Functional Capacity Improvement Related to Inflammatory Marker Reduction After Phase II Cardiac Rehabilitation Program in Post- revascularization Coronary Artery Disease Patients

Background: Improved functional capacity (FC) and inflammatory marker reduction is a good prognostic factor in post-revascularization cardiac patients. However, there is still limited study investigated association of functional capacity and inflammatory marker after cardiac rehabilitation program. We studied the effects of cardiac rehabilitation (CR) program in the improvement of FC and high-sensitive-C Reactive Protein (hs-CRP) reduction and association between those variables. Methods: This was quasi experimental study in post-revascularization CAD patients who attended phase II CR program at CR gymnasium, Dr. Hasan Sadikin General Hospital, Bandung, from October 2014 to May 2015. The CR program included additional education sessions and consistently strict program intensity on 50-80% heart rate reserve based on formula and Borg scale 11 to 15. Functional capacity and hsCRP were measured before and after the program. Functional capacity was assessed by maximal treadmill test through indirect VO2 max measurement. Results: A total of 37 patients aged 56.05±7.3 years old were analyzed in this study. They consisted mainly of men (81.1%) which 78.4% of them underwent percutaneous coronary intervention (PCI). Our study revealed significant FC improvement after completion of this newly-modified CR program from an average of 6.76 to 8.68 METs (28.4%) ( p<0.001). Hs-CRP reduction was also occurred from mean of 0.49 mg/L to 0.20 mg/L (59.2%) of log hs-CRP level (p= 0.005). Linear regression analysis showed the improvement of fitness was associated with baseline FC (p<0.001) and reduction of hs-CRP was associated with baseline hs-CRP (p<0.001), and not influenced by age, gender, ejection fraction and type of procedure. There is moderate correlation (rs= 0.636, p<0.001) between functional capacity improvement and hs-CRP reduction. Each 1 METs improvement can reduce 9.317 mg/L of transformed hs-CRP level (p=0.006, 95%CI 2.942,15.693). Conclusions: CR program significantly increased functional capacity and reduce hsCRP level in post-revascularization CAD patient, and more prominent in a patient with low baseline functional capacity and high hs-CRP level. Functional capacity improvement and hs-CRP reduction were moderately correlated.


INTRODUCTION
2][3] Advances in technology and medicine has brought better survival rate in coronary artery disease patients in the last decades. 4Despite the fact that reduction of coronary artery disease (CAD) morbidity and mortality by improvement in coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) technique, the rate of myocardial reinfarction and CAD-related rehospitalization are still high.In the United States, overall 30-day readmission rate was 14.5% of which 8.3% caused by cardiac disease, and post-acute myocardial infarction 90-day readmission rate was 24%.It was estimated to cost country about $1.1 billion for 30-day readmissions. 5To overcome this situation, cardiac rehabilitation (CR) as secondary prevention program needs to be optimized.
Improved functional capacity (FC) is a better prognostic factor in post-revascularization cardiac patients.It is proven to improve quality of life, decrease cardiovascular event and reduce mortality. 6Improvement of FC could be achieved by aerobic exercise as its cardioprotection and decrease post-stenting late lumen loss effects, contribute to decreasing in restenosis rate. 7Aerobic exercise increased 33% of FC and 16% of maximal oxygen intake (VO 2 max). 6Myers et al. showed every improvement of 1 metabolic equivalents (METs) in functional capacity reduced 12% of mortality risk in cardiovascular patients. 80][11] Inflammation parameter is also used as successful of treatment and secondary prevention indicator. 127][18] Prognostic impact of FC improvement in mortality was thought mediated by its inflammation reduction effect. 18However,there is still limited study investigated association of FC and inflammatory marker after CR program in post revascularization CAD patient.The aim of this study was to investigate the effects CRprogram in improvement of FC and hs CRP level and their association after CR program.

Ethical Statement
All subjects were informed about the possible risks of the investigation before giving written

RESULT
Forty-four patients were enrolled in this study with seven of them were excluded (four drop-outs, one loss to follow-up and two incomplete procedures).A total of 37 subjects were analyzed for functional capacity improvement.Mean age of subject was 56.05±7.3 years old, range 37-73 years old.Thirty subjects (81.1%) were male, seven subjects (18.9%) were female.Majority of our subjects had a minimum of senior high school level of education (70.3%).Mean of body mass index (BMI) was 25.32 kg/m 2 and classified as overweight. 23Subjects with diabetes mellitus (DM), hypertension, dyslipidemia, family history and smoking history were 13.5 %, 59.5 %, 70.3 %,29.7 %, and 75.7% consecutively.
Our coronary angiography profile revealed 37.8% patients had three vessel CAD.Furthermore, most of subjects (89.2%) had preserved ejection fraction (EF >40%) and 78.4% of subjects underwent for PCI.Meanwhile, 21.6% of subjects underwent CABG for a revascularization procedure (Table 1).

