Intravenous (−)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function

Background

Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (−)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated.

Methods and results

Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1 h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca^2 + load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation.

Conclusions

IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.     

Extracellular pyrophosphate is reduced in aortic interstitial valve cells acquiring a calcifying profile: Implications for aortic valve calcification

Objectives: Pyrophosphate (PPi) is a potent inhibitor of ectopic mineralization but its role during aortic valve calcification is not known. Methods: Anti-calcific effect of PPi was investigated by using an in vitro model of serum-driven calcification of collagen sponges and decellularized porcine aortic valve leaflets. Bovine interstitial valve cells (VIC), seeded either within the collagen matrices or in transwell chambers, were used to test cellular ability to inhibit serum-induced calcification. PPi metabolism was investigated in clonal VIC harboring different calcifying potential. Results: In a cell-free system, high serum levels induced a dose-dependent calcification of type I collagen matrices which was prevented by PPi and ATP supplementation. Blockade of serum-driven calcification by PPi and ATP was also observed when using decellularized porcine aortic valve leaflets. A similar anti-calcific effect was also seen for bovine VIC, either statically seeded into the collagen matrices or co-cultured by using a transwell system. However, when we performed co-culture experiments by using clonal VIC harboring different calcifying potential, we observed that the subset of cells acquiring a pro-calcific profile lost the ability to protect the collagen from serum-driven calcification. Pro-calcific differentiation of the clonal VIC was accompanied by increase in ALP along with significant reduction in NPP activity and ATP/PPi extracellular accumulation. These changes were not observed in the clonal subtype with lower propensity towards calcification. Conclusions: We showed that PPi and ATP are potent inhibitors of serum-driven calcification of collagen matrix and that their extracellular accumulation is reduced in calcifying VIC.     

Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170–199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute‐funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ⁰‐thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7–9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention‐to‐treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0–35%) in the hydroxyurea arm and 47% (95% CI = 6–81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (?15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. Am. J. Hematol. 90:1099–1105, 2015. © 2015 Wiley Periodicals, Inc.     

Cloak and Dagger: Alternative Immune Evasion and Modulation Strategies of Poxviruses

As all viruses rely on cellular factors throughout their replication cycle, to be successful they must evolve strategies to evade and/or manipulate the defence mechanisms employed by the host cell. In addition to their expression of a wide array of host modulatory factors, several recent studies have suggested that poxviruses may have evolved unique mechanisms to shunt or evade host detection. These potential mechanisms include mimicry of apoptotic bodies by mature virions (MVs), the use of viral sub-structures termed lateral bodies for the packaging and delivery of host modulators, and the formation of a second, “cloaked” form of infectious extracellular virus (EVs). Here we discuss these various strategies and how they may facilitate poxvirus immune evasion. Finally we propose a model for the exploitation of the cellular exosome pathway for the formation of EVs.     

Psychiatric disorders in chronic daily headache: detection by means of the SCID interview

The identification of possible individual or/and environmental factors responsible for the chronic evolution of headache has represented a critical issue in recent years. The goal of this research was to enroll adult chronic daily headache (CDH) sufferers and to seek for psychiatric disorders, as possible transformation factor, by means of a complex neuropsychological investigation. The psychiatric evaluation was performed using the Structured Clinical Interview (SCID), according to the DSM-IV diagnostic criteria. The overall prevalence of psychiatric disorders according to DSM-IV criteria was 66.1%. No statistical difference was found in psychiatric comorbidity according to gender (women, 68.9% men, 52,4%). The prevalence of psychiatric disorders was 69.7% in drug abusers (classified in accordance with clinical interview) and 57.1% in non-abusers (the difference was not statistically significant). Comparing the three subtypes of CDH, a psychiatric disorder was found in 50% of chronic tension-type headache patients, in 72.2% of those with chronic coexisting migraine and tension-type headache(CT vs. CCMT-TH, p<0.01) and in 70.3% of patients with chronic migraine.     

