The Impact of Positive Inotropic Therapy on Hemodynamics and Organ Function in Acute Heart Failure: A Differentiated View

Background: Little is known about the impact of treatment with inotropic drugs on the interaction of hemodynamics, biomarkers, and end-organ function in patients with acute decompensated heart failure (HF) of different origins and heart rhythms. Methods: Fifty patients with different causes of acute decompensated HF (dilated cardiomyopathy DCM, ischemic cardiomyopathy ICM, atrial fibrillation AF, sinus rhythm/pacemaker lead rhythm SR/PM) were treated with dobutamine or levosimendan. Non-invasive hemodynamics, biomarkers, and parameters of renal organ function were evaluated at hospital admission and after myocardial recompensation (day 5 to 7). Results: Twenty-seven patients with ICM and twenty-three patients with DCM were included. Thirty-nine patients were treated with dobutamine and eleven with levosimendan. Sixteen were accompanied by persistent AF and thirty-four presented either with SR or PM. In the overall cohort, body weight and biomarkers (NT-proBNP/ST2) significantly decreased. GFR significantly increased during therapy with either dobutamine or levosimendan. However, hemodynamic parameters seem to be only improved in patients with DCM, in the levosimendan sub-group, and in patients with SR/PM. Conclusion: Patients with acute decompensated HF benefit from positive inotropic therapy during short-term follow-ups. In particular, patients with DCM, those after levosimendan therapy and those with SR/PM, seem to benefit most from inotropic therapy.


Introduction
Cardiovascular diseases represent one of the most common causes of morbidity, mortality, and hospital admission in Western countries [1].As the aging population increases worldwide and survival from myocardial infarction improves with the accessible administration of thrombolytic therapy and acute percutaneous coronary interventions, the incidence and prevalence of heart failure (HF) further increased over the last decades [2][3][4].The re-hospitalization rate is alarmingly high, which is increasingly critical from an economic point of view due to the current restrictions in the health care system.Despite improvements in care, patients admitted due to acute heart failure (AHF) still have a one-year mortality rate after hospitalization in up to 30% with re-admission rates at about 30% within 30 to 60 days after hospital discharge.When taking economic aspects into account, approximately 1-2% of the total healthcare budget in Europe is attributable to HF [5][6][7].
The origin of AHF with myocardial decompensation is diverse.Besides acute ischemic events, myocardial inflammation, structural degeneration, or even arrhythmia may contribute to hemodynamic deterioration.
In cases of acute and chronic HF, the primary therapeutic goal is defined by hemodynamic stabilization, the optimization of volume status, and the preservation of adequate organ perfusion.Therefore, angiotensin receptor/neprilysin inhibitors (ARNI), mineral receptor antagonists (MRA), sodium-glucose type 2 (SGLT-2) inhibitors, and diuretics are established therapy options.However, in severe cases of AHF consecutively resulting in acute kidney injury, inotropic agents are commonly used to stabilize hemodynamics and thereby improve organ perfusion.Positive inotropic agents like dobutamine and levosimendan are typically administered to stimulate myocardial contractility, thus improving tissue and end-organ perfusion and function [8].Dobutamine is a sympathomimetic amine that predominantly stimulates ß1 adrenergic receptors, resulting in a dose-dependent positive inotropic and chronotropic response [9].The pharmacological effect of levosimendan is characterized by a calcium-dependent positive inotropic response without increasing intracellular calcium amount and myocardial oxygen consumption.Furthermore, levosimendan has a peripheral vasodilative effect [10].
Biomarkers are widely used for therapy controls in acute and chronic HF, being an area of intensive research over the last decades.NT-proBNP is commonly used as the preferred diagnostic biomarker in HF for risk stratification, therapy monitoring, and outcomes.The 2021 ESC heart failure guidelines recommend the use of natriuretic peptides-either NT-proBNP or BNP (class I recommendation and level B evidence)-in patients with suspected heart failure [11].Furthermore, it has been proposed in the recent literature that higher baseline levels of the so-called soluble ST2 (suppressor of tumorigenicity 2), a marker of myocardial fibrosis and remodeling, are associated with a higher risk of death and or re-hospitalization in HF.Moreover, the combined use of biomarkers improves the prognostic value in patients with AHF [8,12,13].Intensified clinical and biomarkerbased patient monitoring and early re-evaluation of therapeutic strategies are crucial for therapy management and can favorably influence outcomes.Therefore, supporting straightforward diagnostic tools, such as non-invasive bedside bio-impedance monitoring (NICaS ® NIMedical, Israel Advanced Technology Industries, Hertzliya Pituach 4676672, Israel), provides an accurate and approved method to obtaining hemodynamic parameters in acute and chronic HF [14][15][16][17][18].
However, decision making about treatments for HF, especially in patients with acute new-onset or AHF and the reputed need for dobutamine or levosimendan, is often operatorbased or follows institutional policy, without any accurate monitoring of the actual impact on the patient.Furthermore, the management of heart failure in the setting of atrial fibrillation (AF) is still challenging.
This study aimed to evaluate the potential differences in the therapeutic benefit of dobutamine and levosimendan on hemodynamics and end-organ perfusion in patients with acute myocardial decompensation facing various underlying pathologies of heart failure.A particular focus was put on the assessment of available biomarkers, non-invasive hemodynamic parameters, and renal organ function.

