. Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise. J Am Coll Cardiol 1996; 28:1567–1572.

74.

73 Baba

Tsuyuki

Kimura

Ninomiya

Aihara

Ebine

. Oxygen uptake efficiency slope as a useful measure of cardiorespiratory functional reserve in adult cardiac patients. Eur J Appl Physiol Occup Physiol 1999; 80:397–401.

75.

Mourot

Perrey

Tordi

Rouillon

JD.

Evaluation of fitness level by the oxygen uptake efficiency slope after a short-term intermittent endurance training. Int J Sports Med 2004; 25:85–91.

76.

Van Laethem

Bartunek

Goethals

Nellens

Andries

Vanderheyden

Oxygen uptake efficiency slope, a new submaximal parameter in evaluating exercise capacity in chronic heart failure patients. Am Heart J 2005; 149:175–180.

77.

76 Davies

Wensel

Georgiadou

Cicoira

Coats

Piepoli

. Enhanced prognostic value from cardiopulmonary exercise testing in chronic heart failure by non-linear analysis: oxygen uptake efficiency slope. Eur Heart J 2006; 27:684–690.

78.

Pichon

Jonville

Denjean

Evaluation of the interchangeability of VO2max and Oxygen Uptake Efficiency Slope. Can J Appl Physiol 2002; 27:589–601.

79.

Marinov

Kostianev

Exercise performance and oxygen uptake efficiency slope in obese children performing standardized exercise. Acta Physiol Pharmacol Bulg 2003; 27:59–64.

80.

Defoor

Schepers

Reybrouck

Fagard

Vanhees

Oxygen uptake efficiency slope in coronary artery disease: clinical use and response to training. Int J Sports Med 2006; 27:730–737.

81.

80 Van Laethem

Van de Veire

De Sutter

Bartunek

De Backer

Goethals

. Prospective evaluation of the oxygen uptake efficiency slope as a submaximal predictor of peak oxygen uptake in aged patients with ischemic heart disease. Am Heart J 2006; 152:297–315.

82.

81 Van Laethem

Van de Veire

De Backer

Bihija

Seghers

Cambier

. Response of the oxygen uptake efficiency slope to exercise training in patients with chronic heart failure. Eur J Heart Fail 2007; 9:625–629.

83.

Baba

Kubo

Morotome

Iwagaki

Reproducibility of the oxygen uptake efficiency slope in normal healthy subjects. J Sports Med Phys Fitness 1999; 39:202–206.

84.

83 Ueshima

Myers

Ribisl

Atwood

Morris

Kawaguchi

. Hemodynamic determinants of exercise capacity in chronic atrial fibrillation. Am Heart J 1993; 125:1301–1305.

85.

Whipp

Ward

Wasserman

Ventilatory responses to exercise and their control in man. Am Rev Respir Dis 1984; 129 (Suppl): S17–S20.

86.

Hsia

CCW

Johnston

Jr.

Exercise physiology and lung diseases. In: Bone

, editor. Comprehensive textbook of pulmonary and critical care medicine. St Louis: Mosby-Yearbook; 1993. pp. 1–20.

87.

86 Wensel

Georgiadou

Francis

Bayne

Scott

Genth-Zotz

. Differential contribution of dead space ventilation and low arterial pCO2 to exercise hyperpnea in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2004; 93:318–323.

88.

Tabet

Beauvais

Thabut

Tartiere

Logeart

Cohen-Solal

A critical appraisal of the prognostic value of the VE/VCO2 slope in chronic heart failure patients. Eur J Cardiovasc Prev Rehabil 2003; 10:267–272.

89.

Van de Veire

Van Laethem

Philippé

De Winter

De Backer

Vanderheyden

De Sutter

VE/VCO2 slope and oxygen uptake efficiency slope in patients with coronary artery disease and intermediate peakVO2. Eur J Cardiovasc Prev Rehabil 2006; 13:916–923.

90.

89 Diller

Dimopoulos

Okonko

Babu-Narayan

Broberg

. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation 2005; 112:828–835.

91.