Do-not-resuscitate orders in patients hospitalized with acute myocardial infarction: the Worcester Heart Attack Study

BACKGROUND: Coronary heart disease is the leading cause of death in Americans. Despite increased interest in end-of-life care, data regarding the use of do-not-resuscitate (DNR) orders in acutely ill cardiac patients remain extremely limited. The objectives of this study were to describe use of DNR orders, treatment approaches, and hospital outcomes in patients with acute myocardial infarction. METHODS: The study sample consisted of 4621 residents hospitalized with acute myocardial infarction at all metropolitan Worcester, Mass, area hospitals in five 1-year periods from 1991 to 1999. RESULTS: Significant increases in the use of DNR orders were observed during the study decade (from 16% in 1991 to 25% in 1999). The elderly, women, and patients with previous diabetes mellitus or stroke were more likely to have DNR orders. Patients with DNR orders were significantly less likely to be treated with effective cardiac medications, even if the DNR order occurred late in the hospital stay. Less than 1% of patients were noted to have DNR orders before hospital admission. Patients with DNR orders were significantly more likely to die during hospitalization than patients without DNR orders (44% vs 5%). CONCLUSIONS: The results of this community-wide study suggest increased use of DNR orders in patients hospitalized with acute myocardial infarction during the past decade. Use of certain cardiac therapies and hospital outcomes are different between patients with and without DNR orders. Further efforts are needed to characterize the use of DNR orders in patients with acute coronary disease.     

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation provides a better definition of cardiovascular burden associated with CKD than the Modification of Diet in Renal Disease (MDRD) Study formula in subjects with type 2 diabetes

Differences in 24 h blood pressure (BP) monitoring parameters such as average 24 h BP, day to night BP ratio and BP variability could have an impact in arterial stiffness. The study hypothesis was that despite similar average BP values in ambulatory blood pressure monitoring subjects with increased 24 h BP variability may have increased arterial stiffness. The study population consisted of 115 consecutive young healthy volunteers. Carotid-femoral PWV was measured in all subjects. Clinic BP was measured and an appropriate cuff was fitted on the non-dominant arm of each subject for a 24 h ambulatory blood pressure monitoring session. Waist to hip ratio as well as BMI was measured. Family history and smoking habits were recorded. In univariate analysis, estimated carotid-femoral PWV showed a significant correlation with age, weight, waist circumference, height, clinic systolic and diastolic BP, 24-h systolic and diastolic BP, 24-h pulse pressure, 24-h systolic and diastolic BP variability, daytime systolic and diastolic BP, daytime pulse pressure, daytime systolic and diastolic BP variability, nighttime systolic BP, nighttime pulse pressure and nighttime systolic BP variability. In multivariate regression analysis, age (B=0.95, P<0.001) and 24 h systolic BP variability (B=0.28, P<0.001) were independent determinanats of arterial stiffness. In conclusions, increased 24 h systolic BP variability is associated with arterial stiffness in young healthy volunteers. Pulse wave velocity in a young healthy population is useful to identify determinants of premature arterial stiffness, thus further elucidating the aspects of early vascular ageing.     

Prospective Diary Evaluation of Unexplained Abdominal Pain and Bowel Dysfunction: A Population-Based Colonoscopy Study

Introduction  

Diagnostic criteria for irritable bowel syndrome (IBS) have not been validated by prospective symptom diary. We investigated the bowel patterns in community subjects with and without non-organic abdominal pain, and compared the symptoms with subjects fulfilling the Rome II criteria (IBS).     

A European survey on the detection and management of iron overload in transfusion-dependent patients with MDS

To better understand the detection and management of iron overload in transfusion-dependent patients with myelodysplastic syndromes (MDS), a 15-min web- or paper-based survey was conducted among 338 European physicians from 27 countries. Respondents had a mean of 18 years of clinical experience. Forty-six percent and 27% of physicians noted that detecting and treating iron overload were either “very important” or “important,” respectively. The main reason for not actively exploring iron overload was related to poor patient prognosis, while the main reasons for not initiating iron chelation therapy were poor patient prognosis and older patient age. Thirty-seven percent and 31% of physicians believed that treating iron overload in these patients was “very important” or “important,” respectively. Ninety percent of physicians prescribed iron chelation therapy, and 38% of transfusion-dependent patients received iron chelation therapy. The key reasons for not initiating iron chelation therapy were related to poor patient prognosis (72%), patient age ≥85 years (50%), and comorbidities (34%). The views of these experienced MDS physicians reflect available international MDS treatment guidelines.