Patients and Measurements
At the University Hospital of Marburg, over a period of 12 months (November 2020-November 2021), data from 50 patients who presented to our emergency department with decompensated heart failure were retrospectively analyzed.All data were obtained during clinical routine treatment.Based on the primary aim of our analysis to evaluate the impact of inotropic therapy on hemodynamics, biomarkers and renal organ function during short-time intra-hospital follow-up, the following inclusion criteria were defined in order to generate reliable results as well as to rule out potential bias with influence on the study results as far as possible: aetiology of HF had to be either chronic ischemic cardiomyopathy (ICM) or dilative cardiomyopathy (DCM).Cardiomyopathy due to a relevant coronary artery disease (CAD) without any acute event within the last 6 months was defined as chronic ICM.DCM was defined as cardiomyopathy with reduced ejec-tion fraction and ventricular enlargement with no evidence of relevant CAD ruled out by coronary angiography within at least one year before inclusion.Patients with HF and signs of acute cardiac decompensation (pulmonary congestion, elevated NT-pro BNP levels >1000 pg/mL, known ICM/DCM) were treated with either dobutamine or levosimendan, according to the specification of current ESC heart failure guidelines.Patients suffering an acute myocardial infarction, patients who require chronic renal replacement therapy, those with severe aortic stenosis, those with significantly compromised hemodynamic situation (RR systolic < 100 mmHg, MAD < 60 mmHg, heart rate > 130/min), and those with ongoing clinically relevant infection (elevated body temperature > 38 • C) were excluded from data analysis.No other patients' data were retrospectively excluded from analysis.Patients´inclusion process is presented in Figure 1.Decision making for the application of even dobutamine or levosimendan was based on the clinical experience and appraisal of the attending physician and concomitant parameters, such as hemodynamics and renal organ function.
the impact of inotropic therapy on hemodynamics, biomarkers and renal organ function during short-time intra-hospital follow-up, the following inclusion criteria were defined in order to generate reliable results as well as to rule out potential bias with influence on the study results as far as possible: aetiology of HF had to be either chronic ischemic cardiomyopathy (ICM) or dilative cardiomyopathy (DCM).Cardiomyopathy due to a relevant coronary artery disease (CAD) without any acute event within the last 6 months was defined as chronic ICM.DCM was defined as cardiomyopathy with reduced ejection fraction and ventricular enlargement with no evidence of relevant CAD ruled out by coronary angiography within at least one year before inclusion.Patients with HF and signs of acute cardiac decompensation (pulmonary congestion, elevated NT-pro BNP levels >1000 pg/mL, known ICM/DCM) were treated with either dobutamine or levosimendan, according to the specification of current ESC heart failure guidelines.Patients suffering an acute myocardial infarction, patients who require chronic renal replacement therapy, those with severe aortic stenosis, those with significantly compromised hemodynamic situation (RR systolic < 100 mmHg, MAD < 60 mmHg, heart rate > 130/min), and those with ongoing clinically relevant infection (elevated body temperature > 38 °C) were excluded from data analysis.No other patients' data were retrospectively excluded from analysis.Patients´ inclusion process is presented in Figure 1.Decision making for the application of even dobutamine or levosimendan was based on the clinical experience and appraisal of the attending physician and concomitant parameters, such as hemodynamics and renal organ function.An echocardiographic examination, as well as non-invasive hemodynamic bioimpedance measurements (NICaS ® ), were performed.Laboratory parameters, including NT-proBNP, ST2, and the glomerular filtration rate (GFR) were taken as part of the clinical routine after the patient had been admitted to the hospital and before starting inotropic therapy (T1).Repeated in-hospital measurements were performed again 24-48 h after finishing the inotropic therapy (day 5-7 for levosimendan and dobutamine patients) in a situation of clinical stabilization and myocardial re-compensation (T2).Final comparisons were performed for the impact on all parameters between the two time points.An echocardiographic examination, as well as non-invasive hemodynamic bioimpedance measurements (NICaS ® ), were performed.Laboratory parameters, including NT-proBNP, ST2, and the glomerular filtration rate (GFR) were taken as part of the clinical routine after the patient had been admitted to the hospital and before starting inotropic therapy (T1).Repeated in-hospital measurements were performed again 24-48 h after finishing the inotropic therapy (day 5-7 for levosimendan and dobutamine patients) in a situation of clinical stabilization and myocardial re-compensation (T2).Final comparisons were performed for the impact on all parameters between the two time points.

