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To investigate the association of left ventricular end-diastolic volume (LVEDV) and the response to cell therapy in patients with nonischemic dilated cardiomyopathy (NICM).

Noncompaction cardiomyopathy is a rare congenital heart disorder characterized by an arrest of the myocardial compaction process. This results in the altered formation of coronary microvessels with a resulting decrease in myocardial perfusion. Transendocardial CD34+cell transplantation has been shown to increase myocardial perfusion and function in patients with non-ischemic heart failure. In our first-in-man case study, we investigated the feasibility, safety and clinical effect of transendocardial CD34+cell therapy in a patient with noncompaction cardiomyopathy.

We investigated the effects of CD34+cell therapy on right ventricular (RV) function in patients with nonischemic dilated cardiomyopathy (DCM). We enrolled 60 patients with DCM who were randomized to CD34+cell therapy (Stem Cells (SC) Group n= 30), or no cell therapy (Controls, n= 30). The SC Group received granulocyte‐colony stimulating factor, and CD34+cells were collected by apheresis and injected transendocardially. Patients were followed for 6 months. At baseline, the groups did not differ in age, gender, left ventricular ejection fraction, N‐terminal probrain natriuretic peptide, or parameters of RV function. At 6 months, we found a significant improvement in RV function in the SC Group (tricuspid annular plane systolic excursion [TAPSE]: +0.44 ± 0.64 cm, p= .001; peak systolic tissue Doppler velocity of tricuspid annulus [St]: +1.5 ± 2.1 cm/s; p= .001; percent of fractional area change [FAC]: +8.6% ± 5%, p= .01), but not in Controls (TAPSE: −0.07 ± 0.32 cm, p= .40; St: −0.1 ± 1.2 cm/s; p= .44; FAC: −1.2% ± 3.2%, p= .50). On repeat electroanatomical mapping, we found an improvement in interventricular septum viability in 19 of 30 patients from the SC Group; this correlated with the improvements in RV function (13/19 in the improved septum group versus 3/11 in the remaining cohort, p= .029). These results suggest that patients with DCM, changes in RV function correlate with changes of viability of interventricular septum. CD34+cell therapy appears to be associated with improved right ventricular function in this patient cohort. (Clinical Trial Registration Information: www.clinicaltrials.gov; NCT02248532). StemCellsTranslationalMedicine2018;7:168–172 Changes of right ventricular function within the 6‐month follow‐up. We found a significant improvement in tricuspid annular plane systolic excursion in the Stem Cells Group (red line) but not in the Control Group (blue line).

Introduction:The underlying mechanisms of coronary allograft vasculopathy (CAV) after heart transplantation remain incompletely understood.Hypothesis:As CD34+cells represent one of the key determinants of coronary vascular homeostasis we investigated the potential association between CAV and CD34+cell count in heart transplant recipients.Methods:In a single-center prospective pilot cohort study we included 59 adult heart transplant recipients without history of congenital heart disease, multi-organ transplantation or oncologic therapy. All patients underwent coronary CT angiography and the presence of CAV was defined in accordance with the ISHT criteria. At the time of CT angiography, we collected blood samples and measured CD34+cell count using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol as well as biomarkers of angiogenesis using Luminex assay kit.Results:CAV was present in 15 patients (25%; Group A) and absent in 42 patients (75%; Group B). The two groups did not differ in age (62±11 years in Group A vs. 60±11 years in Group B, P=0.56), gender (male: 100% vs. 80% in Group B, P=0.07), heart failure etiology (ischemic: 53% vs. 43%, P=0.50), presence of hypertension (60% vs. 63%, P=0.80), diabetes (33% vs. 25%, P=0.54) or renal insufficiency (53% vs. 43%, P=0.50). Also, donor age (44±14 years in Group A vs. 43±12 years in Group B, P=0.66), allograft ischemic time (202±72 min vs. 190±68 min, P=0.57), tacrolimus trough levels (8.8±3.8 μg/L vs. 7.4±1.9 μg/L, P=0.14), MMF dose (2067±442 mg vs. 2178±606 mg; P=0.52) and statin therapy (86% vs. 75%; P=0.36) were comparable. While total leukocyte count was similar in both groups (7.7±2.1x109/L in Group A vs. 6.8±2.2x109/L in Group B, P=0.60), we found significantly lower CD34+cell count in Group A compared to Group B (1.33±0.45x106/L vs. 2.23±1.45x106/L, P=0.02). Conversely, VEGF serum levels were significantly lower in Group A than in Group B (0.09±0.06 ng/L vs. 0.14±0.09 ng/L; P=0.03).Conclusions:Decreased CD34+cell count and increased VEGF serum levels appear to be associated with CAV in heart transplant recipients. Further studies are warranted to investigate the potential of CD34+cells in prevention and treatment of CAV in this patient cohort.

