NPY and cardiac diseases

Hypertension-induced left ventricular hypertrophy (LVH), along with ischemic heart disease, result in LV remodeling as part of a continuum that often leads to congestive heart failure. The neurohormonal model has been used to underpin many treatment strategies, but optimal outcomes have not been achieved. Neuropeptide Y (NPY) has emerged as an additional therapeutic target, ever since it was recognised as an important mediator released from sympathetic nerves in the heart, affecting coronary artery constriction and myocardial contraction. More recent interest has focused on the mitogenic and hypertrophic effects that are observed in endothelial and vascular smooth muscle cells, and cardiac myocytes. Of the six identified NPY receptor subtypes, Y-1, Y-2, and Y-5 appear to mediate the main functional responses in the heart. Plasma levels of NPY become elevated due to the increased sympathetic activation present in stress-related cardiac conditions. Also, NPY and Y receptor polymorphisms have been identified that may predispose individuals to increased risk of hypertension and cardiac complications. This review examines what understanding exists regarding the likely contribution of NPY to cardiac pathology. It appears that NPY may play a part in compensatory or detrimental remodeling of myocardial tissue subsequent to hemodynamic overload or myocardial infarction, and in angiogenic processes to regenerate myocardium after ischemic injury. However, greater mechanistic information is required in order to truly assess the potential for treatment of cardiac diseases using NPY-based drugs.

eNOS overexpression exacerbates vascular closure in the obliterative phase of OIR and increases angiogenic drive in the subsequent proliferative stage

Purpose: In ischemic retinopathies, the misdirection of reparative angiogenesis away from the hypoxic retina leads to pathologic neovascularization. Thus, therapeutic strategies that reverse this trend would be extremely beneficial. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important mediator of vascular endothelial growth factor (VEGF) function facilitating vascular growth and maturation. However, in addition to NO, eNOS can also produce superoxide (O), exacerbating pathology. Here, our aim was to investigate the effect of eNOS overexpression on vascular closure and subsequent recovery of the ischemic retina.

Methods: Mice overexpressing eNOS-GFP were subjected to oxygen-induced retinopathy (OIR) and changes in retinal vascularization quantified. Background angiogenic drive was assessed during vascular development and in aortic rings. NOS activity was measured by Griess assay or conversion of radiolabeled arginine to citrulline, nitrotyrosine (NT), and superoxide by immunolabeling and dihydroethidium fluorescence and VEGF by ELISA.

Results: In response to hyperoxia, enhanced eNOS expression led to increased NOS-derived superoxide and dysfunctional NO production, NT accumulation, and exacerbated vessel closure associated with tetrahydrobiopterin (BH) insufficiency. Despite worse vaso-obliteration, eNOS overexpression resulted in elevated hypoxia-induced angiogenic drive, independent of VEGF production. This correlated with increased vascular branching similar to that observed in isolated aortas and during development. Enhanced recovery was also associated with neovascular tuft formation, which showed defective NO production and increased eNOS-derived superoxide and NT levels.

Conclusions: In hyperoxia, reduced BH bioavailability causes overexpressed eNOS to become dysfunctional, exacerbating vaso-obliteration. In the proliferative phase, however, eNOS has important prorepair functions enhancing angiogenic growth potential and recovery in ischemia. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Job strain as a risk factor for coronary heart disease:a collaborative meta-analysis of individual participant data

BACKGROUND: Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. METHODS: We used individual records from 13 European cohort studies (1985-2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. FINDINGS: 30?214 (15%) of 197?473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10-1·37). This effect estimate was higher in published (1·43, 1·15-1·77) than unpublished (1·16, 1·02-1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15-1·48) and 5 years (1·30, 1·13-1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. INTERPRETATION: Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. FUNDING: Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.

