Minute ventilation/carbon dioxide production in chronic heart failure

Piergiuseppe Agostoni, Susanna Sciomer, Pietro Palermo, Mauro Contini, Beatrice Pezzuto, Stefania Farina, Alessandra Magini, Fabiana De Martino, Damiano Magrì, Stefania Paolillo, Gaia Cattadori, Carlo Vignati, Massimo Mapelli, Anna Apostolo, Elisabetta Salvioni
European Respiratory Review 2021 30: 200141; DOI: 10.1183/16000617.0141-2020

Abstract

In chronic heart failure, minute ventilation (V′E) for a given carbon dioxide production (V′CO2) might be abnormally high during exercise due to increased dead space ventilation, lung stiffness, chemo- and metaboreflex sensitivity, early metabolic acidosis and abnormal pulmonary haemodynamics. The V′E versus V′CO2 relationship, analysed either as ratio or as slope, enables us to evaluate the causes and entity of the V′E/perfusion mismatch. Moreover, the V′E axis intercept, i.e. when V′CO2 is extrapolated to 0, embeds information on exercise-induced dead space changes, while the analysis of end-tidal and arterial CO2 pressures provides knowledge about reflex activities. The V′E versus V′CO2 relationship has a relevant prognostic power either alone or, better, when included within prognostic scores. The V′E versus V′CO2 slope is reported as an absolute number with a recognised cut-off prognostic value of 35, except for specific diseases such as hypertrophic cardiomyopathy and idiopathic cardiomyopathy, where a lower cut-off has been suggested. However, nowadays, it is more appropriate to report V′E versus V′CO2 slope as percentage of the predicted value, due to age and gender interferences. Relevant attention is needed in V′E versus V′CO2 analysis in the presence of heart failure comorbidities. Finally, V′E versus V′CO2 abnormalities are relevant targets for treatment in heart failure.

Abstract

In chronic heart failure, the V′E versus V′CO2 relationship gives information about V′E/perfusion mismatch and exercise-induced dead space changes, has a relevant prognostic power, and may be modified in the presence of comorbidities https://bit.ly/2NwZWHa

Physiological aspects of the V′Eversus V′CO2 relationship and its association with heart failure prognosis

During an exercise with a progressively increasing workload, minute ventilation (V′E) increases in four distinct domains. The first domain is aerobic carbon dioxide production (V′CO2) in parallel with oxygen uptake (V′O2) increase, the second is V′CO2 anaerobic production with acidosis buffered by the available bicarbonate systems, the third is hydrogen (H+) when acidosis becomes unbuffered, and the fourth, evident in a few elite athletes, is related to heat dispersion [1, 2]. The last, rarely observed in normal subjects, is the main ventilatory drive for furred animals with no or extremely limited sweat production. Hyperventilation due to heat dispersion is known as panting. In dogs, panting is associated with extreme vasodilation of the tongue, while in humans panting is exceeded by thermal dispersion through sweat, so that it seldom becomes the driving force for V′E, and only at the very end of exercise. According to the different V′E domains, four slopes on the V′E versus workload relationship can be identified in athletes, but only three can be identified in subjects who are not athletes [2, 3] (figure 1). Consequently, up to the respiratory compensation point (RCP), which separates buffered from unbuffered acidosis, the relationship between V′E and V′CO2 is linear. The buffering capacity of the body during a short-lasting exercise mainly depends on the amount of bicarbonates available, which in turn strictly relates to pre-exercise V′E. In case of voluntary hyperventilation, which usually takes place immediately before and/or in the early phases of exercise, or of hyperventilation related to ambient conditions or to the disease itself, the reduced capacity of lactate buffering shortens the length of the isocapnic buffering period and reduces the V′O2 therein [4, 5]. At high altitude, where hypoxia-induced hyperventilation is the norm, the isocapnic buffering period even disappears (figure 2) [6]. Of note, in heart failure, the V′O2 increase during the isocapnic buffering period is directly associated with overall exercise performance [3, 7].

FIGURE 1
FIGURE 1

A few cardiopulmonary exercise parameters during a ramp exercise protocol. AT: anaerobic threshold; RCP: respiratory compensation point; PETO2: end-tidal oxygen pressure; PETCO2: end-tidal carbon dioxide pressure; V′E: ventilation; V′O2: oxygen uptake; V′CO2: carbon dioxide production. Reproduced from [3] with permission.

FIGURE 2
FIGURE 2

Cardiopulmonary exercise parameters during a ramp exercise protocol: oxygen uptake (V′O2) and carbon dioxide production (V′CO2) a) at sea level and b) at high altitude (Capanna Regina Margherita, Monte Rosa, Italian Alps, 4559 m) and end-tidal oxygen pressure (PETO2) and end-tidal carbon dioxide pressure (PETCO2) c) at sea level and d) at high altitude. V′E: ventilation; RC: respiratory compensation point; AT: anaerobic threshold. Reproduced from [6] with permission.

In heart failure patients, the mere identification of these three ventilation periods during a maximal exercise carries a relevant prognostic power [8]. The lack of identification of the ventilatory thresholds 1 and 2, as defined in the German literature [9], i.e. the anaerobic threshold (AT) and the RCP, respectively, can be due to several causes, such as periodic breathing, erratic breathing, uneven muscle fibre perfusion or metabolism [10]. The nonidentification of AT in an exercise where anaerobic metabolism has been reached, as suggested by a respiratory exchange ratio (V′CO2/V′O2) >1.05, is associated with a poor prognosis [11]. This happens in ≈10% of chronic heart failure patients who perform a maximal or nearly maximal cardiopulmonary exercise testing (CPET) [11]. An intermediate prognosis is that of heart failure patients with an identified AT but an unidentified RCP [8]. Figure 3, derived from the analysis of 1995 heart failure patients belonging to the Metabolic Exercise Cardiac Kidney Index score database, reports the survival of patients with identified AT and RCP (39% of cases), with identified AT and unidentified RCP (46% of cases), and with unidentified AT and RCP (15% of cases). The best prognosis was observed in patients in whom both AT and RCP were identified, whereas the risk of reaching the study end-point (composite of cardiovascular death, urgent heart transplant or left ventricular assist device) increased by 1.4 times in patients with AT but not RCP, and by 2.7 times in patients in whom neither AT nor RCP were identified [8]. Of note, the prognostic power of the identification of the aforementioned thresholds is independent of the V′O2 value reached at the threshold. Thus, as regards heart failure patients’ survival, any AT V′O2 value, albeit very low, is better than an unidentified AT [11].

FIGURE 3
FIGURE 3

5-year survival analysis in heart failure patients in whom anaerobic threshold (AT) and respiratory compensation point (RCP) were not identified (n=292), in whom only AT was identified (n=920) and in whom both AT and RCP (n=783) were identified. HT: heart transplant; LVAD: left ventricular assist device. Reproduced from [8] with permission.

