Heart Fail Rev DOI 10.1007/s10741-013-9407-6

Aerobic exercise effect on prognostic markers for systolic heart failure patients: a systematic review and meta-analysis Gerson Cipriano Jr. • Vivian T. F. Cipriano • Vinicius Z. Maldaner da Silva Graziella F. B. Cipriano • Gaspar R. Chiappa • Alexandra C. G. B. de Lima Lawrence P. Cahalin • Ross Arena

• •

Ó Springer Science+Business Media New York 2013

Abstract From previous systematic reviews and metaanalyses, there is consensus about the positive effect of exercise training on exercise capacity for systolic heart failure (HF); however, the effect on actual prognostic markers such as NTproBNP and minute ventilation/carbon dioxide production (VE/VCO2) slope has not been evaluated. The primary aim of the proposed study is to determine the effect of aerobic exercise training (AEX) on the VE/VCO2 slope and NTproBNP. The following databases (up to February 30, 2013) were searched with no language limitations: CENTRAL (The Cochrane Library 2013, issue 2), MEDLINE (from January 1966), EMBASE (from January 1980), and Physiotherapy Evidence Database (PEDro) (from January 1929). We screened reference lists G. Cipriano Jr. (&)
V. Z. M. da Silva
G. F. B. Cipriano
A. C. G. B. de Lima Sciences and Technologies in Health’s Sciences Program, Department of Physical Therapy, University of Brasilia, QNN 14 ´ rea Especial, Ceilaˆndia Sul, Brası´lia, DF CEP 72220-140, A Brazil e-mail: [email protected]; [email protected] V. T. F. Cipriano Department of Genetics, Graduate School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil G. R. Chiappa Exercise Pathophysiology Research Laboratory, Cardiology Division, Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil L. P. Cahalin Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA R. Arena Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA

of articles and also conducted an extensive hand search of the literature. Randomized controlled trials of exercisebased interventions with 2-month follow-up or longer compared to usual medical care or placebo were included. The study population comprised adults aged between 18 and 65 years, with evidence of chronic systolic heart failure (LVEF \ 45 % and baseline NTproBNP [ 300 pg/ ml). Two review authors independently extracted data on study design, participants, interventions, and outcomes. We assessed the risk of bias using PEDro scale. We calculated mean differences (MD) or standardized mean differences between intervention and control groups for outcomes with sufficient data; for other outcomes, we described findings from individual studies. Eight studies involving a total of 408 participants met the inclusion criteria across the NTproBNP (5 studies with 191 patients) and VE/VCO2 slope (4 studies with 217 patients). Aerobic exercise significantly improved NTproBNP by a MD of -817.75 [95 % confidence interval (CI) -929.31 to -706.19]. Mean differences across VE/VCO2 slope were -6.55 (95 % CI -7.24 to -5.87). Those patients’ characteristics and exercise were similar (frequency = 3–5 times/week; duration = 20–50 min/day; intensity = 60–80 % of VO2 peak) on the included studies. Moreover, the risk of bias across all studies was homogeneous (PEDro scale = 7–8 points). However, based on the statistical analysis, the heterogeneity among the studies was still high, which is related to the variable characteristics of the studies. Aerobic exercise may be effective at improving NTproBNP and the VE/VCO2 slope in systolic HF patients, but these effects are limited to a specific HF population meeting specific inclusion criterion in a limited number of studies. Future randomized controlled studies including diastolic and HF overleap with pulmonary diseases are needed to better understand the exact influence of AEX.

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Keywords Exercise
Natriuretic peptide, brain
Heart failure
Exercise test

Background Heart failure (HF) poses a significant health care burden in many countries. There are more than 5 million people diagnosed with HF, with approximately 650,000 new cases reported each year [1, 2]. Patients afflicted with HF typically do not maintain stable cardiac function for the remainder of their life and consequently require continuous medical management and intermittent hospital admissions. The total cost of HF care in the Unites States exceeds $40 billion annually, with over half of these expenditures spent on hospitalizations [2] In Brazil, for example, cardiovascular diseases represented the third leading cause of hospital admissions, and HF is the most frequent cause of hospitalization within this population [3], and because of the recent growth in the economy and an increasingly aging population, Brazil is expected to be the country with the highest cardiovascular morbid and mortality in 2040 [4]. Moreover, the incidence of HF is expected to accelerate in coming decades as the population ages around the world. Given the magnitude of this problem, it is important to identify clinically effective treatment strategies in the HF population. The importance of regular aerobic exercise for maintaining cardiovascular health is clear. In 2004, the Cochrane systematic review of exercise-based interventions for heart failure was published [5]. This review concluded that exercise training clearly improved short-term (up to oneyear follow-up) exercise capacity. In 2010, Davies et al. [6] reported in an update of this previous systematic review that exercise-based interventions may provide some important improvements in HRQoL in patients with NYHA class II or III systolic heart failure and LVEF \ 40 % and may also reduce heart failure-related hospitalizations. Recently, a number of variables have been assessed for their diagnostic and prognostic capabilities, with hopes they will portend clinically valuable information [7–15]. Moreover, there has been a growing awareness of the additional benefit of applying multivariate scores to evaluate HF patients [14, 16]. Among which, peak oxygen consumption (VO2), the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO2), exercise oscillatory ventilation (EOV), the partial pressure of endtidal CO2 (PETCO2), and B-type natriuretic peptide (BNP) have emerged as independent diagnostic and prognostic markers [15–20]. From these key variables, we found a sufficient number of randomized clinical trials to evaluate the impact of the

