Graphical abstract
In heart failure with reduced ejection fraction (HFrEF), chronic hyperactivation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) leads to adverse cardiac remodeling and symptom progression [1,2]. A multi-level neurohormonal blockade with RAAS inhibitors and β-blockers (BB) is both safe and prognostically beneficial, regardless of HF etiology [ischemic vs. non-ischemic, including dilated cardiomyopathy (DCM)] [3]. However, the precise mechanisms underlying these therapeutic benefits remain an area of ongoing investigation. SNS activity can be assessed in vivo using molecular imaging techniques, particularly single-photon emission computed tomography with iodine-123-metaiodobenzylguanidine (SPECT-MIBG), a radiolabeled norepinephrine analogue [4,5]. While previous studies have demonstrated that BB therapy improves SPECT-MIBG parameters in HFrEF and these results correspond with pathological findings of adrenergic nerve loss in failing human myocardium, the potential impact of rapid up-titration of this kind of HF therapy (including BBs) has not yet been thoroughly investigated [6,7].
Patients aged 18–65 years with newly-diagnosed HFrEF were referred to HF specialists at our tertiary cardiac centre between 2021–2022 (Fig. 1A). After a confirmed diagnosis of DCM was established, 21 consecutive DCM patients (91.5 % male, mean age 47.19 ± 10.21 years) were enrolled and underwent typical HF examinations and SPECT-MIBG (for inclusion criteria see Appendix) [[8], [9], [10]]. All patients received guideline-directed medical therapy (GDMT), which was up-titrated during follow-up [2]. A high initial BB dose (high-BB) was defined as ≥ 50 % of the maximal recommended dose before inclusion. The study protocol received approval from the Ethics Committee (158/KBL/OIL/2021) and was performed in line with the current GCP Guidelines and the Declaration of Helsinki.
Fig. 1.
A. Study Design and Patient Flowchart.Patients with newly diagnosed heart failure with reduced ejection fraction (HFrEF) were referred from regional cardiac clinics to tertiary HF specialists between 2021 and 2022. DCM was diagnosed after excluding (A) significant coronary artery disease by coronary catheterization or computed tomography coronary angiography, (B) primary valvular disease, (C) congenital heart disease, and (D) severe arterial hypertension. As a result, a total of 21 consecutive adult patients met the inclusion and exclusion criteria (see text) were enrolled. Based on initial beta-blockers (BB) dosage, patients were divided into high-BB (n = 10, 47.6 %; defined as ≥ 50 % of the maximal recommended dose) and low-BB groups. All patients underwent baseline evaluations (n = 21), with 20 completing follow-up at 12 months (n = 20*, 95.2 %), including single-photon emission computed tomography with iodine-123-metaiodobenzylguanidine imaging (SPECT-MIBG). During the 12-month observation period, one patient in the low-BB group died due to HF worsening, and three patients did not undergo *12-month SPECT-MIBG due to post-amiodarone hyperthyroidism (n = 1) or failure to discontinue medications before imaging (n = 2).B. ROC Curve of Initial Beta-Blocker Dosage as a Predictor of ≥ 10 % MIBG Washout Rate Reduction.The initial BB dosage was found to be a significant predictor of WR improvement (OR 1.05, 95 % CI 1.01–1.11, p = 0.05) with an area under the ROC curve of 0.75 (95 %CI 0.51–0.99, p = 0.04).C. SPECT-MIBG Imaging Methodology.Planar anterior images of the chest were acquired for a duration of 10 min with a dual-head rotating gamma camera, at 15 min (early phase), and 4 h (delayed phase), following intravenous administration of 200 MBq of 123I-MIBG. Regions of interest (ROI) measuring 7 × 7 pixels were manually delineated over the heart (H) and upper mediastinum (M), and the heart-to-mediastinum (H/M) MIBG activity ratio was calculated from the anterior planar images. Based on the H/M ratios at early and delayed phases (H/M15min, H/M4h), the washout rate (WR) was derived.D. Longitudinal Changes in MIBG Washout Rate Over 12 Months in Patients Stratified by Baseline Beta-Blocker Dosage. Patients receiving high-BB had a significantly higher (worse) baseline WR but exhibited WR improvement after 12 months of HF therapy up-titration, whereas those in the low-BB group showed minimal change.