Ventilation is the sum of alveolar (V′A) and dead space (V′D) ventilation, which is the part of V′E that does not participate in gas exchange. In normal subjects, V′A progressively increases during exercise, while V′D decreases, so that the linear relationship between V′E and V′CO2 has a positive intercept on the V′E axis, i.e. the extrapolation of V′E at V′CO2=0 (figure 4) [12]. Above RCP, V′E increase is mainly due to respiratory rate increase, with a minimal further increase in tidal volume. During exercise, the end-expiratory CO2 pressure (PETCO2) increases up to the isocapnic buffering period, when its highest value is reached. In normal subjects, both PETCO2 and arterial CO2 pressure (PaCO2) remain within their normal ranges up to RCP, but, above it, both PaCO2 and PETCO2 decrease [10, 13]. Accordingly, during exercise, if PETCO2 is low but PaCO2 is in the normal range, V′D must be increased due to V′E/perfusion (Q′) mismatch, with a prevalence of ventilated but not perfused lung zones. Differently, if PaCO2 is low, the increase in V′E is due to other stimuli such as reflexes (chemo-, metaboreflexes), so that the observed V′E/Q′ mismatch is a consequence and not a cause of hyperventilation. These two types of V′E increase have different denominations: hyperpnoea when PaCO2 is in its normal range, and hyperventilation when PaCO2 is low [14–16.] Experimentally, during exercise, a fixed increase in V′D is associated with an upward shift of the V′E versus V′CO2 relationship, whereas a progressive increase in V′D during exercise generates an increased V′E versus V′CO2 relationship slope (figure 4) [12, 17]. In brief, in normal subjects, the V′E versus V′CO2 relationship slope increase is linear up to RCP, with a positive Y-axis (V′E axis) intercept. Remarkably, the Y-axis intercept is not an indicator of V′D unless it has been added externally, but it provides information about V′D changes during exercise [18, 19]. The role of Y-axis intercept evaluation in specific comorbidities such as COPD/pulmonary arterial hypertension are discussed in detail later.

FIGURE 4
FIGURE 4

Schematic representation of ventilation (V′E) and carbon dioxide changes (V′CO2) during exercise in five different conditions: a) normal subject; b) normal subject with added external dead space; c) COPD; d) heart failure; e) pulmonary arterial hypertension. Dead space (V′D) and alveolar (V′A) ventilation are also reported. Reproduced from [12] with permission.

Finally, the analysis of the last part of exercise, i.e. the part above RCP, provides useful information. Indeed, when a further increase in the slope of the V′E versus V′CO2 relationship slope is observed, then the increase of V′E is only due to an increase of respiratory rate, so that V′D increases, but no or very limited increase of V′A is present [20]. In these cases, the PETCO2−PaCO2 difference becomes significantly negative. As a matter of fact, in parallel with the study of the V′E versus V′CO2 relationship, both as slope and as Y-intercept, attention must be dedicated to PETCO2, PaCO2 and PETCO2−PaCO2 difference during workload increase, because, combined, they provide us with clear information about V′D changes and V′E/Q′ mismatch during exercise.

How to report the V′Eversus V′CO2 relationship

The relationship between V′E and V′CO2 can be reported as the ratio or as the exercise relationship slope, but it used to be reported as V′E at V′CO2=1 L·m−1. In normal subjects, the V′E/V′CO2 ratio decreases at the beginning of exercise, then stays still and increases above RCP, reproducing a characteristic U shape (figure 5). However, several shapes of the V′E/V′CO2 ratio can be observed in specific clinical conditions, and looking at the shape can provide useful information, as follows. 1) In case of pre-test hyperventilation, the V′E/V′CO2 ratio progressively declines during exercise; 2) in COPD, the V′E/V′CO2 ratio is high and stays still or shows a limited reduction during exercise; 3) in case of heart failure, the V′E/V′CO2 ratio shifts upward, but usually maintains its U shape; 4) in case of pulmonary hypertension, V′E/V′CO2 ratio values are elevated and steady or progressively increasing in relation to the severity of pulmonary hypertension. The V′E/V′CO2 ratio has been reported at various moments of exercise, including submaximal and peak exercise [21–23.] The less variable V′E/V′CO2 ratio is probably the lowest recorded in a ramp exercise protocol, and it has been suggested as the value to consider as more clinically relevant [24–26.] In an exercise with a progressively increasing workload, the so-called ramp protocol test, the V′E versus V′CO2 relationship slope is physiologically measured from the beginning of exercise, usually after 1 min to avoid alteration of V′E associated with patients’ adaptation to exercise, up to the RCP, above which a second slope of the V′E versus V′CO2 relationship is usually present. In some laboratories, the V′E versus V′CO2 slope is assessed throughout the exercise, and it is consequently a little bit higher, although, when doing so, the clinical significance of the Y-axis intercept becomes at least less clear, if not lost [27, 28]. However, it is likely that both analyses can be accepted, provided that the CPET report clearly states which method has been applied, since reference values are probably different. Both the V′E/V′CO2 ratio and the V′E versus V′CO2 relationship slope (plus its Y-axis intercept) must be assessed in heart failure patients. Indeed, in parallel with the PETCO2 value, the V′E/V′CO2 ratio value during the isocapnic buffering period, when it is flat, gives information on the activation of the ventilation reflex [13], while the relationship slope tells more directly about the efficiency of V′E during exercise and the development of V′D.

FIGURE 5
FIGURE 5

Minute ventilation (V′E)/oxygen uptake (V′O2) and V′E/carbon dioxide production (V′CO2) ratio behaviour in a ramp exercise protocol in a) normal subjects; b) in case of pre-test hyperventilation; c) in COPD; d) in heart failure; and e) in pulmonary arterial hypertension.

Normal values of the slope of the V′Eversus V′CO2 relationship and of V′E/V′CO2 ratio

Sex- and age-specific normal values of the V′E/V′CO2 ratio, both at AT and as the lowest value, of V′E versus V′CO2 relationship slope and Y-axis intercept for normal subjects have been reported by Sun et al. [24], with a lowest V′E/V′CO2 cut-off value for poor prognosis ≥33 [25]. Differently, the normal values of the V′E versus V′CO2 relationship slope have been placed by several authors below an arbitrary value of 35, assuming that there is no influence of sex and age [29–32.] This arbitrary, “good-for-all” cut-off value has been proposed in different studies and even in guidelines [33], although the V′E versus V′CO2 slope increases with age and is higher in females [29]. In their pioneering work, Kleber et al. [34] utilised a percentage of predicted value to define the prognostic power of the V′E versus V′CO2 slope in heart failure. However, the normal population was small (n=101) and included 56 females. Similarly, other normal-value equations were proposed [24, 35, 36] but all from small samples, except very recently, when Salvioni et al. [29] reported normal values of a large population of both genders and all ages. Figure 6 [29] shows the regression equations of V′E versus V′CO2 slope relationship obtained in 1136 normal subjects (773 males and 363 females). The available regression equations to calculate the percentage of predicted V′E/V′CO2 slope are reported in table 1 [29]. Most importantly, Salvioni et al. [29] demonstrated that the percentage of V′E versus V′CO2 slope enhances the prognostic capacity of V′E versus V′CO2 slope in patients with severe heart failure (peak V′O2 <14 mL·min−1·kg−1), who are more in need of a precise life expectancy estimation.

FIGURE 6
FIGURE 6

Linear regression between minute ventilation (V′E)/carbon dioxide production (V′CO2) slope and age in a) normal subjects (n=1136); b) males (n=773); and c) females (n=363). Reproduced from [29] with permission.

View this table:
TABLE 1

Regressions proposed to calculate predicted ventilation/carbon dioxide production slope

Mechanical and pharmacological manipulation of the V′Eversus V′CO2 relationship

The V′E versus V′CO2 slope was assessed after a few manipulation manoeuvres. As mentioned earlier, an increase in external V′D shifts the V′E versus V′CO2 relationship upward, but it does not affect the slope [18]. Differently, in normal volunteers, shortly after an acute saline infusion at a rate allowing an infusion ranging between 25 and 30 mL·kg−1 in <30 min, a significant (≈12%) increase of V′E versus V′CO2 relationship slope was observed [38, 39]. Noteworthy, when alveolar–capillary membrane fluid movement is hampered by alveolar β2-receptor blockade, i.e. when active absorption of fluids from the alveolar space is impeded [40, 41], the V′E versus V′CO2 slope increase is ∼10%, with a further increase when rapid saline infusion and alveolar β2-receptor blockade are combined [39]. Altogether, these data suggest a direct relationship between lung stiffness generated by an increased lung fluid content and V′E inefficiency [42].

