Achieved Targeted Heart Rate Following Ivabradine Therapy Correlates With Left Ventricular Reverse Remodeling In Non-Ischemic Dilated Cardiomyopathy 

Achieved Targeted Heart Rate Following Ivabradine Therapy Correlates With Left Ventricular Reverse Remodeling In Non-Ischemic Dilated Cardiomyopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Achieved Targeted Heart Rate Following Ivabradine Therapy Correlates With Left Ventricular Reverse Remodeling In Non-Ischemic Dilated Cardiomyopathy Jooyeon Lee, Jaewon Oh, Jaehyung Ha, Chan Joo Lee, Seok-Min Kang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5425737/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Sep, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract The effect of ivabradine on left ventricular reverse remodeling (LVRR) in heart failure with reduced ejection fraction (HFrEF) and its correlation with achieved heart rate (HR) by ivabradine in non-ischemic dilated cardiomyopathy (NIDCM) remain uncertain. A retrospective analysis of 255 sinus rhythm NIDCM patients at a tertiary center (2012 ~ 2021) were categorized into four groups based on the ivabradine use (Iva+/-) and achieved HR at 1-year (HR+/-). The HR cut-off of 70bpm was determined via receiver operating characteristic curve analysis for LVRR, defined as an absolute ≥ 10% improvement in LV ejection fraction (LVEF) from baseline, with a final LVEF ≥ 40%. LVRR incidence at 1-year was, 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% Iva+/HR70 + and 71.1% in Iva+/HR70-. Ivabradine treated patients with HR < 70bpm had higher incidence of LVRR than those without ivabradine (Iva+/HR70- vs. Iva-/HR70+, OR 4.85, 95%CI 1.97–11.96 P = 0.001; Iva+/HR70- vs. Iva-/HR70-, OR 3.60, 95% CI 1.41–9.18, P = 0.007) after adjustment for known predictors in a multivariate model. Consistent adherence to beta-blockers and ivabradine, along with guideline-directed medical therapy (GDMT) for HF, and sex were identified as independent predictors of LVRR. Ivabradine therapy achieving HR < 70bpm correlated with increased LVRR incidence in NIDCM patients, underscoring the role of ivabradine in HR reduction adjunctive to GDMT. Health sciences/Cardiology Health sciences/Diseases/Cardiovascular diseases/Cardiomyopathies ivabradine heart rate reverse remodeling heart failure with reduced ejection fraction non-ischemic dilated cardiomyopathy Figures Figure 1 Figure 2 Introduction Dilated cardiomyopathy (DCM) stands as the most prevalent etiology of heart failure (HF). 1–3 Substantial progress in medical treatments targeting improved clinical outcomes for HF have been made. Left ventricular reverse remodeling (LVRR), characterized by improvement in LV systolic function and reduced LV chamber size, is closely linked with a favorable HF prognosis. 4 Notably, HF medications such as beta-blockers, renin-angiotensin-aldosterone system (RAS) inhibitors, mineralocorticoid receptor antagonists (MRA), and angiotensin receptor neprilysin inhibitors (ARNI), have exhibited LVRR in HF with reduced ejection fraction (HFrEF) patients. 5–7 Adjunct to these established practices, ivabradine, a specific I f -channel inhibitor, emerged as a therapeutic option aimed at reducing heart rate in HFrEF patients with sinus rhythm 8,9 , has acquired a class IIA recommendation in current guidelines for HFrEF 1–3 , and shown to positively impact LVRR in previous studies. 10–13 While these investigations demonstrated a correlation between LVRR and heart rate reduction, the precise relationship between LVRR and the achieved heart rate after ivabradine treatment remains incompletely elucidated. Therefore, our study aims to explore the impact of ivabradine on LVRR and assess its influence on the risk of clinical events based on the achieved heart rate in patients with non-ischemic DCM (NIDCM). Result Patients’ characteristics and medication at baseline and follow-up The baseline clinical characteristics of the study population (255 patients) are summarized in Table 1 . The median age was 56 years (interquartile range, IQR 43–67), with a predominant of male (60.1%) and body mass index (BMI) to be 24.3 kg/m 2 (IQR 21.6–26.8). Patients who received ivabradine treatment had lower systolic blood pressure (BP), lower LVEF, and shorter QRS duration. Moreover, patients with ivabradine treatment (Iva+/HR70 + and Iva+/HR70-) had higher baseline HR and experienced more substantial HR reduction at the first year, with this difference becoming more apparent at the second year of the follow-up. Notably, over 85% of patients in ivabradine-treated groups demonstrated a reduction of HR from baseline, and the change in HR was more pronounced compared to patients without ivabradine (Iva-/HR70 + and Iva-/HR70-). (refer to Supplementary Table 1) Table 1 Baseline characteristics according to ivabradine treatment and achieved heart rate Group 1 Iva-/HR70+ (N = 109) Group 2 Iva-/HR70- (N = 73) Group 3 Iva+/HR70+ (N = 35) Group 4 Iva+/HR70- (N = 38) Overall (N = 255) P -value Age, years 54 [45–66] 62 [49–72] 45 [39–62] 58 [43–66] 56 [43–67] 0.008 Male, n (%) 67 (61.5%) 48 (65.8%) 18 (51.4%) 20 (52.6%) 153 (60.0%) 0.386 BMI, kg/m 2 24.2 [22.1–27.3] 23.2 [21.5–26.1] 25.2 [21.2–27.4] 25.8 [22.1–27.4] 24.3 [21.7–26.8] 0.205 Laboratory findings Hb, mg/dL 13.9 ± 2.2 13.9 ± 1.9 14.2 ± 2.3 13.7 ± 2.0 13.9 ± 2.1 0.842 Anemia, n (%) 12 (11.0%) 9 (12.3%) 3 (8.6%) 1 (2.6%) 25 (9.8%) 0.395 eGFR, ml/min/1.73m 2 89.0 [72.9-103.4] 90.6 [68.8-102.3] 87.3 [79.7–99.3] 86.9 [61.0-94.8] 89.1 [71.1-100.1] 0.433 NT-proBNP, pg/mL 1624.0[521.5–3816.0] 1301.5[530.0-4728.0] 1583.0[597.5–3055.0] 2892.0[912.5–6411.0] 1739.0[567.0-3969.0] 0.248 Medical History , n (%) Hypertension 49 (45.0%) 31 (42.5%) 16 (45.7%) 19 (50.0%) 115 (45.1%) 0.901 Diabetes 35 (32.1%) 21 (28.8%) 11 (31.4%) 13 (34.2%) 80 (31.4%) 0.940 Chronic kidney disease 22 (20.2%) 16 (21.9%) 5 (14.3%) 4 (10.5%) 47 (18.4%) 0.425 Cardiac parameters Systolic BP, mmHg 124 [110–138] 120 [107–132] 116 [104–136] 112 [101–122] 120 [106–135] 0.025 Diastolic BP, mmHg 80 [70–85] 79 [70–88] 75 [68–80] 77 [70–90] 78 [70–86] 0.244 Heart rate, bpm 92 [79–104] 81 [74–89] 97 [89–109] 98 [88–109] 89 [78–101] < 0.001 QRS duration, ms 102.0 [94.0-114.0] 108.0 [98.0-142.0] 98.0 [91.0-114.0] 99.0 [92.0-114.0] 102.0 [94.0-122.0] 0.007 LBBB, n (%) 16 (14.7%) 18 (24.7%) 6 (17.1%) 5 (13.2%) 45 (17.6%) 0.300 LAVI, ml/m 2 46.5 [35.4–56.3] 48.1 [36.0-62.6] 45.0 [36.9–55.9] 47.4 [40.0-54.8] 46.8 [36.3–58.2] 0.922 LVEDD, mm 65.3 ± 8.4 66.5 ± 6.9 65.7 ± 8.5 65.8 ± 7.2 65.8 ± 7.8 0.797 LVEF, % 26.0 [21.0–32.0] 24.0 [20.0–31.0] 21.0 [18.0–26.0] 19.5 [17.0–28.0] 24.0 [20.0-29.5] < 0.001 * Data are presented as n (%), mean ± standard deviation or median [interquartile range]. BPM, beat per minute; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HR, heart rate; LAVI, left atrial vole index; LBBB, left ventricular bundle branch block; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type brain natriuretic peptide. Regarding medication regimens at baseline, patients were treated comparably for guideline-directed medical therapy (GDMT) except for the use of MRA, which was more prescribed (90%~) in groups treated with ivabradine. This finding was consistent throughout the follow up. However, patients with ivabradine treatment showed comparably lower adherence to beta-blockers (74.3%, 81.6% vs. 95.4%, 94.5%, P = 0.001) at the one-year follow up and consistently lower adherence at subsequent years ( P = 0.012) (refer to Supplementary Table 2). A total of 77 patients (30.2%) received treatment with ivabradine at the baseline. Among these patients, four patients discontinued ivabradine treatment due to dizziness (n = 1), a switch to beta blockers due to high blood pressure (n = 1), bradycardia (n = 2), and were subsequently excluded. At the one-year mark, 73 (94.8%) patients remained on ivabradine treatment. Meanwhile, five patients have been newly diagnosed with atrial fibrillation, but none of them were using ivabradine at the time of the arrhythmia onset. Clinical characteristics related to LVRR Table 2 presents the clinical characteristics of the study population stratified by achieved LVRR at follow-up. Patients who achieved LVRR at 1 year showed a higher baseline HR and diastolic BP with a significant reduction HR at the follow-up (-20 bpm vs. -13 bpm, P = 0.003). Moreover, the LVRR group showed a smaller baseline LV end-diastolic diameter (LVEDD) and shorter QRS duration with a lower prevalence of LBBB, whereas the baseline LVEF was similar between LVRR and non-LVRR group. Regarding the HF medication regimen, LVRR group exhibited higher adherence to beta blockers at baseline but was comparable at one-year follow up ( P = 0.051). In addition, despite the adherence ACEi/ARB or ARNI, and MRA were comparable across the group, patients treated with more than 50% of target dose was more frequently observed in the LVRR group (refer to Supplementary Table 3). Table 2 Patients’ clinical characteristics according to left ventricular reverse remodeling at 1-year LVRR (N = 134) Non-LVRR (N = 121) P -value Age, years 54 [42–67] 57 [45–68] 0.279 Male, n (%) 70 (52.2%) 83 (68.6%) 0.011 BMI, kg/m 2 24.3 [21.7–26.8] 24.3 [21.6–26.8] 0.810 Laboratory findings Hb, mg/dL 13.7 ± 2.2 14.1 ± 2.0 0.141 Anemia, n (%) 9 (6.7%) 16 (13.2%) 0.125 eGFR, ml/min/1.73m 2 89.3 [70.5–100.0] 88.5 [71.9-101.8] 0.918 NT-proBNP, pg/mL 1695.0 [548.0-5349.0] 1907.0 [605.0-3778.0] 0.696 Medical History , n (%) Hypertension 71 (53.0%) 44 (36.4%) 0.011 Diabetes 46 (34.3%) 34 (28.1%) 0.350 Chronic kidney disease 25 (18.7%) 22 (18.2%) 1.000 Cardiac parameters at baseline Systolic BP, mmHg 122 [109–138] 116 [104–130] 0.059 Diastolic BP, mmHg 80 [70–89] 76 [69–84] 0.028 Heart rate, bpm 92 [81–105] 88 [75–98] 0.006 QRS duration, ms 101.0 [92.0-112.0] 108.0 [96.0-134.0] 0.011 LBBB, n (%) 16 (11.9%) 29 (24.0%) 0.019 LAVI, ml/m 2 48.9 [36.5–58.9] 44.2 [35.8–56.3] 0.377 LVEDD, mm 64.2 ± 6.9 67.5 ± 8.4 0.001 LVEF, % 23.0 [20.0–29.0] 25.0 [20.0–30.0] 0.257 Cardiac parameters at follow-up Systolic BP, mmHg 122 [110–134] 116 [106–126] 0.026 Diastolic BP, mmHg 71 [62–82] 70 [61–77] 0.198 Heart rate, bpm 72 [66–80] 73 [64–82] 0.676 Change in heart rate, bpm -20 [-32 to -7] -13 [-25 to 0] 0.003 LVEF, % 51.0 [46.0–57.0] 31.0 [24.0–36.0] < 0.001 * Data are presented as n (%), mean ± standard deviation or median [interquartile range]. Abbreviations as in Table 1 . LVRR, left ventricular reverse remodeling. The incidence of LVRR at 1 year in four groups were 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% Iva+/HR70 + and 71.1% in Iva+/HR70-, respectively. Compared to patients without ivabradine treatment, patients with well-controlled HR below 70bpm by ivabradine treatment showed a significantly higher incidence of LVRR (Iva+/HR70- vs. Iva-/HR70+, odds ratio (OR) 4.85 [95% confidence interval (CI) 1.97–11.96], P = 0.001; Iva+/HR70- vs. Iva-/HR70-, OR 3.60 [95% CI 1.41–9.18], P = 0.007), after adjusting for known predictors – age, sex, SBP, QRS duration and beta blocker usage. Furthermore, although