Pre-hospital body surface potential mapping improves early diagnosis of acute coronary artery occlusion in patients with ventricular fibrillation and cardiac arrest

Aims: To determine whether 80-lead body surface potential mapping (BSPM) improves detection of acute coronary artery occlusion in patients presenting with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) and who survived to reach hospital. Methods and results: Of 645 consecutive patients with OHCA who were attended by the mobile coronary care unit, VF was the initial rhythm in 168 patients. Eighty patients survived initial resuscitation, 59 of these having had BSPM and 12-lead ECG post-return of spontaneous circulation (ROSC) and in 35 patients (age 69±13 yrs; 60% male) coronary angiography performed within 24. h post-ROSC. Of these, 26 (74%) patients had an acutely occluded coronary artery (TIMI flow grade [TFG] 0/1) at angiography. Twelve-lead ECG criteria showed ST-segment elevation (STE) myocardial infarction (STEMI) using Minnesota 9-2 criteria - sensitivity 19%, specificity 100%; ST-segment depression (STD) =0.05. mV in =2 contiguous leads - sensitivity 23%, specificity 89%; and, combination of STEMI or STD criteria - sensitivity 46%, specificity 100%. BSPM STE occurred in 23 (66%) patients. For the diagnosis of TFG 0/1 in a main coronary artery, BSPM STE had sensitivity 88% and specificity 100% (c-statistic 0.94), with STE occurring most commonly in either the posterior, right ventricular or high right anterior territories. Conclusion: Among OHCA patients presenting with VF and who survived resuscitation to reach hospital, post-resuscitation BSPM STE identifies acute coronary occlusion with sensitivity 88% and specificity 100% (c-statistic 0.94). © 2012 Elsevier Ireland Ltd.

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):a randomised placebo-controlled trial

Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.

Na+/H+ exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

Administration of Na(+)/H(+) exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia-reperfusion injury. However, controversy still exists as to the efficacy of NHE-1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from ischemia-reperfusion injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion and to study the mechanism of action of cariporide. In our studies, we observed that intravenous administration of cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control, when these muscle flaps were subjected to 4 h of ischemia and 48 h of reperfusion (P <0.05; n = 5 pigs/group). Both preischemic and postischemic cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial-free Ca(2+) content and a significant increase in muscle ATP content within 2 h of reperfusion (P <0.05; n = 4 pigs/group). Preischemic and postischemic cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2 h of reperfusion after 4 h of ischemia, compared with the control (P <0.05; n = 3 pigs/group). These observations support our hypothesis that cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion, and the mechanism involves attenuation of neutrophil accumulation and mitochondrial-free Ca(2+) overload and preservation of ATP synthesis in the early stage of reperfusion.

Assessment of the impedance cardiogram recorded by an automated external defibrillator during clinical cardiac arrest

OBJECTIVE: To assess the impedance cardiogram recorded by an automated external defibrillator during cardiac arrest to facilitate emergency care by lay persons. Lay persons are poor at emergency pulse checks (sensitivity 84%, specificity 36%); guidelines recommend they should not be performed. The impedance cardiogram (dZ/dt) is used to indicate stroke volume. Can an impedance cardiogram algorithm in a defibrillator determine rapidly circulatory arrest and facilitate prompt initiation of external cardiac massage?

DESIGN: Clinical study.

SETTING: University hospital.

PATIENTS: Phase 1 patients attended for myocardial perfusion imaging. Phase 2 patients were recruited during cardiac arrest. This group included nonarrest controls.

INTERVENTIONS: The impedance cardiogram was recorded through defibrillator/electrocardiographic pads oriented in the standard cardiac arrest position.