Reflex-mediated (metabo- and chemoreflex) increase in V′E is also associated with a V′E versus V′CO2 slope increase. This phenomenon was shown in exercises performed during acute high-altitude exposure, i.e. with hypobaric hypoxia [43–46.] Conversely, at a simulated altitude of 2000 m, the V′E versus V′CO2 slope increases in heart failure patients. Interestingly, carvedilol in the same laboratory conditions significantly reduces the slope from 39±10 to 32±14, most likely because of a reduction of chemoreceptor stimulation by hypoxia through β1-, β2- and α-receptor blockade [47].

The relationship between V′E and V′CO2, either measured as the ratio or as the relationship slope, is high in heart failure. There are several possible causes, including abnormal increased lung stiffness due to interstitial pulmonary alterations (increased intrathoracic fluids, fibrosis, etc.), increased chemo- and metaboreflex sensitivity, early metabolic acidosis and abnormal pulmonary haemodynamics with secondary pulmonary hypertension and high pulmonary wedge pressure. The combination of all the above mechanisms lead to V′E/Q′ mismatch, so that, for a given V′CO2, V′E is increased. In heart failure, the elevated V′E versus V′CO2 relationship is associated with a low PETCO2, which should be analysed mainly during the isocapnic buffering period (between AT and RCP) when PETCO2 most directly mirrors reflex activity [13]. In a pioneering, large, multicentre study on V′E abnormalities in heart failure, Wasserman et al. [48] showed that, in heart failure patients, 8%, 47% and 45% of V′E increase is due to PaCO2, V′CO2 and V′D volume (VD)/tidal volume (VT) ratio, respectively. More recently, Mezzani et al. [49] documented that the overactivation of reflex response is the main cause of the observed increase of V′E/V′CO2, while haemodynamic impairment plays an additional role in more advanced stages of heart failure. As regards the comparison between heart failure patients with preserved and with reduced ejection fraction, Van Iterson et al. [17] showed during exercise an impaired V′E efficiency in both groups, despite a higher V′E versus V′CO2 slope value in those with reduced ejection fraction as well as a different PaCO2 and VD/VT behaviour. Indeed, in heart failure patients with preserved ejection fraction, hyperpnoea, i.e. low VD/VT and normal PaCO2, seems to be the most prevalent cause of V′E increase, whereas in those with reduced ejection fraction, hyperventilation, i.e. overactivated reflexes and low PaCO2, seems to be the main cause of the increase of V′E [17, 50]. It must be underlined that heart failure patients with preserved ejection fraction actually suffer from a hodgepodge of different diseases, so that averaging data may be misleading. Several reports have shown the relevant role of V′E versus V′CO2 relationship in heart failure prognosis [22, 34, 51–60] with an average cut-off value of 35 [61]. Indeed, a classification of heart failure severity based on V′E versus V′CO2 slope has been suggested [62] and reported in heart failure guidelines [33]. Several heart failure prognostic scores include CPET data [63–71]. Notably, V′E versus V′CO2 slope maintains its strong prognostic role, even in composite heart failure scores [64, 65, 68]. In heart failure, a strong correlation has been described between V′E versus V′CO2 relationship abnormalities and sleep apnoea, which also has a relevant prognostic power in heart failure [72, 73]. Of note, the V′E versus V′CO2 relationship during exercise, regardless of how it is measured, has a relevant prognostic power both in heart failure patients with preserved and reduced ejection fraction, albeit stronger in the former [74]. Finally, the prognostic meaning of specific V′E versus V′CO2 slope values must be evaluated considering patients’ age, date of CPET and healthcare situation. Indeed, the V′E versus V′CO2 slope was reported to be higher in elderly patients [75], while for CPETs performed in 1993–2000, 2000–2005, 2005–2010 and 2010–2015, for a V′E versus V′CO2 of 34, a progressive reduction of the risk of the composite event cardiovascular death, urgent heart transplant or left ventricular assist device at 2 years was observed from ≈20%, to ≈12%, to ≈8% and ≈8%, respectively [76]. Therefore, in chronic heart failure patients, the prognostic meaning of the V′E versus V′CO2 relationship slope must be contextualised for the current local healthcare situation. This is relevant when comparing previous and present survival results as well as studies done in countries with different access to healthcare facilities.

V′Eversus V′CO2 relationship in heart failure therapy

Drugs used for heart failure treatment directly influence the V′E versus V′CO2 relationship [77]. Specifically, angiotensin-converting enzyme (ACE) inhibitors, but not angiotensin receptor blockers, improve both alveolar–capillary membrane diffusion and V′E versus V′CO2 relationship [78, 79], but the V′E versus V′CO2 slope improvement associated with ACE inhibitors is counteracted by the concomitant use of aspirin [78]. Accordingly, it has been suggested that the ACE inhibitor-induced V′E versus V′CO2 slope reduction is mediated by lung stiffness and VD/VT reduction, leading to V′E/Q′ improvement. Like ACE inhibitors, the long-term use of mineral receptor inhibitors, such as spironolactone or eplerenone, improves alveolar–capillary membrane diffusion and exercise performance. However, mineral receptor inhibitors do not seem to affect the V′E versus V′CO2 relationship, casting doubts about the true mechanisms of the action of ACE inhibitors on the V′E versus V′CO2 relationship [80]. In this regard, a modulating role of ACE inhibitors on chemoreflex activity has been suggested [81]. In addition, β-blockers can affect the V′E versus V′CO2 relationship in heart failure, although this effect is more evident with β1-β2-blockers such as carvedilol [77, 82, 83]. The mechanism is a direct reduction of overactivated chemoreflexes partially counteracted by a worsening of the alveolar–capillary membrane diffusion capacity [13, 39, 84]. Of note, although the reduction of V′E response to chemoreflex stimuli is considered a beneficial effect, it may turn into a negative one under specific circumstances such as acute hypoxia [47, 77]. It has been reported that long term sacubitril–valsartan treatment reduces the V′E versus V′CO2 slope, but only in patients with a V′E versus V′CO2 value >34 [85].

V′Eversus V′CO2 relationship in specific aetiologies

The V′E versus V′CO2 relationship during exercise has been studied in specific disease settings of heart failure such as hypertrophic cardiomyopathy, idiopathic cardiomyopathy and cardiac amyloidosis. In patients with hypertrophic cardiomyopathy, the V′E versus V′CO2 relationship is usually preserved within normal values. Nonetheless, the occasional finding of an elevated V′E versus V′CO2 slope value in hypertrophic cardiomyopathy patients has been associated with severe diastolic dysfunction and secondary pulmonary hypertension [86, 87]. In hypertrophic cardiomyopathy patients, a V′E versus V′CO2 slope value >32 has been reported as a powerful predictor of heart failure related events, and it is associated with poor prognosis and sudden cardiac death [88–90]. Of note, an even lower V′E versus V′CO2 slope cut-off value, 29, has been suggested by Sinagra et al. [91] for patients with idiopathic cardiomyopathy. The reason for the low cut-off values is probably that, in both hypertrophic cardiomyopathy and idiopathic cardiomyopathy, there is a high incidence of young patients and male sex. Conversely, in patients with heart failure due to amyloidosis, the V′E versus V′CO2 slope is significantly elevated and much more than in other patients with heart failure due to diastolic dysfunction of other origins [92]. The causes of the elevated V′E versus V′CO2 slope in these patients is likely the increase of backward pulmonary pressure. In amyloidosis, V′E versus V′CO2 relationship is both an indicator of therapy efficacy and a strong independent prognostic marker [92]. Specifically, the combination of V′E versus V′CO2 slope, C-reactive protein, sodium plasma level and serum creatinine, all independent significant prognostic indicators, leads to an AUC of 0.89 for 1-year mortality [92].