in multivariate regression analysis, the difference in LVRR was attenuated in patients treated with ivabradine treatment but with different targeted HR (Iva+/HR70 + vs. Iva+/HR70-, OR 1.65 [95% CI, 0.55–4.94], P = 0.370), the significance of the difference was confirmed with a P for trend of 0.002. Besides, among patients who did not reach the targeted HR, a significantly higher incidence of LVRR was shown in those with ivabradine treatment (Iva+/HR70+) compared to those without ivabradine treatment (Iva-/HR70+) (refer to Fig. 2 ). The independent predictors associated with achieving LVRR were analyzed using logistic regression analysis and are presented in Table 3 . Patients with a history of hypertension, those receiving 50% or more of the target dose of ACEi/ARB or ARNI and baseline BP were independently associated with LVRR but were attenuated after the multivariable adjustment. Ultimately, male ( P = 0.029) and persistent adherence to beta-blockers ( P = 0.005) and ivabradine ( P = 0.013) were identified as the independent predictors of LVRR. Furthermore, every 10bpm decrement of HR during the follow-up was independently associated with LVRR (OR 1.26 [95% CI 1.10–1.44], P = 0.031), whereas the multivariate regression model adjusted with baseline HR was not significant ( P = 0.270). (refer to Supplementary Table 4) Table 3 Univariate and multivariate logistic regression analysis for independent predictors of baseline related to left ventricular reverse remodeling Univariate analysis Multivariate analysis OR 95% CI P -value OR 95% CI P -value Age < 65 year 1.39 0.83–2.35 0.215 Male 0.50 0.30–0.84 0.008 0.50 0.27–0.93 0.029 BMI < 25 0.96 0.59–1.59 0.884 NT-proBNP ≥ 1739 pg/mL 0.92 0.56–1.52 0.749 eGFR < 60 ml/min/1.73m 2 1.06 0.54–2.11 0.860 Hb < 10g/dL 0.47 0.20–1.11 0.086 0.78 0.28–2.18 0.635 Hypertension 1.97 1.19–3.26 0.008 1.42 0.79–2.54 0.237 Diabetes 1.34 0.78–2.28 0.285 Systolic BP, per 10mmHg 1.15 0.99–1.32 0.063 1.05 0.89–1.24 0.556 Diastolic BP, per 10mmHg 1.32 1.06–1.64 0.013 Heart rate, per 10bpm 1.30 1.12–1.50 0.001 LVEDD ≥ 55 mm 1.12 0.41–3.07 0.833 LVEF, per 10% 0.84 0.44–1.62 0.611 QRS duration > 120 ms 0.61 0.35–1.06 0.079 0.62 0.32–1.17 0.139 Ivabradine maintained 2.33 1.32–4.11 0.004 2.45 1.20-5.00 0.013 Beta-blocker maintained 2.91 1.32–6.40 0.008 3.92 1.50-10.22 0.005 Beta-blocker dose ≥ 50% 1.52 0.80–2.89 0.197 ACEi/ARB/ARNI dose ≥ 50% 1.87 1.06–3.28 0.030 1.90 0.98–3.66 0.057 MRA dose ≥ 50% 1.65 0.90-3.00 0.103 Reduction in heart rate at follow up, per 10bpm 1.26 1.10–1.44 0.001 1.19 1.02–1.39 0.031 * Only variables with P < 0.10 in the univariable model were included in the multivariable model. Abbreviations as in Table 1 . ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CI, confidence interval; LVRR, left ventricular reverse remodeling; OR, odds ratio. Clinical events according to achieved heart rate with or without ivabradine The median follow-up duration after the index time was 730 days (interquartile range [IQR] 639–858). Hospital readmission due to worsening of HF occurred in 24 (9.4%) patients and cardiovascular-related death occurred in 1 (0.4%) patient. When comparing the risk of adjudicated clinical events, the event-free survival rate did not show a statistically significant difference between the groups, with a P -value was 0.20 according to the log-rank method (refer to Supplement Fig. 1 ). Discussion In this present study, we observed a high prevalence of LVRR in patients achieving a HR less than 70 bpm after treatment with ivabradine (71.1% in Iva+/HR70- vs. 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% in Iva+/HR70+). Moreover, a consistent beta-blocker adherence adjunct with sustained use of ivabradine independently predicted the occurrence of LVRR. Our study demonstrated the benefit of ivabradine in potentially improving LVRR when used adjunctively with optimal GDMT, but did not show a clear impact on reducing cardiovascular risk through reduction of heart rate. The importance of HR reduction in HF is widely recognized, as reducing HR can have a protective effect on the heart by decreasing energy expenditure, prolonging diastole to increase blood supply, reducing arterial stiffness 14 , and ultimately leading to ventricular unloading 15 . The MERIT–HF, the CIBIS–II, and the COPERNICUS trial have established the role of beta-blockers in lowering the risk of cardiovascular events 16–18 . The positive effect of beta-blockers extend beyond HR reduction where they inhibit the hyperactivated sympathetic tone to prevent the progression of cardiomyocyte apoptosis or interstitial fibrosis, leading to further myocardial injury. 19 Taking a step further, it has been associated with the occurrence of LVRR. 20 However, there is still a topic of debate regarding the maximally titrated dosage, targeted HR, or the degree of HR reduction being more important in beta blocker treatment. Studies investigating its association with clinical outcomes put more emphasis on the dose-dependent improvement 20 , while the relationship between achieved HR and the occurrence of LVRR remain elusive or insignificant. 21 Ivabradine, a newly emerged drug, blocks sinoatrial node I f channels and regulates HR without interfering with cardiac inotropy. 22 The SHIFT trial (Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial) that enrolled systolic HF patients with HR above 70 bpm demonstrated an isolated decrement in achieved HR at 28 days with ivabradine augmentation was associated with a direct reduction in cardiovascular events. 8,9 However, limited research has explored the association between the ivabradine and LVRR in HF, aside of HR reduction. Ceconi et al. presented a reduction in LV volume was associated with a change in HR from baseline in patients with stable coronary artery disease and LV dysfunction after treatment of ivabradine. 11 Similarly, Tsutsui et al. showed that HR reduction was related to the decrease in LV chamber size and an improvement in LVEF. 12 However, the association between the achieved HR by ivabradine and LVRR was not elaborated. Our research, which focuses on investigating the relationship between LVRR and achieved HR in patients with NIDCM, demonstrates a higher occurrence of LVRR in patients with achieved HR < 70 bpm after treatment with ivabradine. Notably, the increased incidence of LVRR observed in our study population may have been attributed to the HR reduction achieved through optimal medical treatment, aligning with the findings from the SHIFT trial. Optimal medical therapy was implemented in majority of subjects – 89.8% patients were under beta-blocker, 88.6% was under ACEi/ARB or ARNI, and 82.4% was under MRA respectively as depicted in Supplementary Table 2. These rates were comparable, if not higher, than those reported in the SHIFT trial. However, the proportion of patients receiving ≥ 50% of target dose of beta blocker was significantly lower in our study (11.0% at baseline and 22.2% at follow up vs. 56%), reflecting the real-world clinical practice of infrequent up-titration to recommended dose of GDMT. 23 This corresponds with the underuse of beta-blocker reported in Asian registry. 24,25 As shown in Table 1 , the baseline systolic BP of patients treated with ivabradine was lower than that of the other groups. Physicians may hesitate to prescribe beta-blockers to patients with hypotension or with other concomitant contraindications, despite the need for more aggressive up-titration. 2 Nevertheless, considering the patients treated with ivabradine were less frequently administered beta-blockers than those without the ivabradine, it isolates the effect of ivabradine on LVRR. Furthermore, in Iva+/HR70 + adherence to beta-blockers was notably lower compared to the other groups at one-year follow up (74.3% vs. 95.4%, 94.5% or 81.6%, P = 0.001). Despite this lower adherence, Iva+/HR70 + exhibited a significantly higher incidence of LVRR, which highlights the inherence significance of ivabradine in HF. Higher heart rates are likely to make ivabradine more effective by blocking a greater number of the I f channels at sinoatrial nodes. 22 Likewise, the greatest reduction in HR from baseline at one year follow-up was observed in Iva+/HR70-, and the significant correlation of the degree of HR reduction with the likelihood of LVRR further supports the highest occurrence of LVRR in Iva+/HR70- in our study. In a mouse model, ivabradine down regulates the neurohormonal interaction by blunting the renin-angiotensin-aldosterone system 26 and the sympathetic nervous system, improving the HR variability. 27 With attenuated apoptosis and intracellular matrix metalloproteinase expression 28 , ivabradine might mitigate the process of adverse remodeling and exert cardio-protection effect. 13,29 Lastly, the SHIFT trial presented that achieving the lower HR (even below 65 or 60 bpm) by ivabradine was associated with a lower risk of clinical events 8,21 , while our study finding was neutral among the groups. This inconsistent result might have been due to the small sample size and short follow-up duration of patients. Nevertheless, unlike previous studies, this study restricts the focus to patients with NIDCM, maintaining homogeneity in the etiology of heart disease. Given the extent of revascularization in HF with ischemic origin, whether complete or incomplete, acts as a significant confounding variable, confining the analysis solely to patients with NIDCM allows for a more precise assessment of the effects of GDMT. 30 Furthermore, patients who underwent cardiac resynchronization therapy were also excluded to eliminate the effect of device-guided treatment and to solely isolate the therapeutic effect of medical treatment. This study has several limitations. Firstly, despite meticulous review of clinical data, the retrospective, single-center study design inherently leaves some confounding factors related to HR, blood pressure (e.g. caffeine intake, pre-measurement rest, circadian influences), and LVRR were incompletely addressed. Secondly, to ensure only inclusion of patients with NIDCM, patients with other HF etiologies were excluded (as described at Fig. 1 ), potentially introducing patient selection bias. Thirdly, the utilization of four pillar medications is strongly advocated for GDMT, while there has been an insufficient data regarding the usage of SGLT2 inhibitors due to delayed approval and insurance coverage in South Korea. Lastly, although the correlation between the achieved HR through ivabradine and LVRR has been validated, the temporal differences may raise uncertainty on whether LVRR is predominantly facilitated by optimized adjunct GDMT in reducing HR, as retrospective study design inherently hindered the isolation of the exclusive effect of ivabradine. Nevertheless, these limitations in study design are likely to have a minimal effect on our study findings. In conclusion, our study has demonstrated that treatment with ivabradine in patients with NIDCM, resulting in an achieved HR of < 70 bpm, is associated with an increased incidence of LVRR despite lower use of beta-blockers. This highlights the importance of close monitoring and intensive up-titration to achieve optimal GDMT. Moreover, to obtain a more accurate understanding and assess the clinical impact of the relationship between the prognosis of NIDCM and the target achieved HR after ivabradine treatment, a larger prospective study is warranted, which would merit further validation. Methods Patients population and study design We conducted the retrospective review of patients newly diagnosed with NIDCM at Severance hospital between 2012 and 2021, identified through the use of ICD-10 code I.420, who regularly visited the outpatient clinic and underwent cardiac magnetic resonance imaging (CMR). (Fig. 1 ) The inclusion criteria consisted of reduced baseline LVEF and dilated LV, where NIDCM was defined as LVEF ≤ 35% with dilated LV (LVEDD index ≥ 33mm/m 2 for male, 32mm/m 2 for female). The cutoff value of 35% for LVEF was determined considering the indication for ivabradine treatment according to the current HF guideline. 