SPECT‑MIBG imaging was performed in accordance with established standard protocols: planar (early and delayed) images acquisition (Fig. 1C) at approximately 15-minutes and 4-hours post-injection, with calculation of heart‑to‑mediastinum ratios (H/M15min, H/M4h) and washout rate (WR) based on standardized region-of‑interest placement (as described in the Appendix). The improvement of WR was defined as WR reduction of ≥ 10 %. Statistical analysis was performed using the Statistica package, and the results were considered statistically significant when the p-value was < 0.10 (see Appendix).
At baseline, the median BB dose was 25.2 % (IQR 22.2–50.0) of the maximal recommended dosage, with 10 patients (47.6 %) receiving a high-BB dose. The high-BB and low-BB groups exhibited comparable medical histories, clinical data, HF symptoms [NYHA 2.0 (2.0–2.0) vs. 2.0 (1.0–2.0), p = 0.27], cardiac biomarkers [NT-proBNP 741.5 (548–1299) vs. 1102 (698–1568)pg/mL; high-sensitivity troponin T 0.017 (0.010–0.023) vs. 0.011 (0.008–0.014)ng/mL], and cardiac dimensions (end-diastolic left ventricle volume, LVEDV 103.68 ± 36.98 vs. 123.88 ± 33.55 mL/m2; all p > 0.10). However, significant differences emerged in SPECT-MIBG parameters. Patients receiving high-BB therapy exhibited a higher baseline WR compared to the low-BB group (12.12 ± 3.55 % vs. 6.08 ± 5.35 %, p = 0.007), but demonstrated WR improvement after 12-months (WR change: −3.83 ± 4.14 % vs. + 1.56 ± 6.29 %, p = 0.07; Fig. 1D, Table S1). BB dosages correlated with WR: initial BB dosage correlated with baseline WR (R = 0.48, p = 0.03), while 12-month BB dosage correlated with corresponding 12-month WR (R = 0.53, p = 0.03).
During follow-up, 9 patients (53 %) showed WR improvement. Both groups (WR-improvers and non-improvers) had comparable baseline clinical characteristics, HF symptoms, laboratory and echocardiographic data (Table 1). However, WR-improvers had numerically smaller LVEDV (97.58 ± 38.93 vs. 127.51 ± 32.31 mL/m2; p = 0.11) and higher ejection fraction (31.22 ± 8.44 vs. 24.63 ± 8.80 %, p = 0.14) than WR-non-improvers. Importantly, WR-improvers had a higher initial BB dosage [50 % (25–50) vs. 25 % (6–25), p = 0.09] and were more likely to be on high-BB [6 (86 %) vs. 3 (30 %), p = 0.02]. Utilization of other GDMT therapies was similar between groups (both at baseline and follow-up; all p > 0.10). Most notably, initial BB dosage was identified as a significant predictor of WR improvement (OR 1.05, 95 % CI 1.01–1.11, p = 0.05) with an area under the ROC curve of 0.75 (95 %CI 0.51–0.99, p = 0.04; Fig. 1B).
Table 1.
Baseline and follow-up characteristic differences between DCM patients who improved and did not improve cardiac sympathetic nervous system (defined as washout rate, WR, reduction of ≥ 10 %) during 12-months heart failure therapy up-titration.
