Age-dependent changes in cardiac performance, motor function, QoL, and mental status in metoprolol-treated chronic heart failure patients

No previous study reports the effect of age on cardiac performance, motor function and quality of life (QoL) in Chinese chronic heart failure (CHF) patients. This single-center, prospective study enrolled CHF patients with resting heart rate (RHR) > 80 bpm, who were treated with metoprolol and were followed up at 1, 3, 6, and 12 months. Changes in cardiac, motor, and QoL parameters between patients aged ≥60 years and those aged <60 years were compared at all time points. P < 0.05 was considered significant. A total of 154 patients were enrolled (median age: 66.39 years; 116 aged ≥60 years, 38 aged <60 years; 95% New York Heart Association class III-IV). RHR decreased significantly in both patient groups (P < 0.0001 for both groups). Patients aged ≥60 years had a significant improvement in both ejection fraction (EF) at 6 and 12 months and in cardiac index (CI) at 3, 6, and 12 months. However, no major difference was observed in motor function in both groups. Significantly higher SF-8 scores showed greater improvement in QoL in the <60 age group at 12 months (P = 0.0008). Metoprolol demonstrated improvement in cardiac performance, motor function, QoL, and anxiety with increase in depression and burnout in both genders; however, the findings were independent of age.

According to the MERIT-HF 15,24 and RESOLVD studies 24 , metoprolol succinate, a cardioselective β-blocker, is one of the β-blockers recommended for preventing the incidence of death in HF patients 2 . Additionally, CHF patients reported improvement in QoL in terms of physical activity, social functions and life satisfaction compared with standard therapy 21 and placebo 25 . Previously, only one study has reported the overall effect of metoprolol on cardiac performance, motor function, and QoL in Chinese patients 26 with no separate evaluation in elderly patients. Thus, indicating the paucity of data on age-dependent cardiac, motor, and QoL outcomes of metoprolol. The present study will add insight about the risk-to-benefit ratio of metoprolol treatment in aged population. Therefore, this study was performed to compare the effect of metoprolol treatment in elderly (aged ≥60 years) and non-elderly Chinese CHF patients (aged <60 years) in terms of change in cardiac function, motor function, QoL, and mental status.

Results
Baseline characteristics. A total of 154 patients (median age 66.39 years; body mass index 23.85 ± 3.62 kg/ m 2 ; 65.5% male patients) were analyzed of the 169 patients included. Of the 154 patients, 116 were elderly (aged ≥60 years) and the remaining 38 patients were non-elderly (aged <60 years) ( Fig. 1). At baseline, family history of cardiac disease and hypertension were reported in 35.0% and 74.6% patients, respectively. Approximately, 95% of patients were categorized as New York Heart Association (NYHA) class III-IV. Other important comorbidities and disease history are presented in Table 1. At baseline, patients aged ≥60 years had significantly higher HR (87.03 ± 4.53 vs. 81.31 ± 6.75, respectively, P < 0.0001) and systolic blood pressure (SBP) (132.81 ± 6.55 vs. 124.74 ± 14.75 respectively, P = 0.0014) compared to patients aged <60 years.

Reduction in sBp and HR.
During the 1-year period, patients with higher SBP and HR were treated with an average metoprolol dose of 99.75 mg. Overall resting heart rate (RHR) as measured by resting electrocardiogram decreased significantly from a baseline value of 82.72 ± 6.73 to 64.86 ± 3.21 bpm at 12 months (P < 0.0001). Similarly, there was a significant drop in SBP from a baseline value of 126.73 ± 13.64 to 123.35 ± 12.31 (P = 0.0230) at the 1 st month follow-up, followed by an increase (124.70 ± 9.67) at the 3 rd month follow-up and 125.11 ± 6.67 at the 6 th month follow-up. At the 12 th month follow-up, SBP levels reached a stable level of 123.37 ± 6.88 mmHg (P = 0.0067), which was comparable with the levels observed at the 1 st month following metoprolol treatment.
