In vivo creatine kinase reaction kinetics at rest and stress in type II diabetic rat heart

The effects of type II diabetes on cardiac creatine kinase (CK) enzyme activity and/or flux are unknown. We therefore measured steady‐state phosphocreatine (PCr) and adenosine triphosphate (ATP) content and forward CK reaction kinetic parameters in Zucker Diabetic Fatty (ZDF) rat hearts, a type II diabetes research model. At baseline the PCr to ATP ratio (PCr/ATP) was significantly lower in diabetic heart when compared with matched controls (1.71 ± 0.21 vs. 2.26 ± 0.24, P < 0.01). Furthermore, the forward CK reaction rate constant (k(f)) was higher in diabetic animals (0.52 ± 0.09 s(−1) vs. 0.35 ± 0.06 s(−1), P < 0.01) and CK flux calculated as a product of PCr concentration ([PCr]) and k(f) was similar between two groups (4.32 ± 1.05 μmol/g/s vs. 4.94 ± 1.23 μmol/g/s, P = 0.20). Dobutamine administration resulted in similar increases in heart rate (~38%) and k(f) (~0.12 s(−1)) in both groups. No significant change in PCr and ATP content was observed with dobutamine. In summary, our data showed reduced PCr/ATP in diabetic myocardium as an indicator of cardiac energy deficit. The forward CK reaction rate constant is elevated at baseline which might reflect a compensatory mechanics to support energy flux through the CK shuttle and maintain constant ATP supply. When hearts were stimulated similar increase in k(f) was observed in both groups thus it seems that CK shuttle does not limit ATP supply for the range of workload studied

Can smartphone wireless ECGs be used to accurately assess ECG intervals in pediatrics? A comparison of mobile health monitoring to standard 12-lead ECG

BACKGROUND:Arrhythmias in children are often paroxysmal, complicating the ability to capture the abnormal rhythm on routine ECG during an outpatient visit. The Alivecor Kardia Mobile (KM) device is a wireless mobile health (mHealth) device that generates a single lead ECG tracing with a FDA-approved algorithm for detection of atrial fibrillation in adults. OBJECTIVE:The goal of this study is to assess the accuracy of interval measurements on KM tracings by directly comparing to standard 12-lead ECGs in pediatric patients. METHODS:This single center, prospective study enrolled pediatric outpatients, age 20ms with 4/9 (44%) having a conduction disorder and 2/9 (22%) having marked sinus arrhythmia. Bland-Altman method of agreement demonstrated strong agreement for QRSd and QTc. The AF algorithm reported 4/30 (13%) false positive "possible AF" diagnoses (rhythm over-read on KM demonstrated n = 3 marked sinus arrhythmia, n = 1 sinus rhythm with aberrated PACs) resulting in a specificity of 87%. CONCLUSION:The Alivecor Kardia device produces accurate single lead ECG tracings in both healthy children and children with cardiac disease or rhythm abnormalities across the pediatric spectrum. This mHealth application provides an accurate, non-invasive, real-time approach for ambulatory ECG monitoring in children and adolescents

The EXERRT Trial: EXErcise to Regadenoson in Recovery Trial : a Phase 3b, Open-label, Parallel Group, Randomized, Multicenter Study to Assess Regadenoson Administration Following an Inadequate Exercise Stress Test as Compared to Regadenoson Without Exercise for Myocardial Perfusion Imaging Using a SPECT Protocol

BACKGROUND: This study assessed the non-inferiority and safety of regadenoson administration during recovery from inadequate exercise compared with administration without exercise. METHODS: Patients unable to achieve adequate exercise stress were randomized to regadenoson 0.4 mg either during recovery (Ex-Reg) or 1 hour after inadequate exercise (Regadenoson) (MPI1). All patients also underwent non-exercise regadenoson MPI 1-14 days later (MPI2). The number of segments with reversible perfusion defects (RPDs) detected using single photon emission computerized tomography imaging was categorized. The primary analysis evaluated the majority agreement rate between Ex-Reg and Regadenoson groups. RESULTS: 1,147 patients were randomized. The lower bound of the 95% confidence interval of the difference in agreement rates (-6%) was above the -7.5% non-inferiority margin, demonstrating non-inferiority of Ex-Reg to Regadenoson. Adverse events were numerically less with Ex-Reg (MPI1). In the Ex-Reg group, one patient developed an acute coronary syndrome and another had a myocardial infarction following regadenoson after exercise. Upon review, both had electrocardiographic changes consistent with ischemia prior to regadenoson. CONCLUSIONS: Administering regadenoson during recovery from inadequate exercise results in comparable categorization of segments with RPDs and with careful monitoring appears to be well tolerated in patients without signs/symptoms of ischemia during exercise and recovery