90 Dimopoulos

Okonko

Diller

Broberg

Salukhe

Babu-Narayan

. Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival. Circulation 2006; 113:2796–2802.

92.

91 Wasserman

Zhang

Gitt

Belardinelli

Koike

Lubarsky

. Lung function and exercise gas exchange in chronic heart failure. Circulation 1997; 96:2221–2227.

93.

Johnston

Jr.

Gas exchange efficiency in congestive heart failure. Circulation 2000; 101:2774–2776.

94.

93 Chua

Ponikowski

Harrington

Anker

Webb-Peploe

Clark

. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1997; 29:1585–1590.

95.

Khoo

Kronauer

Strohl

Slutsky

AS.

Factors inducing periodic breathing in humans: a general model. J Appl Physiol 1982; 53:644–659.

96.

Kremser

O'Toole

Leff

AR.

Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy. Am J Cardiol 1987; 59:900–905.

97.

Ben-Dov

Sietsema

Casaburi

Wasserman

Evidence that the circulatory oscillations accompany ventilatory oscillations during exercise in patients with heart failure. Am Rev Respir Dis 1992; 145:776–781.

98.

Yajima

Koike

Sugimoto

Miyahara

Marumo

Hiroe

Mechanism of periodic breathing in patients with cardiovascular disease. Chest 1994; 106:142–146.

99.

Feld

Priest

A cyclic breathing pattern in patients with poor left venticular function and compensated: a mild form of Cheyne-Stokes respiration? J Am Coll Cardiol 1993; 21:971–974.

100.

Piepoli

Ponikowski

Volterrani

Francis

Coats

AJ.

Aetiology and pathophysiological implications of oscillatory ventilation at rest and during exercise in CHF. Do Cheyne and Stokes have an important message for modern-day patients with heart failure? Eur Heart J 1999; 20:946–953.

101.

100 Leite

Mansur

de Freitas

Chizola

Bocchi

Terra-Filho

. Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation. J Am Coll Cardiol 2003; 41:2175–2181.

102.

101 Agostoni

Wasserman

Guazzi

Cattadori

Palermo

Marenzi

. Exercise-induced hemoconcentration in heart failure due to dilated cardiomyopathy. Am J Cardiol 1999; 83:278–280.

103.

102 Perego

Marenzi

Guazzi

Sganzerla

Assanelli

Palermo

. Contribution of PO2, P50, and Hb to changes in arteriovenous O2 content during exercise in heart failure. J Appl Physiol 1996; 80:623–631.

104.

103 Agostoni

Wasserman

Perego

Marenzi

Guazzi

Assanelli

. Oxygen transport to muscle during exercise in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 79:29–33.

105.

104

Stringer

Hansen

Wasserman

Cardiac output estimated noninvasively from oxygen uptake during exercise. J Appl Physiol 1997; 82:908–912.

106.

105 Wasserman

Hansen

Sue

Stringer

Whipp

, Clinical applications of cardiopulmonary exercise testing. In: Wasserman

Hansen

Sue

Stringer

Whipp

, editors. Principles of exercise testing and interpretation: including pathophysiology and clinical applications. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 198–241.

107.

106

Higginbotham

Morris

Williams

Mc Hale

Coleman

Cobb

Regulation of stroke volume during submaximal exercise and maximal upright exercise in normal man. Circ Res 1986; 58:281–291.

108.

107 Agostoni

Wasserman

Perego

Guazzi

Cattadori

Palermo

. Non-invasive measurement of stroke volume during exercise in heart failure patients. Clin Sci 2000; 98:545–551.

109.

108

Bigi

Desideri

Rambaldi

Cortigiani

Sponzilli

Fiorentini

Angiographic and prognostic correlates of cardiac output by cardiopulmonary exercise testing in patients with anterior myocardial infarction. Chest 2001; 120:825–833.

110.

109

Vanhees

Defoor

Schepers

Brusselle

Reybrouck

Fagard

Comparison of cardiac output measured by two automated methods of CO2 rebreathing. Med Sci Sports Exerc 2000; 32:1028–1034.

111.