Decrease in HR from baseline to 12 months was significant in patients aged <60 years (87.03 ± 4.53 vs. 65.58 ± 3.08, P < 0.0001) and ≥60 years (81.31 ± 6.75 vs. 64.29 ± 6.75, P < 0.0001); however, SBP levels decreased significantly only in patients aged <60 years (P < 0.0001). Although at 12 months, there was greater decrease in HR and SBP in patients aged < 60 years, this group had significantly higher HR (65.58 ± 3.08 vs. 64.29 ± 6.75, P = 0.0319) and similar SBP (124.74 ± 3.22 vs. 122.93 ± 6.62, P = 0.1071) compared with patients aged ≥60 years. Improvement in cardiac performance, motor function, and QoL: a comparison. Among the cardiac function parameters, EF decreased non-significantly from baseline to 1 and 3 months in patients aged <60 years (37.08% ± 6.18% to 34.50% ± 6.44%; P = 0.0791 and 36.47% ± 5.57%; P = 0.655, respectively). Decrease in EF from baseline to 1 and 3 months was significant in patients aged ≥60 years (37.79% ± 5.89% to 35.25% ± 6.08%; P = 0.014 and 35.46% ± 4.92%; P < 0.0001, respectively). However, treatment with metoprolol significantly improved EF at 6 and 12 months in both the age groups (P < 0.0001 for change, Table 2). For cardiac index (CI), a non-significant decrease was observed from baseline to 1 month in patients aged <60 years, whereas  Motor function evaluation with 6-minute walk test (6MWT) showed that patients in the ≥60and <60-year age groups walked similar distances at all the follow-up points. At the 1-month follow-up, patients aged ≥60 years had significantly higher walking distance on the 6MWT compared with patients aged <60 years (344.51 ± 32.23 vs. 331.73 ± 32.08, P < 0.0353). However, patients aged <60 years had non-significantly higher motor function compared with patients aged <60 years at 12 months (416.81 ± 19.26 vs. 416.32 ± 21.35, P = 0.9002, Table 2). Within the ≥60-year age group, a trend of initial decrease in motor function from baseline to up to 3 months was observed; however, the motor function on 6MWT significantly increased at 6 and 12 months compared with baseline (P < 0.0001 for both comparisons, Table 2). Veterans Specific Activity Questionnaire (VSAQ) scores were similar in both the groups at all the time points, indicating no significant differences in motor function. Similar to 6MWT, a decreasing trend was seen in VSAQ scores from baseline to up to 3 months followed by a significant improvement (Table 2).
A comparison of QoL between the two groups via short form-8 questionnaire (SF-8) scales showed no significant difference in scores until 6 months; however, at the 12-month follow-up, patients aged <60 years had significantly higher scores than those aged ≥60 years, indicating a greater improvement in QoL (52.89 ± 1.67 vs. 51.83 ± 2.26, P = 0.0086). In both the age groups, the SF-8 scores decreased initially until 3 months (P < 0.0001 for both), followed by a significant improvement at 6 and 12 months compared with baseline (P < 0.0001 for both, Table 2). Compared to baseline, a significant improvement in the Minnesota Living with Heart Failure questionnaire (MLHFQ) scores at 6 and 12 months was seen (P < 0.0001), which was preceded by worsening of QoL at 1 and 3 months. At 3 months, patients aged ≥60 years had significantly higher MLHFQ scores than those aged <60 years (86.37 ± 5.09 vs. 88.55 ± 4.64, P = 0.0206), with similar scores observed at all other time points (Table 2).
