Peak VO2 and VE/VCO2 slope in betablockers era in patients with heart failure: a brazilian experience

Abstracts

FUNDAMENTO: Estudos têm demonstrado que o consumo de oxigênio de pico (VO2 pico) e a inclinação VE/VCO2 são preditores de sobrevida em pacientes com insuficiência cardíaca (IC). Entretanto, com a adição do betabloqueador no tratamento da IC, os valores de prognóstico do VO2 pico e da Inclinação VE/VCO2 não estão totalmente estabelecidos. OBJETIVO: Avaliar o efeito dos betabloqueadores no valor de prognóstico do VO2 pico e da inclinação VE/VCO2 em pacientes com IC. MÉTODOS: Estudamos 391 pacientes com insuficiência cardíaca, com idade de 49 ± 14 anos e fração de ejeção do ventrículo esquerdo de 38 ± 10%. Total de pacientes que usavam (grupo I - GI) e não usavam (grupo II - GII) betabloqueadores: 229 e 162, respectivamente. Todos os pacientes foram submetidos a teste de esforço cardiopulmonar, em esteira, usando o protocolo de Naughton. RESULTADOS: O VO2 pico < 10 ml.kg-1.min-1 identificou pacientes de alto risco, enquanto valores > 16 ml.kg-1.min-1 categorizaram pacientes com melhor prognóstico em médio prazo. A faixa do VO2 pico entre > 10 e < 16 ml.kg-1.min-1 indicou risco moderado para evento cardíaco em quatro anos de seguimento. O betabloqueador reduziu significativamente a inclinação VE/VCO2 em pacientes com IC. O valor prognóstico da inclinação VE/VCO2 < 34 no grupo betabloqueado pode refletir o impacto desse fármaco nessa variável cardiorrespiratória. CONCLUSÃO: O VO2 pico baixo e a inclinação VE/VCO2 elevado são fortes e independentes preditores de eventos cardíacos na insuficiência cardíaca. Assim, ambas as variáveis continuam a ser preditores importantes de sobrevida em pacientes com insuficiência cardíaca, principalmente na era do betabloqueador.

Betabloqueadores; insuficiência cardíaca; prognóstico

ORIGINAL ARTICLE

Peak VO₂ and VE/VCO₂ slope in betablockers era in patients with heart failure: a Brazilian experience

Guilherme Veiga Guimarães; Mário Sérgio Vaz da Silva; Veridiana Moraes d’Avila; Silvia Moreira Ayub Ferreira; Christiano Pereira Silva; Edimar Alcides Bocchi

Instituto do Coração - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil

Mailing address

SUMMARY

BACKGROUND: Studies have demonstrated that peak oxygen consumption (peak VO₂) and the VE/VCO₂ slope are predictors of survival in patients with heart failure (HF). However, with the advent of betablockers in the treatment of HF, the prognostic values of peak VO₂ and VE/VCO₂ slope have not been fully established.

OBJECTIVE: To evaluate the effect of betablocker use on the prognostic value of peak VO₂ and VE/VCO₂ slope in patients with HF.

METHODS: We studied 391 patients with heart failure, aged 49 ± 14 years and presenting a left ventricular ejection fraction of 38 ± 10%. The total number of patients that used (Group I - GI) or did not use (Group II - GII) betablockers was 229 and 162, respectively. All patients were submitted to a cardiopulmonary stress test on a treadmill, using the Naughton protocol.

RESULTS: A peak VO₂< 10 ml.kg^-1.min^-1 identified high-risk patients, whereas values > 16 ml.kg^-1.min^-1 categorizes patients with a better mid-term prognosis. Peak VO₂ values between > 10 and < 16 ml.kg^-1.min^-1 indicated moderate risk for cardiac event in four years of follow up. The betablocker use significantly reduced the VE/VCO₂ slope in patients with HF. The prognostic value of the VE/VCO₂ slope < 34 in the group using betablocker can reflect the impact of the drug on this cardiorespiratory variable.

CONCLUSION: A low peak VO₂ and an elevated VE/VCO₂ slope are strong and independent predictors of cardiac events in HF. Thus, both variables remain important survival predictors in patients with HF, especially at the age of betablockers.

Key words: Betablockers; heart failure, low; prognosis.