NICaS ® Device and Procedure
The NICaS ® whole body electrical bio-impedance monitoring system (NIMedical, Israel Advanced Technology Industries, Hertzliya Pituach 4676672, Israel) is an FDA-and European CE-sign-approved non-invasive hemodynamic monitoring tool.NICaS ® relies on a combination of pulse contour analysis and the Granov-Goor Index (GGI), which is based on the systolic time intervals (STI).NICaS ® can assess cardiac function and provide information on several parameters, like cardiac output (CO), cardiac index (CI), and systemic vascular resistance (SVR).NICaS ® -measurement procedures and validation studies compared to Swan-Ganz-and PICCO ® -catheterization techniques were reported recently [14][15][16][17][18].

Statistical Analysis
Data are presented as absolute variables and percentages (%) for categorical variables and either median with interquartile range (interquartile range, 25-75th percentile) or mean with SD according to the distribution of the variables.We assessed normality using Shapiro-Wilk, Pearson, as well as Kolmogorov-Smirnov tests.After testing for normal distribution, the Student's t-test or Mann-Whitney U test was implemented to test for differences between the various characteristics.For categorical variables, Fisher's exact test or chi-square test was used, as appropriate.All analyses were made using SPSS 24 (IBM, New York, NY, USA) and GraphPad Prism 6.0 (GraphPad Software, San Diego, CA, USA).A two-sided p-value of less than 0.05 was considered statistically significant.

Ethical Declaration
The data analysis was approved by the local Ethics Committee, complying with the Declaration of Helsinki, (Decision Nr: ek_mr_02_04_19).

