Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period: The multinational randomized LeoDOR trial.

AIM: The LeoDOR trial explored the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute heart failure (HF). METHODS AND RESULTS: In this prospective multicentre, double-blind, two-armed trial, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or matching placebo for 12 weeks. All patients had left ventricular ejection fraction (LVEF) ≤30% during index hospitalization. Levosimendan was administered according to centre preference either as 6 h infusion at a rate of 0.2 µg/kg/min every 2 weeks, or as 24 h infusion at a rate of 0.1 µg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank score consisting of three hierarchical groups. Secondary clinical endpoints included the composite risk of tiers 1 and 2 at 14 and 26 weeks, respectively. Due to the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm), which reduced the statistical power to detect a 20% risk reduction in the primary endpoint to 60%. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint: the mean rank score was 72.55 for the levosimendan group versus 73.81 for the placebo group (p = 0.863). However, there was a signal towards a higher incidence of the individual clinical components of the primary endpoint in the levosimendan group versus the placebo group both after 14 weeks (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.12-7.68; p = 0.021) and 26 weeks (HR 1.64, 95% CI 0.87-3.11; p = 0.122). CONCLUSIONS: Among patients recently hospitalized with HF and reduced LVEF, intermittent levosimendan therapy did not improve post-hospitalization clinical stability.

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction - the SCIENCE trial.

AIMS: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0 ml, p = 0.736) and LVEF (-1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups. CONCLUSION: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.

Contemporary Challenges of Regenerative Therapy in Patients with Ischemic and Non-Ischemic Heart Failure.

It has now been almost 20 years since first clinical trials of stem cell therapy for heart repair were initiated. While initial preclinical data were promising and suggested that stem cells may be able to directly restore a diseased myocardium, this was never unequivocally confirmed in the clinical setting. Clinical trials of cell therapy did show the process to be feasible and safe. However, the clinical benefits of this treatment modality in patients with ischemic and non-ischemic heart failure have not been consistently confirmed. What is more, in the rapidly developing field of stem cell therapy in patients with heart failure, relevant questions regarding clinical trials' protocol streamlining, optimal patient selection, stem cell type and dose, and the mode of cell delivery remain largely unanswered. Recently, novel approaches to myocardial regeneration, including the use of pluripotent and allogeneic stem cells and cell-free therapeutic approaches, have been proposed. Thus, in this review, we aim to outline current knowledge and highlight contemporary challenges and dilemmas in clinical aspects of stem cell and regenerative therapy in patients with chronic ischemic and non-ischemic heart failure.

Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Frailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk-benefit profile is perceived to be less favorable than in nonfrail patients. OBJECTIVES: This study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. METHODS: Frailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death. RESULTS: A frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit. CONCLUSIONS: Frailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

TNF-α Predicts Endothelial Function and Number of CD34+ Cells after Stimulation with G-CSF in Patients with Advanced Heart Failure.

Patients with advanced heart failure (HF) have reduced cardiac output and impaired peripheral blood flow, which diminishes endothelial shear stress and consequently flow-mediated dilatation (FMD). The aim of our study was to find out whether endothelial dysfunction is associated with the number of CD34+ cells and TNF-α levels in patients with ischemic and non-ischemic HF after stimulation with granulocyte colony-stimulating factor (G-CSF). We included 56 patients with advanced HF (LVEF < 35%). Eighteen patients (32.14%) had ischemic and 38 (67.86%) patients had non-ischemic HF. FMD of the brachial artery was performed before the patients underwent 5-day bone marrow stimulation with daily subcutaneous injections of G-CSF (5 µg/kg bid). On the fifth day peripheral blood CD34+ cell count was measured. No statistically significant differences were found between the patient groups in NT-proBNP levels ((1575 (425−2439) vs. 1273 (225−2239)) pg/mL; p = 0.40), peripheral blood CD34+ cell count ((67.54 ± 102.32 vs. 89.76 ± 71.21) × 106; p = 0.32), TNF-α ((8.72 ± 10.30 vs. 4.96 ± 6.16) ng/mL; p = 0.13) and FMD (6.7 ± 5.4 vs. 7.2 ± 5.9%; p = 0.76). In a linear regression model, only FMD (p = 0.001) and TNF-α (p = 0.003) emerged as statistically significant predictors of CD34+ cells counts. Our study suggests that TNF-α is a good predictor of impaired endothelial function and of CD34+ cells mobilization after G-CSF stimulation in patients with advanced HF of ischemic and non-ischemic origin.

