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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A methodology is presented for estimating the wireless body electrode (WE) positions and for calculating the linear transformations that enable the synthesis of a 12-lead ECG or a multichannel ECG from three WEs, which in turn simplifies and improves the acquisition of ECGs. We present, compare, and evaluate three approaches to the synthesis: fully personalized, fully universal, and combined with universal leads and personalized transformations. The evaluation results show that WEs are an acceptable alternative to the standard 12-lead ECG device for patients with chronic myocardial ischemia, if either the fully personalized or combined approach is used. The median correlation coefficients are all higher than 0.94 and 0.92 for the fully personalized and combined approaches, respectively. The corresponding kappa and percentual diagnostic agreements between the synthesized and target 12-lead ECGs are 0.88 (95%) and 0.83 (92%), respectively. The evaluation additionally shows that the personalization of the transformations has more impact on the quality of the synthesized ECGs than the personalization of the WEs’ positions. [ABSTRACT FROM PUBLISHER]

In patients with heart failure, sacubitril/valsartan therapy was associated with a decrease in NT-proBNP and improved echocardiographic parameters, which suggests a potential effect on cardiac reverse remodeling.1,2 Despite optimization of medical management, a significant proportion of heart failure patients progress to an advanced stage of the disease and require implantation of a left ventricular assist device (LVAD). CASE SERIES We analyzed clinical, echocardiographic, and laboratory data in six LVAD patients receiving sacubitril/valsartan therapy. Sacubitril/valsartan therapy was introduced instead of ACE inhibitors at 1 year after LVAD implantation; patients were followed for 6 months. [Extracted from the article]

Introduction: Previous studies have demonstrated that cell therapy may improve diastolic parameters in heart failure. Hypothesis: We sought to investigate the effects of transendocardial CD34+ cell therapy in patients with heart failure with preserved ejection fraction (HFpEF). Methods: In a pilot study we enrolled 14 patients with HFpEF (LVEF>50%, E/e'>15, NYHA III, NTproBNP levels >300 pg/ml). All patients received granulocyte-colony stimulating factor (G-CSF; 10 mcg/kg, 5 days); CD34+ cells were collected by apheresis. We performed electroanatomical mapping of the left ventricle and assessed local diastolic function by measuring local ventricular relaxation times at each of the sampling points. CD34+ cells were then injected transendocardially in the areas of diastolic dysfunction. Each patient received a dose of 80 million CD34+ cells divided into 20 injections. Results: Our study cohort included 9 male and 5 female patients aged 57±9 years, with LVEF of 56.9±6.6%, creatinine of 85±28 μmol/L, and bilirubin of 12.7±4.7 μmol/L. In all patients, electroanatomical mapping consisting of at least 150 sampling points was performed without any adverse events enabling us to adequately measure local diastolic function and identify target areas for cell delivery. At 1 year after cell delivery we found a significant improvement in left ventricular filling pressures as measured by E/e' (from 17.2±6.8 to 12.7±6.1, P=0.03), a decrease in NTproBNP (from 1137±792 pg/ml to 843±710 pg/ml, P=0.03), and a trend of improvement in global systolic strain (from -11.2±1.6% to -12.9±3.7%, P=0.16). Notably, we found a significant improvement of local systolic strain in myocardial segments that were targeted with stem cell injections (-3.4±4.2%, P=0.001). Conclusions: In patients with HFpEF, transendocardial CD34+ cell transplantation is feasible and safe, and appears to be associated with improved diastolic function and decrease in NTproBNP at 1 year after therapy. [ABSTRACT FROM AUTHOR]