Change in mental status. Among the CHF patients aged ≥60 years, the Hospital Anxiety and Depression Scale (HADS) depression score was higher throughout the study duration compared with patients aged <60 years, with no significant difference in the depressive symptoms reported at any of the follow-up visits (Fig. 2a). However, the depression score worsened significantly from baseline to 1 (P = 0.0092), 3 (P = 0.0039), 6 (P = 0.0029), and 12 months (P = 0.0023) in patients aged ≥60 years. Although the depression scores worsened in patients aged <60 years from baseline to 1 (P = 0.1530), 3 (P = 0.1152), 6 (P = 0.0832), and 12 months (P = 0.0612), the change was not significant. Figure 2b presents the HADS anxiety scores, which were consistently lower in the older patients till 6 months compared with patients aged <60 years, with higher scores observed at 12 months. In the patients aged ≥60 years, HADS anxiety scores were consistent till 1 month (P = 0.9125) but decreased significantly at 3, 6, and 12 months from baseline (P < 0.0001 for all comparisons). The decrease in HADS anxiety scores in patients aged <60 years followed a similar trend, with non-significant decrease till 1 month from baseline (P = 0.7372) followed by significant decrease at 3 (P = 0.0039), 6 (P = 0.0019), and 12 months (P = 0.0002). Compared with patients aged <60 years, mean Copenhagen Burnout Inventory (CBI) scores in the patients aged ≥60 years was consistently and non-significantly lower at baseline to 12 months (P = 0.3120, P = 0.8046, P = 0.6684, P = 0.5897, and P = 0.9812 at baseline, 1, 3, 6, and 12-months, respectively) (Fig. 2c). Within the patient group aged ≥60 years, overall CBI scores worsened significantly at 3 (P = 0.0127), 6 (P = 0.0166), and 12 months (P = 0.0062) from baseline. On the other hand, the CBI scores increased in the patients aged <60 years; however, the increase was non-significant.
Age at baseline was not associated with greater risk of depression, i.e. patients aged ≥60 years had similar odds of experiencing depression compared with patients aged <60 years (odds ratio [OR] 1.03, 95% confidence interval (CI) 0.4960-2.1526, P = 0.93). However, male patients had significantly greater odds of depression compared with female patients (OR 2.0621, 95% CI 1.0494-4.0519, P = 0.0357). In the subgroup analysis, except significant greater CI in the HADS score ≥10 group versus the HADS score ≤11 group (P = 0.0421), no significant differences were observed in mean EF, CI, 6MWT, and VSAQ (Supplementary Table 1). However, a significant change in the variables within the group was seen at different time points.

Discussion
We explored the impact of metoprolol treatment on cardiac, motor, and QoL outcomes in CHF patients and reported improvement in all the aspects 26 . Since β-blockers are known to worsen psychological conditions, physicians must rightly choose their patients to treat CHF without deteriorating their QoL and mental status. To the best of our knowledge, this is the first study to compare the cardiac, motor, QoL, and mental/neurological outcomes in patients with CHF. An expected and significant reduction in HR was observed in both the groups from baseline to 12 months, due to the cardioselective action of β1-blockers 27 . In our study, patients aged ≥60 years did not achieve significant SBP reduction, which was in consistence with previous study by Holfler and Morgenstern, where the magnitude of blood pressure (BP) reduction was similar in all the groups without any age-dependent changes 28 . In our study, SBP was observed to be decreased significantly at the 1-month follow-up. However, very minor but consistent increase in SBP was observed till the 12-month follow-up. This is contrary to the previous observations in which no significant change in SBP was observed at 1 month 29 and comparable decrease in SBP was observed after 3 months 30 . A possible reason for this slight increase in SBP in our study could be explained by correlating aging with HF. An increase in the levels of circulating catecholamines has been observed both in CHF and aged individuals along with desensitization of the β-adrenoceptors due to decrease in their number 31,32 . Additionally, a disturbed β-adrenoceptor-mediated vasodilation has also been associated with aging due to hyper-expression and increased activity of G protein coupled receptor kinase (GRK2) in the vascular system with advancing age 33 .
