Circulating endothelial cells as biomarker for cardiovascular diseases.

Background: Endothelial dysfunction is involved in several cardiovascular diseases. Elevated levels of circulating endothelial cells (CECs) and low levels of endothelial progenitor cells (EPCs) have been described in different cardiovascular conditions, suggesting their potential use as diagnostic biomarkers for endothelial dysfunction. Compared to typical peripheral blood leukocyte subsets, CECs and EPCs occur at very low frequency. The reliable identification and characterization of CECs and EPCs is a prerequisite for their clinical use, however, a validated method to this purpose is still missing but a key for rare cell events. Objectives: To establish a validated flow cytometric procedure in order to quantify CECs and EPCs in human whole blood. Methods: In the establishment phase, the assay sensitivity, robustness, and the sample storage conditions were optimized as prerequisite for clinical use. In a second phase, CECs and EPCs were analyzed in heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction, in arterial hypertension (aHT), and in diabetic nephropathy (DN) in comparison to age-matched healthy controls. Results: The quantification procedure for CECs and EPCs showed high sensitivity and reproducibility. CEC values resulted significantly increased in patients with DN and HFpEF in comparison to healthy controls. CEC quantification showed a diagnostic sensitivity of 90% and a sensitivity of 68.0%, 70.4%, and 66.7% for DN, HFpEF, and aHT, respectively. Conclusion: A robust and precise assay to quantify CECs and EPCs in pre-clinical and clinical studies has been established. CEC counts resulted to be a good diagnostic biomarker for DN and HFpEF

Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction

Background Comorbidities negatively affect prognosis more strongly in heart failure with preserved (HFpEF) than with reduced (HFrEF) ejection fraction. Their comparative impact on physical impairment in HFpEF and HFrEF has not been evaluated so far. Methods and results The frequency of 12 comorbidities and their impact on NYHA class and SF-36 physical functioning score (SF-36 PF) were evaluated in 1,294 patients with HFpEF and 2,785 with HFrEF. HFpEF patients had lower NYHA class (2.0 ± 0.6 vs. 2.4 ± 0.6, p 0.05) negative effect in both groups. Obesity, coronary artery disease and peripheral arterial occlusive disease exerted a significantly (p < 0.05) more adverse effect in HFpEF, while hypertension and hyperlipidemia were associated with fewer (p < 0.05) symptoms in HFrEF only. The total impact of comorbidities on NYHA (AUC for prediction of NYHA III/IV vs. I/II) and SF-36 PF (r 2) in multivariate analyses was approximately 1.5-fold higher in HFpEF, and also much stronger than the impact of a 10% decrease in ejection fraction in HFrEF or a 5 mm decrease in left ventricular end-diastolic diameter in HFpEF. Conclusion The impact of comorbidities on physical impairment is higher in HFpEF than in HFrEF. This should be considered in the differential diagnosis and in the treatment of patients with HFpEF

Glucose-induced hemodynamic and metabolic response of skeletal muscle in heart failure patients with reduced vs. preserved ejection fraction-a pilot study

(1) BACKGROUND: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) METHODS: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) RESULTS: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both (p) &lt; 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls ((p) &lt; 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL ((p) = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL ((p) = 0.0016); (4) CONCLUSION: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF

Angiotensin-Neprilysin inhibition in heart failure with preserved ejection fraction

Background: the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. Methods: we randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. Results: there were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. Conclusions: sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.)

Impaired Thymic Export and Apoptosis Contribute to Regulatory T-Cell Defects in Patients with Chronic Heart Failure

Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p<0.01), CD4(+)CD25(+)FOXP3(+)CD45RO(-) CD45RA(+)CD31(+) recent thymic emigrant T(reg) cell (RTE-T(reg)) frequency (p<0.01), and T-cell receptor excision circle levels in T(reg) cells (p<0.01) were lower in CHF patients than in non-CHF controls. Combined annexin-V and 7-AAD staining showed that peripheral T(reg) cells from CHF patients exhibited increased spontaneous apoptosis and were more prone to interleukin (IL)-2 deprivation- and CD95 ligand-mediated apoptosis than those from non-CHF individuals. Furthermore, analyses by both flow cytometry and real-time polymerase chain reaction showed that T(reg)-cell frequency in the mediastinal lymph nodes or Foxp3 expression in hearts of CHF patients was no higher than that of the non-CHF controls.Our data suggested that the T(reg)-cell defects of CHF patients were likely caused by decreased thymic output of nascent T(reg) cells and increased susceptibility to apoptosis in the periphery

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT‐CHF

No abstract available

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Investigation of Different Pre-Treated Multi-Walled Carbon Nanotubes by Raman Spectroscopy

Raman spectroscopy is a common method of studying carbon-based materials such as multi-walled carbon nanotubes (MWCNT). However, the analysis of this technique is non-trivial since recorded spectra may be a convolution of both molecular vibrations and phonon resonances. The energies of these physical processes may occur in the same energy regime, and hence several analytical approaches can be necessary for a full analysis. Due to the negligible quantities of non-graphitic carbon in MWCNT, the present fitting procedure focuses on understanding phonon resonances to elucidate how varying modifications of MWCNT ultimately influence their graphitic bulk structure. We have found this approach to provide greater insight into the structure of MWCNT when low quantities of amorphous carbon are present, when compared with methods which try to interpret both phonon scattering and molecular vibrations simultaneously. Different pre-treatments for the modification of the graphitic structure of MWCNT are compared, including aqueous acidic and gas phase methods, and statistically evaluated. Focusing on phonon resonances enables one to analyze the reaction process of nitrosulfuric acid pre-treatment at different temperatures. Thereby, it is possible to control the ratio between defects and graphitic structures in MWCNT samples and prepare samples with reproducible D/G ratios

Atomically dispersed vanadium oxides on multiwalled carbon nanotubes via atomic layer deposition: A multiparameter optimization

The focus of the present work is to investigate the bonding characteristics of vanadium oxide species to different oxygen functional groups on multiwalled carbon nanotubes (MWCNT). Atomic layer deposition (ALD) was used to deposit atomically dispersed vanadium oxide species on MWCNT. To generate atomically dispersed vanadium, only one ALD cycle was applied for the deposition of vanadium. The MWCNT functional groups that are involved in the deposition process were identified by thermal analysis and grafting experiments. A variety of ALD process parameters were tested, and revealed that purging times between dosing of vanadium precursor and dosing of water as coreactant had a strong influence on the ratio of vanadium species that are physisorbed or chemisorbed to the MWCNT. The ALD process parameters were optimized to focus on the immobilization of the vanadium due to a chemical bond between vanadium species and MWCNT. Because of the direct correlation between catalytic stability and immobility of the vanadium species, the importance of knowledge about the influence of the ALD parameter onto the bond formation is essential. Raman spectroscopy and high resolution scanning transmission electron microscopy images were used to prove the single site structure of the vanadium oxide