Results
Data from a total of 50 patients with acute decompensated congestive heart failure were included in this retrospective analysis.Demographics and baseline characteristics as well as the comorbidities and HF medication were taken from our in-hospital patient documentation system.In the absence of relevant disease-related data, additionally, the outpatient-treating physicians were contacted to obtain this information.The parameters are documented in Tables 1-3.The mean age in the overall cohort was 78 ± 11 years; 74% were male and 26% were female.Twenty-seven (54%) of the patients had an underlying chronic ischemic cardiomyopathy (ICM) and twenty-three (46%) of the patients had dilated cardiomyopathy (DCM).
No patient required renal replacement therapy while the inotropics were applied.However, 13 patients (26%) received temporary renal replacement therapy due to hypervolemia and metabolic acidosis (dobutamine subgroup: 12 patients, levosimendan subgroup: 1 patient) during the in-hospital stay but after finishing the measurement period of time.No other complications were documented during the measurement period of time.Overall, in-hospital mortality ranged about 14% (n = 7), with the breakdown for the different subgroups as follows: At admission, the mean left ventricular ejection fraction (LVEF) was 36 ± 10%.Levels of NT-proBNP and ST2 were elevated at 15765 ± 12246 pg/mL and 100.8 ± 77.6 ng/mL, respectively.Eleven patients received levosimendan (12 mg/24 h), and thirty-nine patients were treated with dobutamine with a mean dosage of 10.5 µg/kg/min.The positive inotropic therapy was initiated at admission.A predefined standard dosage (12 mg) of Levosimendan was administered over 24 h.The mean duration of dobutamine therapy was 4.74 ± 0.75 days.
The hemodynamic parameters were non-invasively monitored with the NiCas ®system according to procedural standards.
In the overall cohort, no significant changes in cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), and LVEF could be observed between the measurements, whereas GFR significantly improved when comparing T1 and T2 and body weight consecutively dropped.Moreover, levels of NT-proBNP and as well ST2 significantly decreased from baseline to the short-term follow-up (Table 4, Figures 2 and 3).

Changes in Hemodynamics, LVEF, and Biomarkers in ICM and DCM Subgroups
Twenty-seven patients of the overall cohort had an underlying ICM, and twenty-three patients had a DCM.

Changes in Hemodynamics, LVEF, and Biomarkers in ICM and DCM Subgroups
Twenty-seven patients of the overall cohort had an underlying ICM, and twenty-three patients had a DCM.

Changes in Hemodynamics, LVEF, and Biomarkers in Levosimendan and Dobutamine Subgroups
In the overall cohort, 39 patients were treated with dobutamine and 11 with levosimendan.

The Comparison of Changes in Hemodynamics, LVEF, and Biomarkers in Patients with Either AF or Sinus Rhythm/Continuous Pacemaker Stimulation (SR/PM)
Sixteen patients had a documented year-long history of paroxysmal or persistent AF and thirty-four patients were either in SR or were stimulated by a DDD or a CRT device, at least economizing myocardial function (SR/PM subgroup).
In the AF subgroup, CO, CI, SVR, LVEF, and GFR did not improve significantly during the treatment with inotropics.Comparing T1 and T2, NT-proBNP, ST2 and body weight significantly dropped during therapy.
Regarding comorbidities and baseline characteristics, no significant differences could be observed comparing these subgroups, except LVEF.Patients suffering from AF were accompanied by higher baseline LVEF than SR/PM patients (41.18% ± 9.8 vs. 33.6 ± 9.2; p = 0.01) (Table 2).Although an increased effect of inotropic therapy on hemodynamics would generally be expected in patients with higher LVEF, in the atrial fibrillation subgroup, the effect of inotropic therapy was significantly smaller.This once again underlines the negative effect of atrial fibrillation.

