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.

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.

Correlation Between Mitochondrial DNA Content Measured in Myocardium and Peripheral Blood of Patients with Non-Ischemic Heart Failure.

BACKGROUND/OBJECTIVES: Heart failure (HF) is associated with disturbances in mitochondrial energy production. This mitochondrial dysfunction is reflected by depletion of mitochondrial DNA (mtDNA) in different tissues. Our aims were to determine if there was a correlation between mtDNA content measured in myocardial tissue and the easily accessible peripheral blood cells of patients with non-ischemic HF; and to determine if there was a correlation between myocardial mtDNA and left ventricular (LV) ejection fraction. METHODS: We prospectively collected paired myocardial tissue and peripheral blood samples from 13 consecutive end-stage non-ischemic HF patients undergoing cardiac transplantation. mtDNA content was assessed with real-time quantitative PCR by calculating the relative ratio of two specific mitochondrial sequences and one nuclear control gene sequence. RESULTS: HF patients with lower myocardial mtDNA content had a significantly lower LV ejection fraction (r = 0.65, p = 0.016). Peripheral blood mtDNA content correlated positively with right ventricular myocardial mtDNA content (r = 0.63, p = 0.021). We also observed that averaged myocardial DNA content tended to correlate with peripheral blood mtDNA content (r = 0.53, p = 0.061). CONCLUSIONS: In non-ischemic HF patients, myocardial mtDNA content is positively correlated with peripheral blood mtDNA content and LV function as assessed by echocardiography.

Relation of B-type natriuretic peptide level in heart failure to sudden cardiac death in patients with and without QT interval prolongation.

Increased levels of B-type natriuretic peptide (BNP) are associated with prolongation of the action potential in ventricular myocardium. We investigated the relation of a BNP increase, QT interval, and sudden cardiac death (SCD) in the presence of heart failure (HF). We enrolled 398 patients with HF, New York Heart Association class III or IV, and left ventricular ejection fraction <40%. At baseline and after 3 months, we measured BNP and the QT interval. A BNP increase was defined as a change in BNP of ≥+10%. The QTc interval was calculated using the Bazett formula. QTc interval prolongation was defined as a change in QTc of ≥+10%. The patients were followed up for 1 year. During a 3-month period, BNP increased significantly in 53% of the patients (group 1) and did not in 47% (group 2). During the same period, the QTc interval was more prolonged in group 1 (+44 ± 12 ms) than in group 2 (+7 ± 6 ms; p = 0.01). During 1 year of follow-up, 20 patients died suddenly (SCD), 16 from pump failure. Although the SCD rates did not differ between the 2 groups (5.7% in group 1 vs 4.2% in group 2, p = 0.53), they were significantly greater in the patients in group 1 with QTc interval prolongation ≥+10% (13.8%, p <0.001). The Kaplan-Meier-derived SCD-free survival rates were 2.9 times greater in patients without QTc interval prolongation than in those with prolonged QTc (p <0.001). QTc interval prolongation was an independent correlate of SCD (p = 0.006), but BNP increase was not (p = 0.32). In conclusion, a BNP increase in patients with HF was associated with an increased risk of SCD only in patients with QTc interval prolongation.

Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure.

BACKGROUND: In retrospective studies, statin therapy has been related to decreased incidence of sudden cardiac death (SCD) in heart failure. We sought to prospectively investigate a relation between atorvastatin therapy and SCD in patients with advanced chronic heart failure. METHODS AND RESULTS: We enrolled 110 patients with heart failure with a left ventricular ejection fraction less than 30% and cholesterol level greater than 150 mg/dL. Fifty-five patients were randomized to atorvastatin (10 mg/day) (statin group); the remaining 55 patients received no statins (controls). Patients were followed for 1 year. At baseline, the two groups did not differ in age, sex, left ventricular ejection fraction, cholesterol, B-type natriuretic peptide, heart rate variability, or QT variability. During follow-up, 29 patients died (26%) and 2 patients (2%) underwent heart transplantation. Of the 29 deaths, 13 were attributed to pump failure, 15 were attributed to SCD, and 1 was attributed to noncardiac causes. All-cause mortality was lower in the statin group (9/55, 16%) than in controls (20/55, 36%) (P = .017). The same was true of the SCD rate (3/55 [5%] vs. 12/55 [22%], P = .012), but not of the pump failure (5/55 [9%] vs. 8/55 [15%], P = .38). SCD-free survival was 2.3-times higher in the statin group than in controls (P = .01). CONCLUSIONS: Atorvastatin therapy seems to be associated with decreased incidence of SCD in patients with advanced chronic heart failure. Larger studies are ongoing to confirm this hypothesis.

