The Effect of Bisoprolol on Heart Failure Preserved Ejection Fraction / Hfpef Patient’s Quality Of Life

Background : Global Public Health Burden of Heart Failure reported the growing prevalence of heart failure which is 64.3 million affected in 2020 worldwide with half of the case classified as Heart Failure Preserved Ejection Fraction (HFpEF). It is well known that someone who has been diagnosed with heart failure will have a poorer quality of life/QoL. β-blocker is a heart rate lowering agent with a potency to improve the patient’s clinical outcomes, one of them is QoL. Objective : This study aimed to observe and evaluate the effect of bisoprolol, a type of β-blocker, in the improvement of HFpEF patient’s QoL. Method : This study is a retrospective cohort following HFpEF patients who received bisoprolol and HFpEF patients who did not receive bisoprolol. The study participants were selected using purposive sampling method. Result : Our study found that from all HFpEF patients who received bisoprolol 102 patients had a good QoL and 2 patients had a poor QoL (p=0.000) according to Minnesota Living With Heart Failure Questionnaire (MLHFQ). The median physical score in the patient who did not receive bisoprolol was 10 while the median score of the patient who received β-blocker was 4 (p=0.000). The mean emotional score for the patients who did not receive β-blocker was 3 while the mean score of the patients who received β-blocker was 1 (p=0.000). Conclusion : We conclude that the use of bisoprolol could improve the HFpEF patient’s QoL evaluated by total score, physical score, and emotional score.

Global Public Health Burden of Heart Failure reported that there was an increasing prevalence of heart failure from 26 million people affected in 2017 to 64.3 million people worldwide in 2020 with half of the case classified as heart failure preserved ejection fraction/H-FpEF1. Heart failure preserved ejection fraction or shortened as HFpEF is one of heart failure classification in which the ejection fraction is >50% based on European Society of Cardiology/ESC 2016 guideline for diagnosis and treatment of acute and chronic heart failure2. Patients with HFpEF are older and highly symptomatic with a poor QoL3. Because of that condition, the challenge to achieve our goals in treating HF patients must be face it, which are to improve their clinical status, functional capacity, and quality of life, prevent hospital admission and reduce mortality. 2 Beta blocker/β-blocker is a heart rate lowering agent that may increase the clinical outcome of heart failure patients. 4 ESC 2016 guideline for diagnosis and treatment of acute and chronic heart failure stated the usage of β-blocker as a first-line recommendation therapy combined with ACE inhibitor. 2 One of the most important outcomes that should be evaluated and become the main goal of therapy as we know above is the patient's quality of life/QoL 2 The Cardiac Insufficiency Bisoprolol Study in Elderly/CIBIS-ELD stated an increase in the quality of life from uptitration of β-blocker in patients with heart failure. 5 Besides showing the effect of β-blocker uptitration on the quality of life, the study also evaluates the effect of β-blocker uptitration on the clinical variable such as heart rate where they found a reduction in the heart rate at the end of the study. 5 Based on this fact, we think that there should be a study to observe and evaluate the effect of β-blocker such as bisoprolol on the quality of life of HFpEF patients.

Methods
Our study was a retrospective cohort performed in Saiful Anwar Hospital, Malang from April to July 2021. HFpEF patients data who were treated with bisoprolol and HFpEF patients who did not receive bisoprolol were collected according to the medical record. We used purposive sampling method with inclusion criteria consisted of: (1) age 30-75 years old diagnosed with heart failure based on the definition stated in the 2016 ESC guideline; (2) echocardiography criteria of LV EF ≥50%; (3) H2FPEF score confirmed as an HFpEF; (4) confirmed as a patient in Saiful Anwar Hospital; (5)  consent to participate in the research. The exclusion criteria were (1) patient died before the study interview (2) patient was waiting for the procedure such as cardiac surgery, pacemaker implantation, CABG or heart transplant (3) patient was in a state of severe emotional stress based on a psychiatric diagnosis from medical record data; (4) patient with chronic diseases such as chronic kidney disease or pulmonary hypertension The categorical variables were analyzed using Chi-square and all continuous variables were analyzed by T-test for data with normal distribution or Mann-Whitney for data not normally distributed. The confidence interval used in this study is 95% (α=0.05).