With respect to cardiac performance, a biphasic response was observed wherein initial decrease till 1 month was followed by a significant improvement in EF and cardiac index until 12 months in both the age groups and no significant difference was seen when compared between the groups. This confirmed the non-age-dependent action of the β1-blocker, metoprolol on both EF and CI 28 . Further evidence suggests the benefits of β-blocker use in CHF patients with reduced Left ventricular ejection fraction (LVEF) 34 and preserved LVEF 35 . Similar to our findings, a study by Neto et al. reported improved EF, lowered LVEF, and cardiac frequency in patients with NYHA II-IV grade CHF 36 . β1-blockers are also known to demonstrate improvement in cardiac index by 0.3 to 0.8 L/min*m 2 due to multiple mechanisms 37 . In our study, the magnitude of cardiac index change was 0.99 L/ min*m 2 in patients aged ≥60 years and 0.96 L/min*m 2 in patients aged <60 years, showing overall a similar effect in both age groups and concordance with previous findings.
The trend of motor improvement was accompanied with a decreasing pattern in motor function in both age groups from baseline to 1 month, followed by an improvement till the end of follow-up. The decrease in 6MWT distance and VSAQ scores in this study may be correlated with decreased cardiac performance at 1 month as patients with CHF usually report myopathy of both cardiac and skeletal muscles 38 . This further validates the finding that cardiovascular diseases are associated with deteriorating motor functions 39,40 . 6MWT is a reliable measure for motor function in multiple studies which have shown a significant improvement in CHF patients 41,42 . Similar to previous findings, in the current study, 6MWT predicted a significant improvement in motor function. However, the improvement was in both groups without any significant difference among the patients of different ages. Similarly, VSAQ has been validated in Chinese patients with HF 43 and has further shown to be associated with poor QoL on MLHFQ scores 44 . QoL in patients with CHF is significantly low due to the effect of HF on the motor functions, constant requirement for healthcare support, which is a burden for patients with lower socioeconomic status 45 . β-blockers, including metoprolol, however have reported a significant improvement in the QoL in CHF patients using SF-36, MLHFQ, and Quality of Life in chronic Heart Failure Questionnaire (QLQ-CHF) 21,25 . However, a recent randomized trial by Mittal et al. showed that metoprolol did not significantly improve the QoL in CHF patients using the SF-36 questionnaire 46 . In another study by Waagstein et al., metoprolol treatment significantly improved HR, cardiac function, motor function, and QoL at 12 months 47 . In our study, the trend of QoL in CHF patients after metoprolol treatment was similar to the cardiac function and motor function trend, showing an initial decline in QoL till 1 month with a subsequent improvement till 12 months. Similar trend of change in cardiac, motor function, and QoL indicated a relation between them.
Although CHF patients are susceptible for developing depression and anxiety due to neurohormonal dysregulation 48 , these symptoms are mostly underestimated leading to progression of comorbidities 49 , thereby increasing the risk of mortality 50,51 . There is mounting evidence supporting the fact that depression and anxiety are highly prevalent in elderly patients impacting their QoL 52,53 . From our previous experience, worsening of in patients with CHF, which was non-related to metoprolol, induced HR reduction but possibly due to administration of other CV drugs or due to involvement of metabolizing enzymes. Further the anxiolytic effect of metoprolol was Scientific RepoRts | (2019) 9:453 | https://doi.org/10.1038/s41598-018-37520-8 observed in CHF patients via RHR reduction 54 . In the present study, patients aged ≥60 years reported consistent and non-significant higher HADS_depression score after metoprolol treatment. This corroborates the findings that metoprolol and other β-blockers are associated with depression 22,55 and the dosage and duration of treatment should be carefully monitored in all patients irrespective of their age. Owing to its direct effects on the central β-receptors 56 , treatment with metoprolol effectively controlled anxiety in both the groups resulting in similar HADS_anxiety scores throughout the study. Evaluation of burnout in CHF patients aged ≥60 years showed significant worsening from baseline to end of follow-up with no significant difference seen compared with the <60 year age group. Since older patients had lower burnout throughout the study and no previous findings have elucidated the difference in patients of different age groups, further studies are warranted to explore the burnout using CBI scores. The study has some major strengths, which include (i) first study to determine the age-dependent changes in CHF patients and (ii) the study included a comprehensive evaluation of cardiac, functional, motor, and mental effects in the patients after metoprolol administration. In addition, our study also had a few limitations due to which the results must be carefully interpreted: (i) the study had only the treatment group and no placebo or active control (β-blocker effective in CHF: carvedilol or bisoprolol) group was included, presence of which could have projected the efficacy of metoprolol in a more effective manner and (ii) the subjective questionnaires could have induced a factor of bias to the findings (however, this was addressed to an extent by the provision of assistance by healthcare practitioners (HCPs) for responding to the questions); (iii) since depression and burnout in HADS_depression and CBI scores worsened, a longer follow-up could have helped in determining the extent of change depending on the duration of therapy; (iv) known history (duration, severity and any other treatments) would also yield more reliable results; and (v) the patients in the <60and ≥60-year age groups were distributed in 1:3 proportion. Therefore, due to a small sample size of patients aged <60 years (n = 38), the conclusions drawn should be carefully extrapolated as the study might be inadequately powered. Larger randomized studies shall be performed to confirm the findings of this study.