1–3 A total of 660 patients were initially enrolled, but cases of HF from alternative etiologies were systematically excluded after a comprehensive review of medical records. Exclusion criteria included : 1) patients with a baseline systolic BP of more than 160 mmHg, suggesting the possibility of HF caused by hypertensive loading conditions; 2) confirmed ischemic etiology of HF through coronary angiography, coronary computed tomography (CT), or myocardial perfusion scan; 3) presence of severe valvular HF necessitating valve operation; and 4) additional exclusions were implemented based on information from CMR, echocardiography, laboratory data, and clinical courses, to eliminate patients with HF caused by other conditions, such as infiltrative disease, tachycardia-induced cardiomyopathy, and arrhythmogenic cardiomyopathy. Lastly, after excluding patients who underwent CRT implantation and those with previously documented paroxysmal atrial fibrillation or who had discontinued HF medications due to poor compliance, a total of 255 patients with sinus rhythm remained in the final analysis. This study was approved by the Institutional Review Board (IRB) of the hospital (IRB number: 4-2022-1665) and confirmed that all methods were performed in accordance with the relevant guidelines and regulations. The Clinical Data Repository System, Electronic Medical Record system, Picture Archiving and Communication System of Severance Hospital were used to retrieve the clinical and imaging data. All medical records of the subjects were anonymized before analysis, and informed consent was waived. Definitions and study protocol Definitions and study protocol The primary outcome of the study was the incidence of LVRR, defined as fulfilling both of the following criteria: 1) an absolute improvement in LVEF of ≥ 10%, and 2) a follow-up LVEF > 40%. 2,4 The optimal cut-off value of achieved heart rate of 70bpm at 1-year was determined using the receiver-operating characteristics (ROC) analysis based on occurrence of LVRR at 1-year (with achieved LVRR : positive, without LVRR : negative) in respective cohort along with Youden method. After evaluating the odds ratio (OR) in all patients treated with or without ivabradine according to the achieved heart rate at follow-up for discrimination of the primary endpoint, it was found that the highest OR for LVRR and maximized sensitivity and specificity in the ROC curve were achieved at a heart rate of 70 bpm. Therefore, we utilized 70 bpm as the cut-off value in our study. To examine the relationship between achieved heart rate and LVRR, the study population was categorized into four groups based on their treatment with ivabradine and the achieved heart rate (HR) at 1 year : Group 1 (Iva-/HR70+) consisted of patients who achieved an HR ≥ 70 bpm without ivabradine, Group 2 (Iva-/HR70-) included patients who achieved an HR < 70 bpm without ivabradine, Group 3 (Iva+/HR70+) consisted of patients who achieved an HR ≥ 70 bpm with ivabradine, and Group 4 (Iva+/HR70-) included patients who achieved an HR < 70 bpm with ivabradine. To evaluate LVRR at 1 year following diagnosis of NIDCM, clinical data at baseline and 1 year were reviewed. This included office BP, electrocardiography derived HR and QRS duration, and HF medication information, as in beta-blockers, RAS inhibitors, MRA, and ARNI, in terms of their medication class and available dose, was reviewed in reference to recommended target doses by clinical practice guidelines. 31 Moreover, patients were then categorized according to prescribed dose : patients not receiving medication, patients treated with ≥ 25% target dose, and patients treated with ≥ 50% target dose. Two-dimensional transthoracic echocardiography was performed at baseline and 1 year in every patient, with LVEF and left atrial volume index estimated by biplane method and LV end diastolic diameter (LVEDD) measured by M-mode tracing or 2D-guided linear measurement. The secondary outcomes included the composite events of cardiovascular-related death and hospital readmission due to worsening of heart failure. All patients were followed up until the occurrence of the events, and all clinical events were identified. The decision to start or discontinue ivabradine was solely made at the discretion of the treating cardiologist. Statistical analysis Continuous variables were expressed as mean ± standard deviation or median (interquartile range [IQR]), while categorical variables were expressed as n. For the comparison of continuous variables with a normal distribution among the four groups, one-way analysis of variance with Bonferroni post-hoc test was used. Kruskal-Wallis test with post-hoc Dunn test was utilized for continuous variables with non-normal distribution. To standardize the analysis approach, Linear Mixed Models were additionally employed to support the findings across all comparisons. Categorical variables among the four groups were analyzed using chi-square test. Baseline characteristics related to LVRR were determined using logistic regression. To identify the association between the achieved heart rate at 1 year and LVRR, multivariate logistic regression was performed, and the OR along with the 95% CI for LVRR was assessed. The clinical variables included in the logistic regression were those with P < 0.10 in the univariate analysis for LVRR. Multicollinearity was assessed by variance inflation factor and no multicollinearity existed. To assess the risk of clinical events, including HF re-hospitalization and cardiovascular death, according to the achieved heart rate at 1 year, survival curves for each group were generated using the Kaplan-Meier method. The comparison between the groups was conducted using the log-rank test. The index time for this analysis was defined as the moment when the follow-up echocardiography at 1 year was conducted. All statistical analyses were performed using R software, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) and all tests were two sides assuming P < 0.05 being statistically significant. Abbreviations ACEi = angiotensin-converting-enzyme inhibitor ARB = angiotensin-receptor blocker ARNI = angiotensin receptor neprilysin inhibitors NIDCM = non-ischemic dilated cardiomyopathy HF = heart failure HFrEF = heart failure with reduced ejection fraction LVRR = left ventricular reverse remodeling MRA = mineralocorticoid receptor antagonist RAS = renin-angiotensin-aldosterone system Declarations Competing Interests The authors declare that they have no conflict of interest and declare no financial or non-financial competing interests. Funding This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1A2C1093325). Author Contribution Conceptualization: Oh J, Kang SM; Data curation: Lee J, Oh J; Investigation: Oh J, Ha J, Lee CJ, Kang SM; Resources: Oh J, Kang SM; Software: Lee J, Oh J; Supervision: Oh J, Kang SM; Writing - original draft: Lee J, Oh J; Writing – review & editing: Lee J, Oh J, Kang SM. All authors reviewed and approved the manuscript, and its submission to Scientific Reports. Data Availability The data generated in this study is available from the corresponding author(s) upon reasonable request. References McDonagh, T. A. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 42 , 3599-3726 (2021). Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145 , e895-e1032 (2022). Youn, J.-C. et al. Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Treatment. Int J Heart Fail 5 , 66-81 (2023). Wilcox, J. E., Fang, J. C., Margulies, K. B. & Mann, D. L. Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel. J Am Coll Cardiol 76 , 719-734 (2020). Aimo, A., Gaggin, H. K., Barison, A., Emdin, M. & Januzzi, J. L., Jr. Imaging, Biomarker, and Clinical Predictors of Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction. JACC Heart Fail 7 , 782-794 (2019). Abboud, A. & Januzzi, J. L. Reverse Cardiac Remodeling and ARNI Therapy. Curr Heart Fail Rep 18 , 71-83 (2021). Rasalam, R. et al. Sodium-glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review. ESC Heart Fail 8 , 4093-4118 (2021). Böhm, M. et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 376 , 886-894 (2010). Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376 , 875-885 (2010). Tardif, J. C. et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J 32 , 2507-2515 (2011). Ceconi, C. et al. Effect of heart rate reduction by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL. Int J Cardiol 146 , 408-414 (2011). Tsutsui, H. et al. Efficacy and Safety of Ivabradine in Japanese Patients With Chronic Heart Failure - J-SHIFT Study. Circ J 83 , 2049-2060 (2019). Ye, F. et al. Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure. J Am Coll Cardiol 80 , 584-594 (2022). Hasenfuss, G. et al. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J 15 , 164-170 (1994). Kelly, R. P. et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation 86 , 513-521 (1992). Hjalmarson, A. et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 283 , 1295-1302 (2000). Packer, M. et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344 , 1651-1658 (2001). The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. The Lancet 353 , 9-13 (1999). Lee, H.-Y. & Baek, S. H. Optimal Use of Beta-Blockers for Congestive Heart Failure. Circ J 80 , 565-571 (2016). Enzan, N. et al. Beta‐Blocker Use Is Associated With Prevention of Left Ventricular Remodeling in Recovered Dilated Cardiomyopathy. J Am Heart Assoc 10 , e019240 (2021). Böhm, M. et al. Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 25 , 1429-1435 (2023). Bucchi, A., Baruscotti, M. & DiFrancesco, D. Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine. J Gen Physiol 120 , 1-13 (2002). Peri-Okonny, P. A. et al. Target Doses of Heart Failure Medical Therapy and Blood Pressure: Insights From the CHAMP-HF Registry. JACC: Heart Fail 7 , 350-358 (2019). Oh, J. et al. Real-World Eligibility for Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction Patients in Korea: Data from the Korean Acute Heart Failure (KorAHF) Registry. Int J Heart Fail 1 , 57-68 (2019). Oh, J. et al. Real-world eligibility for vericiguat in decompensated heart failure with reduced ejection fraction. ESC Heart Fail 9 , 1492-1495 (2022). Milliez, P. et al. Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure. American Am J Physiol Heart Circ Physiol 296 , H435-H441 (2009). Abdin, A. et al. Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial). ESC Heart Fail 10 , 2895-2902 (2023). Chen, S.-L., Hu, Z.-Y., Zuo, G.-F., Li, M.-H. & Li, B. I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice. BMC Cardiovasc Disord 14 , 150 (2014). Kleinbongard, P. et al. Pleiotropic, heart rate-independent cardioprotection by ivabradine. Br J Pharmacol 172 , 4380-4390 (2015). Mule, J. D. et al. The beneficial effect of revascularization on jeopardized myocardium: reverse remodeling and improved long-term prognosis. Eur J Cardiothorac Surg 22 , 426-430 (2002). Maddox Thomas, M. et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol 83 , 1444-1488 (2024). Additional Declarations No competing interests reported. Supplementary Files IvabradineLVRRinDCMPsupplement241108SciRes.docx Cite Share Download PDF Status: Published Journal Publication published 26 Sep, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 18 Mar, 2025 Reviews received at journal 17 Mar, 2025 Reviewers agreed at journal 03 Mar, 2025 Reviews received at journal 25 Jan, 2025 Reviewers agreed at journal 24 Jan, 2025 Reviewers invited by journal 23 Jan, 2025 Editor assigned by journal 07 Jan, 2025 Editor invited by journal 11 Nov, 2024 Submission checks completed at journal 11 Nov, 2024 First submitted to journal 10 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5425737","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":382825416,"identity":"a7e0567b-e7ee-4d81-a631-ab361750867a","order_by":0,"name":"Jooyeon Lee","email":"","orcid":"","institution":"Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jooyeon","middleName":"","lastName":"Lee","suffix":""},{"id":382825419,"identity":"5e055a2a-870e-414d-8194-9f69f72d5f7b","order_by":1,"name":"Jaewon Oh","email":"","orcid":"","institution":"Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jaewon","middleName":"","lastName":"Oh","suffix":""},{"id":382825422,"identity":"e607a9dc-a857-48a3-b95c-4b4ea83cd329","order_by":2,"name":"Jaehyung Ha","email":"","orcid":"","institution":"Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jaehyung","middleName":"","lastName":"Ha","suffix":""},{"id":382825425,"identity":"126f2f40-c323-4f33-b930-476be1d0fae0","order_by":3,"name":"Chan Joo Lee","email":"","orcid":"","institution":"Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chan","middleName":"Joo","lastName":"Lee","suffix":""},{"id":382825427,"identity":"470e8d8c-3878-46fd-8dcc-fcda5786063d","order_by":4,"name":"Seok-Min Kang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYFACNhBhw8AgQaKWNNK1HCZBi/y0Y4mfC36dT9xwu/0Bw48aIrQY3E47LD2z73bihjtnDBh7jhGjRTq9QZq3B6jlRg4DA28DMQ6bnd78m7fnHFBL+gPGv8RoYbiddkya58cBoJYEA2aibAH6Jc2atyHZeOaNHIPDMsT4RX52mvFtnj92sn030h8+fENMiIEBYxuDI8hJB4jVAAR/GOxJUD0KRsEoGAUjDQAAxaw8FEZGb0UAAAAASUVORK5CYII=","orcid":"","institution":"Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Seok-Min","middleName":"","lastName":"Kang","suffix":""}],"badges":[],"createdAt":"2024-11-10 11:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5425737/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5425737/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-09352-w","type":"published","date":"2025-09-26T15:57:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71561169,"identity":"05c9e79c-8c25-4623-a2fe-1c7cff088764","added_by":"auto","created_at":"2024-12-16 16:57:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":115185,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients newly diagnosed with non-ischemic dilated cardiomyopathy in sinus rhythm between 2012 to 2021 at a single tertiary center were included in this analysis and were retrospectively categorized into four groups based on the administration of ivabradine and achieved heart rate at 1 year.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e(bpm, beats per minute; CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; HR, heart rate; LVEF, left ventricular ejection fraction; LVRR, left ventricular reverse remodeling.)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5425737/v1/dc207c9a01a0e05833488f97.png"},{"id":71561166,"identity":"5d1efaa1-d603-477d-912b-a6b8d0d7de02","added_by":"auto","created_at":"2024-12-16 16:57:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26613,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLeft ventricular reverse remodeling at 1-year based on achieved heart rate and ivabradine treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"602\" height=\"465\" src=\"file:///C:/Users/btr8097/AppData/Local/Packages/oice_16_974fa576_32c1d314_2678/AC/Temp/msohtmlclip1/01/clip_image002.jpg\" alt=\"텍스트, 도표, 라인, 기술 도면이(가) 표시된 사진\n\n자동 생성된 설명\"/\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eOdds ratios were analyzed with adjustment of age, sex, baseline systolic blood pressure, left ventricular end-diastolic diameter, QRS duration and beta blocker usage.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e-value : 0.023, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e-value : \u0026lt;0.001, \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e-value : 0.007.\u003c/p\u003e\n\u003cp\u003eHR, heart rate; \u003cem\u003eP\u003c/em\u003e for trend in odds ratio = 0.002.\u003c/p\u003e\n\u003cp\u003eGroups were divided based on the administration of ivabradine and achieved HR at 1-year :\u003c/p\u003e\n\u003cp\u003eGroup 1 (Iva-/HR70+), achieved HR ≥ 70 bpm without ivabradine;\u003c/p\u003e\n\u003cp\u003eGroup 2 (Iva-/HR70-), achieved HR \u0026lt; 70 bpm without ivabradine;\u003c/p\u003e\n\u003cp\u003eGroup 3 (Iva+/HR70+), achieved HR ≥ 70 bpm with ivabradine;\u003c/p\u003e\n\u003cp\u003eGroup 4 (Iva+/HR70-), achieved HR \u0026lt; 70 bpm with ivabradine.\u003cbr\u003e\n\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5425737/v1/7bd09afecc487c393267ff84.png"},{"id":92430913,"identity":"842316b2-f4c8-4860-8b8a-d33d73196c43","added_by":"auto","created_at":"2025-09-29 16:08:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1280476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5425737/v1/993902b6-2ab4-4dfe-9a89-3c81ed6714f4.pdf"},{"id":71561167,"identity":"b81cc9ef-ba9e-4314-88c2-97d6af6ecbd1","added_by":"auto","created_at":"2024-12-16 16:57:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":131278,"visible":true,"origin":"","legend":"","description":"","filename":"IvabradineLVRRinDCMPsupplement241108SciRes.docx","url":"https://assets-eu.researchsquare.com/files/rs-5425737/v1/261fde09230f7d2b88dd051d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Achieved Targeted Heart Rate Following Ivabradine Therapy Correlates With Left Ventricular Reverse Remodeling In Non-Ischemic Dilated Cardiomyopathy ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDilated cardiomyopathy (DCM) stands as the most prevalent etiology of heart failure (HF). \u003csup\u003e1\u0026ndash;3\u003c/sup\u003e Substantial progress in medical treatments targeting improved clinical outcomes for HF have been made. Left ventricular reverse remodeling (LVRR), characterized by improvement in LV systolic function and reduced LV chamber size, is closely linked with a favorable HF prognosis. \u003csup\u003e4\u003c/sup\u003e Notably, HF medications such as beta-blockers, renin-angiotensin-aldosterone system (RAS) inhibitors, mineralocorticoid receptor antagonists (MRA), and angiotensin receptor neprilysin inhibitors (ARNI), have exhibited LVRR in HF with reduced ejection fraction (HFrEF) patients. \u003csup\u003e5\u0026ndash;7\u003c/sup\u003e Adjunct to these established practices, ivabradine, a specific I\u003csub\u003ef\u003c/sub\u003e-channel inhibitor, emerged as a therapeutic option aimed at reducing heart rate in HFrEF patients with sinus rhythm\u003csup\u003e8,9\u003c/sup\u003e, has acquired a class IIA recommendation in current guidelines for HFrEF\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e, and shown to positively impact LVRR in previous studies. \u003csup\u003e10\u0026ndash;13\u003c/sup\u003e While these investigations demonstrated a correlation between LVRR and heart rate reduction, the precise relationship between LVRR and the achieved heart rate after ivabradine treatment remains incompletely elucidated. Therefore, our study aims to explore the impact of ivabradine on LVRR and assess its influence on the risk of clinical events based on the achieved heart rate in patients with non-ischemic DCM (NIDCM).\u003c/p\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics and medication at baseline and follow-up\u003c/h2\u003e \u003cp\u003eThe baseline clinical characteristics of the study population (255 patients) are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 56 years (interquartile range, IQR 43\u0026ndash;67), with a predominant of male (60.1%) and body mass index (BMI) to be 24.3 kg/m\u003csup\u003e2\u003c/sup\u003e (IQR 21.6\u0026ndash;26.8). Patients who received ivabradine treatment had lower systolic blood pressure (BP), lower LVEF, and shorter QRS duration. Moreover, patients with ivabradine treatment (Iva+/HR70\u0026thinsp;+\u0026thinsp;and Iva+/HR70-) had higher baseline HR and experienced more substantial HR reduction at the first year, with this difference becoming more apparent at the second year of the follow-up. Notably, over 85% of patients in ivabradine-treated groups demonstrated a reduction of HR from baseline, and the change in HR was more pronounced compared to patients without ivabradine (Iva-/HR70\u0026thinsp;+\u0026thinsp;and Iva-/HR70-). (refer to Supplementary Table\u0026nbsp;1)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics according to ivabradine treatment and achieved heart rate\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003cp\u003eIva-/HR70+\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003cp\u003eIva-/HR70-\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003cp\u003eIva+/HR70+\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup 4\u003c/p\u003e \u003cp\u003eIva+/HR70-\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;255)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 [45\u0026ndash;66]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 [49\u0026ndash;72]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 [39\u0026ndash;62]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58 [43\u0026ndash;66]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56 [43\u0026ndash;67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (61.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (65.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (51.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (52.