110 Agostoni

Cattadori

Apostolo

Contini

Palermo

Marenzi

. Non-invasive measurement of cardiac output during exercise by inert gas rebreathing technique: a new tool for heart failure evaluation. J Am Coll Cardiol 2005; 46:1779–1781.

112.

111 Metra

Faggiano

D'Aloia

Nodari

Gualeni

Raccagni

. Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure. J Am Coll Cardiol 1999; 33:943–950.

113.

112

Wilson

Groves

Rayos

Circulatory status and response to cardiac rehabilitation in patients with heart failure. Circulation 1996; 94:1567–1572.

114.

113 Agostoni

Cerino

Palermo

Magini

Bianchi

Bussotti

. Exercise capacity in patients with beta-thalassaemia intermedia. Br J Haematol 2005; 131:278–281.

115.

114

Tan

Cardiac pumping and prognosis in heart failure. Lancet 1986; 2:1360–1363.

116.

115

Kass

Beyar

Evaluation of contractile state by maximal ventricular power divided by the square of end-diastolic volume. Circulation 1991; 84:1698–1708.

117.

116

Cotter

Milo-Cotter

Kaluski

Hemodynamic monitoring in acute heart failure. Crit Care Med 2008; 36 (Suppl):S40–S43.

118.

117 Osada

Chaitman

Miller

Yip

Cishek

Wolford

. Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation. J Am Coll Cardiol 1998; 31:577–582.

119.

118

Tan

Bain

Littler

Assessing cardiac pumping capability by exercise testing and inotropic stimulation. Br Heart J 1989; 62:20–25.

120.

119

Lang

Karlin

Hayte

Levy

Lim

Mancini

DM.

Peak cardiac power, measured non-invasively, is a powerful predictor of mortality in chronic heart failure. Circulation 2007; 116 (Suppl II):II–505.

121.

120 Williams

Cooke

Wright

Parsons

Riley

Marshall

. Peak exercise cardiac power output; a direct indicator of cardiac function strongly predictive of prognosis in chronic heart failure. Eur Heart J 2001; 22:1496–1503.

122.

121

Lang

Karlin

Haythe

Tsao

Mancini

DM.

Ease of noninvasive measurement of cardiac output coupled with peak VO2 determination at rest and during exercise in patients with heart failure. Am J Cardiol 2007; 99:404–405.

123.

122

Cohen-Solal

Tabet

Logeart

Bourgoin

Tokmakova

Dahan

A non-invasively determined surrogate of cardiac power (‘circulatory power’) at peak exercise is a powerful prognostic factor in chronic heart failure. Eur Heart J 2002; 23:806–814.

124.

123

Weber

Kinasewitz

Janicki

Fishman

Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982; 65:1213–1223.

125.

124

Higginbotham

Morris

Conn

Coleman

Cobb

FR.

Determinants of variable exercise performance among patients with severe left ventricular dysfunction. Am J Cardiol 1983; 51:52–60.

126.

125

Sullivan

Knight

Higginbotham

Cobb

Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial pressure. Circulation 1989; 80:769–781.

127.

126

Scharf

Merz

Kiowski

Oechslin

Schalcher

Brunner-La Rocca

HP.

Noninvasive assessment of cardiac pumping capacity during exercise predicts prognosis in patients with congestive heart failure. Chest 2002; 122:1333–1339.

128.

127

Tabet

Metra

Thabut

Logeart

Cohen-Solal

Prognostic value of cardiopulmonary exercise variables in chronic heart failure patients with or without beta-blocker therapy. Am J Cardiol 2005; 98:500–503.

129.

128

Swain

Leutholtz

BC.

Heart rate reserve is equivalent to %VO2 reserve, not to VO2%. Med Sci Sports Exerc 1997; 29:410–414.

130.

129

Swain

Leutholtz

King

Haas

Branch

JD.

Relationships between % heart rate reserve and %VO2 reserve in treadmill exercise. Med Sci Sports Exerc 1998; 30:318–321.

131.

130

Franklin

Whaley

Howley

ET.