V′Eversus V′CO2 relationship in heart failure and associated comorbidities

In some comorbidities the Y-intercept of the V′E versus V′CO2 relationship has a central role in the interpretation of diagnosis. If it is above its upper normal value (2.7 L), V′D must have been high from the beginning, with a limited further increase of total V′E during exercise, as happens in COPD [12]. Conversely, if the Y-intercept is below its normal value, it suggests a progressive increase of V′D during exercise as is the case in heart failure, and, to a greater extent, in patients with pulmonary hypertension with and without heart failure. In these cases, the Y-intercept may even have a negative value [17, 19, 20]. Indeed, in a large multicentre study, Apostolo and co-workers [12, 93, 94] showed that, in heart failure, an elevated Y-intercept implies the coexistence of COPD, while a Y-intercept value close to 0 or negative implies the coexistence of pulmonary hypertension.

Special attention should be dedicated to the V′E versus V′CO2 relationship analysis during exercise in patients with heart failure and associated comorbidities such as anxiety/depression, obesity, lung disease, kidney dysfunction and anaemia [95]. Anxiety influences the ventilatory behaviour of heart failure patients as well as that of normal subjects, but usually only in the early phase of exercise. At the beginning of exercise and even before exercise, V′E increases, so that the CO2 stored in the body deposits and PETCO2 decrease, while V′E/V′CO2 ratio increases. As a consequence, the capability to buffer lactic acid is reduced, and so is the length of the isocapnic buffering period; moreover, the capability to identify the AT by ventilatory equivalents is hampered, as is the physiological meaning of PETCO2 and of V′E versus V′CO2 relationship. Depression, which is a frequent and dangerous comorbidity of heart failure, reduces the capacity/willingness of patients to perform a maximal exercise, so that the meaning of peak V′O2 is questionable in these patients. However, this does not affect the V′E versus V′CO2 relationship slope, which is likely to become the most powerful indicator of heart failure severity and prognosis in these patients. As regards heart failure patients with obesity, Piepoli et al. [96] reported a progressive reduction of the V′E versus V′CO2 slope in parallel with body mass index increase. However, peak V′O2 and ventricular ejection fraction also increased, so that the presence of a specific behaviour of the V′E versus V′CO2 slope in overweight heart failure patients is still unknown. Lung diseases are frequently reported comorbidities of heart failure, influencing the treatment and prognosis of both heart failure and lung disease. Specifically, CPET is heavily influenced by the combination of heart failure and lung disease, so that PETCO2 can progressively increase in patients with CO2 retention, the Y-axis intercept of V′E versus V′CO2 relationship slope (figure 4) is high, but, most importantly, the meaning of the V′E versus V′CO2 slope becomes uncertain for heart failure severity assessment and prognosis [12, 18, 93]. In addition, renal insufficiency is frequently associated with heart failure, and it is actually a part of the heart failure syndrome. Scrutinio et al. [97] showed, in a population of almost 3000 heart failure patients, that the V′E versus V′CO2 relationship slope was higher in patients with most severe renal impairment. Finally, anaemia deeply influences heart failure prognosis and directly affects peak V′O2 [98–100.] As regards the V′E versus V′CO2 relationship in heart failure patients with anaemia, there is an unexpected but relevant finding. As a matter of fact, Cattadori et al. [101] showed that, in a population of almost 4000 heart failure patients, 6% of cases had very low haemoglobin levels (<11 g·dL−1), while 17% had a haemoglobin value >15 g·dL−1. In both groups, the V′E versus V′CO2 relationship slope lost its prognostic power. The physiological reasons behind this finding are basically unknown, although a possible role of differences in peripheral O2 delivery and of the consequent metaboreflex on V′E can be speculated [102]. In any case, in the presence of heart failure comorbidities, the prognostic meaning of V′E versus V′CO2 slope must be contextualised in each specific clinical setting.

Conclusions

In conclusion, in the complex clinical scenario of the heart failure syndrome, the ventilatory behaviour during exercise, its shape, and its relationship with V′CO2 hide a variety of information useful for several features, including understanding the physiological cause of ventilatory abnormalities, assessing heart failure relationship with several comorbidities, grading heart failure severity, selecting therapy and planning heart failure follow-up. However, as frequently and erroneously done, we cannot relate to a single, good-for-all number. Indeed, we have to take into account when CPET was performed, patient's age, sex, concomitant treatments, and presence of heart failure comorbidities. Most importantly, we have to look at the V′E versus V′CO2 relationship by visual inspection to evaluate its shape, changes during exercise and Y-axis intercept of the relationship from the beginning of exercise to RCP, but also, separately, from RCP to peak exercise. Finally, V′E versus V′CO2 relationship values, regardless of how they are measured, must be integrated with several clinical and laboratory data to build the most precise mosaic of our heart failure subject with the aim of precisely tailoring their treatment.

Footnotes

  • Previous articles in this series: No. 1: Laveneziana P, Di Paolo M, Palange P. The clinical value of cardiopulmonary exercise testing in the modern era. Eur Respir Rev 2021; 30: 200187.

  • Provenance: Commissioned article, peer reviewed.

  • Number 2 in the Series “Ventilatory efficiency and its clinical prognostic value in cardiorespiratory disorders” Edited by Pierantonio Laveneziana and Paolo Palange

  • Conflict of interest: P. Agostoni reports non-financial support from Menarini, grants from Daiichi Sankyo and Bayer; non-financial support from Novartis and Boehringer; and grants and non-financial support from Actelion, outside the submitted work.

  • Conflict of interest: S. Sciomer has nothing to disclose.

  • Conflict of interest: P. Palermo reports personal fees from Novartis and Malesci, outside the submitted work.

  • Conflict of interest: M. Contini reports personal fees and non-financial support from Dompé Farmaceutici S.p.A. and personal fees from Novartis, outside the submitted work.

  • Conflict of interest: B. Pezzuto has nothing to disclose.

  • Conflict of interest: S. Farina has nothing to disclose.

  • Conflict of interest: A. Magini has nothing to disclose.

  • Conflict of interest: F. De Martino has nothing to disclose.

  • Conflict of interest: D. Magrì has nothing to disclose.

  • Conflict of interest: S. Paolillo has nothing to disclose.

  • Conflict of interest: G. Cattadori has nothing to disclose.

  • Conflict of interest: C. Vignati has nothing to disclose.

  • Conflict of interest: M. Mapelli has nothing to disclose.

  • Conflict of interest: A. Apostolo has nothing to disclose.

  • Conflict of interest: E. Salvioni has nothing to disclose.