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e153 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.2 [22.1\u0026ndash;27.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.2 [21.5\u0026ndash;26.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.2 [21.2\u0026ndash;27.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.8 [22.1\u0026ndash;27.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.3 [21.7\u0026ndash;26.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eLaboratory findings\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (11.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR, ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89.0 [72.9-103.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90.6 [68.8-102.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87.3 [79.7\u0026ndash;99.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86.9 [61.0-94.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89.1 [71.1-100.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.433\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP, pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1624.0[521.5\u0026ndash;3816.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1301.5[530.0-4728.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1583.0[597.5\u0026ndash;3055.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2892.0[912.5\u0026ndash;6411.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1739.0[567.0-3969.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMedical History\u003c/em\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (45.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (42.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (45.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e115 (45.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (32.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (28.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (34.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.940\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (20.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47 (18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.425\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCardiac parameters\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 [110\u0026ndash;138]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120 [107\u0026ndash;132]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116 [104\u0026ndash;136]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112 [101\u0026ndash;122]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e120 [106\u0026ndash;135]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 [70\u0026ndash;85]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 [70\u0026ndash;88]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75 [68\u0026ndash;80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77 [70\u0026ndash;90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e78 [70\u0026ndash;86]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.244\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 [79\u0026ndash;104]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 [74\u0026ndash;89]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97 [89\u0026ndash;109]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98 [88\u0026ndash;109]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89 [78\u0026ndash;101]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQRS duration, ms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102.0 [94.0-114.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108.0 [98.0-142.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e98.0 [91.0-114.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e99.0 [92.0-114.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e102.0 [94.0-122.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLBBB, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (14.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (24.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.300\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLAVI, ml/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.5 [35.4\u0026ndash;56.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.1 [36.0-62.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.0 [36.9\u0026ndash;55.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47.4 [40.0-54.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.8 [36.3\u0026ndash;58.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.922\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEDD, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.797\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.0 [21.0\u0026ndash;32.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0 [20.0\u0026ndash;31.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.0 [18.0\u0026ndash;26.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.5 [17.0\u0026ndash;28.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.0 [20.0-29.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* Data are presented as n (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eBPM, beat per minute; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HR, heart rate; LAVI, left atrial vole index; LBBB, left ventricular bundle branch block; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type brain natriuretic peptide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e Regarding medication regimens at baseline, patients were treated comparably for guideline-directed medical therapy (GDMT) except for the use of MRA, which was more prescribed (90%~) in groups treated with ivabradine. This finding was consistent throughout the follow up. However, patients with ivabradine treatment showed comparably lower adherence to beta-blockers (74.3%, 81.6% vs. 95.4%, 94.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) at the one-year follow up and consistently lower adherence at subsequent years (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012) (refer to Supplementary Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eA total of 77 patients (30.2%) received treatment with ivabradine at the baseline. Among these patients, four patients discontinued ivabradine treatment due to dizziness (n\u0026thinsp;=\u0026thinsp;1), a switch to beta blockers due to high blood pressure (n\u0026thinsp;=\u0026thinsp;1), bradycardia (n\u0026thinsp;=\u0026thinsp;2), and were subsequently excluded. At the one-year mark, 73 (94.8%) patients remained on ivabradine treatment. Meanwhile, five patients have been newly diagnosed with atrial fibrillation, but none of them were using ivabradine at the time of the arrhythmia onset.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical characteristics related to LVRR\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the clinical characteristics of the study population stratified by achieved LVRR at follow-up. Patients who achieved LVRR at 1 year showed a higher baseline HR and diastolic BP with a significant reduction HR at the follow-up (-20 bpm vs. -13 bpm, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Moreover, the LVRR group showed a smaller baseline LV end-diastolic diameter (LVEDD) and shorter QRS duration with a lower prevalence of LBBB, whereas the baseline LVEF was similar between LVRR and non-LVRR group. Regarding the HF medication regimen, LVRR group exhibited higher adherence to beta blockers at baseline but was comparable at one-year follow up (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.051). In addition, despite the adherence ACEi/ARB or ARNI, and MRA were comparable across the group, patients treated with more than 50% of target dose was more frequently observed in the LVRR group (refer to Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; clinical characteristics according to left ventricular reverse remodeling at 1-year\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eLVRR\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;134)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-LVRR\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;121)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e54 [42\u0026ndash;67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 [45\u0026ndash;68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e70 (52.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e24.3 [21.7\u0026ndash;26.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.3 [21.6\u0026ndash;26.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.810\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eLaboratory findings\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR, ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e89.3 [70.5\u0026ndash;100.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88.5 [71.9-101.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.918\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP, pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1695.0 [548.0-5349.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1907.0 [605.0-3778.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.696\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMedical History\u003c/em\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e71 (53.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e46 (34.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (28.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e25 (18.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCardiac parameters at baseline\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e122 [109\u0026ndash;138]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116 [104\u0026ndash;130]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e80 [70\u0026ndash;89]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 [69\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.028\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e92 [81\u0026ndash;105]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 [75\u0026ndash;98]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQRS duration, ms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e101.0 [92.0-112.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108.0 [96.0-134.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLBBB, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16 (11.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLAVI, ml/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e48.9 [36.5\u0026ndash;58.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.2 [35.8\u0026ndash;56.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEDD, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e64.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e23.0 [20.0\u0026ndash;29.