General principles of exercise prescription. In: Franklin

Whaley

Howley

, editors. ACSM's guidelines for exercise testing and prescription. Philadelphia: Lippincott Williams & Wilkins; 2000. pp. 137–164.

132.

131

Meyer

Gabriel

HHW

Kindermann

Is determination of exercise intensities as percentages of VO2max or HRmax adequate? Med Sci Sports Exerc 1999; 31:1342–1345.

133.

132

Byrne

Hills

AP.

Relationships between HR and VO2 in the obese. Med Sci Sports Exerc 2002; 34:1419–1427.

134.

133

Hui

Chan

JW.

The relationship between heart rate reserve and oxygen uptake reserve in children and adolescents. Res Q Exerc Sport 2006; 77:41–49.

135.

134

Lounana

Campion

Noakes

Medelli

Relationship between %HRmax, %HR reserve, %VO2max and VO2 reserve in elite cyclists. Med Sci Sports Exerc 2007; 39:350–357.

136.

135

Rotstein

Meckel

Estimation of VO2 reserve from heart rate during arm exercise and running. Eur J Appl Physiol 2000; 83:545–550.

137.

136

Golberg

Swain

Vinik

AI.

Use of heart rate reserve and rating of perceived exertion to prescribe exercise intensity in diabetic autonomic neuropathy. Diabetes Care 2003; 26:986–990.

138.

137

Brawner

Keteyian

Ehrman

JK.

The relationship of heart rate reserve to VO2 reserve in patients with heart disease. Med Sci Sports Exerc 2002; 34:418–422.

139.

138

Mezzani

Corrà

Giordano

Cafagna

Adriano

Giannuzzi

Unreliability of the % VO2 reserve versus % heart rate reserve relationship for aerobic effort relative intensity assessment in chronic heart failure patients on or off-beta-blocking therapy. Eur J Cardiovasc Prev Rehabil 2007; 14:92–98.

140.

139

Swain

Franklin

BA.

VO2 reserve and the minimal intensity for improving cardiorespiratory fitness. Med Sci Sports Exerc 2002; 34:152–157.

141.

140 Pollock

Gaesser

Butcher

Despres

J-P

Dishman

Franklin

. ACSM Position Stand: The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc 1998; 30:975–991.

142.

141

Durstine

Painter

Franklin

Morgan

Pitetti

Roberts

SO.

Physical activity for the chronically ill and disabled. Sports Med 2000; 30:207–219.

143.

142

Belardinelli

Georgiou

Scocco

Barstow

Purcaro

Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol 1995; 26:975–982.

144.

143

Demopoulos

Bijou

Fergus

Jones

Strom

Le Jemtel

TH.

Exercise training in patients with severe congestive heart failure: enhancing peak aerobic capacity while minimizing the increase in ventricular wall stress. J Am Coll Cardiol 1997; 29:597–603.

145.

144

Rognmo

Hetland

Helgerud

Hoff

SlØrdahl

SA.

High intensity aerobic interval exercise is superior to moderate intensity exercise for increasing aerobic capacity in patients with coronary artery disease. Eur J Cardiovasc Prev Rehabil 2004; 11:216–222.

146.

145 Roveda

Middlekauff

Rondon

Reis

Souza

Nastari

. The effects of exercise training on sympathetic neural activation in advanced heart failure: a randomized controlled trial. J Am Coll Cardiol 2003; 42:854–860.

147.

146

Jones

Carter

The effects of endurance training on parameters of aerobic fitness. Sports Med 2000; 29:373–386.

148.

147

Hansen

Dendale

Berger

Meeusen

Rehabilitation in cardiac patients. What do we know about training modalities? Sports Med 2005; 35:1063–1084.

149.

148

Klainman

Kusniec

Stern

Fink

Farbstein

Contribution of cardiopulmonary indices in the assessment of patients with silent and symptomatic ischemia during exercise testing. Int J Cardiol 1996; 53: 257–263.

150.

149 Munhoz

Hollanda

Vargas

Silveira

Lemos

Hollanda

. Flattening of oxygen pulse during exercise may detect extensive myocardial ischemia. Med Sci Sports Exerc 2007; 39:1221–1226.

