Caffeine increases performance and leads to a cardioprotective effect during intense exercise in cyclists.

The present study was designed to investigate the effects of different caffeine dietary strategies to compare the impact on athletic performance and cardiac autonomic response. The order of the supplementation was randomly assigned: placebo(4-day)-placebo(acute)/PP, placebo(4-day)-caffeine(acute)/PC and caffeine(4-day)-caffeine(acute)/CC. Fourteen male recreationally-trained cyclists ingested capsules containing either placebo or caffeine (6 mg kg-1) for 4 days. On day 5 (acute), capsules containing placebo or caffeine (6 mg kg-1) were ingested 60 min before completing a 16 km time-trial (simulated cycling). CC and PC showed improvements in time (CC vs PP, Δ - 39.3 s and PC vs PP, Δ - 43.4 s; P = 0.00; ƞ2 = 0.33) and in output power (CC vs PP, Δ 5.55 w and PC vs PP, Δ 6.17 w; P = 0.00; ƞ2 = 0.30). At the final of the time-trial, CC and PC exhibited greater parasympathetic modulation (vagal tone) when compared to the PP condition (P < 0.00; ƞ2 = 0.92). Our study provided evidence that acute caffeine intake (6 mg∙kg-1) increased performance (time-trial) and demonstrated a relevant cardioprotective effect, through increased vagal tone.

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/ß5-AKT signaling and reduction of oxidative/nitrosative stress.

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVß5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

Higher omega-3 index is associated with more rapid heart rate recovery in healthy men and women.

BACKGROUND: Previous studies have suggested that omega-3 polyunsaturated fatty acids (n-3 PUFA) can favorably influence cardiac autonomic tone. However, data regarding n-3 PUFA status and heart rate recovery (HRR) in healthy adults are sparse. PURPOSE: To examine the association between n-3 PUFA status and HRR. METHODS: Participants included 13,912 patients who underwent a comprehensive examination at the Cooper Clinic, Dallas TX. Fitness was determined from a maximal exercise test. HRR was calculated by subtracting the heart rate at 1, 3, and 5 min of an active recovery period from the maximal heart rate. Participants were categorized as having a low (<4%), normal (4-8%) or optimal (>8%) Omega-3 Index (O3I) (i.e., erythrocyte levels of eicosapentaenoic and docosahexaenoic acids). Multiple linear regression was used to model the association between O3I and HRR adjusting for age, maximal METs, body mass index, and smoking by sex. RESULTS: Higher categories of O3I were associated with greater HRR at 1 min (men: 23.7, 23.9, 24.6 beats/min; women: 23.9, 24.6, 25.9 and 3 min (men: 52.4, 52.9, 53.6 beats/min; women: 51.9, 53.4, 54.6), p trend <0.01 for all. Corresponding HRR at 5 min were (men: 60.0, 60.2, 60.7 beats/min, p trend=0.09; women: 59.4, 60.8, 61.6, p trend <0.001). The HRR gradients across O3I categories were steeper in women than men at 1, 3, and 5 min (p<0.03 for all sex x O3I category interactions with HRR). CONCLUSIONS: A direct relationship between HRR and O3I values was observed in both men and women, with a steeper gradient in women. These findings suggest a potential cardioprotective mechanism for n-3 PUFA.

Current Understanding of the Relationship of HDL Composition, Structure and Function to Their Cardioprotective Properties in Chronic Kidney Disease.