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.0 [20.0\u0026ndash;30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.257\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCardiac parameters at follow-up\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e122 [110\u0026ndash;134]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116 [106\u0026ndash;126]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e71 [62\u0026ndash;82]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 [61\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e72 [66\u0026ndash;80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 [64\u0026ndash;82]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.676\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange in heart rate, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e-20 [-32 to -7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-13 [-25 to 0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e51.0 [46.0\u0026ndash;57.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.0 [24.0\u0026ndash;36.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* Data are presented as n (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations as in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. LVRR, left ventricular reverse remodeling.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe incidence of LVRR at 1 year in four groups were 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% Iva+/HR70\u0026thinsp;+\u0026thinsp;and 71.1% in Iva+/HR70-, respectively. Compared to patients without ivabradine treatment, patients with well-controlled HR below 70bpm by ivabradine treatment showed a significantly higher incidence of LVRR (Iva+/HR70- vs. Iva-/HR70+, odds ratio (OR) 4.85 [95% confidence interval (CI) 1.97\u0026ndash;11.96], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; Iva+/HR70- vs. Iva-/HR70-, OR 3.60 [95% CI 1.41\u0026ndash;9.18], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), after adjusting for known predictors \u0026ndash; age, sex, SBP, QRS duration and beta blocker usage. Furthermore, although in multivariate regression analysis, the difference in LVRR was attenuated in patients treated with ivabradine treatment but with different targeted HR (Iva+/HR70\u0026thinsp;+\u0026thinsp;vs. Iva+/HR70-, OR 1.65 [95% CI, 0.55\u0026ndash;4.94], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.370), the significance of the difference was confirmed with a \u003cem\u003eP\u003c/em\u003e for trend of 0.002. Besides, among patients who did not reach the targeted HR, a significantly higher incidence of LVRR was shown in those with ivabradine treatment (Iva+/HR70+) compared to those without ivabradine treatment (Iva-/HR70+) (refer to Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe independent predictors associated with achieving LVRR were analyzed using logistic regression analysis and are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Patients with a history of hypertension, those receiving 50% or more of the target dose of ACEi/ARB or ARNI and baseline BP were independently associated with LVRR but were attenuated after the multivariable adjustment. Ultimately, male (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and persistent adherence to beta-blockers (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) and ivabradine (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) were identified as the independent predictors of LVRR. Furthermore, every 10bpm decrement of HR during the follow-up was independently associated with LVRR (OR 1.26 [95% CI 1.10\u0026ndash;1.44], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031), whereas the multivariate regression model adjusted with baseline HR was not significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.270). (refer to Supplementary Table\u0026nbsp;4)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate logistic regression analysis for independent predictors of baseline related to left ventricular reverse remodeling\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;65 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.83\u0026ndash;2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.30\u0026ndash;0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u0026ndash;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u0026lt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.59\u0026ndash;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.884\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP\u0026thinsp;\u0026ge;\u0026thinsp;1739 pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56\u0026ndash;1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.54\u0026ndash;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb\u0026thinsp;\u0026lt;\u0026thinsp;10g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.20\u0026ndash;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.086\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.28\u0026ndash;2.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19\u0026ndash;3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.79\u0026ndash;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.78\u0026ndash;2.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP, per 10mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026ndash;1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.89\u0026ndash;1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP, per 10mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06\u0026ndash;1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate, per 10bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.12\u0026ndash;1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEDD\u0026thinsp;\u0026ge;\u0026thinsp;55 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u0026ndash;3.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF, per 10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.44\u0026ndash;1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQRS duration\u0026thinsp;\u0026gt;\u0026thinsp;120 ms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026ndash;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.32\u0026ndash;1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIvabradine maintained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.32\u0026ndash;4.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.20-5.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBeta-blocker maintained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.32\u0026ndash;6.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.50-10.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBeta-blocker dose\u0026thinsp;\u0026ge;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.80\u0026ndash;2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACEi/ARB/ARNI dose\u0026thinsp;\u0026ge;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06\u0026ndash;3.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.98\u0026ndash;3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRA dose\u0026thinsp;\u0026ge;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90-3.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduction in heart rate at follow up, per 10bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10\u0026ndash;1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.02\u0026ndash;1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* Only variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in the univariable model were included in the multivariable model.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations as in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CI, confidence interval; LVRR, left ventricular reverse remodeling; OR, odds ratio.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eClinical events according to achieved heart rate with or without ivabradine\u003c/h3\u003e\n\u003cp\u003eThe median follow-up duration after the index time was 730 days (interquartile range [IQR] 639\u0026ndash;858). Hospital readmission due to worsening of HF occurred in 24 (9.4%) patients and cardiovascular-related death occurred in 1 (0.4%) patient. When comparing the risk of adjudicated clinical events, the event-free survival rate did not show a statistically significant difference between the groups, with a \u003cem\u003eP\u003c/em\u003e-value was 0.20 according to the log-rank method (refer to Supplement Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this present study, we observed a high prevalence of LVRR in patients achieving a HR less than 70 bpm after treatment with ivabradine (71.1% in Iva+/HR70- vs. 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% in Iva+/HR70+). Moreover, a consistent beta-blocker adherence adjunct with sustained use of ivabradine independently predicted the occurrence of LVRR. Our study demonstrated the benefit of ivabradine in potentially improving LVRR when used adjunctively with optimal GDMT, but did not show a clear impact on reducing cardiovascular risk through reduction of heart rate.\u003c/p\u003e \u003cp\u003eThe importance of HR reduction in HF is widely recognized, as reducing HR can have a protective effect on the heart by decreasing energy expenditure, prolonging diastole to increase blood supply, reducing arterial stiffness\u003csup\u003e14\u003c/sup\u003e, and ultimately leading to ventricular unloading\u003csup\u003e15\u003c/sup\u003e. The MERIT\u0026ndash;HF, the CIBIS\u0026ndash;II, and the COPERNICUS trial have established the role of beta-blockers in lowering the risk of cardiovascular events\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e. The positive effect of beta-blockers extend beyond HR reduction where they inhibit the hyperactivated sympathetic tone to prevent the progression of cardiomyocyte apoptosis or interstitial fibrosis, leading to further myocardial injury. \u003csup\u003e19\u003c/sup\u003e Taking a step further, it has been associated with the occurrence of LVRR. \u003csup\u003e20\u003c/sup\u003e However, there is still a topic of debate regarding the maximally titrated dosage, targeted HR, or the degree of HR reduction being more important in beta blocker treatment. Studies investigating its association with clinical outcomes put more emphasis on the dose-dependent improvement\u003csup\u003e20\u003c/sup\u003e, while the relationship between achieved HR and the occurrence of LVRR remain elusive or insignificant. \u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIvabradine, a newly emerged drug, blocks sinoatrial node I\u003csub\u003ef\u003c/sub\u003e channels and regulates HR without interfering with cardiac inotropy. \u003csup\u003e22\u003c/sup\u003e The SHIFT trial (Systolic Heart Failure Treatment with the I\u003csub\u003ef\u003c/sub\u003e Inhibitor Ivabradine Trial) that enrolled systolic HF patients with HR above 70 bpm demonstrated an isolated decrement in achieved HR at 28 days with ivabradine augmentation was associated with a direct reduction in cardiovascular events. \u003csup\u003e8,9\u003c/sup\u003e However, limited research has explored the association between the ivabradine and LVRR in HF, aside of HR reduction. \u003cem\u003eCeconi et al.\u003c/em\u003e presented a reduction in LV volume was associated with a change in HR from baseline in patients with stable coronary artery disease and LV dysfunction after treatment of ivabradine. \u003csup\u003e11\u003c/sup\u003e Similarly, \u003cem\u003eTsutsui et al.