151.

150

Bussotti

Apostolo

Andreini

Palermo

Contini

Agostoni

Cardiopulmonary evidence of exercise-induced silent ischemia. Eur J Cardiovasc Prev Rehabil 2006; 13:249–253.

152.

151

Meyer

Samek

Pinchas

Baier

Betz

Roskamm

Relationship between ventilation threshold and onset of ischemia in ECG during stress testing. Eur Heart J 1995; 26:623–630.

153.

152

Fortini

Bonechi

Taddei

Gensini

Malfanti

Neri Serneri

GG.

Anaerobic threshold in patients with exercise-induced myocardial ischemia. Circulation 1991; 83 (Suppl):11–50.

154.

153

Zafrir

Fink

Klainman

Sulkes

Spitzer

Relation between aerobic capacity and extent of myocardial ischemia in patients with normal cardiac function. Am HeartJ 1999; 138:1088–1092.

155.

154 Itoh

Tajima

Koike

Osada

Maeda

Kato

. Oxygen uptake abnormalities during exercise in coronary artery disease. In: Wasserman

, editor. Cardiopulmonary exercise testing and cardiovascular health. Armonk: Futura Publishing Company; 2002. pp. 165–172.

156.

155 Belardinelli

Lacalaprice

Carle

Minnucci

Cianci

Perna

. Exercise-induced myocardial ischemia detected by cardiopulmonary exercise testing. Eur Heart J 2003; 24:1304–1313.

157.

156 Takaki

Sakuragi

Nagaya

Suzuki

Goto

Sato

. Postexercise VO2 Hump phenomenon as an indicator for inducible myocardial ischemia in patients with acute anterior myocardial infarction. Int J Cardiol 2006; 111:67–74.

158.

157 Butchart

Gohlke-Bärwolf

Antunes

Tornos

De Caterina

Cormier

.; Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology, European Society of Cardiology. Recommendations for the management of patients after heart valve surgery. Eur Heart J 2005; 26:2463–2471.

159.

158 American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease); Society of Cardiovascular Anesthesiologists, Bonow

Carabello

Chatterjee

de Leon

Jr Faxon

Freed

. ACC/AHA 2006 Guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice Guidelines (Writing Committee to Develop Guidelines on Patients with Valvular Heart Disease). Circulation 2006; 114:e84–e231.

160.

159 Gibbons

Balady

Beasley

Bricker

Duvernoy

Froelicher

. ACC/AHA guidelines for exercise testing: a report of the American College of Cardiology/American Heart Association Task Force on practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 1997; 30:260–315.

161.

160 Sellier

Chatellier

D'Agrosa-Boiteux

Douard

Dubois

Goepfert

.; Investigators of the PERISCOP study. Use of non-invasive cardiac investigations to predict clinical endpoints after coronary bypass graft surgery in coronary artery disease patients: results from the prognosis and evaluation of risk in the coronary operated patient (PERISCOP) study. Eur Heart J 2003; 24:916–926.

162.

161

Pavy

Iliou

Meurin

Tabet

Corone

Safety of exercise training for cardiac patients. Results of the French registry of complications during cardiac rehabilitation. Arch Intern Med 2006; 166:2329–2334.

163.

162

Weissman

Pulmonary function after cardiac and thoracic surgery. Anesth Analg 1999; 88:1272–1279.

164.

163 DeCarlo

Milano

Musumeci

Tartarini

Biadi

Benedetti

. Cardiopulmonary testing in patients with 21 mm St Jude medical aortic stenosis. J Heart Valve Dis 1999; 8:522–528.

165.

164 Le Tourneau

de Groote

Millaire

Foucher

Savoye

Pigny

. Effect of mitral valve surgery on exercise capacity, ventricular ejection fraction and neurohormonal activation in patients with severe mitral regurgitation. J Am Coll Cardiol 2000; 36:2263–2269.

166.

165 Kim

Ahn

Park

Cho

Sung

Hong

. Cardiopulmonary exercise testing before and one year after mitral valve repair for severe mitral regurgitation. Am J Cardiol 2004; 93:1187–1189.