In the general population, the ability of high-density lipoproteins (HDLs) to promote cholesterol efflux is a predictor of cardiovascular events, independently of HDL cholesterol levels. Although patients with chronic kidney disease (CKD) have a high burden of cardiovascular morbidity and mortality, neither serum levels of HDL cholesterol, nor cholesterol efflux capacity associate with cardiovascular events. Important for the following discussion on the role of HDL in CKD is the notion that traditional atherosclerotic cardiovascular risk factors only partially account for this increased incidence of cardiovascular disease in CKD. As a potential explanation, across the spectrum of cardiovascular disease, the relative contribution of atherosclerotic cardiovascular disease becomes less important with advanced CKD. Impaired renal function directly affects the metabolism, composition and functionality of HDL particles. HDLs themselves are a heterogeneous population of particles with distinct sizes and protein composition, all of them affecting the functionality of HDL. Therefore, a more specific approach investigating the functional and compositional features of HDL subclasses might be a valuable strategy to decipher the potential link between HDL, cardiovascular disease and CKD. This review summarizes the current understanding of the relationship of HDL composition, metabolism and function to their cardio-protective properties in CKD, with a focus on CKD-induced changes in the HDL proteome and reverse cholesterol transport capacity. We also will highlight the gaps in the current knowledge regarding important aspects of HDL biology.

Cardioprotective properties of leptin in patients with excessive body mass.

BACKGROUND: Adipose tissue is producing adipokines that play different roles in the pathophysiology of cardiovascular disease. AIMS: The study aimed to assess the role of selected biomarkers in hypertensive patients with overweight and obesity compared with those with normal body-mass index (BMI). METHODS: A total of 62 patients with BMI < 25 kg/m2 (median age 54 (46-58) yrs., 57% males) and 51 with BMI ≥ 25 kg/m2 (median age 53 (48-59) yrs., 37% males) were enrolled. Biochemical parameters, leptin, adiponectin, and resistin; asymmetric dimethylarginine; interleukin 6; and N-terminal propeptide of type III procollagen, were assessed in plasma. The evaluation of hemodynamic parameters was performed using SphygmoCor 9.0 tonometer. Echocardiography was performed using AlokaAlpha 10 Premier device. RESULTS: Overweight and obese patients had significantly higher concentration of leptin (34 vs 18 ng/ml; p = 0.03), ADMA (0.43 vs 0.38 µmol/l, p = 0.04), and lower concentration of adiponectin (5.3 vs 7 µg/ml, p = 0.01). The only significant difference in tonometry analysis was higher aortic pulse pressure (mmHg) in patients with BMI ≥ 25 kg/m2 group (34 vs 30; p = 0.03). These patients had also significantly lower peak systolic velocity and early diastolic velocity in tissue Doppler imaging of the right ventricle free wall at the level of the tricuspid annulus compared with controls (p = 0.02 and p = 0.001, respectively). The level of leptin is correlated negatively with the left ventricular mass index (LVMI) (R Spearman = - 0.5; p = 0.002) and PWV (R = - 0.4; p = 0.01) and ADMA with total and LDL cholesterol (R = - 0.42; p = 0.008), and adiponectin is correlated positively with HDL cholesterol (R = 0.67; p = 0.0001). CONCLUSIONS: Leptin concentrations were inversely proportional to LVMI and PWV in patients with BMI < 25 kg/m2. TRIAL REGISTRATION: Clinicaltrials.gov study ID: NCT04175080.

Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.

Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.

Direct Rivaroxaban-Induced Factor XA Inhibition Proves to be Cardioprotective in Rats.

BACKGROUND: Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets. EXPERIMENTAL APPROACH: We used a rat model of 40-min coronary ligation followed by reperfusion. RIV (3 mg/kg) was given per os 1 h before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 min of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 min of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line). KEY RESULTS: RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, P < 0.05) at blood concentrations similar to human therapeutic (387.7 ±â€Š152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of reperfusion injury salvage kinase and survivor activating factor enhancement pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R. CONCLUSIONS: RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes.

A review of fibroblast growth factor 21 in diabetic cardiomyopathy.