Results
Our study followed 217 patients with 22 patients categorized as poor QoL and 195 patients categorized as good QoL (Table 1). Based on the data analysis, there were statistically significant differences in the QoL on some characteristics including HT (p=0.004), heart rate Table 1. Sample Characteristics (p=0.000), and SBP (p=0.000). Other sample characteristics such as gender (p=0.510), age (0.029), DM (0.365), ischemic (p=0.121), smoker (p=0.221), height (p=0.135), weight (p=0.071), BMI (0.502), NYHA (p=0.401), EF (p=0.721), LAVI (p=0.151), TAPSE (0.486), E/A (0.573) and PCWP (0.365) did not show a significant difference. Table 2 summarized the difference in the QoL between the patient who received bisoprolol and the patient who did not receive β-blocker. We found that 102 patients who received bisoprolol had a good QoL meanwhile 2 other patients who also received bisoprolol had a poor QoL. In the group that did not receive bisoprolol, 93 patients had a good QoL and 20 patients had poor QoL. The mean comparison of bisoprolol (2 categories) showed a p-value of 0.000 (p<0,005) which meant a statistically significant difference of the β-blocker usage in the quality of life. We also found the odds ratio/OR=10.97 which meant that the patients who received bisoprolol had a higher odds of 10.97 times to have a good QoL (CI 95%: 2.49-48.2).  Table 3, the median physical score from patients who did not receive bisoprolol was ten meanwhile the median score from patients who received bisoprolol was four. Statistical analysis with Mann-Whitney showed a significance of 0.000 (p<0.05). This showed that the mean physical score of patients who did not receive bisoprolol and patients who received bisoprolol differed significantly. Our study also found the median emotional score of patients who did not receive bisoprolol was three. In the meantime, the median emotional score from patients who received bisoprolol was one. Statistical analysis with Mann-Whitney showed a p-value of 0.000 (p<0.05) which meant there was a significant difference in mean emotional score in the patient who did not receive bisoprolol and patients who received bisoprolol, with a lower score in the patient who received bisoprolol according to MLHFQ.

Discussion
HFpEF is a heterogeneous syndrome accompanied by a variety of risk factors that contribute to the development of the condition which includes hypertension, obesity, diabetes mellitus, coronary heart disease, valvular heart disease, atrial fibrillation, obstructive pulmonary disease, chronic kidney disease, and anemia. 6,7 We found that hypertension had a significant influence on the QoL in both groups, patients treated with bisoprolol and not treated with bisoprolol (p=0.004). HFpEF patients without any history of hypertension in our study mostly exhibited a good QoL. Literature shows a negative correlation between hypertension and QoL, when the patient has a history of hypertension or severe hypertension, the QoL will be lower. 8 Our study did not act in accordance with this negative correlation because in our study 118 patients with hypertension had a good QoL meanwhile only 20 patients with hypertension had a poor QoL. This might be influenced by a good blood pressure control done by the patient, as mentioned in Lee et al study in which the improvement of quality of life could have an effect on blood pressure control. 8 Heart rate evaluation is among the most studied variable because of its relation with the clinical outcome of a patient with cardiovascular disease, as the study from O'Neal et al who concluded β-blocker can also act as an anti-remodeling in the HFpEF patient. Structurally, there is a difference in the remodeling process of HFpEF and other heart failures. 20 In HFpEF, the heart underwent concentric hypertrophy of the left ventricle even though some of the patients still have a normal left ventricle geometry. 21 The use of β-blocker in the past study showed its role as a cardiac antiremodelling although the underlying mechanism was still unclear. The suggested mechanism was a reduction of left ventricle sphericity and functional regurgitation of the mitral. 22 We should all keep in mind that almost all past studies of the heart failure patient had given the patient ACE-inhibitor before the administration of β-blocker which meant that the anti-remodeling effect was significantly influenced by the use of ACE-inhibitor and we could not estimate the same result if we eliminate the use of ACE-inhibitor. 23

Conclusion
Bisoprolol could improve the quality of life (total score, physical score, and emotional score) of HFpEF patients compared to a patient who did not receive bisoprolol.

