Regional myocardial blood flow, function and metabolism using phosphorus-31 nuclear magnetic resonance spectroscopy during ischemia and reperfusion in dogs

Postreperfusion regional myocardial dysfunction may be associated with depletion of high energy phosphate compounds during ischemia and with their relatively slow repletion during reperfusion. However, few studies have correlated relatively rapid changes in regional myocardial function (sonomicrometers) and blood flow (microspheres) with high energy phosphate concentrations measured using phosphorus-31 nuclear magnetic resonance spectroscopy in intact large animal models of regional myocardial ischemia. The left anterior descending coronary artery of mongrel dogs was abruptly occluded for 17.1 ± 1.9 minutes and then completely released; measurements were made for an additional 22 minutes. Transmural blood flow decreased from 1.07 ± 0.25 to 0.25 ± 0.10 ml/(min × g) and holosystolic expansion was observed in all dogs (segmental systolic shortening decreased from 9.3 ± 3.7 to −6.3 ± 6.0%). Phosphocreatine (PCr) measured during 4.4 minute sampling intervals decreased to steady state within the first sampling period after occlusion and was 45.9 ± 17.0% of control at the end of the occlusion, whereas beta-adenosine triphosphate (beta-ATP) reached its lowest level early after reperfusion (72.7 ± 13.3% of control). The ratio of PCr to inorganic phosphate (Pi) decreased during the occlusion (3.34 ± 0.75 versus 1.01 ± 0.61) but returned to control level early during reperfusion. The ratio of PCr to beta-ATP also decreased during coronary occlusion (2.16 ± 0.39 versus 1.29 ± 0.39) but did not return to control level during reperfusion.Significant correlations were observed between the intensity of ischemia (reduced blood flow) and reductions in regional contractile function, PCr, beta-ATP, myocardial pH and the increase in Pi during the coronary occlusion. Also during ischemia, there were significant correlations between regional contractile function and both myocardial pH and Pi. PCr returned to control level rapidly after reperfusion (95.9 ± 13.2% of control in less than 5 minutes of reperfusion) whereas beta-ATP recovered only partially after 22 minutes (80.0 ± 17.5% of control). The correlation between the fraction of control beta-ATP and the fraction of control regional function at this time was r = 0.84 (p = 0.017).These results demonstrate metabolic correlates to regional myocardial ischemia in an intact dog model using phosphorus-31 spectroscopy. Additionally during reperfusion, beta-ATP, but not PCr, could be associated with the recovery of regional segmental contractile function

Vascular Pathophysiology in Response to Increased Heart Rate

This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate—independent of the underlying trigger—contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed

Diazoxide is a powerful cardioprotectant but is not feasible in a realistic infarct scenario

IntroductionDiazoxide is a powerful cardioprotective agent that activates mitochondrial ATP-dependent K-channels and stimulates mitochondrial respiration. Diazoxide reduced infarct size in isolated rodent heart preparations and upon pretreatment in juvenile pigs with coronary occlusion/reperfusion. We aimed to study the use of diazoxide in a more realistic adult pig model of reperfused acute myocardial infarction when diazoxide was administered just before reperfusion.Methods and resultsIn a first approach, we pretreated anaesthetised adult Göttingen minipigs with 7 mg kg−1 diazoxide (n = 5) or placebo (n = 5) intravenously over 10 min and subjected them to 60 min coronary occlusion and 180 min reperfusion; blood pressure was maintained by use of an aortic snare. The primary endpoint was infarct size (triphenyl tetrazolium chloride staining) as a fraction of area at risk; no-reflow area (thioflavin-S staining) was the secondary endpoint. In a second approach, diazoxide (n = 5) was given from 50 to 60 min coronary occlusion, and blood pressure was not maintained. There was a significant reduction in infarct size (22% ± 11% of area at risk with diazoxide pretreatment vs. 47% ± 11% with placebo) and area of no-reflow (14% ± 14% of infarct size with diazoxide pretreatment vs. 46% ± 20% with placebo). With diazoxide from 50 to 60 min coronary occlusion, however, there was marked hypotension, and infarct size (44% ± 7%) and area of no-reflow were not reduced (35% ± 25%).ConclusionsCardioprotection by diazoxide pretreatment was confirmed in adult pigs with reperfused acute myocardial infarction but is not feasible when diazoxide is administered in a more realistic scenario before reperfusion and causes hypotension

The Arg389Gly Beta1-Adrenoceptor Polymorphism and Catecholamine Effects on Plasma-Renin Activity

ObjectivesThe purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (β1AR) genotype-dependent.BackgroundIn vitro Arg389Gly-β1AR polymorphism exhibits decreased receptor signaling.MethodsWe studied 10 male homozygous Arg389-β1AR subjects and 8 male homozygous Gly389β1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-β1AR. Subjects were infused with dobutamine (1 to 6 μg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed.ResultsWith regard to PRA, dobutamine increased PRA more potently in Arg389-β1AR versus Gly389-β1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-β1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-β1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-β1AR subjects.ConclusionsCodon 389 β1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, β1AR polymorphisms may be useful for predicting therapeutic responses to βAR-blocker treatment

IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

Cardioprotection; Drug development; InfarctionCardioprotección; Desarrollo de fármacos; InfartoCardioprotecció; Desenvolupament de fàrmacs; InfartAcute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.This article is based on the work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). DJH is supported by the Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006). SL is supported by grants from the South African Department of Science and Technology and the South African National Research Foundation. SMD is supported by grants from the British Heart Foundation (PG/19/51/34493 and PG/16/85/32471). GH is supported by the German Research Foundation (SFB 1116 B8). MRM is supported by the Spanish Institute of Health Carlos III (FIS PI19/01196 and CIBER-CV). RS is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. PF is supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program—TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University

Social orientation of banks

The influence of the bank's orientation on clients and the quality of the services provided on the financial efficiency of the commercial institution (sales volume, profitability, cost reduction) was studied. The development of online banking and Internet banking is considered. The relationship between the profitability of the bank and the level of customercentricity is proved. World experience has been compared and generalized, and country specificity has been singled out in different regions of the world. The dependence between the degree of customer satisfaction and their subsequent loyalty to the bank was studied. Prospective directions of expansion of the market of banking services are outlined, and also changes in the psychology of the client that took place due to scientific and technological progress are noted. The basic directions of increase of efficiency of work of the bank personnel are allocated