\u003c/em\u003e showed that HR reduction was related to the decrease in LV chamber size and an improvement in LVEF. \u003csup\u003e12\u003c/sup\u003e However, the association between the achieved HR by ivabradine and LVRR was not elaborated.\u003c/p\u003e \u003cp\u003eOur research, which focuses on investigating the relationship between LVRR and achieved HR in patients with NIDCM, demonstrates a higher occurrence of LVRR in patients with achieved HR\u0026thinsp;\u0026lt;\u0026thinsp;70 bpm after treatment with ivabradine. Notably, the increased incidence of LVRR observed in our study population may have been attributed to the HR reduction achieved through optimal medical treatment, aligning with the findings from the SHIFT trial. Optimal medical therapy was implemented in majority of subjects \u0026ndash; 89.8% patients were under beta-blocker, 88.6% was under ACEi/ARB or ARNI, and 82.4% was under MRA respectively as depicted in Supplementary Table\u0026nbsp;2. These rates were comparable, if not higher, than those reported in the \u003cem\u003eSHIFT\u003c/em\u003e trial. However, the proportion of patients receiving\u0026thinsp;\u0026ge;\u0026thinsp;50% of target dose of beta blocker was significantly lower in our study (11.0% at baseline and 22.2% at follow up vs. 56%), reflecting the real-world clinical practice of infrequent up-titration to recommended dose of GDMT. \u003csup\u003e23\u003c/sup\u003e This corresponds with the underuse of beta-blocker reported in Asian registry. \u003csup\u003e24,25\u003c/sup\u003e As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the baseline systolic BP of patients treated with ivabradine was lower than that of the other groups. Physicians may hesitate to prescribe beta-blockers to patients with hypotension or with other concomitant contraindications, despite the need for more aggressive up-titration. \u003csup\u003e2\u003c/sup\u003e Nevertheless, considering the patients treated with ivabradine were less frequently administered beta-blockers than those without the ivabradine, it isolates the effect of ivabradine on LVRR. Furthermore, in Iva+/HR70\u0026thinsp;+\u0026thinsp;adherence to beta-blockers was notably lower compared to the other groups at one-year follow up (74.3% vs. 95.4%, 94.5% or 81.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Despite this lower adherence, Iva+/HR70\u0026thinsp;+\u0026thinsp;exhibited a significantly higher incidence of LVRR, which highlights the inherence significance of ivabradine in HF.\u003c/p\u003e \u003cp\u003eHigher heart rates are likely to make ivabradine more effective by blocking a greater number of the I\u003csub\u003ef\u003c/sub\u003e channels at sinoatrial nodes. \u003csup\u003e22\u003c/sup\u003e Likewise, the greatest reduction in HR from baseline at one year follow-up was observed in Iva+/HR70-, and the significant correlation of the degree of HR reduction with the likelihood of LVRR further supports the highest occurrence of LVRR in Iva+/HR70- in our study. In a mouse model, ivabradine down regulates the neurohormonal interaction by blunting the renin-angiotensin-aldosterone system\u003csup\u003e26\u003c/sup\u003e and the sympathetic nervous system, improving the HR variability. \u003csup\u003e27\u003c/sup\u003e With attenuated apoptosis and intracellular matrix metalloproteinase expression\u003csup\u003e28\u003c/sup\u003e, ivabradine might mitigate the process of adverse remodeling and exert cardio-protection effect. \u003csup\u003e13,29\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLastly, the \u003cem\u003eSHIFT\u003c/em\u003e trial presented that achieving the lower HR (even below 65 or 60 bpm) by ivabradine was associated with a lower risk of clinical events\u003csup\u003e8,21\u003c/sup\u003e, while our study finding was neutral among the groups. This inconsistent result might have been due to the small sample size and short follow-up duration of patients. Nevertheless, unlike previous studies, this study restricts the focus to patients with NIDCM, maintaining homogeneity in the etiology of heart disease. Given the extent of revascularization in HF with ischemic origin, whether complete or incomplete, acts as a significant confounding variable, confining the analysis solely to patients with NIDCM allows for a more precise assessment of the effects of GDMT. \u003csup\u003e30\u003c/sup\u003e Furthermore, patients who underwent cardiac resynchronization therapy were also excluded to eliminate the effect of device-guided treatment and to solely isolate the therapeutic effect of medical treatment.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, despite meticulous review of clinical data, the retrospective, single-center study design inherently leaves some confounding factors related to HR, blood pressure (e.g. caffeine intake, pre-measurement rest, circadian influences), and LVRR were incompletely addressed. Secondly, to ensure only inclusion of patients with NIDCM, patients with other HF etiologies were excluded (as described at Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e), potentially introducing patient selection bias. Thirdly, the utilization of four pillar medications is strongly advocated for GDMT, while there has been an insufficient data regarding the usage of SGLT2 inhibitors due to delayed approval and insurance coverage in South Korea. Lastly, although the correlation between the achieved HR through ivabradine and LVRR has been validated, the temporal differences may raise uncertainty on whether LVRR is predominantly facilitated by optimized adjunct GDMT in reducing HR, as retrospective study design inherently hindered the isolation of the exclusive effect of ivabradine. Nevertheless, these limitations in study design are likely to have a minimal effect on our study findings.\u003c/p\u003e \u003cp\u003eIn conclusion, our study has demonstrated that treatment with ivabradine in patients with NIDCM, resulting in an achieved HR of \u0026lt;\u0026thinsp;70 bpm, is associated with an increased incidence of LVRR despite lower use of beta-blockers. This highlights the importance of close monitoring and intensive up-titration to achieve optimal GDMT. Moreover, to obtain a more accurate understanding and assess the clinical impact of the relationship between the prognosis of NIDCM and the target achieved HR after ivabradine treatment, a larger prospective study is warranted, which would merit further validation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients population and study design\u003c/h2\u003e \u003cp\u003e We conducted the retrospective review of patients newly diagnosed with NIDCM at Severance hospital between 2012 and 2021, identified through the use of ICD-10 code I.420, who regularly visited the outpatient clinic and underwent cardiac magnetic resonance imaging (CMR). (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e) The inclusion criteria consisted of reduced baseline LVEF and dilated LV, where NIDCM was defined as LVEF\u0026thinsp;\u0026le;\u0026thinsp;35% with dilated LV (LVEDD index\u0026thinsp;\u0026ge;\u0026thinsp;33mm/m\u003csup\u003e2\u003c/sup\u003e for male, 32mm/m\u003csup\u003e2\u003c/sup\u003e for female). The cutoff value of 35% for LVEF was determined considering the indication for ivabradine treatment according to the current HF guideline. \u003csup\u003e1\u0026ndash;3\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e A total of 660 patients were initially enrolled, but cases of HF from alternative etiologies were systematically excluded after a comprehensive review of medical records. Exclusion criteria included : 1) patients with a baseline systolic BP of more than 160 mmHg, suggesting the possibility of HF caused by hypertensive loading conditions; 2) confirmed ischemic etiology of HF through coronary angiography, coronary computed tomography (CT), or myocardial perfusion scan; 3) presence of severe valvular HF necessitating valve operation; and 4) additional exclusions were implemented based on information from CMR, echocardiography, laboratory data, and clinical courses, to eliminate patients with HF caused by other conditions, such as infiltrative disease, tachycardia-induced cardiomyopathy, and arrhythmogenic cardiomyopathy. Lastly, after excluding patients who underwent CRT implantation and those with previously documented paroxysmal atrial fibrillation or who had discontinued HF medications due to poor compliance, a total of 255 patients with sinus rhythm remained in the final analysis.\u003c/p\u003e \u003cp\u003e This study was approved by the Institutional Review Board (IRB) of the hospital (IRB number: 4-2022-1665) and confirmed that all methods were performed in accordance with the relevant guidelines and regulations. The Clinical Data Repository System, Electronic Medical Record system, Picture Archiving and Communication System of Severance Hospital were used to retrieve the clinical and imaging data. All medical records of the subjects were anonymized before analysis, and informed consent was waived.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinitions and study protocol\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eDefinitions and study protocol\u003c/div\u003e \u003cp\u003eThe primary outcome of the study was the incidence of LVRR, defined as fulfilling both of the following criteria: 1) an absolute improvement in LVEF of \u0026ge;\u0026thinsp;10%, and 2) a follow-up LVEF\u0026thinsp;\u0026gt;\u0026thinsp;40%.\u003csup\u003e2,4\u003c/sup\u003e The optimal cut-off value of achieved heart rate of 70bpm at 1-year was determined using the receiver-operating characteristics (ROC) analysis based on occurrence of LVRR at 1-year (with achieved LVRR : positive, without LVRR : negative) in respective cohort along with Youden method. After evaluating the odds ratio (OR) in all patients treated with or without ivabradine according to the achieved heart rate at follow-up for discrimination of the primary endpoint, it was found that the highest OR for LVRR and maximized sensitivity and specificity in the ROC curve were achieved at a heart rate of 70 bpm. Therefore, we utilized 70 bpm as the cut-off value in our study. To examine the relationship between achieved heart rate and LVRR, the study population was categorized into four groups based on their treatment with ivabradine and the achieved heart rate (HR) at 1 year :\u003c/p\u003e \u003cp\u003eGroup 1 (Iva-/HR70+) consisted of patients who achieved an HR\u0026thinsp;\u0026ge;\u0026thinsp;70 bpm without ivabradine, Group 2 (Iva-/HR70-) included patients who achieved an HR\u0026thinsp;\u0026lt;\u0026thinsp;70 bpm without ivabradine, Group 3 (Iva+/HR70+) consisted of patients who achieved an HR\u0026thinsp;\u0026ge;\u0026thinsp;70 bpm with ivabradine, and Group 4 (Iva+/HR70-) included patients who achieved an HR\u0026thinsp;\u0026lt;\u0026thinsp;70 bpm with ivabradine.