Triple therapy at discharge from internal medicine wards in heart failure patients with reduced ejection fraction: results from an observational study.

BACKGROUND: Guidelines recommend triple therapy (TT) with ACE inhibitors or ARBs, beta-blockers and mineralcorticoid receptor antagonists in symptomatic heart failure patients with ejection fraction <35 % (HFrEF). Nevertheless, many patients remain untreated. This study was aimed to evaluate the use of TT in HFrEF patients discharged from internal medicine wards of Tuscany, Italy. METHODS AND RESULTS: We analyzed the database of a multicenter observational study which included 770 patients consecutively hospitalized for HF in 32out of 36 Internal Medicine Units of Tuscany, Italy. The value of ejection fraction was available in 490 of the 725 patients discharged alive. Of the 117 patients with HFrEF, only 46 (39.3%) were on TT at discharge while 71 (60.7%) were not. In the latter group we observed a significantly greater percentage of patients with cognitive deficit (25.3% vs 10.8%, p=0.05). In the same group there was a slightly greater percentage of patients with hypertension (61.9% vs 58.6%), diabetes (43.6% vs 36.9%), GFR<60 ml/min (74.6% vs 67.3%), anemia (52.1% vs 45.6%) and atrial fibrillation (40.8% vs 34.7%), but the differences were not statistically significant. CONSLUSIONS: These results indicate that TT is underutilized in internal medicine wards of Tuscany. Untreated patients had a greater rate of cognitive deficit and were probably sicker, more complex and fragile.

Nanoprecipitated catestatin released from pharmacologically active microcarriers (PAMs) exerts pro-survival effects on MSC.

Catestatin (CST), a fragment of Chromogranin-A, exerts angiogenic, arteriogenic, vasculogenic and cardioprotective effects. CST is a very promising agent for revascularization purposes, in "NOOPTION" patients. However, peptides have a very short half-life after administration and must be conveniently protected. Fibronectin-coated pharmacologically active microcarriers (FN-PAM), are biodegradable and biocompatible polymeric microspheres that can convey mesenchymal stem cell (MSCs) and therapeutic proteins delivered in a prolonged manner. In this study, we first evaluated whether a small peptide such as CST could be nanoprecipitated and incorporated within FN-PAMs. Subsequently, whether CST may be released in a prolonged manner by functionalized FN-PAMs (FN-PAM-CST). Finally, we assessed the effect of CST released by FN-PAM-CST on the survival of MSCs under stress conditions of hypoxia-reoxygenation. An experimental design, modifying three key parameters (ionic strength, mixing and centrifugation time) of protein nanoprecipitation, was used to define the optimum condition for CST. An optimal nanoprecipitation yield of 76% was obtained allowing encapsulation of solid CST within FN-PAM-CST, which released CST in a prolonged manner. In vitro, MSCs adhered to FN-PAMs, and the controlled release of CST from FN-PAM-CST greatly limited hypoxic MSC-death and enhanced MSC-survival in post-hypoxic environment. These results suggest that FN-PAM-CST are promising tools for cell-therapy.

Diazoxide postconditioning induces mitochondrial protein S-nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE.