Discussion
Approximately 3.6 million people in Europe suffer from chronic heart failure [19], with an incidence of 332/100,000 people per year and a prevalence of about 1.8% [20].Despite improved survival due to the application of disease-modifying therapeutic regimes, mortality risk and hospitalization rate due to acute myocardial decompensation remain high [21,22].
According to current guidelines, the use of beta-blockers, ACE inhibitors, AT-II receptor blockers, aldosterone antagonists, diuretics, sacubitril-valsartan, and SGLT-II inhibitors belong to the first-line treatment strategies in chronic heart failure [11].However, in acute congestive heart failure, the importance and clinical side effects of positive inotropic drugs are not well defined yet, especially concerning different underlying myocardial pathologies (DCM/ICM) and concomitant comorbidities such as AF.
AF, as the most common arrhythmia with an increasing prevalence in the older patient population, is in turn associated with the development of heart failure, an increased hospital admission rate, and death [23].In 2010, approximately 33.5 million people worldwide were affected by AF [24].AF and congestive heart failure (CHF) frequently coexist and are directly predisposed to each other [25,26].In approximately two-thirds of CHF patients older than 65 years, AF is a coexistent complication.Besides common risk factors, such as arterial hypertension, valvular heart disease, and myocardial infarction, both diseases often share similar approaches to drug therapy such as beta-blockers, digoxin, and angiotensinconverting enzyme inhibitors.
Here, we evaluated the impact of the two most commonly used inotropic drugs, dobutamine and levosimendan, on hemodynamics, biomarkers, and other clinically relevant parameters in unselected patients with different origins of acute congestive heart failure, with either sinus/pacemaker rhythm and/or atrial fibrillation.This was to better understand the impact of the two differently acting inotropics within varying clinical situations of HF, thus allowing for optimized and individualized therapy management in these fragile patients.
In the overall cohort, the significant reduction in NT-proBNP, ST2, and body weight, as well as the corresponding increase in GFR, depict the general benefit of both positive inotropic substances, levosimendan and dobutamine, in recompensating AHF and preserving renal organ function, although no significant alterations in CO, CI, and SVR could be observed.However, the lack of a control group displays a limitation of such an interpretation.
Furthermore, regarding the different subgroups, in the levosimendan subgroup, a significant increase in CO and CI could be observed, whereas, in the dobutamine subgroup, CO and CI remained unchanged during the short term follow-up.Possibly, this could be related to different a half-life time of the drugs or to a more favorable effect of a calcium-sensitizer over a ß1-adrenergic stimulus.However, these results highlight the prior described advantages of levosimendan in improving the hemodynamics of patients with decompensated HF.
When looking at the DCM and ICM subgroups, a significant improvement in CO and CI could be surprisingly documented only in the DCM subgroup, whereas in the ICM group, CO and CI were not altered significantly.However, in both subgroups, a marked decrease in the biomarkers NT-proBNP and ST2 and also the body weight could be demonstrated, depicting an overall benefit of positive inotropic therapy for both ICM and DCM.The underlying pathophysiology of such different effects on hemodynamics during circulatory support with levosimendan or dobutamine in patients with DCM or ICM cannot be thoroughly evaluated using the data of this small patient cohort.This should be addressed in further studies.Depending on the drug, it can be considered that more dominant inotropic and/or vasodilative effects and different accounts of oxidative myocardial stress may influence these findings.
In patients with AF, no significant improvement in CO and CI could be observed for both levosimendan and dobutamine therapy.Interestingly, there was even a trend toward a reduction in CO and CI.However, in patients with sinus rhythm or continuous pacemaker stimulation (SR/PM subgroup), a remarkable increase in CO and CI could be documented.While in both subgroups NT-proBNP, ST2, and body weight were significantly reduced, reflecting the status of an adequate myocardial re-compensation, e.g., due to an improved diuresis during therapy, only in the SR/PM subgroup did the GFR improve significantly.No relevant change in GFR could be documented in the AF subgroup.These data indicate that an economized myocardial function during sinus rhythm or pacemaker-lead rhythm may improve hemodynamics, thus preserving end-organ perfusion.The controversy in the action of inotropics in cases of sinus rhythms or AF is still under ongoing discussion in the recent literature [27][28][29].Among others, a discrepancy in the described effects may arise due to differing timings between therapy and measurements, or even for different parameters.Our data analysis assumes that patients with SR benefit more from inotropic therapy concerning CO and CI than patients with AF during short-term follow-ups.
Current trials indicate that the rhythm or rate control of AF (anti-arrhythmic drugs or catheter ablation) may have a significant impact on survival or at least improve symptoms and delay the worsening of heart failure.In a retrospective analysis, Deedwania and colleagues state that the restoration and maintenance of sinus rhythm with amiodarone was associated with improved survival in the setting of CHF [30].In a systematic review and meta-analyses, Di Biase et al. revealed that rhythm control via catheter ablation resulted in improved cardiac function, exercise capacity, and quality of life for persistent AF patients with HF, compared with the medical rate control strategy [31].Vecchio et al. prospectively analyzed seventy-nine patients with AF and congestive HF.Their investigation showed that catheter ablation of AF in heart failure presents an adequate success rate, improving symptoms and reducing rehospitalization due to heart failure [32].
Considering the data of our study, in patients with acute congestive heart failure and concomitant arrhythmia due to AF, a conversion in SR should be strived for to improve hemodynamics and renal function.In the case of an existing cardiac pacemaker and failed attempts at rhythm control with medication in the setting of acute decompensation, continuous pacemaker stimulation should be considered; for example, by temporarily optimizing the basal pacemaker frequency.Furthermore, according to the current literature, these data indicate that an ablative strategy for patients with AF and heart failure could improve hemodynamics and organ perfusion, thus benefiting the long-term prognosis of heart failure and decreasing re-hospitalization rates.
Finally, regarding the discussion on the most appropriate biomarker for monitoring congestion and recompensation status during therapy, we compared levels of NT-proBNP and ST2 in this analysis.According to our data, there was a significant reduction in both markers during therapy.Comparing levels of NT-proBNP and ST2, no significant differences could be observed.Therefore, NT-proBNP may continue to be recommended as a maker for monitoring de-and recompensation in the daily clinical routine.

