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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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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