Introduction

The use of betablockers (BB) in the treatment of patients with heart failure (HF) started a new era in the management of this cardiomyopathy. Betablockers are capable of partially antagonizing the sympathetic and the inflammatory activity, with effects on the apoptosis and hypertrophy of cardiomyocytes, leading to an increase in the ejection fraction and attenuation of the ventricular remodeling progression^1-4. Additionally, these drugs increase survival and reduce hospitalization in this group of patients⁵, although, in parallel, they do not improve tolerance to exercise⁶.

The cardiopulmonary stress (CPX) test is a well-established technique for the diagnosis of patients with HF. The peak oxygen consumption (peak VO₂) measured during the CPX is a predictor of mortality in patients with HF and an important criterion in the selection of heart transplant candidates⁷. However, other CPX variables have also demonstrated a prognostic value in HF, such as the ratio between ventilation (VE) and the carbon dioxide production (VCO₂) expressed as the VE/VCO₂ slope⁸. Nevertheless, investigations in our country about the effects of betablockers on the prognostic value of peak VO₂ and VE/VCO₂ slope are limited in this group of patients.

The aim of this study was to assess the effect of betablockers on the prognostic value of peak VO₂ and the VE/VCO₂ slope in patients with heart failure, treated at a cardiology outpatient clinic specialized in this cardiopathy.

Methods

Sample

A total of 391 consecutive patients with HF were studied at the Heart Failure Clinical Unit of Instituto do Coração of Hospital das Clínicas of the University of Sao Paulo School of Medicine, from January 1999 to May 2004. Of these, 162 patients did not use BB agents before the CPX test and during the follow-up due to low tolerance to the drug, as well as due to the fact that it is not a fully established conduct for Chagas’ disease. All 229 patients undergoing treatment with BB had received a stable dose for more than 3 months before the CPX test. The patients’ clinical characteristics are described in Table 1.

Exclusion criteria

Patients who did not have the drug therapy optimized for more than three months or those with chronic atrial fibrillation, interrupted test due to hemodynamic and electrocardiographic complications, respiratory quotient RQ < 1.0⁹, neuromuscular disease, peripheral vascular disease, pulmonary diseases, myocardial infarction < 6 months before or orthopedic limitations, were excluded.

Cardiopulmonary stress test

Initially, all patients were submitted to a 12-derivation electrocardiogram at rest and stress test with continuous monitoring of the electrocardiogram (Max 1; Marquette Electronics; Milwaukee, WI, USA), of blood pressure through auscultation and gas exchanges during the stress test. The stress test was performed on a programmable treadmill (Series 2000; Marquette Electronics; Milwaukee, WI, USA) according to the modified Naughton protocol¹⁰. After 2 minutes in the standing position at rest, all patients were encouraged to perform the exercise until the symptoms (fatigue or dyspnea) made them unable to continue the test. The ventilatory data as well as the oxygen consumption and carbon dioxide production data were obtained at each respiratory cycle, using a computerized system (Vmax 229 model, SensorMedics, Yorba Linda, CA, USA) and the analysis of the collected data was made through the arithmetic mean of intervals obtained every sixty seconds. Peak oxygen consumption (peak VO₂) was considered as the highest VO₂ attained during the exercise¹¹, which was used as the index of maximum physical capacity for each individual. The ventilation slope (VE, ml/min) versus carbon dioxide production (VCO₂, ml/min) was calculated based on the inclination of the straight line between the VE and VCO₂ at rest, at the end of the exercise.

Study design

All assessments performed were part of the clinical procedures and all patients gave their informed consent prior to the scientific publication of the data. The present study is a retrospective and descriptive study, as the phenomena were analyzed and correlated without being manipulated¹². The patients were divided in two groups according to treatment – with or without betablockers. Regarding the prognostic value of peak VO₂, patients were classified as class A (>20 ml.kg^-1.min^-1), B (>16 ml.kg^-1.min^-1 to <20 ml.kg^-1.min^-1), C (>10 ml.kg^-1.min^-1 to <16 ml.kg-1.min^-1) or D (<10 ml.kg^-1.min^-1)^13,14. Regarding the prognostic value of VE/VCO₂ slope, the patients were classified as < 34 or > 34⁸.

Follow-up and analysis of survival

The follow-up of patients was carried out by phone interviews with the patient and/or family members. The study cutoff was death due to cardiovascular causes (sudden death, heart failure progression, myocardial acute infarction or pulmonary embolism) or the need for transplant (status 1)⁷. The patients that died due to non-cardiac causes in the follow-up period were excluded from the study.