\u003c/p\u003e \u003cp\u003eTo evaluate LVRR at 1 year following diagnosis of NIDCM, clinical data at baseline and 1 year were reviewed. This included office BP, electrocardiography derived HR and QRS duration, and HF medication information, as in beta-blockers, RAS inhibitors, MRA, and ARNI, in terms of their medication class and available dose, was reviewed in reference to recommended target doses by clinical practice guidelines. \u003csup\u003e31\u003c/sup\u003e Moreover, patients were then categorized according to prescribed dose : patients not receiving medication, patients treated with \u0026ge;\u0026thinsp;25% target dose, and patients treated with \u0026ge;\u0026thinsp;50% target dose.\u003c/p\u003e \u003cp\u003eTwo-dimensional transthoracic echocardiography was performed at baseline and 1 year in every patient, with LVEF and left atrial volume index estimated by biplane method and LV end diastolic diameter (LVEDD) measured by M-mode tracing or 2D-guided linear measurement. The secondary outcomes included the composite events of cardiovascular-related death and hospital readmission due to worsening of heart failure. All patients were followed up until the occurrence of the events, and all clinical events were identified. The decision to start or discontinue ivabradine was solely made at the discretion of the treating cardiologist.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range [IQR]), while categorical variables were expressed as n. For the comparison of continuous variables with a normal distribution among the four groups, one-way analysis of variance with Bonferroni post-hoc test was used. Kruskal-Wallis test with post-hoc Dunn test was utilized for continuous variables with non-normal distribution. To standardize the analysis approach, Linear Mixed Models were additionally employed to support the findings across all comparisons. Categorical variables among the four groups were analyzed using chi-square test. Baseline characteristics related to LVRR were determined using logistic regression. To identify the association between the achieved heart rate at 1 year and LVRR, multivariate logistic regression was performed, and the OR along with the 95% CI for LVRR was assessed. The clinical variables included in the logistic regression were those with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in the univariate analysis for LVRR. Multicollinearity was assessed by variance inflation factor and no multicollinearity existed. To assess the risk of clinical events, including HF re-hospitalization and cardiovascular death, according to the achieved heart rate at 1 year, survival curves for each group were generated using the Kaplan-Meier method. The comparison between the groups was conducted using the log-rank test. The index time for this analysis was defined as the moment when the follow-up echocardiography at 1 year was conducted. All statistical analyses were performed using R software, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) and all tests were two sides assuming \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 being statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACEi = angiotensin-converting-enzyme inhibitor\u003c/p\u003e\n\u003cp\u003eARB = angiotensin-receptor blocker\u003c/p\u003e\n\u003cp\u003eARNI = angiotensin receptor neprilysin inhibitors\u003c/p\u003e\n\u003cp\u003eNIDCM = non-ischemic dilated cardiomyopathy\u003c/p\u003e\n\u003cp\u003eHF = heart failure\u003c/p\u003e\n\u003cp\u003eHFrEF = heart failure with reduced ejection fraction\u003c/p\u003e\n\u003cp\u003eLVRR = left ventricular reverse remodeling\u003c/p\u003e\n\u003cp\u003eMRA = mineralocorticoid receptor antagonist\u003c/p\u003e\n\u003cp\u003eRAS = renin-angiotensin-aldosterone system\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest and declare no financial or non-financial competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1A2C1093325).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Oh J, Kang SM; Data curation: Lee J, Oh J; Investigation: Oh J, Ha J, Lee CJ, Kang SM; Resources: Oh J, Kang SM; Software: Lee J, Oh J; Supervision: Oh J, Kang SM; Writing - original draft: Lee J, Oh J; Writing \u0026ndash; review \u0026amp; editing: Lee J, Oh J, Kang SM. All authors reviewed and approved the manuscript, and its submission to Scientific Reports.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data generated in this study is available from the corresponding author(s) upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcDonagh, T. A.\u003cem\u003e et al.\u003c/em\u003e 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. \u003cem\u003eEur Heart J\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 3599-3726 (2021).\u003c/li\u003e\n\u003cli\u003eHeidenreich, P. 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A.\u003cem\u003e et al.\u003c/em\u003e Target Doses of Heart Failure Medical Therapy and Blood Pressure: Insights From the CHAMP-HF Registry. \u003cem\u003eJACC: Heart Fail\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 350-358 (2019).\u003c/li\u003e\n\u003cli\u003eOh, J.\u003cem\u003e et al.\u003c/em\u003e Real-World Eligibility for Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction Patients in Korea: Data from the Korean Acute Heart Failure (KorAHF) Registry. \u003cem\u003eInt J Heart Fail\u003c/em\u003e \u003cstrong\u003e1\u003c/strong\u003e, 57-68 (2019).\u003c/li\u003e\n\u003cli\u003eOh, J.\u003cem\u003e et al.\u003c/em\u003e Real-world eligibility for vericiguat in decompensated heart failure with reduced ejection fraction. \u003cem\u003eESC Heart Fail\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 1492-1495 (2022).\u003c/li\u003e\n\u003cli\u003eMilliez, P.\u003cem\u003e et al.\u003c/em\u003e Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure. \u003cem\u003eAmerican Am J Physiol Heart Circ Physiol\u003c/em\u003e \u003cstrong\u003e296\u003c/strong\u003e, H435-H441 (2009).\u003c/li\u003e\n\u003cli\u003eAbdin, A.\u003cem\u003e et al.\u003c/em\u003e Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial). \u003cem\u003eESC Heart Fail\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 2895-2902 (2023).\u003c/li\u003e\n\u003cli\u003eChen, S.-L., Hu, Z.-Y., Zuo, G.-F., Li, M.-H. \u0026amp; Li, B. I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice. \u003cem\u003eBMC Cardiovasc Disord\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 150 (2014).\u003c/li\u003e\n\u003cli\u003eKleinbongard, P.\u003cem\u003e et al.\u003c/em\u003e Pleiotropic, heart rate-independent cardioprotection by ivabradine. \u003cem\u003eBr J Pharmacol\u003c/em\u003e \u003cstrong\u003e172\u003c/strong\u003e, 4380-4390 (2015).\u003c/li\u003e\n\u003cli\u003eMule, J. D.\u003cem\u003e et al.\u003c/em\u003e The beneficial effect of revascularization on jeopardized myocardium: reverse remodeling and improved long-term prognosis. \u003cem\u003eEur J Cardiothorac Surg\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 426-430 (2002).\u003c/li\u003e\n\u003cli\u003eMaddox Thomas, M.\u003cem\u003e et al.\u003c/em\u003e 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction. \u003cem\u003eJ Am Coll Cardiol\u003c/em\u003e\u003cstrong\u003e83\u003c/strong\u003e, 1444-1488 (2024).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ivabradine, heart rate, reverse remodeling, heart failure with reduced ejection fraction, non-ischemic dilated cardiomyopathy","lastPublishedDoi":"10.21203/rs.3.rs-5425737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5425737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe effect of ivabradine on left ventricular reverse remodeling (LVRR) in heart failure with reduced ejection fraction (HFrEF) and its correlation with achieved heart rate (HR) by ivabradine in non-ischemic dilated cardiomyopathy (NIDCM) remain uncertain. A retrospective analysis of 255 sinus rhythm NIDCM patients at a tertiary center (2012\u0026thinsp;~\u0026thinsp;2021) were categorized into four groups based on the ivabradine use (Iva+/-) and achieved HR at 1-year (HR+/-). The HR cut-off of 70bpm was determined via receiver operating characteristic curve analysis for LVRR, defined as an absolute\u0026thinsp;\u0026ge;\u0026thinsp;10% improvement in LV ejection fraction (LVEF) from baseline, with a final LVEF\u0026thinsp;\u0026ge;\u0026thinsp;40%. LVRR incidence at 1-year was, 46.8% in Iva-/HR70+, 46.6% in Iva-/HR70-, 62.9% Iva+/HR70\u0026thinsp;+\u0026thinsp;and 71.1% in Iva+/HR70-. Ivabradine treated patients with HR\u0026thinsp;\u0026lt;\u0026thinsp;70bpm had higher incidence of LVRR than those without ivabradine (Iva+/HR70- vs. Iva-/HR70+, OR 4.85, 95%CI 1.97\u0026ndash;11.96 \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; Iva+/HR70- vs. Iva-/HR70-, OR 3.60, 95% CI 1.41\u0026ndash;9.18, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) after adjustment for known predictors in a multivariate model. Consistent adherence to beta-blockers and ivabradine, along with guideline-directed medical therapy (GDMT) for HF, and sex were identified as independent predictors of LVRR. Ivabradine therapy achieving HR\u0026thinsp;\u0026lt;\u0026thinsp;70bpm correlated with increased LVRR incidence in NIDCM patients, underscoring the role of ivabradine in HR reduction adjunctive to GDMT.\u003c/p\u003e","manuscriptTitle":"Achieved Targeted Heart Rate Following Ivabradine Therapy Correlates With Left Ventricular Reverse Remodeling In Non-Ischemic Dilated Cardiomyopathy ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 16:57:32","doi":"10.21203/rs.3.rs-5425737/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-18T16:48:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-18T03:00:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321059381086593856668806826399442723345","date":"2025-03-03T19:50:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-25T09:44:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256116888782354998742009003752899379958","date":"2025-01-24T11:41:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-23T15:05:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-07T16:38:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-11T11:07:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-11T09:07:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-11-10T11:45:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"24ad2a57-d422-4af7-9293-c1dbd4437f3f","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":40773050,"name":"Health sciences/Cardiology"},{"id":40773051,"name":"Health sciences/Diseases/Cardiovascular diseases/Cardiomyopathies"}],"tags":[],"updatedAt":"2025-09-29T16:06:34+00:00","versionOfRecord":{"articleIdentity":"rs-5425737","link":"https://doi.org/10.1038/s41598-025-09352-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-09-26 15:57:31","publishedOnDateReadable":"September 26th, 2025"},"versionCreatedAt":"2024-12-16 16:57:32","video":"","vorDoi":"10.1038/s41598-025-09352-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-09352-w","workflowStages":[]},"version":"v1","identity":"rs-5425737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5425737","identity":"rs-5425737","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}