Functional Capacity Improvement
Our study found significant improvement in FC from 6.76±1.94 to 8.68±1.60METs (p<0.001), with a difference of 1.92 METs after completed this CR program.The median of METs differences was 1.68 METs.Then, we analyzed FC improvement related factors.Our bivariate analysis showed age, gender, diabetes mellitus, hypertension, dyslipidemia, smoking history, and type of procedure were not associated with FC level improvement after completed CR program.However, the EF had a low negative correlation(r s =-0.358, p=0.030), baseline FC had a moderate negative correlation (r s = -0.552,p<0.001), and baseline hs-CRP level had a lowpositive correlation (r s = 0.461, p=0.004) with FC improvement (Table 2).There was an association between baseline FC and FC improvement after adjusting for confounders (Table 3).Patient with 1 METs lower of baseline FC will obtain functional capacity improvement of 0.401 higher after CR.Baseline hs-CRP has a tendency to predict FC improvement.However, in model 1 adjustment, this relation was not significant (Table 3).We suggest age or gender is a strong confounder interrupted baseline hs-CRP effect towards FC improvement.Linear regression analysis also showed ejection fraction was not a significant predictor of FC improvement.

Hs-CRP Reduction
Fourteen patients (37.8%) had high baseline of hs-CRP level (>3 mg/L).Hs-CRP level was also reduced significantly after completion of CR program (p = 0.005).A total of 29 subjects (78.4%) had a hs-CRP reduction (mean log baseline of hs-CRP was 0.49 mg/L reduced to 0.20 mg/L), with difference 0.29 mg/L (59.2%) of log hs-CRP level (Figure 2).There was a significant difference in hs-CRP reduction between two types of procedure.Baseline FC level and baseline hs-CRP were lowly and highly correlated with hs-CRP reduction, respectively.After adjusting for baseline FC and other confounders, there was association between baseline hs-CRP level and hs-CRP reduction (Table 4).Patient with 1 mg/L higher of baseline hs-CRP on average would obtain hs-CRP reduction of 0.877 mg/L higher after CR.However, baseline FC and type of procedure were not significant predictors for hs-CRP reduction.
Hs-CRP natural course of reduction was considered not interrupt our hs-CRP assessment in this study.Based on available data, we initiate CR program within 14 (8-35) days after procedure.While, hs-CRP reduction was started after first week and back to normal one month after PCI or major surgery. 24,25n purpose to confirm hs-CRP level reduction due to exercise effect instead of type of cases or time related hs-CRP reduction, we compared hs-CRP level between the theoretically higher hs-CRP cases (PCI in acute coronary syndrome case and CABG groups) and the elective PCI group.Based on independent T test, there were no significant difference in log baseline hs-CRP (P=0.176) and log hs-CRP reduction (P=0.728) between two groups.
If we compare between PCI and CABG groups.There were significant difference in log baseline hs-CRP (P=0.007) and log hs-CRP level reduction (P=0.003) between two groups.However, there was significant log hs-CRP reduction between pre and post CR program in evey subgroup of cases (CABG and PCI group).It may propose positive confirmation of our hypothesis that hs-CRP level reduction caused by CR program independent of type of procedure and hs-CRP reduction related time.In this study, hs-CRP reduction have a high probability caused by phase II CR program.

Association of FC and hs-CRP Improvement
There was moderate correlation (r s = 0.636, p<0.001) between FC improvement and hs-CRP reduction.Furthermore, FC improvement can predict hs-CRP level reduction.Each  This characteristic was favorable to this study since education was an important element for rehabilitation program compliance and it could be reflected in small number of drop out patient in the study. 27We initiate CR program earlier; within 2 weeks after procedure.Initiation of CR after 1 week leads to a 90% increase in participation rates compared to a initiation after 4 weeks. 28