Introduction:In patients with noncompaction cardiomyopathy (NCC) no heart failure (HF) therapy has been shown to improve the left ventricle ejection fraction (LVEF). Sudden cardiac death (SCD) or need for heart transplantation (HTx) or left ventricle assist device (LVAD) implantation have been described. The effect of novel HF therapy, such as angiotensin receptor and neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2i) remains unclear.Hypothesis:We sought to analyze a potential recovery of cardiac function in patients with NCC after introducing the novel HF therapy.Methods:We have prospectively enrolled 41 (33 male, 8 female) patients with NCC, confirmed by cardiac MRI from 2018 to 2021. The average age was 49±16.3 years. At inclusion, echocardiography was performed to determine the left ventricle end-diastolic diameter and volume (EDD and EDV) and LVEF; serum levels of NT-proBNP have also been obtained. ARNI and SGLT2i have been introduced into patients’ therapy and up titrated to maximal tolerated dose. After 1 year follow up investigations, performed at patients' inclusion, have been repeated.Results:Of 41 patients enrolled 23 patients (56%) had echocardiographic evidence of myocardial recovery (Group A), defined by improvement of LVEF above 40% (LVEF increased from 31±6.6% to 48±5.2%. 9 patients (22%) showed no significant LVEF improvement (Group B, LVEF increased from 26±8.0% to 33±2.6%). 9 patients were excluded (2 due to SCD, 7 had HTx or LVAD implantation performed). The two groups did not differ in sex (male 41% vs. 39% in Group B, P=0.51), age (51±17.2 years vs. 46±15.2 years, P=0.72), sodium (140±2.6mEq/L vs. 138±1.8mEq/mL, P=0.22), creatinine (82±24μmol/L vs. 87±18 μmol/L, P=0.51) or bilirubin levels (17±12μmol/L vs. 21±12μmol/L, P=0.42). When compared to Group B at inclusion, Group A had significantly higher LVEF (31,6±6,6% vs. 26,5±8,0% in Group B, P=0.033) and lower NTproBNP levels (1619±1505pg/mL vs. 4902±3795pg/mL, P<0.001).Conclusions:In patients with NCC, the introduction of novel HF therapy seems to be connected with significant reverse remodelation of the myocardium. The improvement has been shown to be more pronounced in NCC patients with better LVEF and lower neurohormonal activation.

Introduction.Although impaired global diastolic function is a key determinant of heart failure with preserved ejection fraction (HFpEF), the impact of local diastolic dysfunction is less clear.Hypothesis.We analyzed the distribution and myocardial viability correlates of local diastolic dysfunction in patients with HFpEF.Methods.We enrolled 30 patients with HFpEF (NYHA class III, LVEF >50%, E/e' >15, and NT-proBNP >300 pg/ml) who were referred to our center for cell transplantation. Before transplantation, all patients underwent electroanatomical mapping; viable myocardium was defined as unipolar voltage (UV) ≥8.27 mV and non-viable myocardium was defined as UV <8.27 mV. Local diastolic function was assessed by a novel algorithm based on the measurement of local mechanical diastolic delay (LMD). At each sampling point, LMD was measured as timing difference between global end diastolic time (based on left ventricular volume) and maximum local diastolic time (based on local wall movement of the mapping point).Results.Most of the patients were male (77%), with a mean age of 62±10 years, creatinine of 1.05±0.40 mg/dl, E/e’ of 18.0±3.5, and LVEF of 57.6±6.1%. Using electroanatomical mapping we generated a total of 4820 mapping points in 30 patients. The mean local mechanical diastolic delay was 47±33 msec, and the coefficient of variation was 0.70. The distribution of local mechanical diastolic delay in points with preserved myocardial viability and decreased myocardial viability is presented in Figure 1. We found a significant inverse correlation between UV and LMD (r= -0.18, P=0.001).Conclusions.In patients with HFpEF, areas of local diastolic dysfunction are unevenly distributed and appear so correlate with areas of decreased myocardial viability.Figure 1.Distribution of LMD in areas of decreased and preserved myocardial viability.