  • Received May 14, 2020.
  • Accepted June 21, 2020.
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References

  1. ↵
    1. Wasserman K
    . Breathing during exercise. N Engl J Med 1978; 298: 780–785. doi:10.1056/NEJM197804062981408
    OpenUrlCrossRefPubMed
  2. ↵
    1. Chua TP,
    2. Ponikowski P,
    3. Harrington D, et al.
    Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1997; 29: 1585–1590. doi:10.1016/S0735-1097(97)00078-8
    OpenUrlFREE Full Text
  3. ↵
    1. Carriere C,
    2. Corrà U,
    3. Piepoli M, et al.
    Isocapnic buffering period: from physiology to clinics. Eur J Prev Cardiol 2019; 26: 1107–1114. doi:10.1177/2047487319829950
    OpenUrl
  4. ↵
    1. Whipp BJ,
    2. Davis JA,
    3. Wasserman K
    . Ventilatory control of the ‘isocapnic buffering’ region in rapidly-incremental exercise. Respir Physiol 1989; 76: 357–367. doi:10.1016/0034-5687(89)90076-5
    OpenUrlCrossRefPubMed
  5. ↵
    1. Tanehata M,
    2. Adachi H,
    3. Oshima S, et al.
    The time from anaerobic threshold (AT) to respiratory compensation point reflects the rate of aerobic and anaerobic metabolism after the AT in chronic heart failure patients. Jpn Circ J 1999; 63: 274–277. doi:10.1253/jcj.63.274
    OpenUrlPubMed
  6. ↵
    1. Agostoni P,
    2. Valentini M,
    3. Magrí D, et al.
    Disappearance of isocapnic buffering period during increasing work rate exercise at high altitude. Eur J Cardiovasc Prev Rehabil 2008; 15: 354–358.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Yen YS,
    2. Su DCJ,
    3. Yuan KS, et al.
    Isocapnic buffering phase: a useful indicator of exercise endurance in patients with coronary artery disease. Phys Sportsmed 2018; 46: 228–232. doi:10.1080/00913847.2018.1426967
    OpenUrl
  8. ↵
    1. Carriere C,
    2. Corrà U,
    3. Piepoli M, et al.
    Anaerobic threshold and respiratory compensation point identification during cardiopulmonary exercise tests in chronic heart failure. Chest 2019; 156: 338–347. doi:10.1016/j.chest.2019.03.013
    OpenUrl
  9. ↵
    1. Westhoff M,
    2. Rühle KH,
    3. Greiwing A, et al.
    Ventilatorische und metabolische (Laktat-)Schwellen Positionspapier der Arbeitsgemeinschaft Spiroergometrie. [Positional paper of the German working group “cardiopulmonary exercise testing” to ventilatory and metabolic (lactate) thresholds]. Dtsch Med Wochenschr 2013; 138: 275–280. doi:10.1055/s-0032-1332843
    OpenUrlCrossRef
  10. ↵
    1. Agostoni P,
    2. Dumitrescu D
    . How to perform and report a cardiopulmonary exercise test in patients with chronic heart failure. Int J Cardiol 2019; 288: 107–113. doi:10.1016/j.ijcard.2019.04.053
    OpenUrl
  11. ↵
    1. Agostoni P,
    2. Corrà U,
    3. Cattadori G, et al.
    Prognostic value of indeterminable anaerobic threshold in heart failure. Circ Heart Fail 2013; 6: 977–987. doi:10.1161/CIRCHEARTFAILURE.113.000471
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Apostolo A,
    2. Laveneziana P,
    3. Palange P, et al.
    Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure. Int J Cardiol 2015; 189: 134–140. doi:10.1016/j.ijcard.2015.03.422
    OpenUrlCrossRefPubMed
  13. ↵
    1. Agostoni P,
    2. Apostolo A,
    3. Cattadori G, et al.
    Effects of β-blockers on ventilation efficiency in heart failure. Am Heart J 2010; 159: 1067–1073. doi:10.1016/j.ahj.2010.03.034
    OpenUrlCrossRefPubMed
  14. ↵
    1. Wensel R,
    2. Georgiadou P,
    3. Francis DP, et al.
    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. doi:10.1016/j.amjcard.2003.10.011
    OpenUrlCrossRefPubMed
    1. Robertson HT
    . Dead space: the physiology of wasted ventilation. Eur Respir J 2015; 45: 1704–1716. doi:10.1183/09031936.00137614
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Farina S,
    2. Bruno N,
    3. Agalbato C, et al.
    Physiological insights of exercise hyperventilation in arterial and chronic thromboembolic pulmonary hypertension. Int J Cardiol 2018; 259: 178–182.
    OpenUrl
  17. ↵
    1. Van Iterson EH,
    2. Johnson BD,
    3. Borlaug BA, et al.
    Physiological dead space and arterial carbon dioxide contributions to exercise ventilatory inefficiency in patients with reduced or preserved ejection fraction heart failure. Eur J Heart Fail 2017; 19: 1675–1685. doi:10.1002/ejhf.913
    OpenUrl
  18. ↵
    1. Gargiulo P,
    2. Apostolo A,
    3. Perrone-Filardi P, et al.
    A non invasive estimate of dead space ventilation from exercise measurements. PLoS One 2014; 9: e87395. doi:10.1371/journal.pone.0087395
    OpenUrlCrossRefPubMed
  19. ↵
    1. Farina S,
    2. Correale M,
    3. Bruno N, et al.
    The role of cardiopulmonary exercise tests in pulmonary arterial hypertension. Eur Respir Rev 2018; 27: 170134. doi:10.1183/16000617.0134-2017
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Agostoni P,
    2. Farina S,
    3. Apostolo A, et al.
    Inside ventilatory regulation in pulmonary hypertension: several hidden data are still undiscovered. Eur J Prev Cardiol 2014; 21: 268–271. doi:10.1177/2047487313497866
    OpenUrlCrossRefPubMed
  21. ↵
    1. MacGowan GA,
    2. Janosko K,
    3. Cecchetti A, et al.
    Exercise-related ventilatory abnormalities and survival in congestive heart failure. Am J Cardiol 1997; 79: 1264–1266. doi:10.1016/S0002-9149(97)00097-0
    OpenUrlCrossRefPubMed
  22. ↵
    1. Robbins M,
    2. Francis G,
    3. Pashkow FJ, et al.
    Ventilatory and heart rate responses to exercise: better predictors of heart failure mortality than peak oxygen consumption. Circulation 1999; 100: 2411–2417. doi:10.1161/01.CIR.100.24.2411
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. de Jonge N,
    2. Kirkels H,
    3. Lahpor JR, et al.
    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. doi:10.1016/S0735-1097(01)01268-2
    OpenUrlFREE Full Text
  24. ↵
    1. Sun XG,
    2. Hansen JE,
    3. Garatachea N, et al.
    Ventilatory efficiency during exercise in healthy subjects. Am J Respir Crit Care Med 2002; 166: 1443–1448. doi:10.1164/rccm.2202033
    OpenUrlCrossRefPubMed
  25. ↵
    1. Myers J,
    2. Arena R,
    3. Oliveira RB, et al.
    The lowest V′E/V′CO2 ratio during exercise as a predictor of outcomes in patients with heart failure. J Card Fail 2009; 15: 756–762. doi:10.1016/j.cardfail.2009.05.012
    OpenUrlCrossRefPubMed
  26. ↵
    1. Ingle L,
    2. Sloan R,
    3. Carroll S, et al.
    Prognostic significance of different measures of the ventilation-carbon dioxide relation in patients with suspected heart failure. Eur J Heart Fail 2011; 13: 537–542. doi:10.1093/eurjhf/hfq238