MEASUREMENTS AND MAIN RESULTS: Phase 1: Stroke volumes from gated myocardial perfusion imaging scans were correlated with parameters from the impedance cardiogram system (dZ/dt(max) and the peak amplitude of the Fast Fourier Transform of dZ/dt between 1.5 Hz and 4.5 Hz). Multivariate analysis was performed to fit stroke volumes from gated myocardial perfusion imaging scans with linear and quadratic terms for dZ/dt(max) and the Fast Fourier Transform to identify significant parameters for incorporation into a cardiac arrest diagnostic algorithm. The square of the peak amplitude of the Fast Fourier Transform of dZ/dt was the best predictor of reduction in stroke volumes from gated myocardial perfusion imaging scans (range = 33-85 mL; p = .016). Having established that the two pad impedance cardiogram system could detect differences in stroke volumes from gated myocardial perfusion imaging scans, we assessed its performance in diagnosing cardiac arrest. Phase 2: The impedance cardiogram was recorded in 132 "cardiac arrest" patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with sensitivities and specificities (+/- exact 95% confidence intervals) of 89.1% (85.4-92.1) and 99.6% (99.4-99.7; training) and 81.1% (77.6-84.3) and 97% (96.7-97.4; validation).

CONCLUSIONS: The impedance cardiogram algorithm is a significant marker of circulatory collapse. Automated defibrillators with an integrated impedance cardiogram could improve emergency care by lay persons, enabling rapid and appropriate initiation of external cardiac massage.

Conformational Change of Mitochondrial Complex I Increases ROS Sensitivity During Ischemia

Aims: Myocardial ischemia/reperfusion (I/R) is associated with mitochondrial dysfunction and subsequent cardiomyocyte death. The generation of excessive quantities of reactive oxygen species (ROS) and resultant damage to mitochondrial enzymes is considered an important mechanism underlying reperfusion injury. Mitochondrial complex I can exist in two interconvertible states: active (A) and deactive or dormant (D). We have studied the active/deactive (A/D) equilibrium in several tissues under ischemic conditions in vivo and investigated the sensitivity of both forms of the heart enzyme to ROS.

Results: We found that in the heart, t½ of complex I deactivation during ischemia was 10?min, and that reperfusion resulted in the return of A/D equilibrium to its initial level. The rate of superoxide generation by complex I was higher in ischemic samples where content of the D-form was higher. Only the D-form was susceptible to inhibition by H2O2 or superoxide, whereas turnover-dependent activation of the enzyme resulted in formation of the A-form, which was much less sensitive to ROS. The mitochondrial-encoded subunit ND3, most likely responsible for the sensitivity of the D-form to ROS, was identified by redox difference gel electrophoresis.

Innovation: A combined in vivo and biochemical approach suggests that sensitivity of the mitochondrial system to ROS during myocardial I/R can be significantly affected by the conformational state of complex I, which may therefore represent a new therapeutic target in this setting.

Conclusion: The presented data suggest that transition of complex I into the D-form in the absence of oxygen may represent a key event in promoting cardiac injury during I/R.

Glutathione peroxidase 1 genotype is associated with an increased risk of coronary artery disease

Objective Oxidative stress is implicated in the pathogenesis of many human diseases including atherosclerosis. Human glutathione peroxidase 1 (hgpx1) participates in limiting cellular damage caused by oxidation. A characteristic polyalanine sequence polymorphism in exon 1 of hgpx1 produces three alleles with five, six or seven alanine (ALA) repeats in this sequence. The objective of this study was to determine whether hgpx1 genotype is associated with an altered risk of coronary artery disease (CAD).

Methods The frequency of the ALA6 allele was determined in 207 men with angiographic evidence of significant CAD compared to a control group (n = 146), by analysing the lengths of polymerase chain reaction fragments containing the ALA repeat polymorphism. Additional information was collected on severity of CAD, presence or absence of a prior acute myocardial infarction (AMI), smoking status, body mass index (BMI) and other clinical data.

Results There was a significant association between individuals with at least one ALA6 allele and an increased risk of CAD after adjustment for age, BMI and smoking status (odds ratio, 2.07, 95% confidence interval, 1.08-3.99, P = 0.029). However, there was no association between hgpx1 genotype and a previous history of AMI or hgpx1 genotype and severity of CAD.

Conclusion We conclude that individuals possessing one or two ALA6 alleles appear to be at a modest increased risk of CAD. This observation merits further investigation in other patient populations.