Functional Capacity Improvement
This study demonstrated phase II CR program, consisted of hospital gymnasium and home exercise training completed with healthy lifestyle education, could produce significant improvement with an average of 1.92 METs (28.4%) in FC and this study result was consistent with several previous studies in phase II CR program.0][31][32] Our good result in this study could be explained by the low FC baseline of subjects as it might result in significant difference.A CR improve exercise capacity, and may be caused by an adaptive response involved in an increased capacity of endogenous anti oxidative systems or more efficient oxidative metabolites.Exercise training rises the capillary density of the skeletal muscle, promotes a transformation from type II to type I muscle fiber, and increases the amount and oxidative enzyme activities of mitochondria.These peripheral mechanisms play significant part in the increase in VO 2 max by exercise training.The increase in exercise capacity is also assumed to be caused by myocardial ischemic threshold improvement in patients with CAD. 33Diabetes mellitus, hypertension, dyslipidemia, smoking and type of intervention were not associated with FC improvement.The CR program is an excellent measure to improve CAD patients' quality of life and reduce morbidity and mortality. 34Different from this study, Branco et al. 35 showed greater mean functional capacity improvement in age > 45 years old, non diabetes mellitus and post-CABG patients.
Our patients' age characteristic (97.3%) >45 years old, diabetes mellitus control status and earlier initiation of CR might lead differences in these findings.Early CR program will reduce deconditioning period of post-CABG patients and improve FC baseline in post-CABG patients. 36Therefore, it might result in no significant difference between post-PCI and CABG patients' post-CR FC improvement.Multivariate analysis demonstrated the baseline FC was the only independent predictors of FC improvement after completion of phase II CR program.
This finding emphasized the phase II CR program be significantly improved FC independent of the presence of CAD risk factors and type of procedure.CR program appeared to give more benefit in a patient with worse condition (low FC level) independent to other factors.Previous studies were consistent with these findings.Shiram et al. 37 showed initial exercise capacity as the only independent variable predicting improvement in exercise performance after rehabilitation program.Ades et al. 38 study also showed the baseline physical function score was the only baseline variable that predicted change in physical function score after rehabilitation.Patients with the lowest baseline physical function score were the most likely to show an improvement in physical function score after rehabilitation. 38,39jection fraction was not an independent predictor of FC improvement in linear regression analysis.This result was consistent with a study performed by Sousa et al. 40 , which demonstrated FC improvement achieved after completion of CR program was independent of initial left ventricle function.Maximal oxygen intake depends on several parameters, such as ventilation, oxygen diffusion at lung level, peripheral perfusion and diffusion, and mitochondrial function which in several conditions have more important role than oxygen transport by circulation itself. 41 Based on our study, reduction in hs-CRP level after CR program more prominent in higher baseline of hs-CRP level.This finding also explained the higher reduction of hs-CRP in this study than previous studies.Statin was not considered to affect our study result since all enrolled patients consumed statin more than one week and hs-CRP decreased significantly after one week of statin treatment (at the time we measured hs-CRP baseline level). 47ur study revealed a high hs-CRP reduction (59.2%), which might indicate CR program impact on hs-CRP reduction besides the statins.This result consistent with Milani et al. 13 study which identify benefit of phase II CR training programs to reduce hs-CRP with similar or greater effect than statin drugs.
We found baseline hs-CRP was the only significant predictor of hs-CRP reduction after CR program.The antiinflammatory effect of exercise in person with coronary heart disease may be greater because of their higher inflammatory levels. 48In Lakka et al 49 study with 652 sedentary healthy adult, hs-CRP reduced by 1.34mg/L in individuals who had high (3.0mg/L)baseline hs-CRP levels, but did not change among those with low (1.0 mg/L) or moderate (1.0-3.0 mg/L) baseline hs-CRP levels.The difference in the hs-CRP change among the baseline hs-CRP group was still significant after adjustment for all correlates variables such as body weight, glucose, insulin, LDL, HDL, triglycerides, systolic and diastolic blood pressure, and maximal oxygen uptake.Though there is a tendency of significant correlation between type of procedure and hs-CRP reduction, type of case or procedure was not significant predictor in multivariate analysis.Higher baseline of hs-CRP caused higher hs-CRP level reduction after CR program in CABG group compared to PCI group.][52][53][54] Association between FC and hs-CRP level is interrelated.Patient with good FC has lower level of hs-CRP and vice versa, patient with lower FC had a higher hs-CRP level. 18,55,56Functional capacity improved prognosis mechanism is partly mediated by hs-CRP lowering effect. 18Furthermore, high hs-CRP itself is a marker for impaired functional capacity. 57,58This study found FC improvement positively correlated with hs-CRP reduction after program.The direct mechanism of FC improvement to reduce hs-CRP level is still unknown, and might be explained by exercise related effect to hs-CRP reduction.Our study results were remarkable compared with other previous studies, since the less frequency of our CR program (two times a week).Difficulty in access to CR center, social and administrative problems had been concerns in our setting.However, prescribed home exercise could overcome this condition.In our center, phase II CR program started earlier; in two weeks after procedure despite in most of previous CR studies, the programs were initialized four weeks after revascularization procedure.In our setting, earlier CR program was needed to be performed since our culture of post-myocardial infarct or revascularization patients frequently lead to sedentary lifestyle.

Limitations
There are several limitations in this study.Firstly, cardiopulmonary exercise test with respiratory gas analysis (CPX) was not used as a gold standard of VO 2 max calculation in FC measurement. 19,59Equipment costs limited direct VO 2 max measurement in this study.Secondly, control group was not involved in this study as a comparison of non-intervention group.Control group would give more benefit data for FC difference and hs-CRP reduction after intervention.Thirdly, supervision and documentation of patient's home exercise activity were not conducted.Home prescribed exercise during CR phase II documentation might add more data for its effect in functional capacity improvement.Lastly, there is still a possibility for drugs combination, such as statin, angiotensin converting enzyme (ACE)-inhibitors, angiotensin receptor blockers (ARBs) and beta blockers (BBs) to bring attenuation effect on hs-CRP level.Another study could be performed by putting these limitations into account.Our finding of association between FC improvement and hs-CRP level reduction can be a hypothesis for the next study to show FC only surrogate marker in patient clinical improvement and clinical improvement can be caused by hs-CRP reduction. In

Figure 1 .-
Figure 1.Flow of participants through the trial CAD= coronary artery disease, TMT= treadmill test, hs-CRP= high sensitive C-Reactive Protein

Table 1 . Baseline characteristics of participants
Figure 2. Improvement in functional capacity and in log hs-CRPlevel after CR program