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.

Edema agudo pulmonar associado à obstrução das vias aéreas. Relato de caso

BAKGROUND AND OBJECTIVES: Negative pressure pulmonary edema has been defined as non-cardiogenic edema, with transudation of fluid to the interstitial space of the lungs due to an increase in negative intrathoracic pressure secondary to obstruction of the upper airways. This is the case of a healthy patient who underwent general anesthesia and developed acute pulmonary edema after extubation. CASE REPORT: A 23-year old female patient, physical status ASA II, underwent gynecologic videolaparoscopy under general anesthesia. The procedure lasted 3 hours without intercurrence. After extubation the patient developed laryngeal spasm and reduction in oxygen saturation. The patient improved after placement of an oral cannula and administration of oxygen under positive pressure with a face mask. Once the patient was stable she was transferred to the recovery room where, shortly after her arrival, she developed acute pulmonary edema with elimination of bloody serous secretion. Treatment consisted of elevation of the head, administration of oxygen via a face mask, furosemide and fluid restriction. Chest X-ray was compatible with acute pulmonary edema and normal cardiac area. Electrocardiogram (ECG), echocardiogram and cardiac enzymes were normal. The condition of the patient improved and she was discharged from the hospital the following day, asymptomatic. CONCLUSIONS: Acute pulmonary edema associated with obstruction of the upper airways can aggravate surgical procedures with low morbidity, affecting mainly young patients. Early treatment should be instituted because it has a fast evolution and, in most cases, resolves without lasting damages. © Sociedade Brasileira de Anestesiologia, 2008.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

The angiotensin-converting enzyme insertion/deletion polymorphism and its associations with carotid artery wall thickness and coronary heart disease: The atherosclerosis risk in communities study

Coronary heart disease (CHD) is the leading cause of death in the United States. Recently, renin-angiotensin system (RAS) was found associated with atherosclerosis formation, with angiotensin II inducing vascular smooth muscle cell growth and migration, platelet activation and aggregation, and stimulation of plasminogen activator inhibitor-1. Angiotensin II is converted from angiotensin I by angiotensin I-converting enzyme (ACE) and this enzyme is mainly genetically determined. The ACE gene has been assigned to chromosome 17q23 and an insertion/deletion (I/D)polymorphism has been characterized by the presence/absence of a 287 bp fragment in intron 16 of the gene. The two alleles form three genotypes, namely, DD, ID and II and the DD genotype has been linked to higher plasma ACE levels and cell ACE activity.^ In this study, the association between the ACE I/D polymorphism and carotid artery wall thickness measured by B-mode ultrasound was investigated in a biracial sample, and the association between the gene and incident CHD was investigated in whites and if the gene-CHD association in whites, if any, was due to the gene effect on atherosclerosis. The study participants are from the prospective Atherosclerosis Risk in Communities (ARIC) Study, including adults aged 45 to 65 years. The present dissertation used a matched case-control design for studying the associations of the ACE gene with carotid artery atherosclerosis and an unmatched case-control design for the association of the gene with CHD. A significant recessive effect of the D allele on carotid artery thickness was found in blacks (OR = 3.06, 95% C.I: 1.11-8.47, DD vs. ID and II) adjusting for age, gender, cigarette smoking, LDL-cholesterol and diabetes. No similar associations were found in whites. The ACE I/D polymorphism is significantly associated with coronary heart disease in whites, and while stratifying data by carotid artery wall thickness, the significant associations were only observed in thin-walled subgroups. Assuming a recessive effect of the D allele, odds ratio was 2.84 (95% C.I:1.17-6.90, DD vs. ID and II) and it was 2.30 (95% C.I:1.22-4.35, DD vs. ID vs. II) assuming a codominant effect of the D allele. No significant associations were observed while comparing thick-walled CHD cases with thin-walled controls. Following conclusions could be drawn: (1) The ACE I/D polymorphism is unlikely to confer appreciable increase in the risk of carotid atherosclerosis in US whites, but may increases the risk of carotid atherosclerosis in blacks. (2) ACE I/D polymorphism is a genetic risk factor for incident CHD in US whites and this effect is separate from the chronic process of atherosclerosis development. Finally, the associations observed here are not causal, since the I/D polymorphism is in an intron, where no ACE proteins are encoded. ^

Enzyme activity, body measures and heart mass of Sepia officinalis sampled in the English Channel and Adriatic Sea