167.

166 Meurin

Iliou

Ben Driss

Pierre

Corone

Cristofini

Tabet

; Working Group of Cardiac Rehabilitation of the French Society of Cardiology. Early exercise training after mitral valve repair: a multicentric prospective French study. Chest 2005; 128:1638–1644.

168.

167

Douard

Chevalier

Labbe

Choussat

Broustet

JP.

Physical training improves exercise capacity in patients with mitral stenosis after balloon valvuloplasty. Eur Heart J 1997; 18:464–469.

169.

168

Wilson

Martin

Schwartz

Ferraro

Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984; 69:1079–1087.

170.

169

Sullivan

Cobb

FR.

Central hemodynamic response to exercise in patients with chronic heart failure. Chest 1992; 101(Suppl):340S–346S.

171.

170

Clark

Poole-Wilson

Coats

AJ.

Exercise limitation in chronic heart failure: central role of the periphery. J Am Coll Cardiol 1996; 28:1092–1102.

172.

171

Floras

JS.

Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993; 22:72A–84A.

173.

172

Weber

Janicki

McElroy

PA.

Determination of aerobic capacity and the severity of chronic cardiac and circulatory failure. Circulation 1987; 76 (6Pt2):VI40–VI45.

174.

173 Agostoni

Emdin

Corra

Veglia

Magri

Tedesco

. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients. Eur Heart J 2008; 29:2367–2372.

175.

174

Piepoli

Clark

Volterrani

Adamopoulos

Sleight

Coats

AJ.

Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training. Circulation 1996; 93:940–952.

176.

175

Tumminello

Guazzi

Lancellotti

Pierard

LA.

Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance. Eur Heart J 2007; 28:673–678.

177.

176

Puri

Baker

Dutka

Oakley

Hughes

Cleland

JG.

Reduced alveolar capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance. Circulation 1995; 91:2769–2774.

178.

177

Clark

Coats

AJ.

Usefulness of arterial blood gas estimations during exercise in patients with chronic heart failure. Br Heart J 1994; 71: 528–530.

179.

178 Corra

Giordano

Bosimini

Mezzani

Piepoli

Coats

. Oscillatory ventilation during exercise in patients with chronic heart failure. Clinical correlates and prognostic implications. Chest 2002; 121:1572–1580.

180.

179 Ponikowski

Anker

Chua

Francis

Banasiak

Coats

AJS

. Oscillatory breathing pattern during wakefulness in patients with chronic heart failure-Clinical implications and role of augmented peripheral chemosensitivity. Circulation 1999; 100:2418–2424.

181.

180

Agostoni

Apostolo

Albert

RK.

Mechanisms of periodic breathing during exercise in patients with chronic heart failure. Chest 2008; 133:197–203.

182.

181

Wasserman

Sun

Hansen

JE.

Effect of biventricular pacing on the exercise pathophysiology of heart failure. Chest 2007; 132:250–261.

183.

182

Leclercq

Upgrading from right ventricular pacing to biventricular pacing in pacemaker patients with chronic heart failure: Heart failure. Heart 2008; 94:102–107.

184.

183 De Jonge

Kirkels

Lahpor

Klöpping

Hulzebos

de la Rivière

. Exercise performance in patients with end-stage heart failure after implantation of a left ventricular assist device and after heart transplantation: an outlook for permanent assisting? J Am Coll Cardiol 2001; 37: 1794–1799.

185.

184 Maybaum

Mancini

Xydas

Starling

Aaronson

Pagani

. LVAD Working Group. Cardiac improvement during mechanical circulatory support: a prospective multicenter study of the LVAD Working Group. Circulation 2007; 115:2497–2505.

186.

185

Guazzi

Myers

Arena

Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol 2005; 46:1883–1890.

187.

186

Braith

Edwards

DG.

Exercise following heart transplantation. Sports Med 2000; 30:171–192.

188.

187

Givertz

Hartley

Colucci

WS.

Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation 1997; 96:232–237.

189.