A pilot clinical trial of cell therapy in heart failure with preserved ejection fraction.

AIMS: We investigated the effects of CD34+ cell therapy in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: In a prospective pilot study, we enrolled 30 patients with HFpEF. In Phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent CD34+ cell transplantation. Using electroanatomical mapping, we measured local mechanical diastolic delay and myocardial viability to guide the targeting of cell injections. Patients were followed for 6 months after cell transplantation (Phase 2), and the primary endpoint was the difference in change in E/e' between Phase 1 and Phase 2. In Phase 1, the decrease in E/e' was significantly less pronounced than in Phase 2 (-0.33 ± 1.72 vs. -3.77 ± 2.66, p = 0.001). During Phase 1, there was no significant change in global systolic strain (GLS; from -12.5 ± 2.4% to -12.8 ± 2.6%, p = 0.77), N-terminal pro-B-type natriuretic peptide (NT-proBNP; from 1463 ± 1247 pg/ml to 1298 ± 931 pg/ml, p = 0.31), or 6-min walk test (6MWT; from 391 ± 75 m to 402 ± 93 m, p = 0.42). In Phase 2, an improvement was noted in NT-proBNP (from 1298 ± 931 pg/ml to 887 ± 809 pg/ml, p = 0.02) and 6MWT (from 402 ± 93 m to 438 ± 72 m, p = 0.02). Although GLS did not change significantly in Phase 2 (from -12.8 ± 2.6% to -13.8 ± 2.7%, p = 0.36), we found improved local systolic strain at cell injection sites (-3.4 ± 6.8%, p = 0.005). CONCLUSIONS: In this non-randomized trial, transendocardial CD34+ cell therapy in HFpEF was associated with an improvement in E/e', NT-proBNP, exercise capacity, and local myocardial strain at the cell injection sites. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02923609.

Cell Therapy in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is the most common cause of hospitalisation for heart failure. However, only limited effective treatments are available. Recent evidence suggests that HFpEF may result from a systemic proinflammatory state, microvascular endothelial inflammation and microvascular rarefaction. Formation of new microvasculature in ischaemic tissues is dependent on CD34+ cells, which incorporate into the newly developing vasculature and produce pro-angiogenic cytokines. In HFpEF patients, worsening of diastolic function appears to correlate with decreased numbers of CD34+ cells. Therefore, it is plausible that increasing the myocardial numbers of CD34+ cells could theoretically lead to improved microvascular function and improved diastolic parameters in HFpEF. In accordance with this hypothesis, recent pilot clinical data suggest that CD34+ cell therapy may indeed be associated with improved diastolic function and better functional capacity in HFpEF patients and could thus represent a promising novel therapeutic modality for this patient population.

Transendocardial CD34+ Cell Therapy Improves Local Mechanical Dyssynchrony in Patients With Nonischemic Dilated Cardiomyopathy.

We investigated the effects of cell therapy on local mechanical dyssynchrony (LMD) in patients with nonischemic dilated cardiomyopathy (NICM). We analyzed electromechanical data of 30 NICM patients undergoing CD34+ cell transplantation. All patients underwent bone marrow stimulation; CD34+ cells were collected by apheresis and injected transendocardially. At baseline and at 6 months after therapy, we performed electromechanical mapping and measured unipolar voltage (UV) and LMD at cell injection sites. LMD was defined as a temporal difference between global and segmental peak systolic displacement normalized to the average duration of the RR interval. Favorable clinical response was defined as increase in the left ventricular ejection fraction (LVEF) ≥5% between baseline and 6 months. Using paired electromechanical point-by-point analysis, we were able to identify 233 sites of CD34+ cell injections in 30 patients. We found no overall differences in local UV between baseline and 6 months (10.7 ± 4.1 mV vs 10.0 ± 3.6 mV, P = 0.42). In contrast, LMD decreased significantly (17 ± 17% at baseline vs 13 ± 12% at 6 months, P = 0.00007). Favorable clinical response at 6 months was found in 19 (63%) patients (group A), and 11 (37%) patients did not respond to cell therapy (group B). At baseline, the two groups did not differ in age, gender, LVEF, or N terminal-pro brain natriuretic peptide (NT-proBNP) levels. Similarly, we found no differences in baseline UV (9.5 ± 2.9 mV in group A vs 8.6 ± 2.4 mV in group B, P = 0.41) or LMD at cell injection sites (17 ± 19% vs 16 ± 14%, P = 0.64). In contrast, at 6 months, we found higher UV in group A (10.0 ± 3.1 mV vs 7.4 ± 1.9 mV in group B, P = 0.04). Furthermore, when compared with group B, patients in group A displayed a significantly lower LMD (11 ± 12% vs 16 ± 10%, P = 0.002). Thus, it appears that favorable clinical effects of cell therapy in NICM patients may be associated with a decrease of LMD at cell injection sites.