FGF21 (fibroblast growth factor 21) is a regulator of metabolism and performs an important role in glucose and lipid metabolism and the maintenance of energy balance. FGF21 is principally expressed in the liver, but it can also be found in the pancreas, skeletal muscle, and adipose tissue. It is known that levels of serum FGF21 are significantly elevated in obese, insulin-resistant patients, and those with metabolic syndrome. Elevated levels of FGF21 in serum during the early stages of various metabolic diseases are considered a compensatory response by the organism. Therefore, FGF21 is considered a hormone in response to stress and an early diagnostic marker of disease. Diabetic cardiomyopathy is a special type of cardiac complication, characterized as a chronic myocardial disorder caused by diabetes. The pathological process includes increased oxidative stress, energy metabolism in myocardial cells, an inflammatory response, and myocardial cell apoptosis. A growing body of evidence suggests that FGF21 has the potential to be an effective drug for the treatment of diabetic cardiomyopathy. Here, we review recent progress on the characteristics of FGF21 in its protective role, especially in pathological processes such as suppressing apoptosis in the myocardium, reducing inflammation in cardiomyocytes, reducing oxidative stress, and promoting fatty acid oxidation. In addition, we explore the possibility that diabetic cardiomyopathy can be delayed through the application of FGF21, providing possible therapeutic targets of the disease.

The Assessment of Serum Drug Levels to Diagnose Non-Adherence in Stable Chronic Heart Failure Patients.

BACKGROUND: The aim of our study was to evaluate the prevalence of drug non-adherence in stable chronic heart failure (CHF) patients using serum drug levels (SDL) assessment. METHODS: CHF patients were prospectively enrolled during scheduled outpatient visit. Except standard procedures an unanticipated blood sampling for the SDL assessment was obtained. Analysis was focused on the prescribed heart failure and antihypertensive medication and was performed by liquid chromatography coupled with mass spectrometry. The patient was labelled as non-adherent if at least one of drugs assessed was not found in the serum. In the first half of patients multiple SDL have been evaluated during the follow-up. RESULTS: Eighty one patients were enrolled. The non-adherence was proven in twenty of them (25%). In the subgroup of thirty eight patients with multiple SDL evaluation the non-adherence raised significantly with increasing number of visits assessed together (21% for single visit, 29% for two of three visits assessed together and 34% for all three visits evaluated together, all p < 0.001). CONCLUSION: The non-adherence was proven in significant part of stable CHF patients using SDL assessment. This method seems to be reliable and effective and should be a part of clinical assessment in selected patients with CHF.

Influence of OATP1B1 and OATP1B3 mutations and glomerular filtration rate on trough serum digoxin concentration in the Chinese population: A prospective cohort study.

Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher trough SDC (1.20 ±â€Š0.50 ng/mL) than recommended trough SDC for heart failure patients. Trough SDC was not significantly influenced by mutations of OATP1B1 388A>G (P = .890), 521T>C (P = .054), and OATP1B3 699G>A (P = .854). Patients with OATP1B1 521T>C mutant-type carrier had slightly higher trough SDC (0.98 ±â€Š0.53 ng/mL) than those with wild-type carrier (0.74 ±â€Š0.40 ng/mL) when they have repaired renal function.Heart failure patients with severe renal dysfunction (GFR<60 mL/min) and/or OATP1B1 521T>C mutant-type carriers are recommended a smaller dosage of digoxin and strict therapeutic drug monitoring.

The endogenous cardiotonic steroid Marinobufagenin and decline in estimated glomerular filtration rate at follow-up in patients with arterial hypertension.

BACKGROUND: Marinobufagenin (MBG) is an endogenous cardiotonic steroid (CTS) that inhibits the Na+/K+-ATPase. Human MBG is significantly increased in end-stage renal disease and immunization against MBG attenuates cardiovascular fibrosis in a rat model of uremic cardiomyopathy. Mineralocorticoid antagonists (MRA) block MBG binding sites and decrease proteinuria in chronic kidney disease (CKD) patients. We therefore aimed to investigate the association of MBG and albuminuria, as a marker of renal damage, as well as MBG and decline of glomerular filtration rate (GFR). METHODS: The Graz endocrine causes of hypertension (GECOH) study is a single center study of adults routinely referred for screening of endocrine hypertension. Plasma MBG was measured by an enzyme-linked immunoassay, and in a post-hoc analysis, follow-up creatinine levels were obtained. Patients with proteinuria >3.5g/day at baseline were excluded from further evaluation. RESULTS: We measured MBG concentrations in 40 hypertensive subjects and excluded one patient due to pre-existing proteinuria. Plasma MBG was significantly correlated with albuminuria (Spearman ρ = .357; p = .028) and proteinuria (ρ = .336; p = .039). In linear regression analysis, the association remained significant after adjustment for age, sex, and BMI (ß = .306; p = .036), and for mean systolic blood pressure (ß = .352; p = .034). In follow-up analyses (N = 30), MBG was significantly associated with decline in GFR after adjustment for time-to-follow-up (ß = -.374; p = .042). CONCLUSION: The findings suggest that MBG plasma concentrations were associated with albuminuria as well as decline in kidney function. Whether MBG predicts hard renal endpoints warrants further investigations.

Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants.

OBJECTIVES: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations. DESIGN: A prospective single group open-label pharmacokinetics study. SETTINGS: Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia. PATIENTS: Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery. INTERVENTIONS: Milrinone at a dose of 0.73 µg/kg/min for 3 hours followed by 0.16 µg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected. MEASUREMENTS AND MAIN RESULTS: Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 µg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 µg/kg/min for 3 hours followed by 0.15 µg/kg/min (postmenstrual age < 27 wk) or 0.20 µg/kg/min (postmenstrual age ≥ 27 wk). CONCLUSIONS: Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.

La escala de vasoactivos inotrópicos como predictora de mortalidad de adultos con shock cardiogénico tratados con y sin ECMO / Vasoactive inotropic score as a predictor of mortality in adult patients with cardiogenic shock: medical therapy versus ECMO

Introducción y objetivos: Este estudio investigó si la escala de vasoactivos inotrópicos (VIS) es un predictor independientemente de la mortalidad en el shock cardiogénico (SC). Métodos: Estudio observacional retrospectivo. Se estudió a los pacientes que ingresaron entre enero de 2012 y diciembre de 2015 en la unidad de cuidados intensivos cardiacos, y finalmente se incluyó a 493 pacientes con SC. Para cuantificar el apoyo farmacológico, se dividió a los pacientes en quintiles de VIS: 1-10, 11-20, 21-38, 39-85 y > 85 puntos. El objetivo primario fue la mortalidad hospitalaria. Resultados: La mortalidad hospitalaria de los quintiles de VIS, en orden creciente, fue del 8,2, el 14,1, el 21,1, el 32,0 y el 65,7% respectivamente (p < 0,001). El análisis multivariable indicó que los valores de VIS de 39-85 (ORa = 3,85; IC95%, 1,60-9,22; p = 0,003) y > 85 puntos (ORa = 10,83; IC95%, 4,43-26,43; p < 0,001) siguieron siendo predictores de mortalidad hospitalaria. En la regresión logística múltiple para eliminar cualquier efecto de confusión, se halló que la probabilidad de muerte (tratamiento solo médico frente a combinado con oxigenador extracorpóreo de membrana) se cruzaron entre sí cuando el valor de VIS era de 130 puntos. En contraste con la correlación lineal entre la VIS y la mortalidad de los pacientes tratados solo con terapia médica, hubo poca asociación entre VIS ≥ 130 puntos y la mortalidad hospitalaria de los pacientes tratados además con membrana de oxigenación extracorpórea. Conclusiones: Un alto grado de apoyo con vasoactivos inotrópicos durante las primeras 48 h se asocia significativamente con mayor mortalidad hospitalaria de pacientes adultos con SC

