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Effectiveness of Metoprolol in Improving Cardiac and Motor Functions in Patients with Chronic Heart Failure: A Prospective Study

Purpose To assess gender-, age-, and the dose-related influence of metoprolol on cardiac function, motor function, quality-of-life (QoL), and mental status in Chinese chronic heart failure (CHF) patients. Patients and Methods This single-center, prospective study enrolled CHF patients with resting heart rate (HR) >80 bpm and used metoprolol continuous release tablets. Patients were initiated with 12.5-mg metoprolol. All patients were assessed for change in cardiac function, motor function, QoL, and mental status according to gender (men vs women), age (<60 vs ≥60 years), and metoprolol dose administered (47.5 mg [n=37], 71.25 mg [n=7], 118.75 [n=74], and 142.5 mg [n=19]). Results Overall, 154 CHF patients (101 men and 53 women), with median age 66.39 years, were enrolled. In total, 116 and 38 patients were aged ≥60 and <60 years, respectively. We observed a slight decrease in systolic blood pressure (SBP) in women compared with men. HR had increased with an increase in ejection fraction (EF) from baseline to 1 month (35.24±6.15 and 34.79±6.25) and increased to 50.00±4.45 and 50.72±4.09 among both the genders. Cardiac index (CI) and motor function had improved along with better QoL after metoprolol treatment in both the genders. In both age groups (<60 and ≥60 years), improvement in cardiac function, motor function, and QoL was observed; however, there was a difference in mental status. The dose effect of metoprolol on cardiac function, motor function, QoL, and mental status showed a gradual decrease in EF with dose increments, with no change in CI. Motor function, QoL, and mental status did not show much difference with uptitration of metoprolol dose. Conclusion Psychological responses to metoprolol treatment differ with gender, with no age-related changes in terms of cardiac function, motor function, QoL, or mental status, except increases in depression, burnout, and anxiety.


Introduction
Chronic heart failure (CHF) is emerging as a major global health problem associated with structural or functional alterations of the myocardium involving adrenergic receptor stimulation and adrenergic system activation, leading to myocardial fibrosis and remodeling. 1,2 Despite advancements in the management of CHF, the risk of morbidity and mortality remains substantially high, with a prevalence of approximately 5.7 million in the US and is expected to increase to 8 million by 2030 3 and over 4.2 million in China. 4 Moreover, it puts a huge economic burden on the healthcare system as this chronic condition of CHF leads to poor quality-of-life (QoL) 5,6 and loss of work productivity. 7 Beta-blockers remain the mainstay of treatment for patients with CHF because of their inherent property to counteract the sympathetic over-activity associated with left ventricular dysfunction, in addition to lowering the heart rate (HR), contractility, and blood pressure, thus lowering the mortality of CHF. 2,8,9 The beneficial effects of beta-blockers are further supported by a meta-analysis of randomized control trials (RCTs) showing total reduction of mortality and heart failure-related sudden death in patients with CHF. [10][11][12][13][14] Metoprolol, a cardio-selective beta-blocker, has shown reduction in CHF mortality 2 and improved QoL and mobility. 12,15,16 However, this well-established beneficial effect of beta-blocker is associated with CNS side-effects such as depression [17][18][19] and anxiety, 20 which are ultimately responsible for decreased QoL and increased risk of mortality among patients with CHF. 21 However, some studies show contrasting results, with no increase in depressive symptoms. 22 In addition, it is unknown whether the neuropsychiatric adverse effects and increase in depression and anxiety in CHF are associated with metoprolol or are pre-existing but remain unnoticed during the initiation of the therapy, which places beta-blockers in a controversial position despite their well-established benefits. Furthermore, reduction in spontaneous motor activity was observed with the use of beta-blockers, and preclinical studies have shown that psychological states such as depression and anxiety are known to alter the motor function. 23 We conducted the present study to add to the current knowledge on the effect of metoprolol treatment on cardiac function, motor function, QoL, and mental status considering gender-, age-, and dose-related impact of metoprolol on Chinese patients with CHF.