In the eurythermal cuttlefish Sepia officinalis, performance depends on hearts that ensure systemic oxygen supply over a broad range of temperatures. We therefore aimed to identify adjustments in energetic cardiac capacity and underlying mitochondrial function supporting thermal acclimation and adaptation that could be crucial for the cuttlefish's competitive success in variable environments. Two genetically distinct cuttlefish populations were acclimated to 11, 16 and 21°C. Subsequently, skinned and permeabilised heart fibres were used to assess mitochondrial functioning by means of high-resolution respirometry and a substrate-inhibitor protocol, followed by measurements of cardiac citrate synthase and cytosolic enzyme activities. Temperate English Channel cuttlefish had lower mitochondrial capacities but larger hearts than subtropical Adriatic cuttlefish. Warm acclimation to 21°C decreased mitochondrial complex I activity in Adriatic cuttlefish and increased complex IV activity in English Channel cuttlefish. However, compensation of mitochondrial capacities did not occur during cold acclimation to 11°C. In systemic hearts, the thermal sensitivity of mitochondrial substrate oxidation was high for proline and pyruvate but low for succinate. Oxygen efficiency of catabolism rose as temperature changed from 11 to 21°C via shifts to oxygen-conserving oxidation of proline and pyruvate and via reduced relative proton leak. The changes observed for substrate oxidation, mitochondrial complexes, relative proton leak and heart mass improve energetic efficiency and essentially seem to extend tolerance to high temperatures and reduce associated tissue hypoxia. We conclude that cuttlefish sustain cardiac performance and, thus, systemic oxygen delivery over short- and long-term changes of temperature and environmental conditions by multiple adjustments in cellular and mitochondrial energetics.

Methodological comparisons of heart rate variability analysis in patients with type 2 diabetes and angiotensin converting enzyme polymorphism

Angiotensin converting enzyme (ACE) polymorphism has been shown to be important in hypertension progression and also in diabetes complications, especially associated with heart disease. Heart rate variability (HRV) is an established measure for classification of autonomic function regulating heart rate, based on the interbeat interval time series derived from a raw ECG recording. Results of this paper show that the length (number of interbeat intervals) and preprocessing of the tachogram affect the HRV analysis outcome. The comparison was based on tachogram lengths of 250, 300, 350, and 400 RR-intervals and five preprocessing approaches. An automated adaptive preprocessing method for the heart rate biosignal and tachogram length of 400 interbeat intervals provided the best classification. HRV results differed for the Type 2 Diabetes Mellitus (T2DM) group between the I/I genotype and the I/D and D/D genotypes, whereas for controls there was no significant difference in HRV between genotypes. Selecting an appropriate length of recording and automated preprocessing has confirmed that there is an effect of ACE polymorphism including the I/I genotype and that I/I should not be combined with I/D genotype in determining the extent of autonomic modulation of the heart rate.

Caveat Anicula! Beware of the Quiet Little Old Ladies : Demographics, Pharmacotherapy, Survival and Readmissions in a 10 Year Cohort of Heart Failure Patients with Preserved Systolic Function

Objective--To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD). Design and setting--A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital.Main outcome measures-- Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival.Results--Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912). Conclusions--Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

Pre-Admission and Post-Hospital Management of Heart Failure in Patients not Enrolled in Specialist Programs

Aim: To review the management of heart failure in patients not enrolled in specialist multidisciplinary programs. Method: A prospective clinical audit of patients admitted to hospital with either a current or past diagnosis of heart failure and not enrolled in a specialist heart failure program or under the direct care of the cardiology unit. Results: 81 eligible patients were enrolled (1 August to 1 October 2008). The median age was 81 9.4 years and 48% were male. Most patients (63%) were in New York Heart Association Class II or Class III heart failure. On discharge, 59% of patients were prescribed angiotensin converting enzyme inhibitors and 43% were prescribed beta-blockers. During hospitalisation, 8.6% of patients with a past diagnosis of heart failure were started on an angiotensin converting enzyme inhibitor and 4.9% on a beta-blocker. There was evidence of suboptimal dosage on admission and discharge for angiotensin converting enzyme inhibitors (19% and 7.4%) and beta-blockers (29% and 17%). The results compared well with international reports regarding the under-treatment of heart failure. Conclusion: The demonstrated practice gap provides excellent opportunities for the involvement of pharmacists to improve the continuation of care for heart failure patients discharged from hospital in the areas of medication management review, dose titration and monitoring.

What We Have Here is a Failure to Communicate! Improving Communication between Tertiary to Primary Care for Chronic Heart Failure Patients

Background:  The aims of this study were to determine the documentation of pharmacotherapy optimization goals in the discharge letters of patients with the principal diagnosis of chronic heart failure. Methods:  A retrospective practice audit of 212 patients discharged to the care of their local general practitioner from general medical units of a large tertiary hospital. Details of recommendations regarding ongoing pharmacological and non-pharmacological management were reviewed. The doses of medications on discharge were noted and whether they met current guidelines recommending titration of angiotensin-converting enzyme inhibitors and beta-blockers. Ongoing arrangements for specialist follow up were also reviewed. Results:  The mean age of patients whose letters were reviewed was 78.4 years (standard deviation ± 8.6); 50% were men. Patients had an overall median of six comorbidities and eight regular medications on discharge. Mean length of stay for each admission was 6 days. Discharge letters were posted a median of 4 days after discharge, with 25% not posted at 10 days. No discharge letter was sent in 9.4% (20) of the cases. Only six (2.8%) letters had any recommendations regarding future titration of angiotensin-converting enzyme inhibitors and 6.6% (14) for beta-blockers. Recommendations for future non-pharmacological management, for example, diuretic action plans, regular weight monitoring and exercise plans were not found in the letters in this audit. Conclusion:  Hospital discharge is an opportunity to communicate management plans for treatment optimization effectively, and while this opportunity is spurned, implementation gaps in the management of cardiac failure will probably remain.