Navigating between Scylla and Charybdis: challenges and strategies for implementing guideline-directed medical therapy in heart failure with reduced ejection fraction.

Guideline-directed medical therapy (GDMT) has the potential to reduce the risks of mortality and hospitalisation in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, real-world data indicate that many patients with HFrEF do not receive optimised GDMT, which involves several different medications, many of which require up-titration to target doses. There are many challenges to implementing GDMT, the most important being patient-related factors (comorbidities, advanced age, frailty, cognitive impairment, poor adherence, low socioeconomic status), treatment-related factors (intolerance, side-effects) and healthcare-related factors that influence availability and accessibility of HF care. Accordingly, international disparities in resources for HF management and limited public reimbursement of GDMT, coupled with clinical inertia for treatment intensification combine to hinder efforts to provide GDMT. In this review paper, authors aim to provide solutions based on available evidence, practical experience, and expert consensus on how to utilise evolving strategies, novel medications, and patient profiling to allow the more comprehensive uptake of GDMT. Authors discuss professional education, motivation, and training, as well as patient empowerment for self-care as important tools to overcome clinical inertia and boost GDMT implementation. We provide evidence on how multidisciplinary care and institutional accreditation can be successfully used to increase prescription rates and adherence to GDMT. We consider the role of modern technologies in advancing professional and patient education and facilitating patient-provider communication. Finally, authors emphasise the role of novel drugs (especially sodium-glucose co-transporter 2 inhibitors), and a tailored approach to drug management as evolving strategies for the more successful implementation of GDMT.

Factors associated with degraded trabecular bone score in heart transplant recipients.

Trabecular bone score (TBS) is a textural index that provides indirect evaluation of trabecular microarchitecture. It improves fracture risk assessment in several high-risk populations. We aimed to evaluate the role of TBS assessment in heart transplant recipients (HTR). In a cross-sectional study with 87 HTR (69 males and 18 females), we assessed TBS and evaluated potential associations between TBS and factors related to increased fracture risk. We also evaluated the correlations between the presence of vertebral fractures (VF) and degraded TBS. We confirmed degraded TBS in the majority of HTR. 27.6% of HTR had partially degraded, 27.6% had degraded TBS. HTR with degraded TBS were older, had higher body mass index, lower bone mineral density (BMD), and T-score. As opposed to stable BMD over different time points, TBS significantly differed among different post-transplant time periods. TBS did not correlate with current methylprednisolone or past zoledronic acid treatment, presence of hypogonadism or diabetes. TBS did not have additional value over BMD in predicting the presence of VF. Most fractures occurred in patients with osteopenia and in patients with partly degraded TBS. Studies with longitudinal designs and larger sample sizes are warranted to further assess the potential role of TBS in HRT.

Efficacy and Mode of Action of Mesenchymal Stem Cells in Non-Ischemic Dilated Cardiomyopathy: A Systematic Review.

Non-ischemic dilated cardiomyopathy (NIDCM) constitutes one of the most common causes to non-ischemic heart failure. Despite treatment, the disease often progresses, causing severe morbidity and mortality, making novel treatment strategies necessary. Due to the regenerative actions of mesenchymal stem cells (MSCs), they have been proposed as a treatment for NIDCM. This systematic review aims to evaluate efficacy and mode of action (MoA) of MSC-based therapies in NIDCM. A systematic literature search was conducted in Medline (Pubmed) and Embase. A total of 27 studies were included (3 clinical trials and 24 preclinical studies). MSCs from different tissues and routes of delivery were reported, with bone marrow-derived MSCs and direct intramyocardial injections being the most frequent. All included clinical trials and 22 preclinical trials reported an improvement in cardiac function following MSC treatment. Furthermore, preclinical studies demonstrated alterations in tissue structure, gene, and protein expression patterns, primarily related to fibrosis and angiogenesis. Consequently, MSC treatment can improve cardiac function in NIDCM patients. The MoA underlying this effect involves anti-fibrosis, angiogenesis, immunomodulation, and anti-apoptosis, though these processes seem to be interdependent. These encouraging results calls for larger confirmatory clinical studies, as well as preclinical studies utilizing unbiased investigation of the potential MoA.