Study Design and Patient Population
This is a single-center, prospective study. The complete study design and patient inclusion criteria have been described elsewhere. 16 In brief, all the enrolled CHF patients had a resting HR of >80 bpm, were with or without neuropsychiatric disorders such as depression and anxiety, and were treated at the Second Affiliated Hospital of Kunming Medical University between February 2013 and April 2016. Patients were excluded if they had a resting HR <60 bpm, SBP <90 mm Hg, metoprolol usage in the past 3 months, contraindications for beta-blockers, administration of class I or class III antiarrhythmic agents, <6 months' expected survival, a pacemaker, a history of coronary bypass surgery, or a recent heart attack.

Ethical Approval
The Second Affiliated Hospital of Kunming Medical College University approved the study protocols and complied with Good Clinical Practices, the Declaration of Helsinki, and its subsequent revisions. All the included patients provided written informed consent prior to their enrollment.

Treatment Intervention and Follow-Up
We collected baseline patient data before treatment with an initial daily dose of 23.75-or 47.5-mg metoprolol continuous release tablets (Betaloc ® ZOK, AstraZeneca, Sweden), and the dose was escalated by 23.75 mg every 7 days until the target HR level (60-70 bpm) was achieved during the follow-up. The average dose used to reach the target goal was 99.75 mg (47.5-142.5 mg). All the patients were followed up at 1, 3, 6, and 12 months from intervention for final outcome measurement.

Study Outcomes and Measurement
The study outcome was to compare change in cardiac function, motor function, QoL, and mental status at 1, 3, 6, and 12 months from baseline according to gender (men . Change in all the study outcomes was also evaluated within the groups. Cardiac function was measured in terms of EF (%) and cardiac index (CI [L/min/m 2 ]). We measured motor function using a standard 6-minute walk test (6MWT) and Veterans Specific Activity Questionnaire (VSAQ). QoL was measured by an 8-item short form questionnaire (SF-8), in which the higher score denotes improved QoL, and the Minnesota Living with Heart Failure Questionnaire (MLHFQ), in which the highest score denotes worst QoL.
Mental and burnout status was assessed using the Hospital Anxiety and Depression Scale (HADS) and Copenhagen Burnout Inventory (CBI) questionnaire, respectively.

Statistical Analysis
The statistical software R (version 3.6.2, R core team, R Foundation for Statistical Computing, Vienna, Austria) was used to perform all the analyses. Descriptive statistics were used to present the baseline characteristics as mean ±standard deviation (SD), median (range), numbers, and percentages. We used Student's t-test to compare the mean values for all the parameters between the two groups. Change in values for EF, CI, 6MWT, VSAQ, SF-8, MLHFQ, HADS, and CBI scores at the various followup periods were compared with baseline values using repeated measure one-way analysis of variance (ANOVA), followed by post hoc Bonferroni correction analysis. P<0.05 was considered to be statistically significant for all the analyses.

Sociodemographic Characteristic
A total of 169 patients were included in the study, of which 11 were excluded owing to intolerance to metoprolol dose increments and four patients were lost to follow-up. The remaining 154 patients were included for the final data analysis (median age= 66.39 years; men, n=101; women, n=53). Baseline sociodemographic characteristics and other comorbidities of the included patients are presented in Table 1.

