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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.

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: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.

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%.