188

Scott

Omar

McComb

Dark

Bexton

RS.

Long-term pacing in heart transplant recipients is usually unnecessary. Pacing Clin Electrophysiol 1991; 14:1792–1796.

190.

189 Squires

Leung

Cyr

Allison

Johnson

Ballman

. Partial normalization of the heart rate response to exercise after cardiac transplantation: frequency and relationship to exercise capacity. Mayo Clin Proc 2002; 77:1295–1300.

191.

190 Richard

Verdier

Duvallet

Rosier

Leger

Nignan

. Chronotropic competence in endurance trained heart transplant recipients: heart rate is not a limiting factor for exercise capacity. J Am Coll Cardiol 1999; 33:192–197.

192.

191

Braith

Limacher

Mills

Jr Leggett

Pollock

Staples

ED.

Exercise-induced hypoxemia in heart transplant recipients. J Am Coll Cardiol 1993; 22:768–776.

193.

192 Schaefer

Piquard

Doutreleau

Mettauer

Epailly

Eisenmann

. Reduced exercise capacity is associated with reduced nitric oxide production after heart transplantation. J Thorac Cardiovasc Surg 2001; 122:821–822.

194.

193 Schmidt

Pleiner

Bayerle-Eder

Wiesinger

Rödler

Quittan

. Regular physical exercise improves endothelial function in heart transplant recipients. Clin Transplant 2002; 16:137–143.

195.

194

Schaufelberger

Eriksson

Lönn

Rundqvist

Sunnerhagen

Swedberg

Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation. Eur J Heart Fail 2001; 3:59–67.

196.

195

Lampert

Mettauer

Hoppeler

Charloux

Charpentier

Lonsdorfer

Skeletal muscle response to short endurance training in heart transplant recipients. J Am Coll Cardiol 1998; 32:420–426.

197.

196

Grassi

Marconi

Meyer

Rieu

Cerretelli

Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J Appl Physiol 1997; 82:1952–1962.

198.

197 Nanas

Terrovitis

Charitos

Papazachou

Margari

Tsagalou

. Ventilatory response to exercise and kinetics of oxygen recovery are similar in cardiac transplant recipients and patients with mild chronic heart failure. J Heart Lung Transplant 2004; 23:1154–1159.

199.

198 Van Laethem

Goethals

Verstreken

Walravens

Wellens

De Proft

. Response of the oxygen uptake efficiency slope to orthotopic heart transplantation: lack of correlation with changes in central hemodynamic parameters and resting lung function. J Heart Lung Transplant 2007; 26:921–926.

Standards for the use of cardiopulmonary exercise testing for the functional evaluation of cardiac patients: a report from the Exercise Physiology Section of the European Association for Cardiovascular Prevention and Rehabilitation

Abstract

Keywords

Introduction

Use of cardiopulmonary exercise testing for the evaluation of O2 transport and utilization efficiency

Ventilatory anaerobic threshold

Maximal oxygen uptake

Critical power

VO2 on-kinetics

VO2 off-kinetics

Use of cardiopulmonary exercise testing for the evaluation of ventilation efficiency and control

VO2 versus ventilation relationship: the oxygen uptake efficiency slope

Ventilation versus VCO2 relationship: the VE versus VCO2 slope

Exercise oscillatory ventilation

Use of cardiopulmonary exercise testing for the evaluation of central hemodynamics

VO2 and cardiac output

Circulatory power

Use of cardiopulmonary exercise testing for the evaluation of exercise relative intensity

Use of cardiopulmonary exercise testing for the functional evaluation of specific populations

Patients with exercise-induced ischemia

Patients with recent coronary and valvular surgery

Patients with chronic heart failure

Patients with recent or previous heart transplantation

Conclusion

Footnotes

Acknowledgements

References

Use of cardiopulmonary exercise testing for the evaluation of O₂ transport and utilization efficiency

VO₂ on-kinetics

VO₂ off-kinetics

VO₂ versus ventilation relationship: the oxygen uptake efficiency slope

Ventilation versus VCO₂ relationship: the VE versus VCO₂ slope

VO₂ and cardiac output