Larger End-Diastolic Volume Associates With Response to Cell Therapy in Patients With Nonischemic Dilated Cardiomyopathy.

OBJECTIVE: To investigate the association of left ventricular end-diastolic volume (LVEDV) and the response to cell therapy in patients with nonischemic dilated cardiomyopathy (NICM). PATIENTS AND METHODS: Five-year registry data from 133 consecutive patients with NICM who underwent CD34+ cell treatment were analyzed. All patients received granulocyte-colony stimulating factor; CD34+ cells were collected by apheresis and delivered by transendocardial injections. Patients with baseline LVEDV less than 200 mL (group A; n=72) and patients with LVEDV 200 to 370 mL (group B; n=54) were included. Patients with LVEDV greater than 370 mL were excluded (n=7). Favorable ejection fraction response was pre-defined by improvement in left ventricular ejection fraction (LVEF) greater than or equal to 5% at 1 y post-cell therapy. RESULTS: At baseline, groups A and B were comparable with regards to age (52±11 y in group A vs 53±10 y in group B; P=.95), sex (male: 79% vs 83%, respectively; P=.55), creatinine (1.07±0.28 mg/dL vs 1.03±0.21 mg/dL, respectively; P=.21), or N-terminal probrain natriuretic peptide (1454±1658 pg/mL vs 1589±1338 pg/mL, respectively; P=.80). Baseline LVEF was higher in group A (32.8±8.7%) than in group B (30.2±8.7%; P=.03). During follow-up, there were four deaths in group A (5.6%), and 2 in group B (3.7%, P=.63). At 1-year post-cell therapy, LVEDV decreased significantly in group B (-56±30 mL; P=.003), but not in group A (+12±97 mL; P=.13). On multivariate analysis, baseline LVEDV was an independent correlate of favorable response in LVEF to therapy (P=.02). CONCLUSION: Larger LVEDV was associated with more pronounced increase in LVEF after transendocardial CD34+ cell therapy in NICM patients, informing target individuals with the highest likelihood of regenerative response. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02445534.

Stem Cell Therapy for Chronic and Advanced Heart Failure.

PURPOSE OF REVIEW: The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD). RECENT FINDINGS: In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.

Long-Term Effects of Angiotensin Receptor-Neprilysin Inhibitors on Myocardial Function in Chronic Heart Failure Patients with Reduced Ejection Fraction.

BACKGROUND: We sought to evaluate the long-term effects of angiotensin receptor blocker-neprilysin inhibitor (ARNI) therapy on reverse remodeling of the failing myocardium in HFrEF patients. METHODS: We performed a prospective non-randomized longitudinal study on 228 HFrEF patients treated with ARNI at our center. Prior to ARNI introduction all patients received stable doses of ACEI/ARB for at least six months. Clinical, biochemical and echocardiography data were obtained at ARNI introduction and 12-month follow-up. Results At follow-up, we found significant improvements in LVEF (29.7% ± 8% vs. 36.5% ± 9%; p < 0.001), LVOT-VTI (14.8 ± 4.2 cm vs. 17.2 ± 4.2 cm; p < 0.001), TAPSE (1.7 ± 0.5 cm vs. 2.1 ± 0.6 cm; p < 0.001) and LV-EDD (6.5 ± 0.8 cm vs. 6.3 ± 0.9 cm; p = 0.001). NT-proBNP serum levels also decreased significantly (1324 (605, 3281) pg/mL vs. 792 (329, 2022) pg/mL; p = 0.001). A total of 102 (45%) of patients responded favorably to ARNI (ΔLVEF < +5%; Group A) and 126 (55%) patients achieved ΔLVEF ≥ +5% (Group B). The two groups differed significantly in age, heart failure etiology, baseline LVEF and baseline NT-proBNP. On multivariable analysis, nonischemic heart failure, LVEF < 30% and NT-proBNP < 1500 pg/mL emerged as independent correlates of favorable response to ARNI therapy. CONCLUSION: ARNI therapy appears to improve echocardiographic parameters of left and right ventricular function in HFrEF patients above the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Endocrine disorders after heart transplantation: national cohort study.