    OpenUrlCrossRefPubMed
  27. ↵
    1. Bard RL,
    2. Gillespie BW,
    3. Clarke NS, et al.
    Determining the best ventilatory efficiency measure to predict mortality in patients with heart failure. J Heart Lung Transplant 2006; 25: 589–595. doi:10.1016/j.healun.2005.11.448
    OpenUrlCrossRefPubMed
  28. ↵
    1. Tabet JY,
    2. Beauvais F,
    3. Thabut G, et al.
    A critical appraisal of the prognostic value of the VE/VCO2 slope in chronic heart failure. Eur J Cardiovasc Prev Rehabil 2003; 10: 267–272.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Salvioni E,
    2. Corrà U,
    3. Piepoli M, et al.
    Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction. ESC Heart Fail 2020; 7: 371–380.
    OpenUrl
    1. Francis DP,
    2. Shamim W,
    3. Davies LC, et al.
    Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO2 slope and peak VO2. Eur Heart J 2000; 21: 154–161. doi:10.1053/euhj.1999.1863
    OpenUrlCrossRefPubMed
    1. Arena R,
    2. Myers J,
    3. Guazzi M
    . The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidence-based review. Heart Fail Rev 2008; 13: 245–269. doi:10.1007/s10741-007-9067-5
    OpenUrlCrossRefPubMed
  32. ↵
    1. Guazzi M,
    2. Adams V,
    3. Conraads V, et al.
    EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2012; 126: 2261–2274. doi:10.1161/CIR.0b013e31826fb946
    OpenUrlFREE Full Text
  33. ↵
    1. Balady GJ,
    2. Arena R,
    3. Sietsema K, et al.
    Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010; 122: 191–225. doi:10.1161/CIR.0b013e3181e52e69
    OpenUrlFREE Full Text
  34. ↵
    1. Kleber FX,
    2. Vietzke G,
    3. Wernecke KD, et al.
    Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation 2000; 101: 2803–2809. doi:10.1161/01.CIR.101.24.2803
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Koch B,
    2. Schäper C,
    3. Ittermann T, et al.
    Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study. Eur Respir J 2009; 33: 389–397. doi:10.1183/09031936.00074208
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Neder JA,
    2. Nery LE,
    3. Peres C, et al.
    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. doi:10.1164/ajrccm.164.8.2103007
    OpenUrlCrossRefPubMed
    1. Poulin MJ,
    2. Cunningham DA,
    3. Paterson DH, et al.
    Ventilatory response to exercise in men and women 55 to 86 years of age. Am J Respir Crit Care Med 1994; 149: 408–415.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Robertson HT,
    2. Pellegrino R,
    3. Pini D, et al.
    Exercise response after rapid intravenous infusion of saline in healthy humans. J Appl Physiol 2004; 97: 697–703. doi:10.1152/japplphysiol.00108.2004
    OpenUrlCrossRefPubMed
  39. ↵
    1. Paolillo S,
    2. Pellegrino R,
    3. Salvioni E, et al.
    Role of alveolar β2-adrenergic receptors on lung fluid clearance and exercise ventilation in healthy humans. PLoS One 2013; 8: e61877. doi:10.1371/journal.pone.0061877
    OpenUrlCrossRefPubMed
  40. ↵
    1. Mutlu GM,
    2. Koch WJ,
    3. Factor P
    . Alveolar epithelial β2-adrenergic receptors: their role in regulation of alveolar active sodium transport. Am J Respir Crit Care Med 2004; 170: 1270–1275. doi:10.1164/rccm.200404-470CP
    OpenUrlCrossRefPubMed
  41. ↵
    1. Mutlu GM,
    2. Factor P
    . Alveolar epithelial β2-adrenergic receptors. Am J Respir Cell Mol Biol 2008; 38: 127–134. doi:10.1165/rcmb.2007-0198TR
    OpenUrlCrossRefPubMed
  42. ↵
    1. Malfatto G,
    2. Caravita S,
    3. Giglio A, et al.
    Pulmonary congestion at rest and abnormal ventilation during exercise in chronic systolic heart failure. J Am Heart Assoc 2015; 4: e001678. doi:10.1161/JAHA.114.001678
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Windsor JS,
    2. Rodway GW
    . Supplemental oxygen effects on ventilation in acclimatized subjects exercising at 5700 m altitude. Aviat Space Environ Med 2007; 78: 426–429.
    OpenUrlPubMed
    1. Lawler J,
    2. Powers SK,
    3. Thompson D
    . Linear relationship between VO2max and VO2max decrement during exposure to acute hypoxia. J Appl Physiol 1988; 64: 1486–1492. doi:10.1152/jappl.1988.64.4.1486
    OpenUrlPubMed
    1. Ward SA,
    2. Grocott MPW,
    3. Levett DZH
    . Exercise testing, supplemental oxygen, and hypoxia. Ann Am Thorac Soc 2017; 14: S140–S148. doi:10.1513/AnnalsATS.201701-043OT
    OpenUrl
  46. ↵
    1. Valentini M,
    2. Revera M,
    3. Bilo G, et al.
    Effects of β-blockade on exercise performance at high altitude: a randomized, placebo-controlled trial comparing the efficacy of nebivolol versus carvedilol in healthy subjects. Cardiovasc Ther 2012; 30: 240–248. doi:10.1111/j.1755-5922.2011.00261.x
    OpenUrlCrossRefPubMed
  47. ↵
    1. Agostoni P,
    2. Contini M,
    3. Magini A, et al.
    Carvedilol reduces exercise-induced hyperventilation: a benefit in normoxia and a problem with hypoxia. Eur J Heart Fail 2006; 8: 729–735. doi:10.1016/j.ejheart.2006.02.001
    OpenUrlCrossRefPubMed
  48. ↵
    1. Wasserman K,
    2. Zhang YY,
    3. Gitt A, et al.
    Lung function and exercise gas exchange in chronic heart failure. Circulation 1997; 96: 2221–2227. doi:10.1161/01.CIR.96.7.2221
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Mezzani A,
    2. Giordano A,
    3. Komici K, et al.
    Different determinants of ventilatory inefficiency at different stages of reduced ejection fraction chronic heart failure natural history. J Am Heart Assoc 2017; 6: e005278. doi:10.1161/JAHA.116.005278
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Agostoni P,
    2. Guazzi M
    . Exercise ventilatory inefficiency in heart failure: some fresh news into the roadmap of heart failure with preserved ejection fraction phenotyping. Eur J Heart Fail 2017; 19: 1686–1689. doi:10.1002/ejhf.940
    OpenUrl
  51. ↵
    1. Ponikowski P,
    2. Francis DP,
    3. Piepoli MF, et al.
    Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation 2001; 103: 967–972. doi:10.1161/01.CIR.103.7.967
    OpenUrlAbstract/FREE Full Text
    1. Gitt AK,
    2. Wasserman K,
    3. Kilkowski C, et al.
    Exercise anaerobic threshold and ventilatory efficiency identify heart failure patients for high risk of early death. Circulation 2002; 106: 3079–3084. doi:10.1161/01.CIR.0000041428.99427.06
    OpenUrlAbstract/FREE Full Text
    1. Mejhert M,
    2. Linder-Klingsell E,
    3. Edner M, et al.
    Ventilatory variables are strong prognostic markers in elderly patients with heart failure. Heart 2002; 88: 239–243. doi:10.1136/heart.88.3.239