Ethics Approval and Consent to participate
This study was approved by local Institutional Review Board, and all participants have provided written informed consent prior to involvement in the study.

Consent for publication
Not applicable.

Availability of data and materials
Data used in our study were presented in the main text.

Competing interests
Not applicable.

Funding source
Not applicable. that greater count of heart rate at rest is a factor that influences the clinical outcome in the HFpEF patient. 9 Our study found that patients who had fewer heartbeats per minute mostly had a good QoL while patients with greater heartbeats per minute had a poor QoL. An increase in heart rate by 5-10 beats per minute will increase the mortality risk in the general mortality or mortality related to cardiovascular and also in the risk of hospitalization in the heart failure patient such as HFpEF patient, which is this finding had a great effect on the patient's QoL. 10 An increase in the heart rate, reflects the increase in energy cost, activation of the sympathetic system, and excretion of catecholamines in heart failure patients. The upsurge of catecholamines in HFpEF patients might be accountable for a poorer outcome in patients with HFpEF both physically and psychologically. 11 There are some neurotransmitters that have an effect on someone's mood that will also affect the QoL at the end. 11 An increase in the heart rate facilitated by activation of the sympathetic system can also affect the blood pressure and initiate an upsurge in catecholamines as compensation. This can lead to a change in the patient's physical and psychological state.

Authors contributions
Evaluation of the QoL by MLHFQ categorized 102 patients who received bisoprolol into a good QoL (47,0%). From the Fisher exact test, we found p=0.000 (p<0.05) which meant there was a significant difference in the QoL between the patient who received bisoprolol and the patient who did not receive bisoprolol. In our study, the patient who did not receive bisoprolol mostly had a poor QoL. This finding was supported by CIBIS ELD who found that the dose up-titration of β-blocker could improve the HFpEF patient's QoL evaluated by the SF-36 questionnaire. 5,12 Kojima also had a similar discovery, he found that the use of β-blocker affects the QoL in a span of one year. 13 We hope that the improvement of HFpEF patient's QoL when treated by β-blocker, like we found in our study, could give a new insight into the management of HFpEF even though there was still a big dispute. 14 In the progression of heart failure, there is a hyperactivation of the sympathetic system, which manifest as an increase in the heart rate and an increase in the stimulation of β-adrenergic receptor at cardiomyocytes result an activation of Beta1AR-stimulating G (Gs) protein-adenylate cyclase-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA). 15 In the chronic condition, this can lead to persistent stimulation of β1-adrenergic receptor which result in cardiomyocytes apoptosis, hypertrophy, and also fibrosis of the heart. Β-blocker has a therapeutic role in the pathophysiology of HFpEF where it can lower the sympathetic system activation and hope to inhibit the persistent stimulation of β1-adrenergic receptor 15 and inhibit the delay of left ventricle relaxation as the result of the heart's inflexibility that can lead to an increase in diastolic filling pressure of the ventricle and reduction of the cardiac output. 16 Another beneficial effect of beta blocker is the direct protection of myocardial from catecholamine toxicity. When HFpEF patients experience a reduction of cardiac output, the body will try to compensate for it by doing a counter-regulation. One mechanism is by increasing the regulation effect of the sympathetic system, unfortunately, this  Table 3. Mean Comparison of β-blocker to Physical Score and Emotional Score