BACKGROUND: Endocrine disorders in patients after heart transplantation (HT) remain understudied. We aimed to assess endocrine profiles and management of HT recipients in the early post- transplant period. METHODS: We conducted a retrospective cohort study on 123 consecutive HT recipients in the Advanced Heart Failure and Transplantation Programme between 2009 and 2018. All recipients had per-protocol endocrine follow-up within the first postoperative year. The median time to first post-transplant endocrine follow-up was 3 months (IQR 2-4). We assessed the incidence of vitamin D deficiency, bone mineral density, history of low energy fractures, hypogonadism in male recipients, posttransplant diabetes mellitus, and thyroid and parathyroid function. RESULTS: We enrolled 22 women and 101 men of median age 57 years (IQR 50-63). Post-transplant diabetes mellitus developed in 14 patients (11.4%). 18 of 25 patients (14.6%) with preexisting type 2 diabetes mellitus required intensification of antidiabetic therapy. 38 male patients (40.4%) had hypogonadism. 5 patients (4.6%) were hypothyroid and 10 (9.3%) latent hyperthyroid. Secondary hyperparathyroidism was present in 19 (17.3%), 25-hydroxyvitamin D deficiency in 64 (54.7%) of patients. Osteoporosis was present in 26 (21.1%), osteopenia in 59 (48.0%) patients. 47 vertebral fractures, 3 hip and 1 humerus fractures occurred in 21 patients. Most of the patients had coincidence of two or three disorders, while less than 5% did not have any endocrine irregularities. All patients received calcium and vitamin D supplements. Forty-six patients (37.4%) were treated with zoledronic acid, 12 (9.8%) with oral bisphosphonates. Two patients were treated with teriparatide. CONCLUSIONS: The prevalence of multiple endocrine disorders early after heart transplantation is high. Assessment and management of increased fracture risk and all other potentially affected endocrine axes should be considered as a standard of care in this early period.

Favorable Response to CD34+ Cell Therapy Is Associated with a Decrease of Galectin-3 Levels in Patients with Chronic Heart Failure.

BACKGROUND: Galectin-3 plasma levels (gal-3) were shown to correlate with the scar burden in chronic heart failure (CHF) setting. As scar burden predicts response to stem cell therapy, we sought to explore a correlation between gal-3 and response to CD34+ cell transplantation in patients with CHF. METHODS: We performed a post hoc analysis of patients, enrolled in 2 prospective trials investigating the clinical effects of CD34+ cell therapy in patients with ischemic cardiomyopathy (ICMP) and nonischemic dilated cardiomyopathy (DCMP). CD34+ cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially using NOGA system. Patients were followed for 3 months and demographic, echocardiographic, and biochemical parameters and gal-3 were analyzed at baseline and at follow-up. Response to cell therapy was defined as an LVEF increase of ≥5%. RESULTS: 61 patients were included in the analysis. The mean age of patients was 52 years and 83% were male. DCMP and ICMP were present in 69% and 31% of patients, respectively. The average serum creatinine was 86 ± 23 µmol/L, NT-proBNP 1132 (IQR 350-2279) pg/mL, and LVEF 30 ± 6%. Gal-3 at baseline and at 3 months did not differ significantly (13.4 ± 5.5 ng/mL vs. 13.1 ± 5.8 ng/mL; p = 0.72), and there were no differences in baseline gal-3 with respect to heart failure etiology (15.1 ± 7.2 ng/mL in ICMP vs. 12.7 ± 4.3 ng/mL in DCMP; p = 0.12). Comparing responders (N = 49) to nonresponders (N = 18), we found no differences in baseline gal-3 (13.6 ± 5.7 ng/mL vs. 13.2 ± 4.9 ng/mL; p = 0.80). However, responders had significantly lower gal-3 at 3-month follow-up (12.1 ± 4.0 ng/mL vs. 15.7 ± 8.4 ng/mL; p < 0.05). Also, responders demonstrated a significant decrease in gal-3 over 3 months, while in nonresponders, an increase in gal-3 occurred (-1.5 ± 5.4 ng/mL vs. +2.7 ± 4.3 ng/mL; p = 0.01). CONCLUSIONS: In patients with chronic heart failure undergoing CD34+ cell therapy, a decrease in galectin-3 plasma levels is associated with beneficial response to this treatment modality. Further prospective data is warranted to confirm our findings and to deepen our understanding of the role of gal-3 in the field of stem cell therapy.