    OpenUrlAbstract/FREE Full Text
    1. Corrà U,
    2. Pistono M,
    3. Mezzani A, et al.
    Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence. Circulation 2006; 113: 44–50. doi:10.1161/CIRCULATIONAHA.105.543173
    OpenUrlAbstract/FREE Full Text
    1. Davies LC,
    2. Wensel R,
    3. Georgiadou P, et al.
    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. doi:10.1093/eurheartj/ehi672
    OpenUrlCrossRefPubMed
    1. Nanas S,
    2. Anastasiou-Nana M,
    3. Dimopoulos S, et al.
    Early heart rate recovery after exercise predicts mortality in patients with chronic heart failure. Int J Cardiol 2006; 110: 393–400. doi:10.1016/j.ijcard.2005.10.032
    OpenUrlCrossRefPubMed
    1. Jankowska EA,
    2. Witkowski T,
    3. Ponikowska B, et al.
    Excessive ventilation during early phase of exercise: a new predictor of poor long-term outcome in patients with chronic heart failure. Eur J Heart Fail 2007; 9: 1024–1031. doi:10.1016/j.ejheart.2007.07.001
    OpenUrlCrossRefPubMed
    1. Guimaraes GV,
    2. Silva MS,
    3. d'Avila VM, et al.
    Peak VO2 and VE/VCO2 slope in betablockers era in patients with heart failure: a Brazilian experience. Arq Bras Cardiol 2008; 91: 39–48. doi:10.1590/S0066-782X2008001300007
    OpenUrlPubMed
    1. Pascual-Figal DA,
    2. Penafiel P,
    3. Nicolas F, et al.
    Valor pronóstico del BNP y la prueba de esfuerzo cardiopulmonar en la insuficiencia cardiaca sistólica en tratamiento con bloqueadores beta. [Prognostic value of BNP and cardiopulmonary exercise testing in patients with systolic heart failure on beta-blocker therapy]. Rev Esp Cardiol 2008; 61: 260–268. doi:10.1157/13116653
    OpenUrlPubMed
  60. ↵
    1. Myers J,
    2. Christle JW,
    3. Tun A, et al.
    Cardiopulmonary exercise testing, impedance cardiography, and reclassification of risk in patients referred for heart failure evaluation. J Card Fail 2019; 25: 961–968. doi:10.1016/j.cardfail.2019.08.013
    OpenUrl
  61. ↵
    1. Poggio R,
    2. Arazi HC,
    3. Giorgi M, et al.
    Prediction of severe cardiovascular events by VE/VCO2 slope versus peak VO2 in systolic heart failure: a meta-analysis of the published literature. Am Heart J 2010; 160: 1004–1014. doi:10.1016/j.ahj.2010.08.037
    OpenUrlCrossRefPubMed
  62. ↵
    1. Arena R,
    2. Myers J,
    3. Abella J, et al.
    Development of a ventilatory classification system in patients with heart failure. Circulation 2007; 115: 2410–2417. doi:10.1161/CIRCULATIONAHA.107.686576
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. Aaronson KD,
    2. Schwartz JS,
    3. Chen TM, et al.
    Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997; 95: 2660–2667. doi:10.1161/01.CIR.95.12.2660
    OpenUrlAbstract/FREE Full Text
  64. ↵
    1. Agostoni P,
    2. Corrà U,
    3. Cattadori G, et al.
    Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: a multiparametric approach to heart failure prognosis. Int J Cardiol 2013; 167: 2710–2718. doi:10.1016/j.ijcard.2012.06.113
    OpenUrlCrossRefPubMed
  65. ↵
    1. Guazzi M,
    2. Boracchi P,
    3. Arena R, et al.
    Development of a cardiopulmonary exercise prognostic score for optimizing risk stratification in heart failure: the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE) study. J Card Fail 2010; 16: 799–805. doi:10.1016/j.cardfail.2010.04.014
    OpenUrlCrossRefPubMed
    1. Levy WC,
    2. Aaronson KD,
    3. Dardas TF, et al.
    Prognostic impact of the addition of peak oxygen consumption to the Seattle Heart Failure Model in a transplant referral population. J Heart Lung Transplant 2012; 31: 817–824. doi:10.1016/j.healun.2012.04.006
    OpenUrlCrossRefPubMed
    1. Myers J,
    2. Arena R,
    3. Dewey F, et al.
    A cardiopulmonary exercise testing score for predicting outcomes in patients with heart failure. Am Heart J 2008; 156: 1177–1183. doi:10.1016/j.ahj.2008.07.010
    OpenUrlCrossRefPubMed
  68. ↵
    1. Myers J,
    2. Oliveira R,
    3. Dewey F, et al.
    Validation of a cardiopulmonary exercise test score in heart failure. Circ Heart Fail 2013; 6: 211–218. doi:10.1161/CIRCHEARTFAILURE.112.000073
    OpenUrlAbstract/FREE Full Text
    1. O'Connor CM,
    2. Whellan DJ,
    3. Wojdyla D, et al.
    Factors related to morbidity and mortality in patients with chronic heart failure with systolic dysfunction: the HF-ACTION predictive risk score model. Circ Heart Fail 2011; 5: 63–71. doi:10.1161/CIRCHEARTFAILURE.111.963462
    OpenUrlPubMed
    1. Kato TS,
    2. Stevens GR,
    3. Jiang J, et al.
    Risk stratification of ambulatory patients with advanced heart failure undergoing evaluation for heart transplantation. J Heart Lung Transplant 2013; 32: 333–340. doi:10.1016/j.healun.2012.11.026
    OpenUrlCrossRefPubMed
  71. ↵
    1. Stempfle HU,
    2. Alt A,
    3. Stief J, et al.
    The Munich score: a clinical index to predict survival in ambulatory patients with chronic heart failure in the era of new medical therapies. J Heart Lung Transplant 2008; 27: 222–228. doi:10.1016/j.healun.2007.10.016
    OpenUrlCrossRefPubMed
  72. ↵
    1. Lanfranchi PA,
    2. Braghiroli A,
    3. Bosimini E, et al.
    Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999; 99: 1435–1440. doi:10.1161/01.CIR.99.11.1435
    OpenUrlAbstract/FREE Full Text
  73. ↵
    1. Arzt M,
    2. Harth M,
    3. Luchner A, et al.
    Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea. Circulation 2003; 107: 1998–2003. doi:10.1161/01.CIR.0000065227.04025.C2
    OpenUrlAbstract/FREE Full Text
  74. ↵
    1. Nadruz W Jr.,
    2. West E,
    3. Sengeløv M, et al.
    Prognostic value of cardiopulmonary exercise testing in heart failure with reduced, midrange, and preserved ejection fraction. J Am Heart Assoc 2017; 6: e006000. doi:10.1161/JAHA.117.006000
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Carubelli V,
    2. Metra M,
    3. Corrà U, et al.
    Exercise performance is a prognostic indicator in elderly patients with chronic heart failure – application of metabolic exercise cardiac kidney indexes score. Circ J 2015; 79: 2608–2615. 10.1253/circj.CJ-15-0026.
    OpenUrl
  76. ↵
    1. Paolillo S,
    2. Veglia F,
    3. Salvioni E, et al.
    Heart failure prognosis over time: how the prognostic role of oxygen consumption and ventilatory efficiency during exercise has changed in the last 20 years. Eur J Heart Fail 2019; 21: 208–217. doi:10.1002/ejhf.1364
    OpenUrlPubMed
  77. ↵
    1. Contini M