Introduction: End-diastolic volume (EDV) between 200 and 370 mL has been associated with favorable clinical response to cell therapy in ischemic heart failure. Hypothesis: We sought to investigate the effects of EDV, a marker of disease severity, on the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). Methods: Five-year registry data from 134 consecutive patients with DCM (LVEF<40%, NHYA III) who underwent CD34+ cell transplantation was analyzed. All patients received granulocyte-colony stimulating factor (G-CSF; 10 mcg/kg, 5 days); CD34+ cells were collected by apheresis and delivered by transendocardial injection in areas of electromechanical missmatch. Patients with baseline EDV<200 mL were included in Group A (N=72), patients with EDV 200-370 mL were included in Group B (N=54); patients with EDV>370 mL were excluded (N=7). Favorable clinical response was defined by improved LVEF≥5% at 1 year post-cell therapy. Results: At baseline, Groups A and B did not differ in age (52±11 years in Group A vs. 53±10 years in Group B, P=0.95), sex (male: 79% vs. 83%, P=0.55), creatinine (1.07±0.28 mg/dL vs. 1.03±0.21 mg/dL, P=0.21), bilirubin (0.98±0.55 mg/dL vs. 1.00±0.51 mg/dL, P=0.58), or NTproBNP levels (1454±1658 pg/mL vs. 1589±1338 pg/mL, P=0.80). Baseline LVEF was higher in Group A (32.8±8.7%) than in Group B (30.2±8.7%, P=0.03). During follow-up, there were 4 deaths in Group A (6%), and 2 in Group B (4%, P=0.63); heart transplantation was performed in 4 patients from Group A (6%) and in 5 patients in Group B (9%, P=0.42). Favorable clinical response was found in 31/72 patients (43%) in Group A vs. 35/54 (65%) in Group B (P=0.016). Furthermore, EDV significantly decreased at 1 year in Group B (-56±30 mL, P=0.003), but not in Group A (+12±97 mL, P=0.13). On multivariate analysis, baseline EDV was an independent correlate of 1-year clinical outcome (P=0.02). Conclusions: EDV predicted clinical outcome following transendocardial CD34+ cell therapy in a nonischemic DCM patient population, informing target individuals with the highest likelihood of regenerative response. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim of the Review. The aim of this review is to discuss recent advances in clinical aspects of stem cell therapy in chronic nonischemic heart failure (DCMP) with emphasis on patient selection, stem cell types, and delivery methods. Recent Findings. Several stem cell types have been considered for the treatment of DCMP patients. Bone marrow-derived cells and CD34+ cells have been demonstrated to improve myocardial performance, functional capacity, and neurohumoral activation. Furthermore, allogeneic mesenchymal stem cells were also shown to be effective in improving heart function in this patient population; this may represent an important step towards the development of a standardized stem cell product for widespread clinical use in patients with DCMP. Summary. The trials of stem cell therapy in DCMP patients have shown some promising results, thus making DCMP apparently more inviting target for stem cell therapy than chronic ischemic heart failure, where studies to date failed to demonstrate a consistent effect of stem cells on myocardial performance. Future stem cell strategies should aim for more personalized therapeutic approach by establishing the optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient’s age and stage of the disease. [ABSTRACT FROM AUTHOR]

Introduction: Noncompaction cardiomyopathy (NCC) is a congenital heart disease characterized by an arrest of the myocardial compaction process. Although NCC patients have impaired formation of microvasculature, the functional impact of these changes remains undefined. Hypothesis: We sought to analyze a potential correlation between myocardial ischemia and heart failure progression in patients with NCC. Methods: We enrolled 20 (12 male, 8 female) patients with NCC, diagnosed by cardiac MRI. The average age was 46±15.3 years. Echocardiography was performed to determine left ventricular end diastolic diameter and volume (EDD and EDV), ejection fraction (LVEF), with global longitudinal strain (GLS) postprocessing. At patient inclusion we also measured serum levels of NT-proBNP. Myocardial SPECT was performed at rest and on stress, determining summed difference score (SDS). Significant myocardial ischemia was defined as SDS≥2. Results: Of 20 patients enrolled, 9 patients (45%) had evidence of myocardial ischemia (Group A), 11 patients (55%) showed no significant ischemic changes (Group B). The two groups did not differ in sex (male 67% in Group A vs. 55% in Group B, P=0.58), age (45±14,6 years vs. 46±14,6 years, P=0.92), creatinine (79±14 μmol/L vs. 74±12 μmol/L, P=0.48) or bilirubin (12±7 μmol/L vs. 11±3 μmol/L, P=0.51). When compared to Group B, Group A had significantly higher EDD (6.3±0.9 cm vs. 5.3±0.6 cm, P=0.018), lower NTproBNP levels (1950±2004 pg/mL vs. 294±429 pg/mL in Group B, P=0.02) and a tendency toward lower LVEF (36.6±16.7% vs. 51.8±16.8% in Group B, P=0.06), higher EDV (179.2±53.9 mL vs. 138.7±47.4 mL, P=0.09), and lower GLS (-11.4±7% vs. -15.4±4%, P=0.12). Overall, higher SDS was associated with lower LVEF (r=-0.46, P=0.04), higher EDV (r=0.53, P=0.02), higher levels of NT-proBNP (r=0,82, P<0.001), and a tendency toward lower GLS (r=0.40, P=0.06). Conclusions: In patients with NCC, the presence of myocardial ischemia is associated with worse left ventricular function, dilation of left ventricle and more pronounced neurohumoral activation. Further studies are needed to investigate whether treatment approaches targeting myocardial ischemia, such as CD34+ cell therapy, may halt the progression of disease in this patient cohort. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Although there is evidence of beneficial effects of CD34+ therapy in non-ischemic dilated cardiomyopathy (DCM), the individual patient response is highly variable. Hypothesis: We investigated the value of biomarkers of angiogenesis and endothelial dysfunction in predicting clinical response to transendocardial CD34+ cell transplantation in DCM patients. Methods: We enrolled 34 DCM patients (NYHA class III, LVEF<40%) in whom CD34+ cells were mobilized by G-CSF and collected via apheresis. Electromechanical mapping was performed to define areas of myocardial scar (unipolar voltage <8.3mV and local linear shortening <6%) and hibernation (unipolar voltage ≥8.3mV and local linear shortening <6%) and CD34+ cells were injected transendocardially in the hibernating areas. Patients were followed for 6 months and responders were defined as patients with LVEF increase of >5%. At the time of CD34+ cell transplantation we performed analysis of 27 biomarkers of angiogenesis and endothelial dysfunction. Results: Of 34 patients, 25 (74%) responded to CD34+ cell therapy (responders), and 9 (26%) were classified as non-responders. The groups did not differ in age (55±12 years in responders vs. 59±9 years in non-responders, P=0.43), gender (male: 88% vs. 78%, P=0.36) and baseline LVEF (31±9% vs. 33±7%, P=0.69). When compared to non-responders, responders had lower levels of NT-proBNP (1159±1043 ng/L in responders vs. 2667±2252 ng/L in non-responders, P=0.005), endocan (0.46±0.18 ng/mL vs. 0.62±0.21 ng/mL, P=0.04), thrombospondin-2 (13±5 ng/mL vs. 22±13 ng/mL, P=0.008), activin A (209±51 pg/mL vs. 299±62 pg/mL, P=0.002) and neuropilin-1 (175±35 ng/mL vs. 225±62 ng/mL, P=0.006). Interestingly, we found a significant correlation between these biomarkers and scar burden on electromechanical mapping (endocan: P=0.025, thrombospondin-2: P=0.01, activin A: P=0.015, neuropilin-1: P=0.018). Conclusion: Higher levels of endocan, thrombospondin-2, activin A and neuropilin-1 correlate with poor clinical response and higher scar burden in DCM patients undergoing transendocardial CD34+ cell transplantation. Thus, these biomarkers could represent a non-invasive tool for predicting response to CD34+ cell therapy. [ABSTRACT FROM AUTHOR]