Materials and Methods
study design and patient population. Complete study design and criteria for including participants have been described elsewhere 26 . Briefly, this prospective study enrolled CHF patients (HR > 80 bpm) with or without neuropsychiatric disorders treated at The Second Affiliated Hospital of Kunming Medical University between February 2013 and April 2016. Patients were excluded if they had (i) HR < 60 bpm; (ii) SBP < 90 mmHg; (iii) history of metoprolol use in the last 3 months; (iv) <6 months of expected survival; (v) pacemaker implanted; (vi) contraindication to β-blockers; (vii) been administered class I or class III anti-arrhythmic drugs; (viii) recent heart attack; and (ix) undergone coronary bypass surgery. The study complied with Good Clinical Practices, declaration of Helsinki and its subsequent revisions. All the patients were included in the study only after obtaining a signed informed consent. All the experimental protocols were approved by The Second Affiliated Hospital of Kunming Medical University licensing committee and the study was conducted in accordance with relevant guidelines and regulations. treatment plan. Data collection was performed for patients with history of initial metoprolol dosing of 23.75 or 47.5 mg (Betaloc ® ZOK, AstraZeneca, Sweden). The dose was subsequently increased by 23.75 mg/week until target HR of 60-70 bpm was achieved in few patients during follow-up. study outcomes and measurements. The study outcome was to compare cardiac function, motor function, QoL, and mental status at 1, 3, 6, and 12-months from baseline in elderly patients aged ≥60 years versus patients aged <60 years. A trend of change in all the outcomes was also evaluated within the groups.
The measurement scales and method for assessment of SBP, RHR, cardiac function (EF and CI), motor function (6MWT and VSAQ), and QoL (SF-8 and MLHFQ) are described elsewhere 26 . Mental assessment was performed using the HADS and CBI scale. HADS is a self-administered questionnaire, with seven questions each for depression and anxiety. Patients with HADS score 8-10 and 11-21 were considered borderline normal and abnormal, respectively 57 . The CBI questionnaire measures personal, work-, and client-related burnout by patients' perspective 58 Patients. who experienced difficulty in completing the HADS and CBI questionnaires were assisted by the HCPs. A subgroup analysis was performed to compare the EF, CI, 6MWT, and VSAQ between patients with HADS_ depression score ≥11 versus HADS_depression score ≤10 at baseline. The subgroup analysis was performed irrespective of the age of the patients. statistical analysis. Descriptive statistics was used to present the baseline characteristics as mean ± standard deviation (SD), median (range), numbers, and percentages. Values for EF, CI, 6MWT, VSAQ, SF-8, MLHFQ, HADS, and CBI in both age groups and genders were presented as mean ± SD. Student's t-test was used to compare the mean values for all the parameters between the two groups. A P value of <0.05 was considered statistically significant.

Conclusion
Treatment with metoprolol demonstrated an effective improvement in cardiac performance, motor function, QoL, and anxiety in patients from both the groups, whereas an increase in the depression and burnout was noted. Despite the changes within the groups, the patients belonging to both ≥60-year and <60-year age groups had similar changes after treatment, indicating the consistent efficacy of metoprolol for CHF patients irrespective of the age.