Study Limitations
We recognize that our analysis is limited due to its small number of patients and singlecenter experience.However, only a few data exist regarding the impact of positive inotropic drugs like levosimendan or dobutamine on hemodynamics, biomarkers, and real organ functions in patients with acute decompensated HF due to different underlying pathologies (ICM/DCM).The purpose of this study was to investigate the effect of levosimendan and dobutamine during the acute phase of decompensated HF patients, but not to evaluate clinical long-term outcomes.The clinical relevance regarding the long-term outcome and survival of the patients requires further investigation in larger prospective randomized studies.

Conclusions
According to the data of our clinical analysis, all patients with acute decompensated HF benefit from positive inotropic therapy during short-term follow-ups.This finding seems to be independent of the underlying structural myocardial disease (DCM/ICM), the preferred inotropic (dobutamine/levosimendan), and heart rhythm (AF/SR/PM).In all patients of our cohort, biomarkers and body weight decreased, whereas the GFR increased at least as a trend, suggesting an improvement in myocardial contractility and thus an increase in renal organ perfusion and function during inotropic support.
Nevertheless, crucial hemodynamic parameters like CO and CI seem to be significantly affected during therapy only in patients of the DCM, levosimendan, and SR/PM subgroups.Ultimately, our recent data demonstrate that patients with AF benefit least from inotropic therapy.In these patients, on the contrary, inotropic therapy may even trend for the harms of myocardial function and cardiac output.Thus, in summary, the goal of therapy in AHF and AF should be to rhythmize the heart in order to obtain the possibility of an optimized medical treatment, e.g., using inotropics, to preserve prognostic-relevant end-organ perfusion and function.

Figure 1 .
Figure 1.Patient cohort for data analysis.

Figure 1 .
Figure 1.Patient cohort for data analysis.

Figure 2 .
Figure 2. Changes in hemodynamics and LVEF in the overall cohort.In the overall cohort, no significant changes in cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), and left ventricular ejection fraction (LVEF) could be observed (T1: admission, T2: follow-up, ns: not significant, p ≥ 0.05).

Figure 4 .
Figure 4. Changes in hemodynamics and LVEF in ICM and DCM subgroups.In the ICM subgroup, no significant changes in CO, CI, SVR, and LVEF were observed.However, in patients with underlying

Table 1 .
Demographics, baseline characteristics and comorbidities of the overall cohort and in DCM and ICM subgroups.

Table 2 .
Demographics, baseline characteristics and comorbidities of the overall cohort and in AF and SR/PM subgroups.

Table 3 .
Heart failure medication of the patients at submission and at discharge.