Postconditioning (PostC) can be obtained either with brief cycles of ischemia/reperfusion (I-PostC) or with a direct targeting of mitochondria with Diazoxide (pharmacological PostC, P-PostC). I-PostC may induce the activation of RISK and SAFE pathways and may favor nitric oxide production with S-Nitrosylation of proteins and redox signaling. It is not clear whether Diazoxide can lead to similar effects. We compared the effects of I-PostC and P-PostC on (a) kinases of RISK- and SAFE pathway, (b) S-Nitrosylation of mitochondrial proteins and (c) reduction of death signals (PKCδ, cleaved caspase-3 and Beclin-1) in cytosolic and mitochondrial fractions. Isolated rat hearts underwent (1) perfusion without ischemia (Sham), (2) ischemia/reperfusion (30-min ischemia plus 2-h reperfusion), (3) I-PostC (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia), (4) P-PostC (Diazoxide 30 µM in the first of 3-min of reperfusion) or (5) I-PostC + MPG or P-PostC + MPG (MPG, 2-mercaptopropionylglycine 300 µM). Using Western blot and biotin switch assay, we found that P-PostC induced a redox sensible phosphorylation/translocation of Akt, ERK1/2 and GSK3ß into the mitochondria, but not of phospho-STAT3, which was translocated into the mitochondria by I-PostC only. Either I-PostC or P-PostC increased mitochondrial S-Nitrosylated proteins (e.g., VDAC) and reduced the levels of phospho-PKCδ, cleaved caspase-3 and Beclin-1. Therefore, direct targeting of mitochondria with Diazoxide (a) activates the RISK pathway via a redox signaling, (b) favors discrete mitochondrial protein S-Nitrosylation, including VDAC and (c) decreases signals of death. Intriguingly, phospho-STAT3 translocation is induced by I-PostC, but not by P-PostC, thus suggesting a redox-independent mechanism in the SAFE pathway.

Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients. METHODS: According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited. RESULTS: SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P < 0.03). No significant differences (P > 0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P < 0.04). ABPI was not different among ACE gene genotypes. CONCLUSION: Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.

Combined dietary and exercise intervention for control of serum cholesterol in the workplace.

PURPOSE: To elucidate a potential combined dietary and exercise intervention affect on cardiovascular risk reduction of the National Aeronautics and Space Administration Headquarters employees. DESIGN: A nonexperimental, longitudinal, clinical-chart review study (1987 to 1996) of an identified intervention group and a reference (not a control) group. SETTING: The study group worked in an office environment and participated in the annual medical examinations. SUBJECTS: An intervention group of 858 people with initially elevated serum cholesterol, and a reference group of 963 people randomly sampled from 10% of the study group. MEASURES: Serum cholesterol data were obtained for both groups, respectively, from pre- and postintervention and annual examinations. The reference group was adjusted by statistical exclusion of potential intervention participants. Regression equations (cholesterol vs. study years) for the unadjusted/adjusted reference groups were tested for statistical significance. INTERVENTION: An 8-week individualized, combined dietary and exercise program was instituted with annual follow-ups and was repeated where warranted. RESULTS: Only the unadjusted (but not the adjusted) reference group with initial mean total serum cholesterol levels above 200 mg/dL shows a significant 9-year decline trend and significant beta coefficient tests. An intervention effect is suggested. Mean high density lipoprotein cholesterol rose slightly in the intervention group but was maintained in the reference group. CONCLUSION: With potential design limitations, the NASA intervention program focusing on a high risk group may be associated to some degree, if not fully, with an overall cardiovascular risk profile improvement.

Review of 5 years of a combined dietary and physical fitness intervention for control of serum cholesterol.

A chart review covering the first 5 years of clinical experience with a combined dietary and exercise intervention program for the reduction of hypercholesterolemia at the National Aeronautics and Space Administration headquarters demonstrated the program's success in maintaining high-density lipoprotein cholesterol (HDL-C) levels while significantly lowering total serum cholesterol levels. This combined program also resulted in improved ratios of total serum cholesterol to HDL-C and lowered levels of low-density lipoprotein cholesterol, thus further reducing the risk for cardiovascular disease. The National Aeronautics and Space Administration Cardiovascular Risk Reduction Program was developed after it was determined that although dietary intervention alone improved total cholesterol levels, it often resulted in a more than proportionate decrease in HDL-C and a worsening of the ratio of cholesterol to HDL-C. An approach was needed that would positively affect all factors of the lipid profile. The findings from the program indicate that reduction of cardiovascular risk can be accomplished easily and effectively at the worksite through dietary intervention, personal monitoring, and a reasonable exercise program.