Introduction:The underlying mechanisms of regional myocardial dysfunction in patients with heart failure with preserved ejection fraction (HFpEF) remain poorly defined.Hypothesis:We investigated physiological correlates of regional diastolic dysfunction in HFpEF using a novel technique based on point-by-point measurement of local diastolic delay.Methods:We enrolled 30 patients with HFpEF (LVEF >50%, E/e' >15, NT-proBNP >300 pg/ml). In all patients we performed electroanatomical mapping of the left ventricle and assessed regional diastolic function by a novel algorithm based on the measurement of local diastolic delay. Local diastolic delay was considered significant if the time delay between global left ventricular end diastolic time and local diastolic time was >50 msec. At the time of mapping, we performed clinical evaluation, echocardiography and measured plasma levels of 27 biomarkers of angiogenesis and endothelial dysfunction.Results:Our cohort included 23 male and 7 female patients, aged 46-70 years. Using electroanatomical mapping we measured regional diastolic function in 4820 mapping points. The mean local diastolic delay was >50 msec in 12 patients (Group A), and <50 msec in 18 patients (Group B). The groups did not differ in age (64±11 years in Group A vs. 51±8 years in Group B, P=0.22), gender, (male: 83% vs. 73%, P=0.48), creatinine (1.08±0.31 mg/dL vs. 1.10±0.30 mg/dL, P=0.52), LVEF (56±4% vs. 58±7%, P=0.42), or NT-proBNP levels (1570±1310 pg/mL vs. 1230±1240 pg/mL, P=0.22). However, in Group A, we found higher values of E/e’ (18.2±3.4 vs. 17.0±2.8 in Group B, P=0.04), and lower myocardial viability (unipolar voltage: 7.73±1.8 mV vs. 9.03±2.1 mV, P=0.02). When compared to Group B, patients in Group A displayed lower levels of pro-angiogenic biomarkers (vascular endothelial growth factor: 33±22 pg/mL vs. 47±24 pg/mL, P=0.01; platelet-derived growth factor: 47±23 pg/mL vs. 78±34 pg/mL, P=0.02), and higher levels of anti-angiogenic biomarkers (agiopoietin-2: 7.0±3.8 ng/mL vs. 2.7±1.0 ng/mL, P=0.01; endostatin: 87±33 ng/mL vs. 65±21 ng/mL, P=0.02).Conclusion:In patients with HFpEF, regional diastolic dysfunction appears to be associated with increased E/e’, decreased myocardial viability, and impaired angiogenesis.

Introduction:The results of cell therapy in chronic heart failure (CHF) patients have been inconsistent, possibly also due to poorly defined patient selection criteria.Hypothesis:To better define good responders to cell therapy we sought to evaluate the predictors of long-term outcome of transendocardial CD34+cell therapy in CHF patient population.Methods:Pooled data from 108 patients included in a single center registry were analyzed for baseline clinical, laboratory and echocardiographic parameters. All patients received granulocyte-colony stimulating factor for 5 days; CD34+cells were collected by apheresis and injected transendocardially guided by electroanatomical mapping. Target sites for cell injections were defined as areas with unipolar voltage >8.3 mV and linear local shortening <6%. Patients were followed for 5 years after the procedure.Results:Of 108 patients 93 (87%) were alive (Group A) and 15 (13%) were dead (Group B) at 5 years. 12 (80%) patients died due to pump failure and 3 (20%) due to sudden cardiac death. At baseline the two groups did not differ in age (52?10 years in Group A vs. 57?8 years in Group B, P=0.12), gender (male: 80% vs. 100%, P=0.07), CHF etiology (ischemic: 43% vs. 40%, P=0.85), liver dysfunction (34% vs. 37%, P=0.12), glucose (6.1?1.8 mmol/L vs. 5.8?1.2 mmol/L, P=0.53), hemoglobin (14.5?1 mg/dl vs. 14.1?1.3 mg/dL, P=0.37) or the presence of ICD therapy (40% vs. 27%, P=0.31). However, we found significant differences in baseline left ventricular ejection fraction (LVEF: 29?7% in Group A vs. 24?6% in Group B, P<0.05), left ventricular end-diastolic diameter (LVEDD: 6.6?0.7 cm vs. 7.1?0.7 cm, P<0.05), renal dysfunction (24% vs. 53%, P<0.05) and red cell distribution width (RDW: 14.1?1.2% vs. 15.1?1.4%, P<0.05). On multivariate analysis LVEF >30% and RDW less than 14.2% were identified as the independent predictors of favorable 5-year outcome after CD34+ cell therapy.Conclusions:Transendocardial CD34+cell therapy appears to be associated with favorable long-term outcome in patients with CHF. The beneficial effects may be particularly pronounced in patients with less severe left ventricular systolic dysfunction and lower degree of CHF-related bone marrow suppression.