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exercise training on peak VO2, the VE/VCO2 slope, and BNP. BNP has been shown to be an important diagnostic [21] and prognostic [22] marker in HF, and recent evidence has demonstrated that the use of BNP to guide treatment of patients with HF may be associated with better clinical outcome [23] and reduced healthcare costs [24]. Biologically active BNP is released from cardiomyocytes in response to wall tension, which according to the law of Laplace is determined by the pressure within and the radius of the chamber. Previous research has also demonstrated a link between improved vascular function and reduced BNP in HF [25]. Evidence demonstrating that EX training attenuates pathological hypertrophy [26] and improves endothelial dysfunction has also been put forth [27] It is therefore reasonable to hypothesize that the improvement in endothelial function as a result of AEX training program will have a positive impact on BNP. There are a few systematic studies evaluating the impact of AEX on NTproBNP in HF patients, especially in those with a diagnosis of systolic heart failure [13, 15, 28]. Since peak VO2 has long been recognized as an important prognostic marker [29] based on its relation with ventricular function (pumping capacity), vascular function (O2 delivery), and skeletal muscle metabolic capacity (O2 utilization), we found several high-quality and robust meta-analysis evaluating the impact of AEX on this primary exercise marker in HF patients [30–36]. These studies collectively show an increase in peak VO2 after different exercise training modalities. Moreover, Swank et al. [37] demonstrated that a modest increase in peak VO2 is related to better clinical outcomes in HF patients, with a lower risk of the all-cause mortality and all-cause hospitalization. As an index of ventilatory efficiency, the VE/VCO 2 slope has been shown to reflect ventilation/perfusion mismatching in the lungs (related, in part, to an impaired cardiac output response to exercise), early lactate accumulation, and abnormalities in respiratory control [38]. The VE/VCO 2 slope has emerged as a cardiopulmonary exercise testing (CPX) variable demonstrating that among patients with HF, it holds diagnostic value [39] and is a robust prognostic marker [10, 40]. In addition, their application is now advocated in guidelines on HF management [17] given the demonstrated relationship between the VE/VCO 2 slope and skeletal muscle function [41] and initial evidence demonstrating the positive impact of high-intensity exercise training on the VE/VCO 2 slope [42], it is plausible to hypothesize that a broad array of AEX approaches likewise has a favorable impact on this variable. Moreover, in contrast to peak VO 2, there is to

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our knowledge no meta-analysis evaluating the AEX effect on the VE/VCO 2 slope.

Objectives The primary aim of the proposed study is to determine the effect of exercise-based intervention on VE/VCO2 slope and NTproBNP.

Methods Criteria for considering studies for this review Types of studies Randomized controlled trials of exercise-based interventions with 2-month follow-up or longer compared to usual medical care or placebo in chronic systolic heart failure patients. Types of participants The study population comprised adults aged between 18 and 65. Only those studies with criteria for diagnosis of systolic heart failure (based on clinical findings and objective indices such as assessment of ejection fraction, LVEF \ 45 % and biomarkers, baseline NTproBNP [ 300 pg/ml) have been included. Studies including patients with normal systolic function (for example restrictive cardiomyopathy or hypertensive disease) were excluded. Studies that included patients with normal systolic function but poor diastolic function or who had previously been offered cardiac rehabilitation for either myocardial infarction or heart failure were excluded [43].