| WR improvers n = 9 (53 %) |
WR non-improvers N = 8 (n = 47 %) |
p-value | |
|---|---|---|---|
| Baseline clinical status | |||
| Female [n (%)] | 1 (11.11 %) | 1 (8.33 %) | 0.83 |
| Age [years] | 47.78 ± 11.14 | 47.38 ± 9.49 | 0.94 |
| Body mass index [kg/m2] | 2.20 ± 0.27 | 2.04 ± 0.32 | 0.29 |
| Atrial fibrillation [n (%)] | 4 (44.4 %) | 2 (25.0 %) | 0.40 |
| NYHA class | 1.94 ± 0.53 | 1.69 ± 0.46 | 0.30 |
| QRS [ms] | 80 (80–––110) | 85 (80–––130) | 0.74 |
| Mean heart rate from 48-hours ECG monitoring [bpm] | 69.67 ± 12.5 | 70.25 ± 16.41 | 0.93 |
| Ventricular tachyarrhythmia [n (%)] | 4 (44.4 %) | 2 (25.0 %) | 0.40 |
| 6MWT distance [m] | 503.22 ± 108.26 | 543.88 ± 168.63 | 0.56 |
| peak VO2max at CPET [ml/min/kg] | 17.3 (16.2–––20.3) | 19.75 (18.45–––20.35) | 0.47 |
| Baseline echocardiography | |||
| LV end-diastolic volume [ml/m2] | 97.58 ± 38.93 | 127.51 ± 32.31 | 0.11 |
| LV ejection fraction [%] | 31.22 ± 8.44 | 24.63 ± 8.80 | 0.14 |
| Global longitudinal strain [%] | −9.44 ± 4.03 | −10.50 ± 3.16 | 0.56 |
| LV mass index [g/m2] | 116.29 ± 35.99 | 143.08 ± 33.98 | 0.14 |
| Righ ventricle enddiastolic area [cm2/m2] | 12.16 ± 1.56 | 15.74 ± 4.44 | 0.04 |
| Fractional area change [%] | 33.56 ± 9.18 | 43.13 ± 10.92 | 0.07 |
| TAPSE [mm] | 19.22 ± 1.48 | 21.63 ± 6.39 | 0.29 |
| Left atria volume indexed [ml/m2] | 44.46 ± 16.42 | 60.15 ± 27.32 | 0.17 |
| E wave [m/s] | 0.62 ± 0.27 | 0.69 ± 0.21 | 0.56 |
| E/A ratio | 0.9 ± 0.33 | 1.07 ± 0.77 | 0.66 |
| E/e’ ratio | 8.0 (7.0–––8.8) | 7.7 (7.1–––10.5) | 0.89 |
| TR peak velocity [m/s] | 2.25 ± 0.45 | 2.15 ± 0.41 | 0.64 |
| Baseline laboratory results | |||
| Haemoglobin [g/dl; N 14.0–18.0] | 15.69 ± 1.23 | 14.96 ± 1.38 | 0.27 |
| Creatinine [μmol/l; N 62–106] | 103.78 ± 18.85 | 92.50 ± 14.84 | 0.19 |
| High-sensitive troponin T [ng/ml; N < 0.014] | 0.015 (0.01–––0.042) | 0.011 (0.007–––0.013) | 0.12 |
| NT-proBNP [pg/ml; N < 125] | 1188 (585–––1568) | 946 (623–––1222) | 0.53 |
| HF therapy at inclusion | |||
| ACEi/ARB/ARNI [%max] | 25 (25–––50) | 25 (12.5–––50) | 0.81 |
| Beta-blockers [n, %] | 9 (100 %) | 5 (62.5 %) | 0.04 |
| Beta-blockers [%max] | 50 (25–––50) | 25 (6.25–––25.1) | 0.09 |
| MRA [%max] | 50 (50–––50) | 50 (0–––75) | 0.56 |
| SGLT2 inhibitors [n, %] | 7 (77.78 %) | 3 (37.5 %) | 0.09 |
| Loop diuretics [mg/day] | 30 (30–––60) | 0 (0–––75) | 0.36 |
| 12-month follow-up | |||
| NYHA class [[1], [2], [3], [4]] | 1.5 (1–––2) | 1.5 (1–––2) | 0.81 |
| LV end-diastolic volume [ml/m2] | 85.11 ± 24.66 | 97.42 ± 19.36 | 0.27 |
| LV ejection fraction [%] | 37.67 ± 9.91 | 38.25 ± 13.26 | 0.92 |
| High-sensitive troponin T [ng/ml; N < 0.014] | 0.008 (0.007–––0.031) | 0.008 (0.006–––0.011) | 0.63 |
| NT-proBNP [pg/ml; N < 125] | 435 (352–––692) | 247.5 (194–––639.5) | 0.23 |
| ACEi/ARB/ARNI [%max] | 75 (50–––100) | 50 (50–––100) | 0.89 |
| Beta-blockers [n, %] | 9 (100 %) | 8 (100 %) | 1.00 |
| Beta-blockers [%max] | 75 (37.5–––100) | 50 (40.63–––87.5) | 0.63 |
| MRA [%max] | 100 (100–––100) | 100 (100–––100) | 0.74 |
| SGLT2 inhibitors [n, %] | 9 (100 %) | 8 (100 %) | 1.00 |
| Loop diuretics [mg/day] | 30 (0–––30) | 22.5 (0–––35) | 0.81 |
Notations – %max – the percentage of the maximal recommended dosage.