Gender-Related Changes in Post-Metoprolol Treatment
An average metoprolol dose of 99.75 mg was required to reach the target HR. EF in both men and women increased from baseline (37.60±5.91 and 37.64±6.10) to 1 month (35.24±6.15 and 34.79±6.25) and increased to 50.00±4.45 and 50.72±4.09, respectively, at the end of 12 months with no statistically significant between-gender difference (P>0.05; Table 2). However, across the different time points, a statistically significant difference was observed in EF between men and women (P<0.05). CI increased from baseline (1.78±0.22 and 1.79±0.21) to 12 months (2.70±0.25 and 2.78±0.23) with no statistically significant difference between men and women, respectively. However, a statistically significant difference was observed across different time points, except from baseline to 1 month (P<0.05).
A decrease in HR was observed in both the genders with no statistically significant between-gender difference. However, across the time points, change in HR was statistically significant (P<0.05). SBP slightly increased from baseline to 12 months in men and decreased in women, with statistically significant between-gender difference from baseline to 12 months (Table 2). Across the time points, SBP showed a statistically significant difference from baseline to 12 months.
With respect to motor function, distance walked in 6MWT increased in both men and women, and this DovePress association across the different time points was found to be statistically significant. VSAQ scores increased from baseline (6.41±1.03 and 6.73±1.15 in men and women, respectively) to 12 months, with statistically significant between-gender difference only at 12 months and showed P<0.05 across the different time points (Table 2). Increase in SF-8 scores, denoting improvement in QoL, was observed from baseline to 12 months in men and women (Table 2). Moreover, a decrease in MLHFQ scores, denoting better QoL between men and women, was observed with a statistically significant difference across the different time points for both SF-8 and MLHFQ scores (P<0.05).
HADS scores for depression gradually increased from baseline (9.32±2.95 and 7.87±2.15) to 12 months, with a statistically significant difference between men and women, respectively (Table 3), and across the time points (P<0.05). HADS anxiety scores also increased from baseline to 12 months, with statistically significant betweengender differences only at 1 and 12 months and P<0.05 across all the time points except from baseline to 1 month. CBI scores increased from baseline to 12 months among men and decreased in women, with no statistically significant between-gender difference (P>0.05).

Age-Related Changes
A non-significant increase in EF and CI was observed in both patients aged <60 and ≥60 years (P>0.05). In comparison with different time points, a statistically significant difference was observed for both EF and CI (P<0.05). HR and SBP showed a non-significant reduction in both the age groups, with the changes being constant at baseline and month 1, 3, and 6 and drastic reduction at the end of 12 months (Table 4). In comparison with different time points, a statistically significant difference was observed only from baseline to 12 months for HR and SBP. Motor function assessed by 6MWT showed a gradual non-significant increase among both patients aged <60 and ≥60 years, except at the end of 1 month (P<0.05). VSAQ scores also increased among both the age groups from baseline to 12 months (Table 4).
With regard to QoL, a sudden decrease in SF-8 scores from baseline (44.10±2.60 and 43.97±2.75) to 1 month (39.42±1.64 and 39.37±1.67 in patients aged <60 and ≥60 years, respectively) and gradual increase in scores at 3, 6, and 12 months were observed between both the age groups, with a statistically significant difference at 12 months (P<0.05). MLHFQ scores also showed a sudden increase from baseline to 1 and 3 months and gradually decreased at 6 and 12 months between both the age groups, with a statistically significant difference at the end of 3 months (P<0.05; Table 4). Change in scores in comparison with outcomes of motor function and QoL at different time points from baseline to 12 months has shown a statistically significant difference.
With regard to mental status, a gradual increase in HADS depression scores was observed in both the age groups, with no statistically significant difference between the age groups. However, HADS anxiety scores decreased from baseline to 12 months, and CBI scores showed an increasing trend among both the age groups (Table 5), with a statistically significant difference between different time points, except from baseline to 1 month, for both HADS depression and CBI scores.

Metoprolol Dose-Related Changes at the End of 12 Months
EF gradually decreased from 51.41±3.75 to 48.63±5.13 with an increase in the dose of metoprolol from 47.5 to 142.5 mg. CI did not show much change with increase in the dose of metoprolol. Motor function and QoL showed statistically non-significant differences with respect to different doses of metoprolol (Table 6). Mental status scores evaluated by HADS depression, HADS anxiety, and CBI scores also showed no statistically significant difference (P>0.05) with respect to different doses of metoprolol (Table 7).
Repeated measure ANOVA with Bonferroni correction was used to establish significant differences at different time points (Supplementary Tables 1 and 2).