Estimation of contribution of changes in classic risk factors to trends in coronary-event rates across the WHO MONICA Project populations

Background. From the mid-1980s to mid-1990s, the WHO MONICA Project monitored coronary events and classic risk factors for coronary heart disease (CHD) in 38 populations from 21 countries. We assessed the extent to which changes in these risk factors explain the variation in the trends in coronary-event rates, across the populations. Methods. In men and women aged 35-64 years, non-fatal myocardial infarction and coronary deaths were registered continuously to assess trends in rates of coronary events. We carried out population surveys to estimate trends in risk factors. Trends in event rates were regressed on trends in risk score and in individual risk factors. Findings. Smoking rates decreased in most male populations but trends were mixed in women; mean blood pressures and cholesterol concentrations decreased, body-mass index increased, and overall risk scores and coronary-event rates decreased. The model of trends in 10-year coronary-event rates against risk scores and single risk factors showed a poor fit, but this was improved with a 4-year time lag for coronary events. The explanatory power of the analyses was limited by imprecision of the estimates and homogeneity of trends in the study populations. Interpretation. Changes in the classic risk factors seem to partly explain the variation in population trends in CHD. Residual variance is attributable to difficulties in measurement and analysis, including time lag, and to factors that were not included, such as medical interventions. The results support prevention policies based on the classic risk factors but suggest potential for prevention beyond these.

Limbal stem cells of the corneal epithelium

Stem cells have certain unique characteristics, which include longevity, high capacity of self-renewal with a long cell cycle time and a short S-phase duration, increased potential for error-free proliferation, and poor differentiation. The ocular surface is made up of two distinct types of epithelial cells, constituting the conjunctival and the corneal epithelia. Although anatomically continuous with each other at the corneoscleral limbus, the two cell phenotypes represent quite distinct subpopulations. Stem cells for the cornea reside at the corneoscleral limbus. The limbal palisades of Vogt and the interpalisade rete ridges are believed to be repositories of stem cells. The microenvironment of the limbus is considered to be important in maintaining the stemness of stem cells. Limbal stem cells also act as a 'barrier' to conjunctival epithelial cells and normally prevent them from migrating on to the corneal surface. Under certain conditions, however, the limbal stem cells may be partially or totally depleted, resulting in varying degrees of stem cell deficiency with resulting abnormalities in the corneal surface. Such deficiency of limbal stem cells leads to 'conjunctivalization' of the cornea with vascularization, appearance of goblet cells, and an irregular and unstable epithelium. This results in ocular discomfort and reduced vision. Partial stem cell deficiency can be managed by removing the abnormal epithelium and allowing the denuded cornea, especially the visual axis, to resurface with cells derived from the remaining intact limbal epithelium. In total stem cell deficiency, autologous limbus from the opposite normal eye or homologous limbus from living related or cadaveric donors can be transplanted on to the affected eye. With the latter option, systemic immunosuppression is required. Amniotic membrane transplantation is a useful adjunct to the above procedures in some instances. Copyright (C) 2000 Elsevier Science Inc.

Corneal toxicity and inflammation secondary to retained perfluorodecalin

PURPOSE: To describe a case with bullous keratopathy and anterior segment inflammation associated with heavy liquids. DESIGN: Observational case report. METHODS: Review of clinical and histopathologic changes. RESULTS: A 65-year-old patient underwent a pars plana vitrectomy for a rhegmatogenous retinal detachment. Perfluorodecalin was used as a temporary retinal tamponade. After surgery, bubbles of heavy liquid were noted in the anterior chamber. Fifteen months later, severe corneal edema developed, associated with corneal vascularization and keratic precipitates. Removal of heavy liquid through a paracentesis was attempted but the cornea remained edematous, and a penetrating keratoplasty was performed. In the histopathologic examination inflammatory changes from retention of perfluorodecalin were observed. There was a decompensated cornea with florid bullous keratopathy, inflammatory infiltration with vascularization, and deposition of perfluorodecalin within keratocytes and perivascular macrophages. CONCLUSION: Presence of heavy liquids in the anterior chamber may be associated with an intense inflammatory response and corneal decompensation. © 2005 by Elsevier Inc. All rights reserved.