Background: Data from preclinial models suggest that cell therapy may be associated with antiarrythmic effects due to improved cell-to-cell coupling. Hypothesis: We sought to investigate potential anti-arrhythmogenic effects of transendocardial CD34+ cell therapy in patients with chronic heart failure (CHF). Metods: We performed registry data analysis of 48 patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34+ cell therapy. Patients demonstrating ventricular arrhythmias (VA) in 12 months prior to cell therapy were included in the analysis. All patients were followed for 12 months after cell therapy. Demographic, echocardiographic and biochemical parameters were analysed. All patients uderwent electroanatomical mapping and myocardial scar was defined as unipolar voltage (UV)<8.3mV and linear local shortening (LLS)<6%. Areas of slow conduction were defined as areas with fragmented QRS signal. QRS fragmentation was defined as a multicomponent QRS signal and the cut-off value for normal QRS fragmentation was ≤ 4 positive peak deflections. Results: Of 20 patients included, 6 (30%, Group A) did not experience VA and 14 (70%, Group B) continued to have VA in 12 months after cell therapy. The two groups did not differ in gender (male; 67% in Group A vs. 93% in Group B; P=0.14), age (57±10 years vs. 53±8 years; P=0.31), chronic kidney disease (17% vs. 21%; P=0.82), NT-proBNP levels (1375±958 pg/mL vs. 1679±1629 pg/mL; P=0.69), left ventricular ejection fraction (31±6% vs. 29±8%; P=0.55), LV end-diastolic volume (221±126 mL vs. 229±85 mL; P=0.89) and amiodarone therapy (16% vs. 14%; P=0.89). In Group A significantly higher percentage of cell injections was performed in areas of slow conduction when compared to Group B (47±11% vs. 29±16%; P=0.03). Additionally, in Group B, the number ob ICD activations after cell therapy was reduced (3.6±2.7 ICD activations before cell therapy vs. 2.1±2.0 ICD activations after cell therapy; P=0.14). Conclusions: Transendocardial CD34+ cell therapy may reduce the VA burden in CHF when applied to the areas of slow conduction of the left ventricle. Prospective data are needed to confirm the anti-arrhythmic potential of cell therapy in chronic heart failure patients. [ABSTRACT FROM AUTHOR]