Search methods for identification of studies We searched Central Register of Controlled Trials (The Cochrane Library 2013, Issue 2), MEDLINE (1966–February 2013), Physiotherapy Evidence Database (PEDro), and LILACS (1980–2013). Two reviewers analyzed the results independently. Searches were limited to RCTs, systematic reviews, and meta-analyses; and a filter was applied to limit to humans. No language or other limitations were imposed. Search terms strategy for outcome 1: VE/VCO2 slope (only Mesh Terms) (Appendix 1) (Exercise [Mesh] OR ‘‘Exercise Therapy’’ [Mesh] OR ‘‘Physical Education and Training’’ [Mesh] OR ‘‘Physical and Rehabilitation Medicine’’ [Mesh] AND (‘‘Exercise Test’’ [Mesh] OR ‘‘Oxygen Consumption’’ [Mesh] OR ‘‘Exercise Tolerance’’ [Mesh] OR ‘‘Physical Fitness’’ [Mesh] OR ‘‘Physical Exertion’’ [Mesh] OR ‘‘Physical Endurance’’ [Mesh] OR ‘‘Blood Gas Monitoring, Transcutaneous’’ [Mesh] OR ‘‘Carbon Dioxide’’ [Mesh] OR Capnography [Mesh] OR ‘‘Respiratory Insufficiency’’ [Mesh]. Search terms strategy for outcome 2: NTproBNP (only Mesh Terms) (Exercise [Mesh] OR ‘‘Exercise Therapy’’ [Mesh] OR ‘‘Physical Education and Training’’ [Mesh] OR ‘‘Physical and Rehabilitation Medicine’’ [Mesh] AND (‘‘Natriuretic Peptide, Brain’’ [Mesh] OR ‘‘Atrial Natriuretic Factor’’ [Mesh] OR ‘‘Natriuretic Peptides’’ [Mesh] OR ‘‘pro-brain natriuretic peptide (1–76)’’ [Mesh].

Data collection and analysis Types of interventions Study selection Exercise-based interventions either alone or as a component of comprehensive cardiac rehabilitation (defined as programs including components such as health education and psychological interventions in addition to exercise interventions) were included. The comparison group was usual medical care (for example monitoring, drug therapy, and advice) or control group as defined by the study. Types of outcome measures 1. 2.

Cardiopulmonary exercise testing prognostic marker— VE/VCO2 slope. Biological prognostic marker—NTproBNP (pg/ml).

The references identified by the search strategy were screened by title and abstract, and clearly, irrelevant studies were discarded. For selection, abstracts had to clearly identify the study design, an appropriate population, and relevant components of the intervention as described above. The main outcome extracted was VE/ VCO2 slope and NTproBNP (pg/ml). The full-text reports of all potentially relevant trials were obtained and assessed independently by two review authors (GCJ and VTFC) for eligibility based on the defined inclusion criteria. Any disagreements were resolved by discussion (Fig. 1).

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attrition, and control), and results were extracted (Tables 1, 2). Data extraction were undertaken independently by a single review author (GCJ) and checked by a second review author (VZMS). Inter-reviewer disagreements were resolved by consensus. The agreement ratio prior to amending any discrepancies was assessed using the kappa statistic and was found to be greater than 0.90. Study authors were contacted to seek clarification on the issues of reporting or to obtain further outcome details. Excluded studies and reasons for their exclusion are detailed in the ‘‘Characteristics of excluded studies’’ (Table 3). Quality assessment

Fig. 1 Flowchart summary of study selection process

Data extraction Relevant data regarding inclusion criteria (study design; participants; interventions including type of exercise, frequency, duration, intensity, and modality; comparisons; and outcomes), risk of bias (randomization, blinding,

The risk of bias in eligible trials was assessed independently by a single review author (GCJ) and verified by a second author (VZMS). Included studies were independently rated for quality by 2 reviewers using the PEDro scale, which is a checklist used to measure the quality of reports based on the Delphi list, developed by Verhagen et al. [44]. The PEDro scale included eligibility criteria (not used to calculate score), random allocation, concealment of allocation, similarity at baseline, subject blinding, therapist blinding, assessor blinding, adequacy of followup, intention-to-treat analysis, between-group statistical analysis, and reports of both point estimates and measures of variability. Items were marked as either present (yes/1) or absent (no/0), and a score out of 10 was obtained. Also, to assess for evidence of publication bias, Begg’s funnel

Table 1 Characteristics of the included studies—clinical and demographics Outcome

VE/VCO2 slope

NTproBNP

Study

Population

Total

Exercise-based treatment

Control group

n

Male gender n (%)

n

Age (years)

n

Age (years)

Myers et al. [54]

HF with LVEF \ 40 %—isquemic and nonisquemic

50

50

100.00 %

24

55 ± 9.0

26

57 ± 7.0

Belardinelli et al. [52]

HF with LVEF \ 40 %

120

96

80.00 %

60

60 ± 15.0

60

59 ± 14.0 42 ± 17.6

Laoutaris et al. [53]

HF—pre HTx with ventricular assist devices

15

14

93.33 %

10

37 ± 17.7

5

Servantes et al. [55]

HF with LVEF \ 40 % and peak VO2 \ 20

32

27

84.38 %

18

52 ± 9.3

14

50 ± 9.4

Conraads et al. [58]

HF with dyssynchrony after CRT

17

8

47.06 %

8

57 ± 2.0

9

61 ± 4.0

Giallauria et al. [48]

HF with LVEF \ 45 % after MI

44

39

88.64 %

22

55 ± 2.0

22

54 ± 3.0

Giallauria et al. [49]

HF with LVEF [ 30 % after MI

40

33

82.50 %

20

69 ± 2.3

20

68 ± 2.6

Maria Sarullo et al. [50]

HF with LVEF \ 40 %

60

45

75.00 %

30

53 ± 6.1

30

53 ± 4.9

Sandri et al. [51]

HF with LVEF \ 40 %—associate diastolic dysf.