Discussion
In this study, we explored the effect of metoprolol on change in cardiac function, motor function, QoL, and mental status of CHF patients with respect to gender, age, and different metoprolol doses. Our findings highlight that metoprolol treatment with respect to gender showed improved cardiac and motor function, better QoL, and increased depression but decreased anxiety scores. With regard to age, metoprolol treatment had shown improved cardiac and motor function and improved QoL with higher  depression and decreased anxiety scores. Furthermore, there were no significant differences with different doses of metoprolol in cardiac, motor, QoL, and mental status in patients with CHF. Gender-related differences in the pharmacokinetics of metoprolol are well established. 24 In our study, a reduction in HR from baseline to 12 months was observed in both the genders. SBP was higher in women at all time points, and reduction in SBP was observed at 12 months. A similar pattern of responses was also reported in previous studies. 16,25 Moreover, in our study, both EF and CI were similar between men and women. Motor function was evaluated using 6MWT and VSAQ scores, which are reliable tools to evaluate functional capacity and prognosis. 26,27 In our study, metoprolol also improved the motor function of male and female patients with CHF. In both men and women, improvement in the QoL was observed as a biphasic response with both SF-8 and MLHFQ scales after metoprolol treatment. Previous studies using various questionnaires have also demonstrated improvement in QoL with metoprolol usage among patients with CHF. 16,28,29 Neurohormonal dysfunction due to pathophysiological modifications caused by prolonged anxiety and depression can lead to cardiac abnormalities. 30,31 In addition, symptoms of depression and anxiety are often unrecognized, 32 which results in disease progression. 33 Our study results demonstrated that metoprolol treatment increased the HADS depression scores and decreased the anxiety scores among both men and women.
In our study, in patients aged <60 and ≥60 years, significant and expected reductions in HR and SBP were observed; however, the reductions were observed only at 12 months of metoprolol treatment, and no changes were observed at baseline and 1, 3, and 6 months in both the age groups.
Cardiac function post-metoprolol treatment evaluated by EF and CI showed a biphasic response, with an initial decrease at 1 month and significant improvement of both EF and CI by 12 months in both the age groups (<60 and ≥60 years). This further confirms that the beta-blocker action of metoprolol on both EF and CI is independent of age. 34 A study conducted by Neto et al 35 also reported similar findings. Motor function evaluated by 6MWT and VSAQ also showed an initial decrease at 1 month and improvement by 12 months post-metoprolol treatment. This finding correlates with the decrease in cardiac function at 1 month as patients with CHF encounter myopathy of both cardiac and skeletal muscles, 36 which further validated the deterioration of motor function in these patients. 37,38

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QoL after metoprolol treatment has also shown a similar trend as cardiac and motor function in patients with CHF, with an initial decline in QoL at the end of 1 month and subsequent improvement by 12 months. Patients with CHF are prone to anxiety and depression due to neurohormonal dysregulation, 32 and evidence suggests that elders are more susceptible to depression and anxiety, which impact their QoL. 39,40 Our study showed higher HADS depression scores, indicating improvement in depression, but lower HADS anxiety scores, denoting that patients with CHF express more anxiety, and higher CBI scores with better burn out status in both the age groups (<60 and ≥60 years).
In our study, we also examined the dose-mediated effect of metoprolol on cardiac, motor, QoL, and mental status of patients with CHF. A slight decrease in EF and no change in CI were observed with an increase in the dose of metoprolol. A study conducted by Zhang et al 41 also showed no significant changes in the cardiac function with different doses of metoprolol. No dose-dependent changes with metoprolol were observed in motor function and QoL. However, a good correlation between QoL and clinical outcomes was reported by other studies. 42,43 Metoprolol use in the treatment of CHF could worsen preexisting depression or lead to depression. 31 In our study, mental status measured with HADS depression, HADS anxiety, and CBI scores did not show much difference with dose increment of metoprolol.
The strength of our study was that we have provided comprehensive evidence involving the effect of gender, age, and metoprolol dose on cardiac, motor, QoL, and mental status of patients with CHF at baseline and 1, 3, 6, and 12 months. Our study also had certain limitations. First, we did not include a control group or use placebo to compare the outcomes with the treatment groups. Second, most of the questionnaires were self-administered instead of an interview-based method, which might have resulted in variances in responses. Third, we followed patients with CHF for 1 year, and thus, long-term mortality and metoprolol influence on different outcomes could not be captured. Finally, other confounding factors including age, sample size, and comorbidity medications taken could have influenced the study findings.

Conclusion
Gender-related differences were mostly observed in mental status after metoprolol treatment, suggesting that psychological response to metoprolol differs between men and women. Metoprolol has demonstrated age-independent improvement in cardiac function, motor function, and QoL, whereas an increase in depression and burnout as well as improvement in anxiety scores were observed. Uptitration of metoprolol to target dose showed no significant difference in clinical outcomes.

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