Abbreviations: 6MWT - six minute walk test, ACEi - angiotensin-converting enzyme inhibitors, ARB - angiotensin receptor blockers, ARNI - angiotensin receptor-neprilysin inhibitor, CPET - cardiopulmonary exercise test, LV - left ventricle, MRA - mineralocorticoid receptor antagonist, NTproBNP – N-terminal pro-brain natriuretic peptide, NYHA class – New York Heart Association class, SGLT2i - sodium-glucose cotransporter-2 inhibitors, TAPSE - tricuspid annular plane systolic excursion, TR – tricuspid regurgitation, VO2max - maximal oxygen uptake during cardiopulmonary exercise test.
This was a single-centre, prospective observational study with a small sample size (but with sufficient power to detect the effect – see Appendix), which may limit the generalizability of the findings [11]. Nevertheless, the study population consisted of a homogenous population of young, therapy-naïve DCM patients with minimal comorbidities or confounding medications that could affect cardiac SNS function or MIBG kinetics, thereby serving as a “clear model” for evaluating SNS dysfunction in HFrEF. This allowed for an in-depth assessment of SNS dysfunction and its modulation by early β-blocker titration without external interference. It should be acknowledged that significant differences in baseline WR were observed between groups. These differences, however, can reflect clinical decision-making process, as WR was previously reported as a surrogate marker of HF severity (here we also report lower LVEF and possible more severe HF symptoms prior to inclusion), and more symptomatic patients with more LV remodeling could more likely receive early up-titration of HF therapy, including BB. Nevertheless, we cannot entirely exclude the possibility of regression to the mean influencing our results, particularly given the small sample size and observational nature of the study. Furthermore, due to the observational nature of the study, full randomization was not feasible, and treatment allocation was not controlled; however, the high- and low-BB groups differed only in terms of baseline LVEF, which did not impact the relation between baseline BB dosage and WR improvement (OR 11.28, p = 0.08, when adjusted for LVEF). Lastly, the cost of SPECT-MIBG is several times higher that of commonly used scintigraphy methods, which limits its availability and the level of experience with this technique in many cardiac centres.
A key observation was the absence of significant SNS improvement in nearly half of the DCM patients, despite GDMT initiation. A lack of SNS improvement has previously been associated with adverse long-term outcomes [[12], [13], [14]]. While this study demonstrated for the first time that only rapid BB up-titration led to SNS improvement. Importantly, baseline SNS status appeared to be irrelevant to its follow-up course; only patients with more severe baseline SNS dysfunction experienced improvement, provided BB up-titration was implemented promptly. This finding aligns with the higher rate of beneficial left ventricle reverse remodeling (improved ejection fraction and volume) observed in patients exhibiting SNS improvement, as indicated by a lower WR following timely GDMT [1,15]. These results underscore the potential benefits of early and aggressive BB up-titration in improving cardiac SNS activity and may help inform future therapeutic strategies in HFrEF.
Note
All authors take responsibility for all aspects of reliability and freedom from bias of the data presented and their discussed interpretation.
Source of funding: This work was supported by the National Science Centre, Poland [2020/37/N/NZ5/03306 to ED and 2019/35/B/NZ5/02946 to PR].
Disclosures: The authors declare that they have no competing interests.
Availability of data and materials: The datasets analyzed in this study are available from the corresponding author upon reasonable request.
CRediT authorship contribution statement
Ewa Dziewięcka: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft. Katarzyna Holcman: Investigation, Methodology. Magdalena Kostkiewicz: Investigation, Methodology. Wojciech Szot: Investigation, Methodology. Sylwia Wiśniowska-Śmiałek: Investigation. Mateusz Winiarczyk: Data curation, Investigation. Natalia Przytuła: Data curation, Investigation. Agnieszka Stępień-Wroniecka: Data curation, Investigation. Katarzyna Graczyk: Data curation, Investigation. Małgorzata Mazur: Data curation. Agata Leśniak-Sobelga: Investigation. Jarosław Gąsiorek: Data curation. Agnieszka Czapska: Data curation. Jan Jamroś: Data curation. Karolina Garlicka: Data curation. Paweł Rubiś: Conceptualization, Investigation, Methodology, Supervision, Writing – review & editing.
Declaration of competing interest
The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements: none
none
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcha.2025.101784.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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