Strategies for multivessel revascularization in patients with diabetes

In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease.

The effect of socioeconomic deprivation on corneal graft survival in the United Kingdom

Objective: To investigate the effect of socioeconomic deprivation on cornea graft survival in the United Kingdom.

Design: Retrospective cohort study.

Participants: All the recipients (n = 13?644) undergoing their first penetrating keratoplasty (PK) registered on the United Kingdom Transplant Registry between April 1999 and March 2011 were included.

Methods: Data of patients' demographic details, indications, graft size, corneal vascularization, surgical complication, rejection episodes, and postoperative medication were collected at the time of surgery and 1, 2, and 5 years postoperatively. Patients with endophthalmitis were excluded from the study. Patients' home postcodes were used to determine the socioeconomic status using a well-validated deprivation index in the United Kingdom: A Classification of Residential Neighborhoods (ACORN). Kaplan–Meier survival and Cox proportional hazards regression were used to evaluate the influence of ACORN categories on 5-year graft survival, and the Bonferroni method was used to adjust for multiple comparisons.

Main Outcome Measures: Patients' socioeconomic deprivation status and corneal graft failure.

Results: A total of 13?644 patients received their first PK during the study periods. A total of 1685 patients (13.36%) were lost to follow-up, leaving 11?821 patients (86.64%) for analysis. A total of 138 of the 11?821 patients (1.17%) developed endophthalmitis. The risk of graft failure within 5 years for the patients classified as hard-pressed was 1.3 times that of the least deprived (hazard ratio, 1.3; 95% confidence interval, 1.1–1.5; P = 0.003) after adjusting for confounding factors and indications. There were no statistically significant differences between the causes of graft failure and the level of deprivation (P = 0.14).

Conclusions: Patients classified as hard-pressed had an increased risk of graft failure within 5 years compared with the least deprived patients.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

Disordered vascular compliance in haemochromatosis

Background: A relationship may exist between body iron stores, endothelial dysfunction and overall cardiovascular risk.

Aims: To compare vascular compliance, biochemical endothelial function and antioxidant status between patients with homozygous hereditary haemochromatosis and healthy controls.

Methods: Haemochromatosis patients and healthy controls were recruited. Measures of vascular compliance were assessed by applanation tonometry. Serological markers of endothelial function (plasma lipid hydroperoxides, cell adhesion molecules), antioxidant levels (ascorbate, lipid soluble antioxidants) and high-sensitivity C-reactive protein (CRP) were also measured.

Results: Thirty-five hereditary haemochromatosis patients (ten females, mean age 54.6) and 36 controls (27 female, mean age 54.0) were recruited. Haemochromatosis patients had significantly higher systolic and diastolic blood pressures. Pulse wave velocity (PWV) was significantly higher in male haemochromatosis patients (9.90 vs. 8.65 m/s, p = 0.048). Following adjustment for age and blood pressure, male haemochromatosis patients continued to have a trend for higher PWVs (+1.37 m/s, p = 0.058). Haemochromatosis patients had significantly lower levels of ascorbate (46.11 vs. 72.68 lmol/L, p = 0.011), retinol (1.17 vs. 1.81 lmol/L, p = 0.001) and g-tocopherol (2.51 vs. 3.14 lmol/L, p = 0.011). However, there was no difference in lipid hydroperoxides (0.46 vs. 0.47 nmol/L, p = 0.94), cell adhesion molecule levels (ICAM: 348.12 vs. 308.03 ng/mL, p = 0.32 and VCAM: 472.78 vs. 461.31 ng/mL, p = 0.79) or high-sensitivity CRP (225.01 vs. 207.13 mg/L, p = 0.32).

Conclusions: Haemochromatosis is associated with higher PWVs in males and diminished antioxidants across the sexes but no evidence of endothelial dysfunction or increased lipid peroxidation.