30

38

126.67 %

15

50 ± 5.0

15

49 ± 5.0

Continuous data represented as mean ± standard deviation; categorical or continuous data represented as NO, and number of patients (% of total) HF heart failure, LVFE left ventricular ejection fraction, HTx heart transplantation, CRT cardiac resynchronization therapy, MI myocardium infarction

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Heart Fail Rev Table 2 Characteristics of the included studies—intervention description Outcome

VE/VCO2 slope

NTproBNP

Study

Activity

Intervention description Frequency (days/ week)

Session duration (min/session)

Protocol duration (weeks)

Intensity

Myers et al. [54]

Aerobic (bike and walking)

4

45

8

60–80 % HRR

Belardinelli et al. [52]

Aerobic (bike)

3

40

48

70 % VO2 peak

Laoutaris et al. [53]

Aerobic (bike or treadmill)

3–5

45

10

12–14 Borg Scale

Servantes et al. [55]

Aerobic (walking)

3

45

12

HR at VT1

Conraads et al. [58]

Aerobic (bike ? walking)

3

50

20

HR at 90 % VT1

Giallauria et al. [48]

Aerobic (bike)

3

40

12

70 % VO2peak

Giallauria et al. [49]

Aerobic (bike)

3

40

12

60 % VO2 peak

Maria Sarullo et al. [50]

Aerobic (bike)

3

30

12

60–70 % VO2 peak

Sandri et al. [51]

Aerobic (bike)

4

20

4

70 % VO2 peak

Categorical or continuous data represented as NO HRR heart rate reserve, VO2 peak peak oxygen consumption, HR heart rate, and VT1 first ventilatory threshold

plots and Egger’s regression test were examined [45] and were considered adequate when p [ 0.05 (Fig. 3). Data analysis Data were processed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [46]. For continuous variables, net changes were compared (that is exercise group minus control group to give differences) by weighted mean difference (WMD) and 95 % confidence interval (CI). The standard deviation was calculated for each study based on the change score method. Heterogeneity among included studies was explored qualitatively (by comparing the characteristics of included studies) and quantitatively (using the chi-squared test of heterogeneity and the I2 statistic). Where appropriate, the results from included studies were combined for each outcome to give an overall estimate of treatment effect. A fixed-effect model meta-analysis was used based on qualitative evaluation of the heterogenicity and the low risk of bias. All analyses were conducted using Review Manager version 5.0 and comprehensive meta-analysis by Biostat software.

Results The initial search led to the identification of 265 studies for NTproBNP outcome and 7,213 for VE/VCO2 slope, from which 25 and 12 studies, respectively, were considered as potentially relevant and were retrieved for detailed analysis. Only 5 [47–51] and 4 [52–55] articles, respectively,

met the eligibility criteria for NTproBNP and VE/VCO2 slope. Figure 1 shows the flow diagram of studies in this review. The level of concordance between the two reviewers examined by kappa statistic was 0.91 [IC 95 % (0.81; 1.0)]. Two potential articles could not be accessed due to database restrictions, one for each outcome [56, 57]. Tables 1 and 2 summarize the characteristics of these studies. Among the included studies, they were all classified as RCTs [48–55, 58]. The publications range from 2006 to 2012. For the NTproBNP analysis, 191 individuals were included. The mean age ranges from 49 to 69 years, and 163 (85.34 %) were male. For the VE/VCO2 slope analysis, 217 individuals were included. The mean age ranges from 38 to 60 years, and 187 (86.17 %) were male. Publication bias The methodological quality from the studies included is presented in Table 4. Based on PEDro score, eleven studies reported average value of seven points and were considered good quality studies since the maximum value obtained is 8 points [53]. Furthermore, the examination of Begg’s funnel plots for NTproBNP and VE/VCO2 slope demonstrated considerable symmetry, suggesting that there was no significant publication bias (Figs. 2 and 3). Egger’s regression test was also used to confirm this symmetry (p = 0.583 for NTproBNP and p = 0.314 for VE/VCO2 slope). Exercise-based training on NTproBNP Five studies evaluated the exercise-based training effect on NTproBNP prognostic marker [48–51, 58]. Figure 4 shows

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VE/VCO2 slope

NTproBNP

Outcome

Table 3 Characteristics of the excluded studies

The peptide marker is BNP and not NTproBNP The peptide marker is BNP and not NTproBNP Study did not report values It is not an exercise-based program Data are reported in median

Gary et al. [63] Jonsdo´ttir et al. [64] Kiilavuori et al. [65] Leetmaa et al. [66] Lima et al. [67]