Introduction and objectives: This study investigated whether the vasoactive inotropic score (VIS) is independently predictive of mortality in cardiogenic shock (CS). Methods: This study was retrospective, observational study. Patients who were admitted to the cardiac intensive care unit from January 2012 to December 2015 were screened, and 493 CS patients were finally enrolled. To quantify pharmacologic support, the patients were divided into 5 groups based on a quintile of VIS: 1 to 10, 11 to 20, 21 to 38, 39 to 85, and > 85. The primary outcome was in-hospital mortality. Results: In-hospital mortalities in the 5 VIS groups in increasing order were 8.2%, 14.1%, 21.1%, 32.0%, and 65.7%, respectively (P < .001). Multivariable analysis indicated that VIS ranges of 39 to 85 (aOR, 3.85; 95%CI, 1.60-9.22; P = .003) and over 85 (aOR, 10.83; 95%CI, 4.43-26.43; P < .001) remained significant prognostic predictors for in-hospital mortality. With multiple logistic regression to remove any confounding effects, we found that the localized regression lines regarding the odds of death intersected each other's (medical therapy alone and combined extracorporeal membrane oxygenation group) path at VIS = 130. In contrast to linear correlation between VIS and mortality for patients treated with medical therapy alone, there was little association between a VIS of 130 or more and the probability of in-hospital mortality for patients who were treated with extracorporeal membrane oxygenation. Conclusions: A high level of vasoactive inotropic support during the first 48 hours was significantly associated with increased in-hospital mortality in adult CS patients

The Effect of Autoantibody against M2-Muscarinic Acetylcholine Receptor in Heart Failure Patients on Digoxin Treatment.

BACKGROUND: Autoantibody against M2-muscarinic acetylcholine receptor (anti-M2AChR) has a biological effect similar to a vagus agonist. Digoxin has a function of vagus nervous system stimulation. We hypothesized that anti-M2AChR is highly correlated with digoxin in patients with chronic heart failure (CHF). METHODS: Synthetic M2AChR peptides served as the target antigen in an ELISA were used to screen the sera of 80 CHF patients, who were separated into a negative (-) or positive (+) anti-M2AChR group according to their anti-M2AChR reactivity. Echocardiography and serum digoxin concentration (SDC) were performed at baseline and after 1 year of digoxin in combination with the standard treatment regime. The end-point events were compared over 1 year of follow-up. RESULTS: Seventy-two CHF patients completed the final data analysis, including 32 (+)anti-M2AChR and 40 (-)anti-M2AChR patients. The resting heart rate of the positive group was higher than that of the negative group at baseline (p < 0.05; 89.0 ± 1.6 vs. 83.8 ± 1.1 bpm). Both groups showed improvement in the left ventricular end-diastolic and end-systolic dimensions and ejection fraction with digoxin in combination with the standard treatment regime for 1 year (all p < 0.01). However, the 32 patients with (-)anti-M2AChR had greater improvements than the 40 patients with (+)anti-M2AChR, and this was accompanied by a marked decrease of rehospitalization (all p < 0.01) but not of cardiovascular mortality after 1 year. The SDC of patients with (-)anti-M2AChR was significantly lower than that of patients with (+)anti-M2AChR (p < 0.05; 0.63 ± 0.05 vs.1.16 ± 0.06 ng/mL) and had a positive correlation with anti-M2AChR (r = 0.81, p < 0.001). CONCLUSION: These results suggested that anti-M2AChR could be a useful biomarker of vagus nerve overactivation and is associated with a poor response to digoxin treatment in CHF patients.

Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression.

The past several years have been marked by confusion and controversy concerning whether estrogens are cardioprotective. The issue is of utmost public health importance because coronary heart disease (CHD) remains the leading cause of death among postmenopausal women. Fortunately, a unifying hypothesis has emerged that reproductive stage is a major determinant of the effect of estrogens on atherosclerosis progression, complications, and plaque vulnerability. PREMENOPAUSAL YEARS: Premenopausal atherosclerosis progression seems to be an important determinant of postmenopausal atherosclerosis and thus the risk for CHD. Clearly, plasma lipids/lipoproteins influence this progression; however, estradiol deficiency seems to be the major modulator. Both monkeys and women with premenopausal estrogen deficiency develop premature atherosclerosis, an effect that can be prevented in both species by estrogen-containing oral contraceptives. PERIMENOPAUSAL/EARLY POSTMENOPAUSAL YEARS: During this stage, there are robust estrogen benefits. Monkeys given estrogens immediately after surgical menopause have a 70% inhibition in coronary atherosclerosis progression. Estrogen treatment prevented progression of atherosclerosis of women in the Estrogen in the Prevention of Atherosclerosis Trial. A meta-analysis of women younger than 60 years given hormone therapy had reduced total mortality (relative risk = 0.61, 95% CI: 0.39-0.95). LATE POSTMENOPAUSAL YEARS: This stage is one in which there are no or possible deleterious estrogen effects. Monkeys lose CHD benefits of estrogens when treatment is delayed. The increase in CHD events associated with initiating hormone therapy 10 or more years after menopause seems to be related to up-regulation of the plaque inflammatory processes and plaque instability and may be down-regulated by statin pretreatment.