Statistical analysis

The continuous data were expressed as means and standard deviations. The Mann-Whitney test was used for the variables that did not have a normal distribution. Univariate as well as multivariate Cox regression analysis was used to evaluate the prognostic value of peak VO₂ and the VE/VCO₂ slope. The primitive variable value was generated with "receiver-operating characteristic" (ROC) curves at regular intervals, and the best threshold was automatically identified, minimizing the value of the expression [(1 – sensitivity)² + (1 –specificity)²]. The area under the curve was obtained in accordance to Hanley and McNeil¹⁵. The Kaplan Meier test was used to analyze survival regarding peak VO₂ and the VE/VCO₂ slope. The statistical analysis of the differences between the survival curves were carried out by the long-rank test. Statistical differences with a p value < 0.05 were considered significant. The statistical analyses were carried out with the SPSS^TM software package, version 11.5.

Results

The analysis of the cardiorespiratory response to heart rate (HR) at rest and the VE/VCO₂ slope were significantly lower in the group of patients with BB. The maximum HR, maximum systolic (SAP) and diastolic arterial pressure (DAP), as well as SAP and DAP at rest, peak VO₂ and time of exercise did not show any statistical difference between the groups (Table 2).

The mean follow-up period was 853 ± 442 days. In the group of patients with betablocker, 6 were class D, 88 were class C and 52 were class A. Of the patients without betablocker, 8 were class D, 63 were class C, 57 were class B and 34 were class A. In the group of patients with betablocker, 177 of them presented the VE/VCO₂ slope < 34 and 52 of them > 34; in the group without betablocker, 100 and 62 patients presented the VE/VCO₂ slope < 34 and > 34, respectively.

Prognostic analysis

The analysis of the survival curve of the peak VO₂ showed that the group with betablocker presented a significant difference regarding class D when compared with the other classes (p<0.05). There was also a significant difference regarding class C when compared to classes B and A (p=0.00). However, there was no difference between classes A and B. During the follow-up period, 2, 2.4, 16 and 33.3% of the patients died in classes A, B, C and D, respectively (Figure 1).

In the group without betablocker, the analysis of the survival curve of the peak VO₂ showed a statistical difference only in class D, when compared to the other classes. A total of 11.8, 12, 12.7 and 50% of the patients died in classes A, B, C and D, respectively (Figure 2).

The analysis of the survival curve of patients with betablocker showed that the VE/VCO₂ slope presented a significant difference (p< 0.001) between the patients with values < 34 or > 34 and 7 and 13 of the patients died, respectively, during the study period (Figure 3). In the group without betablocker, no statistical difference was observed at the analysis of the survival curve of the VE/VCO₂ slope < 34 with 10% and > 34 with 19% of deaths (Figure 4).

The result of the ROC curve analysis is shown in Table 3 and in Figures 1, 2, 3 and 4. The prognostic classification for the peak VO₂ and VE/VCO₂ slope was statistically significant for both in the group with betablocker; however, only the VE/VCO₂ slope curve presented statistical significance in the group without betablocker. The area under the ROC curve was 0.80 for the peak VO₂ as well as for the VE/VCO₂ slope of the patients under betablocker use, whereas in the group without betablocker, the area under the ROC curve was 0.60 and 0.65, respectively.

Discussion

Our results showed that the cardiopulmonary stress test maintained the prognostic value in individuals with HF at the age of betablockers. Peak VO₂ and the VE/VCO₂ slope were predictors of survival in patients with HF and betablocker use, showing high sensitivity and specificity in this group of patients treated with betablockers.

The reference value of peak VO₂ used in the present study was the one based on the classification of Weber-Janicki¹⁴. Our patients with peak VO₂< 16 ml.kg^-1.min^-1 had a worse prognosis when compared to patients with peak VO₂ > 16 ml.kg^-1.min^-1, regardless of the etiology and cardiac function.

Several authors have demonstrated that peak VO₂ is an important prognostic variable in patients with HF with betablocker use, which supports our findings, regardless of the cutoff used in the study^14,16-19. These studies have demonstrated that the peak VO₂ assessed on a treadmill remains a useful tool to determine prognosis in patients with HF with betablocker use. The peak VO₂ was considered a univariate predictor and independent from event-free survival and the betablocker therapy did not influence the status of absolute prediction of peak VO2 in relation to survival^14-21.