Study did not have control group It is a non-randomized study

Gademan et al. [77]

Beckers et al. [74]

Study did not have control group

Patients had 6-month exercise-based treatment prior study

Zuazagoitia et al. [73]

Dimopoulos et al. [76]

It is a protocol registration study

Yamamoto et al. [72]

Smart et al. [75]

Data are reported in median Study did not report values

Winter et al. [71]

Data are reported in median

It is a non-randomized study

Conraads et al. [62]

It is a retrospective non-randomized study It is a protocol registration study

Study did not report the exercise protocol

Brehm et al. [61]

Nishi et al. [69] Whellan et al. [70]

Baseline NTproBNP was lower than 300 pg/ml

Nilsson et al. [68]

Included patients are primary atrial fibrillation diagnoses

Osbak et al. [59]

Reason for exclusion

Passino et al. [60]

Study

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7 1 1

1

7

8 1

1

the results based on the Forest plot comparison. The results demonstrate that AEX produced a significant change in NTproBNP compared to a control group (WMD = -817.75, 95 % CI -929.31 to -706.19, p \ 0.001, I2 = 66 %). The mean age of the exercise-based group and control was very similar (57 ± 3 and 57 ± 4, respectively). Furthermore, the exercise protocol used in the five studies was very similar (frequency = 3–4 times/week; duration = 20–50 min/day; intensity = 60–80 % of VO2 peak, preferable exercise modality = cycling).

0 0

0

0 0

1

1

1

1

7

1 0 0

1

1

1

1

7

1 0 0

1

1

1

1

7

1 1 0 0

1

1

1

1

8 1 1

1

1

1

0 0

0

0 0

1

1

1

7

7

1

1

1

1

1

1 1

1 1

1

0

0

0

0

1 Categorical or continuous data represented as NO

1 Sandri et al. [51]

1

1

1 1 1 Maria Sarullo et al. [50]

1

1 1 1 Giallauria et al. [49]

0

1 1 1 Giallauria et al. [48]

0

1 NTproBNP

1 1 Conraads et al. [58]

0

1

1 1 1 1 Servantes et al. [55]

1 1 Laoutaris et al. [53]

1

1

1 0

0

1

1

1

1

Myers et al. [54]

VE/VCO2 slope

Belardinelli et al. [52]

Point measure Blinding therapists Randomized Concealed allocation in allocation? treatments? Study

Eligibility criteria

Fig. 2 Funnel plot of comparison: exercise-based intervention versus usual care, outcome 1 = NTproBNP

Exercise-based training on VE/VCO2 slope

Outcome

Table 4 Characteristics of the included studies—bias evaluation

Similar groups?

Blinding subjects?

Blinding assessors

Outcome measures

Intention to treat

Statistical results of the groups

Total PEDro score

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Four studies evaluated the effects of AEX on the VE/VO2 slope outcome [52–55]. Figure 5 shows the results based on the Forest plot comparison. The results demonstrate that AEX produced a significant change in VE/VO2 slope compared to a control group (WMD = -6.55, 95 % CI -7.24 to -5.87, p \ 0.001, I2 = 87 %). The mean age of the exercise-based group and control was also very similar for this outcome (51 ± 13 and 52 ± 12, respectively). Additionally, the exercise protocol used in these four studies was also very similar (frequency = 3–5 times/week; duration = 40–45 min/day; intensity = 60–80 % of VO2 peak, preferable exercise modality = cycling and walking (Table 2).

Discussion The present studies provide preliminary evidence that an exercise-based intervention may be associated with significant improvements in novel cardiopulmonary and biological prognostic markers for heart failure patients. The low level of bias and significant improvement in both NTproBNP and the VE/VCO2 slope associated with AEX is a relevant finding to help the management of patients with HF.

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Fig. 3 Funnel plot of comparison: exercise-based intervention versus usual care, outcome 2 = VE/VCO2 slope

One previous meta-analysis and one systematic review [28, 78] found a positive effect of an exercise-based treatment on NTproBNP. Although recent studies have reported that NTproBNP is more prognostic in mild to severe HF patients [43], we evidenced this lack of information on this subgroup (mild to severe HF patients is not a subgroup—it is likely all patients with HF with mild, moderate, and severe HF—mild to severe HF encompasses all). Thereby, including only patients with baseline NTproBNP greater than 300 pg/ml, we found a similar positive effect on this outcome in patients with HF who were subjected to an exercise-based treatment. Additionally, although we observed a high degree of statistical heterogeneity in the included studies, we found slightly