Does the hormone "endogenous ouabain" exist in the human circulation?

Studies in the early 1990s suggested that a hormone identical to ouabain or an isomer of ouabain is secreted by the adrenal glands into the circulation and plays a role in the regulation of arterial pressure and cardiac and renal function. This hormone, known as endogenous ouabain (EO), was claimed to contribute to the pathophysiology of a number of disorders including heart failure, renal failure, pregnancy-induced, and essential hypertension. However, some research groups have been unable to confirm the presence of EO in the human circulation and the issue remains in dispute. In that the implications are of considerable importance to clinicians who, like the authors, lack biochemical expertise, it would be useful if the dispute could be addressed by disinterested scientists with long-standing and acknowledged expertise in analytical chemistry who could opine as to whether the evidence is, or is not, sufficient to state categorically that EO does (or does not) exist in the circulation in man. This brief review does not present new data but, rather, recommends that adjudication is needed regarding this important issue. © 2018 BioFactors, 44(3):219-221, 2018.

Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants After Cardiac Surgery.

BACKGROUND: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. METHODS: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. RESULTS: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2*IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. CONCLUSIONS: In this pilot study, urine TIMP-2*IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

A DNA-Based Assay for Digoxin Detection.

The most common method for quantifying small-molecule drugs in blood samples is by liquid chromatography in combination with mass spectrometry. Few immuno-based assays are available for the detection of small-molecule drugs in blood. Here we report on a homogeneous assay that enables detection of the concentration of digoxin spiked into in a plasma sample. The assay is based on a shift in the equilibrium of a DNA strand displacement competition reaction, and can be performed in 30 min for concentrations above 10 nM. The equilibrium shift occurs upon binding of anti-digoxigenin antibody. As a model, the assay provides a potential alternative to current small-molecule detection methods used for therapeutic drug monitoring.

Inotropic Effects of Nicorandil on Cardiac Contractility Assessed by Left Ventricular Pressure-Volume Relationship Analyses in Anesthetized Monkeys.

Nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (KATP) channel agonist; however, its effects on integrated cardiac function have not been fully understood. This study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. Nicorandil was given intravenously at therapeutic doses of 0.2 and 2 mg/kg over 10 minutes to cynomolgus monkeys (n = 5) with a pause of 10 minutes between the 2 doses. Nicorandil at 0.2 mg/kg caused decreases in systemic blood pressure and left ventricular end-diastolic pressure by its vasodilating action. Nicorandil at 2 mg/kg also exhibited positive inotropic action demonstrated by increased slopes of preload recruitable stroke work relationship, which is a load-independent inotropic parameter. In load-dependent inotropic parameters, positive inotropy of nicorandil was also indicated by the shortened QA interval and increased contractility index; however, significant changes were not observed in the maximal upstroke velocity of left ventricular pressure. Moreover, reflex tachycardia accompanied by shortening of QT/QTc intervals was observed. Overall, the isoflurane-anesthetized monkey model with pressure-volume loop analysis revealed cardiac variables of nicorandil, including a positive inotropy contributable to cardiac performance in addition to its vasodilatory effect. These findings provide useful information when considering the prescription of nicorandil in patients.