Impact of Gender on the Myocardial Metabolic Response to Obesity

ObjectivesWe sought to determine the gender-specific effects of obesity on myocardial metabolism, work, and efficiency.BackgroundMyocardial metabolism abnormalities may contribute to the development of obesity-related heart failure. Increased myocardial oxygen consumption (MVO2) and fatty acid (FA) metabolism and decreased efficiency occur with obesity in women. It is unknown whether similar changes occur with obesity in men.MethodsWe quantified cardiac work, efficiency, myocardial blood flow (MBF), MVO2, glucose, and FA metabolism with echocardiography and positron emission tomography in nonobese and obese men and women (N = 86).ResultsThere were significant differences between the obese (n = 35) and nonobese (n = 51) subjects in age, body composition, plasma lipids, and insulin resistance in addition to differences between the men (n = 30) and women (n = 56) in body composition and plasma lipids. Female gender independently predicted increased cardiac work (p < 0.001). Female gender also related to lower efficiency (p < 0.05). Obesity and female gender independently predicted greater MBF (p < 0.01, p < 0.0005, respectively) and MVO2 (p < 0.0005, p < 0.0001). Myocardial glucose uptake was not different among the 4 subject groups, but obesity and gender interacted in predicting glucose uptake (p < 0.05). Lower myocardial glucose utilization was independently predicted by female gender (p < 0.05), and it independently predicted lower myocardial glucose utilization/plasma insulin (p < 0.05). Obesity and gender significantly interacted in the determination of glucose utilization/plasma insulin (p = 0.01). There were no differences in FA uptake among the 4 groups, and although increasing obesity correlated with greater myocardial FA utilization and oxidation; female gender (p < 0.005, p < 0.01) and plasma triglycerides (p < 0.05, p < 0.005) were their independent predictors.ConclusionsWomen's and men's myocardial metabolic responses to obesity are not exactly the same. Obesity and gender modulate MBF and MVO2, are related to myocardial substrate metabolism, and sometimes interact in its prediction. Gender modifies efficiency. Gender-related differences in myocardial metabolism may affect the development of/adaptation to obesity-related cardiac disease

Sex Affects Myocardial Blood Flow and Fatty Acid Substrate Metabolism in Humans with Nonischemic Heart Failure

In animal models of heart failure (HF), myocardial metabolism shifts from the normal preference for high-energy fatty acid (FA) metabolism towards the more efficient fuel, glucose. However, FA (vs. glucose) metabolism generates more ATP/mole; thus FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. We studied 19 well-matched men and women with nonischemic HF with similar ejection fractions (all ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/min), FA uptake (mL/g/min), utilization (nmol/g/min) (P<0.005, <0.005, <0.05, respectively) and trended towards higher FA oxidation than men (P=0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. In an exploratory analysis of the longitudinal follow-up of these subjects (mean 7 y), we found that 4 men had a major cardiovascular event, while one woman died of non-cardiac causes. Higher MBF related to improved event-free survival (HR=0.31, P=0.02). In sum, in nonischemic HF, women have higher MBF and FA uptake and metabolism than men, and these changes are not due to differences in other variables that can affect myocardial metabolism (e.g., age, obesity, or insulin resistance). Moreover, higher MBF portends a better prognosis. These sex-related differences should be taken into account in the development and targeting of novel agents aimed at modulating in MBF and metabolism in HF

OXPAT/PAT-1 is a PPAR-Induced Lipid Droplet Protein that Promotes Fatty Acid Utilization

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as OXPAT. Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse adipose tissue, striated muscle, and liver by physiological (fasting), pathophysiological (insulin deficiency), pharmacological (peroxisome proliferator-activated receptor [PPAR] agonists), and genetic (muscle-specific PPARα overexpression) perturbations that increase fatty acid utilization. In humans with impaired glucose tolerance, PPARγ agonist treatment induces adipose OXPAT mRNA. Further, adipose OXPAT mRNA negatively correlates with BMI in nondiabetic humans. Our collective data in cells, mice, and humans suggest that OXPAT is a marker for PPAR activation and fatty acid oxidation. OXPAT likely contributes to adaptive responses to the fatty acid burden that accompanies fasting, insulin deficiency, and overnutrition, responses that are defective in obesity and type 2 diabetes

Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC.</p> <p>Methods</p> <p>Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using ¹¹C-glucose and ¹¹C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography.</p> <p>Results</p> <p>Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/μU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/μU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001).</p> <p>Conclusion</p> <p>Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin.</p> <p>Trial Registration</p> <p>NIH Clinical Trials <a href="http://clinicaltrials.gov/ct2/show/NCT00656851">NCT00656851</a></p