better results than the previous meta-analysis (I2 = 66 vs I2 = 75 %). Moreover, by including two more recent studies in our meta-analysis, we observed a greater effect size in our study with a mean reduction of -810 instead of -620 g/ml. The main difference in the intervention parameters in our study comes from Sandri et al. [51] who showed for the first time a significant reduction in NTproBNP with only 1 month of exercise-based intervention. The results of this study may have contributed to the modest degree of heterogeneity that we observed, but this study is important since improvements in NTproBNP appear to be achievable in a short period of time, which may stimulate HF patients to begin exercising. To our knowledge, this is the first meta-analysis to evaluate the exercise-based treatment on the VE/VCO2 slope which is recognized as one of the primary variables from the cardiopulmonary exercise test to evaluate the prognosis in HF patients [18]. Considering the small number of the randomized control studies analyzing the effect of the exercise-based treatment on the VE/VCO2 slope, we were still able to include four high-quality studies matching our inclusion criteria. The analyzed studies included patients with ventilatory class II and III (30–44.9), and the meta-analysis showed a significant reduction in the VE/VCO2 slope, -6.55 (95 % CI -7.24 to -5.87). This result seems to be promising when considering that within-subject variability for this variable has previously been shown to be an average of 5.0 % [79],

Fig. 4 Comparison 1—exercise-based intervention versus usual care, outcome 1 = NTproBNP. For better resolution graph 1,000 pg/ml = 1 9 10-3 pg/ml)

Fig. 5 Comparison 1—exercise-based intervention versus usual care, outcome 2 = VE/VCO2 slope

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while our findings (-6.55) indicate that a 14–18 % change in the VE/VCO2 slope is possible following AEX, potentially moving a patient to a more favorable ventilatory class (III–IV) [17], which is clinically important and meaningful. The heterogeneity statistics for this meta-analysis were greater than the NTproBNP analyses, but the level of bias was extremely low, based on the PEDro scale which revealed 7–8 points out of 10, as well as the Egger’s regression test result (p = 0.31). The exercise protocol used was very similar, but the better results were showed by Belardinelli et al. [52], which evaluated the VE/VCO2 slope after 1 year of regular treatment. Therefore, we found a lack of evidence in short-term follow-up for VE/VCO2 slope outcome. The major limitation to this study is related to the heterogeneity of the studies, which may be related to the variable patient characteristics in a small number of randomized control studies. Although the level of heterogeneity was moderate to high, the included studies were of a high quality and had similar patient populations that we believe strengthens our study findings. Another limitation is related to the inability to gain access to several articles that were published in different databases and were not provided to us after directly contacting the authors.

Conclusion Aerobic exercise may be effective at improving NTproBNP and VE/VCO2 slope in systolic HF patients, but these effects are limited to a specific HF population meeting specific inclusion criterion in a limited number of studies. Future randomized controlled studies including diastolic and HF overleap with pulmonary diseases are needed to better understand the exact influence of AEX. Conflict of interest

None.

Appendix 1: Comprehensive search strategy Search terms strategy for outcome 1: VE/VCO2 slope (Mesh and Entry Terms) (Exercise [Mesh] OR Exercises OR ‘‘Exercise, Physical’’ OR ‘‘Exercises, Physical’’ OR ‘‘Physical Exercise’’ OR ‘‘Physical Exercises’’ OR ‘‘Exercise, Aerobic’’ OR ‘‘Aerobic Exercises’’ OR ‘‘Exercises, Aerobic’’ OR ‘‘Aerobic Exercise’’ OR ‘‘Exercise Therapy’’ [Mesh] OR ‘‘Therapy, Exercise’’ OR ‘‘Exercise Therapies’’ OR ‘‘Therapies, Exercise’’ OR ‘‘Physical Education and Training’’ [Mesh] OR ‘‘Physical Education, Training’’ OR ‘‘Physical