Introduction:Although angiotensin receptor-neprilysin inhibitors (ARNI) have been shown to improve survival of patients with heart failure with reduced ejection fraction (HFrEF), data on the effects of ARNIs on echocardiographic parameters in this patient cohort are lacking.Hypothesis:We sought to evaluate the effects of ARNI on echocardiographic parameters in a broad HFrEF patient population.Methods:We analysed prospectively collected clinical, biochemical and echocardiographic data of 228 HFrEF patients treated with ARNI at our center between 2016 and 2019. The data were obtained at ARNI introduction (baseline) and at 12 month follow-up. Favorable response to ARNI therapy was defined as an increase in left ventricular ejection fraction (LVEF) ?5% at 12 month follow-up. Renal dysfunction was defined as estimated glomerular filtration rate <90mL/min/1.73m2.Results:Of 228 patients 190 (83%) were male with the average age of 57?11 years. Ishemic and non-ischemic heart failure were present in 83 (36%) and 145 (64%) of patients, respectively; 51 (22%) had renal dysfunction, 52 (23%) diabetes and 122 (53%) had history of arterial hypertension. At 12 month follow-up we found a significant improvement in LVEF (29.7?8% at baseline vs. 36.5?9% at follow-up; p<0.05), LVOT VTI (14.8?4.2 cm vs. 17.2?4.2 cm; p<0.05), TAPSE (1.8?0.5 cm vs. 2.1?0.6 cm; p<0.05) and LV EDD (6.5?0.8 cm vs. 6.3?0.9 cm; p<0.05). Additionally, NT-proBNP serum levels decreased significantly on ARNI therapy (2494?3108 pg/mL vs. 1787?8291 pg/mL; p<0.05). When comparing responders (N=126, 55%) to nonresponders (N=102; 45%), we found significant differences in age (55?10 years in responders vs. 59?11 years in nonresponders; p<0.05), heart failure etiology (ishemic: 28% vs. 47%; p<0.05), baseline LVEF (27?8% vs. 33?7%; p<0.05) and baseline NT-proBNP (2065?2090 pg/mL vs. 2911?3796 pg/mL; p<0.05). On multivariable analysis, nonischemic heart failure and LVEF <30% emerged as independent predictors of favorable response to ARNI therapy.Conclusion:ARNIs appear to significantly improve echocardiographic parameters of left and right ventricular function in HFrEF patients. These effects may be particulary prononuced in patients with nonischemic heart failure and LVEF <30%.

Introduction:The underlying mechanisms of right ventricular (RV) dysfunction in non-ischemic dilated cardiomyopathy (NICM) remain poorly defined.Hypothesis:We investigated a correlation between alterations in angiogenesis and RV function in patients with NICM.Methods:We enrolled 40 NICM patients with NYHA class III and LVEF<40%. All patients received granulocyte-colony stimulating factor for 5 days; CD34+cells were collected by apheresis and injected transendocardially. At baseline and 6 months after cell therapy we measured plasma biomarkers of angiogenesis and assessed RV function by measuring tricuspid annular plane systolic excursion (TAPSE), peak systolic velocity of tricuspid annulus (St), and fractional area change (FAC) using echocardiography. RV dysfunction was defined as TAPSE<17 mm, St< 9.5 cm/s and FAC< 35%. Improved RV function was defined as concomitant improvements in TAPSE, St and FAC.Results:At baseline, RV dysfunction was present in 25/40 patients (Group A), and 15/40 patients had preserved RV function (Group B). The groups did not differ in age (55?10 years in Group A vs. 57?6 years in Group B, P=0.72), gender (male: 84% vs. 78%, P=0.75), creatinine (0.94?0.33 mg/dL vs. 0.95?0.30 mg/dL, P=0.55), LVEF (32?8% vs. 31?7%, P=0.40), or NTproBNP levels (1870?1505 pg/mL vs. 1520?1225 pg/mL, P=0.72). When compared to Group B, patients in Group A displayed lower levels of pro-angiogenic biomarkers: vascular endothelial growth factor (VEGF): 30?20 pg/mL vs. 54?25 pg/mL, P=0.01; platelet-derived growth factor (PDGF): 53?23 pg/mL vs. 82?23 pg/mL, P=0.01, and higher levels of anti-angiogenic biomarkers: agiopoietin-2: 6.4?4.2 ng/mL vs. 2.3?0.7 ng/mL, P=0.01, endostatin: 86?29 ng/mL vs. 63?29 ng/mL, P=0.03. At 6 months, RV function improved in 26/40 patients. In this cohort, we found an increase in pro-angiogenic biomarkers (VEGF: +14?4 pg/mL, P=0.03; PDGF: +22?5 pg/mL, P=0.01), and a decrease of anti-angiogenic markers (angiopoietin-2: -3.1?1.0 ng/mL, P=0.01; endostatin: -26?9 ng/mL, P=0.02).Conclusion:In patients with NICM, RV dysfunction may be associated with impaired angiogenesis. In these patients, improvement of RV function after CD34+cell therapy appears to correlate with improved angiogenetic response.