Nevertheless, studies where the evaluation of the physical capacity was carried out in a cycle ergometer showed that peak VO₂ is a variable with low prognostic value^8,22. This may be due to the lower muscle mass involved in this type or ergometer, providing limited predictive information^23,24.

In healthy people, peak VO₂ obtained at the cycle ergometer was 10 to 15% lower than that obtained at the treadmill stress test^21,24.

Other potential limitations of peak VO₂ at the assessment of prognosis is its dependence on the intensity of the patient’s stress, which is directly related to the examiner and the emotional state²⁵, as well as the metabolic capacity of the skeletal muscle, which can define, in parallel, values that are higher than peak VO₂^21-24, being associated with the sedentary or physically active lifestyle of the patients with HF¹³.

The increased VE/VCO₂ slope is related to the decrease in the pulmonary perfusion capacity and cardiac output, contributing with the prognostic value in HF²⁶. Additionally, it is usually stress-independent and represents the reflex conditions of the patients with HF^22,27.

Studies have adopted threshold values to define patterns of better and worse prognosis of patients with HF for the VE/VCO₂ slope^16,22,28; in the present study, we used < 34 and > 34, respectively. Our results were similar to those observed in the previous studies regarding prognosis in HF.

The prognostic value of the VE/VCO₂ slope in patients with betablockers when compared to those without BB might be due to the clinical condition, generally not associated with neuroautonomic instability, but to the signs of imbalance in the ventilatory control system^17,22.

Some hypotheses have been described to explain such response during exercise, such as the excess activation of muscular ergoreceptors as well as central and peripheral chemoreceptors^29,30.

The central chemoreceptors are associated with the ventilatory control in patients with HF, who have intact physical capacity, whereas the peripheral chemoreceptors and ergoreceptors are more important in those with decreased tolerance to exercise^15,20,27. The potential benefit of the betablocker in the excessive ventilation response during exercise in patients with HF can be due to the re-establishment of the hemodynamic profile and sympathetic drive²⁰. In the present study, we observed direct evidence of the effect of the betablocker on the ventilatory response during the exercise. The association between the VE/VCO₂ slope and prognosis was indeed significant in patients treated with betablockers.

Study limitations

The management of patients with heart failure at our institution favors the use of Carvedilol, in relation to other betablockers. However, we have not evaluated the reasons for the specific prescription of the betablocker type. Our results can be applied to patients with HF treated with different betablocker agents, despite their pharmacological dissimilarity. We did not include in the present study the clinical and hemodynamic variables as well as the neurohormonal measurements that could help with the risk stratification in patients with intermediate functional capacity. Additionally, this study was a retrospective one. Although our findings are in accordance with previous studies, prospective studies are necessary.

Clinical implications

The use of betablockers in HF has shown a significant improvement in survival and quality of life in this group of patients, although it has little effect on peak VO₂. The peak VO₂ cutoff < 10 ml.kg^-1.min^-1 identifies patients at high risk, whereas values > 16 ml.kg^-1.min^-1 categorizes patients with a better midterm prognosis. The peak VO₂ range between > 10 and < 16 ml.kg^-1.min^-1 indicates moderate risk for cardiac event within four years of follow-up.

Previous studies demonstrated that the betablocker significantly reduces the VE/VCO₂ slope in patients with HF. The prognostic value of the VE/VCO₂ slope < 34 in the group with betablocker may reflect the impact of this drug on this cardiorespiratory variable.

Conclusion

The cardiopulmonary stress test seems to maintain the prognostic value in patients with heart failure at the age of betablockers. A low VO₂ peak and an elevated VE/VCO₂ slope are strong and independent predictors of cardiac events in HF. The peak VO₂ and the VE/VCO₂ slope are easily measurable, with high sensitivity and specificity obtained through the cardiorespiratory test and the prognostic value has clinical relevance in a subgroup of patients presenting symptoms that are not compatible with the functional capacity.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of doctoral submitted by Mário Sérgio Vaz da Silva, from Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo.

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Publication Dates

• Publication in this collection
  25 July 2008
• Date of issue
  July 2008

History

• Received
  14 May 2007
• Reviewed
  05 Oct 2007
• Accepted
  10 Dec 2007