Rural and Urban Differentials in Primary Care Management of Chronic Heart Failure: New Data from the CASE Study

Objective: To determine whether primary care management of chronic heart failure (CHF) differed between rural and urban areas in Australia. Design: A cross-sectional survey stratified by Rural, Remote and Metropolitan Areas (RRMA) classification. The primary source of data was the Cardiac Awareness Survey and Evaluation (CASE) study. Setting: Secondary analysis of data obtained from 341 Australian general practitioners and 23 845 adults aged 60 years or more in 1998. Main outcome measures: CHF determined by criteria recommended by the World Health Organization, diagnostic practices, use of pharmacotherapy, and CHF-related hospital admissions in the 12 months before the study. Results: There was a significantly higher prevalence of CHF among general practice patients in large and small rural towns (16.1%) compared with capital city and metropolitan areas (12.4%) (P < 0.001). Echocardiography was used less often for diagnosis in rural towns compared with metropolitan areas (52.0% v 67.3%, P < 0.001). Rates of specialist referral were also significantly lower in rural towns than in metropolitan areas (59.1% v 69.6%, P < 0.001), as were prescribing rates of angiotensin-converting enzyme inhibitors (51.4% v 60.1%, P < 0.001). There was no geographical variation in prescribing rates of β-blockers (12.6% [rural] v 11.8% [metropolitan], P = 0.32). Overall, few survey participants received recommended “evidence-based practice” diagnosis and management for CHF (metropolitan, 4.6%; rural, 3.9%; and remote areas, 3.7%). Conclusions: This study found a higher prevalence of CHF, and significantly lower use of recommended diagnostic methods and pharmacological treatment among patients in rural areas.

Oxidation of succinate in heart, brain, and kidney mitochondria in hypobaria and hypoxia

Exposure of rats to hypobaric stress for periods of up to 36 h caused a consistent change in the succinate-NT reductase activity of the heart mitochondria whereas there was no significant change in the activities of either succinate dehydrogenase and succinate-NT reductase of the brain and the kidney. Mitochondrial succinate dehydrogenase of the heart, the brain and the kidney was activated 2- to 7-fold with the substrate and malonate. The activations obtained with oxalate, citrate and dinitrophenol were relatively lower in comparison to succinate and malonate. Benzohydroquinone and 2-nitrophenol had no stimulatory effect on the heart, the brain and the kidney mitochondria. THE ACTIVATIONS OBTAINED WITH THE VARIOUS EFFECTORS PARTIALLY (OR COMPLETELY IN THE CASE OF SUCCINATE) REVERSED ON WASHING THE MITOCHONDRIAL SAMPLES WITH THE SUCROSE HOMOGENIZING MEDIUM. The effect of ubiquinol, which also activated the enzyme, was only partially reversed after the second preincubation with succinate in the brain and the kidney whereas in the heart the activity was fully reversed. The increased activity of succinate dehydrogenase obtained with ATP and ADP was further enhanced by Mg2+ exclusively in the brain mitochondria, suggesting the possibility of Mg2+-AIP complex as the active species. Succinate-NT reductase of the heart, the brain and the kidney mitochondria showed a high activation with ubiquinone whereas its reduced form had no stimulatory effect.

Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA(2) activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA(2) activity and mass.

Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease

Background: Elevated homocysteine is associated with ischaemic heart disease (IHD). The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene results in reduced MTHFR enzyme activity and reduced methylation of homocysteine to methionine resulting in mild hyperhomocysteinaemia. Case-control association studies of the role of the C677T MTHFR polymorphism in IHD have produced conflicting results. We therefore used newly described family-based association tests to investigate the role of this polymorphism in IHD, in a well-defined population. Methods: A total of 352 individuals from 129 families (discordant sibships and parent-child trios) were recruited. Linkage disequilibrium between the polymorphism and IHD was tested for using the combined transmission disequilibrium test (TDT)/sib-TDT and pedigree disequilibrium test (PDT). Homocysteine levels were measured. Results: Both the TDT/sib-TDT and PDT analyses found a significantly reduced transmission of the T allele to affected individuals (P=0.016 and P=0.021). There was no significant difference in homocysteine levels between affected and unaffected siblings. TT homozygotes had mean homocysteine levels significantly higher than those of TC heterozygotes (P