Education’’ OR ‘‘Education, Physical’’ OR ‘‘Physical and Rehabilitation Medicine’’ [Mesh] OR ‘‘Medicine, Physical’’ OR ‘‘Physical Medicine’’ OR ‘‘Physiatry’’ OR ‘‘Physical Medicine and Rehabilitation’’ OR ‘‘Physiatrics’’) AND (‘‘Exercise Test’’ [Mesh] OR ‘‘Exercise Tests’’ OR ‘‘Test, Exercise’’ OR ‘‘Tests, Exercise’’ OR ‘‘Bicycle Ergometry Test’’ OR ‘‘Bicycle Ergometry Tests’’ OR ‘‘Ergometer Test, Bicycle’’ OR ‘‘Ergometry Tests, Bicycle’’ OR ‘‘Test, Bicycle Ergometry’’ OR ‘‘Tests, Bicycle Ergometry’’ OR ‘‘Treadmill Test’’ OR ‘‘Test, Treadmill’’ OR ‘‘Tests, Treadmill’’ OR ‘‘Treadmill Tests’’ OR ‘‘Step Test’’ OR ‘‘Step Tests’’ OR ‘‘Test, Step’’ OR ‘‘Tests, Step’’ OR ‘‘Stress Test’’ OR ‘‘Arm Ergometry Test’’ OR ‘‘Arm Ergometry Tests’’ OR ‘‘Ergometry Test, Arm’’ OR ‘‘Ergometry Tests, Arm’’ OR ‘‘Test, Arm Ergometry’’ OR ‘‘Tests, Arm Ergometry’’ OR ‘‘Cardiopulmonary Exercise Test’’ OR ‘‘Cardiopulmonary Exercise Tests’’ OR ‘‘Exercise Test, Cardiopulmonary’’ OR ‘‘Exercise Tests, Cardiopulmonary’’ OR ‘‘Test, Cardiopulmonary Exercise’’ OR ‘‘Tests, Cardiopulmonary Exercise’’ OR ‘‘Oxygen Consumption’’ [Mesh] OR ‘‘Consumption, Oxygen’’ OR ‘‘Consumptions, Oxygen’’ OR ‘‘Oxygen Consumptions’’ OR ‘‘Exercise Tolerance’’ [Mesh] OR ‘‘Tolerance, Exercise’’ OR ‘‘Physical Fitness’’ [Mesh] OR ‘‘Fitness, Physical’’ OR ‘‘Physical Conditioning, Human’’ OR ‘‘Conditioning, Human Physical’’ OR ‘‘Conditionings, Human Physical’’ OR ‘‘Human Physical Conditioning’’ OR ‘‘Human Physical Conditionings’’ OR ‘‘Physical Conditionings, Human’’ OR ‘‘Physical Exertion’’ [Mesh] OR ‘‘Exertion, Physical’’ OR ‘‘Exertions, Physical’’ OR ‘‘Physical Exertions’’ OR ‘‘Physical Effort’’ OR ‘‘Effort, Physical’’ OR ‘‘Efforts, Physical’’ OR ‘‘Physical Efforts’’ OR ‘‘Physical Endurance’’ [Mesh] OR ‘‘Endurance, Physical’’ OR ‘‘Endurances, Physical’’ OR ‘‘Physical Endurances’’ OR ‘‘Blood Gas Monitoring, Transcutaneous’’ [Mesh] OR ‘‘Transcutaneous Blood Gas Monitoring’’ OR ‘‘Cutaneous Oximetry’’ OR ‘‘Cutaneous Oximetries’’ OR ‘‘Oximetries, Cutaneous’’ OR ‘‘Oximetry, Cutaneous’’ OR ‘‘Oximetry, Transcutaneous’’ OR ‘‘Oximetries, Transcutaneous’’ OR ‘‘Transcutaneous Oximetries’’ OR ‘‘Transcutaneous Oximetry’’ OR ‘‘Oxygen Partial Pressure Determination, Transcutaneous’’ OR ‘‘Transcutaneous Capnometry’’ OR ‘‘Capnometries, Transcutaneous’’ OR ‘‘Capnometry, Transcutaneous’’ OR ‘‘Transcutaneous Capnometries’’ OR ‘‘Carbon Dioxide Partial Pressure Determination, Transcutaneous’’ OR PtcO2 OR TcPCO2 OR ‘‘Carbon Dioxide’’ [Mesh] OR ‘‘Dioxide, Carbon’’ OR ‘‘Carbonic Anhydride’’ OR ‘‘Anhydride, Carbonic’’ OR Capnography [Mesh] OR Capnographies OR ‘‘Respiratory Insufficiency’’ [Mesh] OR ‘‘Respiratory Failure’’ OR ‘‘Respiratory Depression’’ OR ‘‘Ventilatory Depression’’ OR ‘‘Depressions, Ventilatory’’).

