Assessment of Metabolic Phenotypes in Patients with Non-ischemic Dilated Cardiomyopathy Undergoing Cardiac Resynchronization Therapy

Studies of myocardial metabolism have reported that contractile performance at a given myocardial oxygen consumption (MVO2) can be lower when the heart is oxidizing fatty acids rather than glucose or lactate. The objective of this study is to assess the prognostic value of myocardial metabolic phenotypes in identifying non-responders among non-ischemic dilated cardiomyopathy (NIDCM) patients undergoing cardiac resynchronization therapy (CRT). Arterial and coronary sinus plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA), and 22 amino acids were obtained from 19 male and 2 female patients (mean age 56 ± 16) with NIDCM undergoing CRT. Metabolite fluxes/MVO2 and extraction fractions were calculated. Flux balance analysis (FBA) was performed with MetaFluxNet 1.8 on a metabolic network of the cardiac mitochondria (189 reactions, 230 metabolites) reconstructed from mitochondrial proteomic data (615 proteins) from human heart tissue. Non-responders based on left ventricular ejection fraction (LVEF) demonstrated a greater mean FFA extraction fraction (35% ± 17%) than responders [18 ± 10%, p = 0.0098, area under the estimated ROC curve (AUC) was 0.8238, S.E. 0.1115]. Calculated adenosine triphosphate (ATP)/MVO2 using FBA correlated with change in New York Heart Association (NYHA) class (rho = 0.63, p = 0.0298; AUC = 0.8381, S.E. 0.1316). Non-responders based on both LVEF and NYHA demonstrated a greater mean FFA uptake/MVO2 (0.115 ± 0.112) than responders (0.034 ± 0.030, p = 0.0171; AUC = 0.8593, S.E. 0.0965). Myocardial FFA flux and calculated maximal ATP synthesis flux using FBA may be helpful as biomarkers in identifying non-responders among NIDCM patients undergoing CRT

A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart

Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

BEDSIDE ESTIMATION OF PATIENT HEIGHT FOR CALCULATING IDEAL BODY WEIGHT IN THE EMERGENCY DEPARTMENT

Background: Ideal body weight (IBW), which can be calculated using the variables of true height and sex, is important for drug dosing and ventilator settings. True height often cannot be measured in the emergency department (ED). Objectives: Determine the most accurate method to estimate IBW using true height-based IBW that uses true height estimated by providers or patients compared to true height estimated by a regression formula using measured tibial length, and compare all to the conventional 70 kg male/60 kg female standard IBW. Methods: Prospective, observational, double-blind, convenience sampling of stable adult patients in a tertiary care ED from September 2004 to April 2006. Derivation set (215 patients) had blinded provider and patient true height estimates and tibial length measurements compared to gold-standard standing true height. A validation set (102 patients) then compared the accuracy of IBW using true height calculated from the regression formula vs. IBW using gold-standard true height. Regression formula for men tibial length-IBW (kg) = 25.83 + 1.11 × tibial length; for women tibial length-IBW = 7.90 + 1.20 × tibial length; R2 = 0.89, p \u3c 0.001. Inter-rater correlation of tibial length was 0.94. Results: Derivation set: percent within 5 kg of true heightbased IBW for men/women = Patient: 91.1%:/85.7%; Physician: 66.1%/45.1%; Nurse: 65.7%/ 47.3%; tibial length: 66.1%/63.7%; and 70 kg male/60 kg female standard 46%/ 75%. Validation set: tibial length-IBW estimates were within 5 kg of true height-ideal body weight in only 56.2% of men and 42.2% of women. Conclusions: Patient-reported height is the best bedside method to estimate true height to calculate ideal body weight. Physician and nurse estimates of true height are substantially less accurate, as is true height obtained from a regression formula that uses measured tibial length. All methods were more accurate than using the conventional 70 kg male/60 kg female IBW standard

BEDSIDE METHOD TO ESTIMATE ACTUAL BODY WEIGHT IN THE EMERGENCY DEPARTMENT

Background: Actual body weight (ABW) is important for accurate drug dosing in emergency settings. Oftentimes, patients are unable to stand to be weighed accurately or clearly state their most recent weight. Objective: Develop a bedside method to estimate ABW using simple anthropometric measurements. Methods: Prospective, blinded, cross-sectional convenience sampling of adult Emergency Department (ED) patients. A multiple linear regression equation from Derivation Phase (n = 208: 121 males, 87 females) found abdominal and thigh circumferences (AC and TC) had the best fit and an inter-rater correlation of 0.99 and 0.96, respectively: Male ABW (kg) = -47.8 + 0.78 * (AC) + 1.06 * (TC); Female ABW = -40.2 + 0.47 * (AC) + 1.30 * (TC). Results: Derivation phase: Number of patients (%) with a body weight estimation (BWE) \u3e 10 kg from ABW for males/females were: 7 (6%)/1 (1%)for Patients, 46 (38%)/28 (32%) for Doctors, 38 (31%)/24 (27%) for Nurses, 75 (62%)/43 (49%) for 70 kg/60 kg convention, and 14 (12%)/8 (9%) using the anthropometric regression model. For validation phase (55 males, 44 females): Gold standard ABW mean (SD) male/female = 83.6 kg (14.3)/71.5 kg (18.9) vs. anthropometric regression model = 86.3 kg (14.7)/73.3 kg (15.1). R2 = 0.89, p \u3c 0.001. The number (%) for males/females with aBWE \u3e 10 kg using the anthropometric regression model = 8 (15%)/11 (27%). Conclusions: For male patients, a regression model using supine thigh and abdominal circumference measurements seems to provide a useful and more accurate alternative to physician, nurse, or standard 70-kg male conventional estimates, but was less accurate for use in female patients