Metabolic acidosis in prometryn (triazine herbicide) self-poisoning.

INTRODUCTION: Prometryn is a triazine herbicide, which is one of the most extensively used groups of herbicides. The mechanism of acute triazine herbicide toxicity in humans is not known. We report a first case of acute prometryn poisoning. CASE REPORT: A 62-year-old male ingested 50 g of prometryn and ethanol in a suicide attempt. On arrival two hours after ingestion, he was somnolent and vomited. Seven hours after ingestion laboratory tests showed metabolic acidosis with a calculated anion gap of 47.5 mmol/L and lactate of 23.4 mmol/L. Gas chromatography/mass spectrometry revealed serum prometryn concentrations of 48.1 mg/L. Hemodialysis corrected metabolic acidosis, but the serum prometryn concentration increased to 67.7 mg/L. The lactate level after hemodialysis was 11.7 mmol/L and returned within normal limits 47 hours after ingestion. The patient was discharged without any sequelae after psychiatric evaluation. CONCLUSION: In high anion gap metabolic acidosis we should consider poisoning with prometryn and other triazine herbicides. Hemodialysis corrects metabolic derangements, but it does not lower serum prometryn concentration.

Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTc interval duration in patients with advanced chronic heart failure.

BACKGROUND: Although statins decrease the incidence of ventricular arrhythmias in patients with atherosclerotic heart disease, their potential antiarrhythmic effects in heart failure remain undefined. METHODS AND RESULTS: Of 80 heart failure patients enrolled, 40 were randomized to receive atorvastatin (statin group); the remaining 40 served as controls. At baseline and after 3 months, we measured heart rate variability (HRV), QT variability (QTV), and QTc interval using interactive high-resolution electrocardiogram analysis. The 2 groups did not differ in baseline HRV standard deviation of normal-to-normal intervals (SDNN) (RR): 24.6 +/- 2.8 ms in statin group versus 24.8 +/- 3.1 ms in controls, P = .72; square root of the mean of squared differences between successive intervals (rMSSD) (RR): 21.2 +/- 2.7 ms versus 21.7 +/- 2.9 ms, P = .43), QTV SDNN (QT): 6.4 +/- 1.5 ms versus 6.4+/-1.7, P = .96; rMSSD QT): 9.0 +/- 2.4 ms versus 8.7 +/- 2.9 ms, P = .65, and QTc interval 450 +/- 30 ms versus 446 +/- 27 ms, P = .59. At 3 months, the statin group displayed higher HRV SDNN RR): 27.2 +/- 4.9 ms versus 24.4 +/- 2.8 ms in controls, P = .003; rMSSD RR: 24.7 +/- 4.2 ms versus 21.3 +/- 5.6 ms, P = .004, lower QTV SDNN (QT): 5.1 +/- 1.9 ms versus 6.5 +/- 2.1, P = .004; rMSSD (QT): 6.6 +/- 2.8 ms versus 8.8 +/- 3.1 ms, P = .002, and shorter QTc interval 437 +/- 29 ms versus 450 +/- 25 ms, P = .03 than the control group. CONCLUSIONS: Atorvastatin increases HRV, decreases QTV, and shortens QTc interval, and may thereby reduce the risk of arrhythmias in patients with advanced heart failure.