    . Cardiopulmonary exercise test as a tool to choose therapy in heart failure. Ann Am Thorac Soc 2017; 14: S67–S73. doi:10.1513/AnnalsATS.201611-887FR
    OpenUrl
  78. ↵
    1. Guazzi M,
    2. Marenzi G,
    3. Alimento M, et al.
    Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997; 95: 1930–1936. doi:10.1161/01.CIR.95.7.1930
    OpenUrlAbstract/FREE Full Text
  79. ↵
    1. Guazzi M,
    2. Palermo P,
    3. Pontone G, et al.
    Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure. Am J Cardiol 1999; 84: 1038–1043. doi:10.1016/S0002-9149(99)00495-6
    OpenUrlCrossRefPubMed
  80. ↵
    1. Agostoni P,
    2. Magini A,
    3. Andreini D, et al.
    Spironolactone improves lung diffusion in chronic heart failure. Eur Heart J 2005; 26: 159–164. doi:10.1093/eurheartj/ehi023
    OpenUrlCrossRefPubMed
  81. ↵
    1. Scott AC,
    2. Wensel R,
    3. Davos CH, et al.
    Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure. Eur Heart J 2004; 25: 1806–1813. doi:10.1016/j.ehj.2004.07.018
    OpenUrlCrossRefPubMed
  82. ↵
    1. Kataoka M,
    2. Satoh T,
    3. Yoshikawa T, et al.
    Comparison of the effects of carvedilol and metoprolol on exercise ventilatory efficiency in patients with congestive heart failure. Circ J 2008; 72: 358–363. doi:10.1253/circj.72.358
    OpenUrlCrossRefPubMed
  83. ↵
    1. Laveneziana P,
    2. Agostoni P,
    3. Mignatti A, et al.
    Effect of acute β-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure. J Card Fail 2010; 16: 548–555. doi:10.1016/j.cardfail.2010.02.006
    OpenUrlCrossRefPubMed
  84. ↵
    1. Contini M,
    2. Apostolo A,
    3. Cattadori G, et al.
    Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. Int J Cardiol 2013; 168: 2134–2140. doi:10.1016/j.ijcard.2013.01.277
    OpenUrlCrossRefPubMed
  85. ↵
    1. Vitale G,
    2. Romano G,
    3. Di Franco A, et al.
    Early effects of sacubitril/valsartan on exercise tolerance in patients with heart failure with reduced ejection fraction. J Clin Med 2019; 8: 262.
    OpenUrl
  86. ↵
    1. Magrì D,
    2. Santolamazza C
    . Cardiopulmonary exercise test in hypertrophic cardiomyopathy. Ann Am Thorac Soc 2017; 14: S102–S109. doi:10.1513/AnnalsATS.201611-884FR
    OpenUrl
  87. ↵
    1. Arena R,
    2. Owens DS,
    3. Arevalo J, et al.
    Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy. Med Sci Sports Exerc 2008; 40: 799–805. doi:10.1249/MSS.0b013e31816459a1
    OpenUrlCrossRefPubMed
  88. ↵
    1. Ong KC,
    2. Geske JB,
    3. Hebl VB, et al.
    Pulmonary hypertension is associated with worse survival in hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2016; 17: 604–610. doi:10.1093/ehjci/jew024
    OpenUrlCrossRefPubMed
    1. Magri D,
    2. Limongelli G,
    3. Re F, et al.
    Cardiopulmonary exercise test and sudden cardiac death risk in hypertrophic cardiomyopathy. Heart 2016; 102: 602–609. doi:10.1136/heartjnl-2015-308453
    OpenUrlAbstract/FREE Full Text
  90. ↵
    1. Magrì D,
    2. Re F,
    3. Limongelli G, et al.
    Heart failure progression in hypertrophic cardiomyopathy – possible insights from cardiopulmonary exercise testing. Circ J 2016; 80: 2204–2211. doi:10.1253/circj.CJ-16-0432
    OpenUrl
  91. ↵
    1. Sinagra G,
    2. Iorio A,
    3. Merlo M, et al.
    Prognostic value of cardiopulmonary exercise testing in idiopathic dilated cardiomyopathy. Int J Cardiol 2016; 223: 596–603. doi:10.1016/j.ijcard.2016.07.232
    OpenUrl
  92. ↵
    1. Yunis A,
    2. Doros G,
    3. Luptak I, et al.
    Use of ventilatory efficiency slope as a marker for increased mortality in wild-type transthyretin cardiac amyloidosis. Am J Cardiol 2019; 124: 122–130. doi:10.1016/j.amjcard.2019.03.035
    OpenUrl
  93. ↵
    1. Smith JR,
    2. Van Iterson EH,
    3. Johnson BD, et al.
    Exercise ventilatory inefficiency in heart failure and chronic obstructive pulmonary disease. Int J Cardiol 2019; 274: 232–236. doi:10.1016/j.ijcard.2018.09.007
    OpenUrl
  94. ↵
    1. Teopompi E,
    2. Tzani P,
    3. Aiello M, et al.
    Ventilatory response to carbon dioxide output in subjects with congestive heart failure and in patients with COPD with comparable exercise capacity. Respir Care 2014; 59: 1034–1041. doi:10.4187/respcare.02629
    OpenUrlAbstract/FREE Full Text
  95. ↵
    1. Piepoli MF,
    2. Corrà U,
    3. Agostoni P
    . Cardiopulmonary exercise testing in patients with heart failure with specific comorbidities. Ann Am Thorac Soc 2017; 14: S110–S115. doi:10.1513/AnnalsATS.201610-803FR
    OpenUrl
  96. ↵
    1. Piepoli MF,
    2. Corrà U,
    3. Veglia F, et al.
    Exercise tolerance can explain the obesity paradox in patients with systolic heart failure: data from the MECKI Score Research Group. Eur J Heart Fail 2016; 18: 545–553. doi:10.1002/ejhf.534
    OpenUrlCrossRefPubMed
  97. ↵
    1. Scrutinio D,
    2. Agostoni P,
    3. Gesualdo L, et al.
    Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction. Circ J 2015; 79: 583–591. doi:10.1253/circj.CJ-14-0806
    OpenUrl
  98. ↵
    1. Berry C,
    2. Poppe KK,
    3. Gamble GD, et al.
    Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis. QJM 2016; 109: 377–382. doi:10.1093/qjmed/hcv087
    OpenUrlCrossRefPubMed
    1. Mentz RJ,
    2. Kelly JP,
    3. von Lueder TG, et al.
    Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014; 64: 2281–2293. doi:10.1016/j.jacc.2014.08.036
    OpenUrlFREE Full Text
  100. ↵
    1. Anand IS,
    2. Gupta P
    . Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation 2018; 138: 80–98. doi:10.1161/CIRCULATIONAHA.118.030099
    OpenUrlAbstract/FREE Full Text
  101. ↵
    1. Cattadori G,
    2. Agostoni P,
    3. Corrà U, et al.
    Heart failure and anemia: effects on prognostic variables. Eur J Intern Med 2017; 37: 56–63. doi:10.1016/j.ejim.2016.09.011
    OpenUrl
  102. ↵
    1. Segreti A,
    2. Grigioni F,
    3. Campodonico J, et al.
    Chemoreceptor hyperactivity in heart failure: is lactate the culprit? Eur J Prev Cardiol 2020; in press [https://doi.org/10.1177/2047487320915548].
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Minute ventilation/carbon dioxide production in chronic heart failure
Piergiuseppe Agostoni, Susanna Sciomer, Pietro Palermo, Mauro Contini, Beatrice Pezzuto, Stefania Farina, Alessandra Magini, Fabiana De Martino, Damiano Magrì, Stefania Paolillo, Gaia Cattadori, Carlo Vignati, Massimo Mapelli, Anna Apostolo, Elisabetta Salvioni
European Respiratory Review Mar 2021, 30 (159) 200141; DOI: 10.1183/16000617.0141-2020
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