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Search terms strategy for outcome 2: NTproBNP (Mesh and Entry Terms) (Exercise [Mesh] OR Exercises OR ‘‘Exercise, Physical’’ OR ‘‘Exercises, Physical’’ OR ‘‘Physical Exercise’’ OR ‘‘Physical Exercises’’ OR ‘‘Exercise, Aerobic’’ OR ‘‘Aerobic Exercises’’ OR ‘‘Exercises, Aerobic’’ OR ‘‘Aerobic Exercise’’ OR ‘‘Exercise Therapy’’ [Mesh] OR ‘‘Therapy, Exercise’’ OR ‘‘Exercise Therapies’’ OR ‘‘Therapies, Exercise’’ OR ‘‘Physical Education and Training’’ [Mesh] OR ‘‘Physical Education, Training’’ OR ‘‘Physical Education’’ OR ‘‘Education, Physical’’ OR ‘‘Physical and Rehabilitation Medicine’’ [Mesh] OR ‘‘Medicine, Physical’’ OR ‘‘Physical Medicine’’ OR ‘‘Physiatry’’ OR ‘‘Physical Medicine and Rehabilitation’’ OR ‘‘Physiatrics’’) AND (‘‘Natriuretic Peptide, Brain’’ [Mesh] OR ‘‘Peptide, Brain Natriuretic’’ OR ‘‘Brain Natriuretic Peptide’’ OR ‘‘BNP32’’ OR ‘‘BNP 32’’ OR Nesiritide OR ‘‘B-Type Natriuretic Peptide’’ OR ‘‘Natriuretic Peptide, B-Type’’ OR ‘‘BNP Gene Product’’ OR ‘‘Type-B Natriuretic Peptide’’ OR ‘‘Natriuretic Peptide, Type-B’’ OR ‘‘Type B Natriuretic Peptide’’ OR ‘‘Natriuretic Peptide Type-B’’ OR ‘‘Natriuretic Peptide Type B’’ OR ‘‘Natriuretic Factor-32’’ OR ‘‘Natriuretic Factor 32’’ OR ‘‘Brain Natriuretic Peptide-32’’ OR ‘‘Brain Natriuretic Peptide 32’’ OR ‘‘Natriuretic Peptide-32, Brain’’ OR ‘‘Peptide-32, Brain Natriuretic’’ OR ‘‘Ventricular Natriuretic Peptide, B-type’’ OR ‘‘Ventricular Natriuretic Peptide, B type’’ OR Natrecor OR ‘‘Atrial Natriuretic Factor’’ [Mesh] OR Auriculin OR ANP OR ‘‘Natriuretic Peptides, Atrial’’ OR ANF OR Atriopeptins OR ‘‘Atrial Natriuretic Peptides’’ OR ‘‘Peptides, Atrial Natriuretic’’ OR ‘‘beta-Atrial Natriuretic Peptide’’ OR ‘‘beta Atrial Natriuretic Peptide’’ OR ‘‘beta-ANP’’ OR ‘‘beta ANP’’ OR ‘‘alpha-ANP Dimer’’ OR ‘‘alpha ANP Dimer’’ OR ‘‘alpha-Atrial Natriuretic Peptide’’ OR ‘‘alpha Atrial Natriuretic Peptide’’ OR ‘‘ANP-(99–126)’’ OR ‘‘Atriopeptin (99–126)’’ OR ‘‘Cardionatrin I’’ OR ‘‘Atrial Natriuretic Factor (99–126)’’ OR ‘‘ANF (1–28)’’ OR ‘‘Atriopeptin (1–28)’’ OR ‘‘Atrial Natriuretic Factor (1–28)’’ OR ‘‘gamma ANP (99–126)’’ OR ‘‘alpha ANP’’ OR ‘‘Cardiodilatin (99–126)’’ OR ‘‘ANP Prohormone (99–126)’’ OR ‘‘ANF (99–126)’’ OR ‘‘ANP (1–28)’’ OR ‘‘Atrial Natriuretic Factor Precursors’’ OR ‘‘Prepro-Cardiodilatin-Atrial Natriuretic Factor’’ OR ‘‘Prepro Cardiodilatin Atrial Natriuretic Factor’’ OR ‘‘Prepro-ANP’’ OR ‘‘Prepro ANP’’ OR ‘‘ANF Precursors’’ OR ‘‘Cardiodilatin Precursor’’ OR ‘‘Prepro-CDD-ANF’’ OR ‘‘Prepro CDD ANF’’ OR ‘‘gamma-Atrial Natriuretic Peptide’’ OR ‘‘gamma Atrial Natriuretic Peptide’’ OR ‘‘Atriopeptin Prohormone (1–126)’’ OR ‘‘Proatrial Natriuretic Factor’’ OR Pronatriodilatin OR ‘‘Atriopeptin 126’’ OR ‘‘Cardionatrin IV’’ OR ‘‘Atrial Natriuretic Factor Prohormone’’ OR ‘‘Atrial Natriuretic Factor (1–126)’’ OR ‘‘Atrial Natriuretic

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Peptide (1–126)’’ OR Atriopeptigen OR ‘‘ANF (1–126)’’ OR ‘‘ANP (1–126)’’ OR ‘‘Atrial Pronatriodilatin’’ OR ‘‘Pro-ANF’’ OR ‘‘Pro ANF’’ OR ProANF OR ‘‘Natriuretic Peptides’’ [Mesh] OR ‘‘Peptides, Natriuretic’’ OR ‘‘Natriuretic Peptide Hormones’’ OR ‘‘Peptide Hormones, Natriuretic’’ OR ‘‘pro-brain natriuretic peptide (1–76)’’ [Mesh] OR ‘‘N-terminal pro-BNP’’ OR ‘‘NTproBNP’’ OR ‘‘proBNP (1–76)’’ OR ‘‘proBNP(1–76)’’ OR ‘‘N-BNP peptide’’ OR ‘‘NT-BNP’’ OR ‘‘Amino-terminal pro-brain natriuretic peptide’’ OR ‘‘NT-proBNP’’).

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