Increase In Myocardial Contractility Research Articles

Acute hemodynamic effect of oral ketones in patients with acutely decompensated heart failure and low cardiac output syndrome: a prospective randomized study.

Abstract Background Preliminary studies showed positive inotropic effect of mild ketosis in patients with heart failure with reduced ejection fraction (HFrEF). Purpose To evaluate the acute hemodynamic effect of oral administration of beta-hydroxybutyrate (OHB) in patients with HFrEF and low cardiac output syndrome. Methods Patients with acutely decompensated HFrEF treated with inotropic therapy were randomized (1:1) to enteral bolus of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) administered three times with 3-hour intervals or to euvolemic placebo. The serum concentration of OHB, biochemical markers, and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were repeatedly measured before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 20 patients with decompensated HFrEF (age: 57 ± 8 years; left ventricular ejection fraction: 21 ± 4%; non-ischemic cardiomyopathy: 16 [80%], median INTERMACS class: 3 [IQR 2 - 4]), who were treated with milrinone (0.5 ± 0.1 ug/kg/min, n=18) or levosimendan (0.1 ug/kg/min up to 25 mg, n=2). Patients in the OHB group (n = 10) did not differ from the placebo group (n = 10) in baseline clinical, biochemical, hemodynamic or echocardiographic characteristics. Baseline OHB concentration was normal (<0.6 mmol/L) in all patients. Administration of OHB increased serum concentration from 0.3 ± 0.2 mmol/L to a maximum of 2.4 ± 0.7 mmol/L (<0.001). Concentrations of OHB peaked at 1.5 ± 0.5 hours after administration of each OHB drink, and the maximum concentration was achieved at 4.1 ± 2.5 hours (Figure 1). No changes in OHB concentration were observed in the placebo group. In both study groups, there was a significant increase of CI at 3 hours compared to baseline, but the increase was significantly greater in the OHB group (OHB: 3.2 ± 0.6 vs. 2.1 ± 0.4 L/min/m2; placebo: 2.3 ± 0.4 vs. 2.0 ± 0.3 L/min/m2; both p<0.001 compared to baseline; p < 0.001 for OHB vs. placebo at 3 hours). The maximum relative increase of CI was 60 ± 24% in the OHB group (p <0.001) and 18 ± 8% in the placebo group (p< 0.01). The change of CI correlated with the change of OHB concentration in the OHB group (r = 0.58, p<0.001) but not in the placebo group (r = 0.1, p = 0.3). The changes in CI were not related to heart rate or concentration of norepinephrine, which did not change significantly throughout the study in both groups. Conclusion Oral administration of OHB leads to a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to inotropic support in patients with decompensated HFrEF.

TRPC6 modulates zinc mobilization to regulate stretch-induced increases in myocardial contractility

TRPC6 modulates zinc mobilization to regulate stretch-induced increases in myocardial contractility

Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM.

This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in essential (ELC, MYL3 gene) or regulatory (RLC, MYL2 gene) light chains of myosin. Phosphomimetic S15D-RLC was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild-type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by the S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted with fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared with those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM-treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice.

Contractile function of fasting and digesting broad-snouted caiman (Caiman latirostris)

Feeding regimes are a critical process to ensure survival and reproduction, which modulate several behavioral and physiological patterns of ectotherms, especially cardiovascular adjustments. However, crocodilian myocardial contractile function after food intake remains understudied. We investigated the importance of ventricular myocardial contractility during digestion in the broad-snouted caiman, Caiman latirostris Daudin, 1801. Isometric ventricle preparations and Ca2+-handling protein expression were used to investigate the effects of prolonged fasting (30 days) and feeding (48 h after feeding on meals at 15% of body mass) on cardiac function. Upon feeding, there was no significant difference in relative ventricular mass. The cardiac response of the caiman to digestion was characterized by upregulation of the Na+/Ca2+ exchanger expression and an increase in myocardial contractility (positive inotropism and lusitropism) within the physiological range of heart rate. The digesting caiman's ventricular myocardium was able to maintain faster kinetics of contraction and relaxation, allowing for significantly increased cardiac pumping capacity at higher pacing frequencies. Our results demonstrated that the myocardium of broad-snouted caimans exhibits specializations in excitation–contraction coupling, which can provide a means to support high cardiovascular performance during digestion.

Stretch-induced reactive oxygen species contribute to the Frank-Starling mechanism.

Myocardial stretch physiologically activates NADPH oxidase 2 (NOX2) to increase reactive oxygen species (ROS) production. Although physiological low-level ROS are known to be important as signalling molecules, the role of stretch-induced ROS in the intact myocardium remains unclear. To address this, we investigated the effects of stretch-induced ROS on myocardial cellular contractility and calcium transients in C57BL/6J and NOX2-/- mice. Axial stretch was applied to the isolated cardiomyocytes using a pair of carbon fibres attached to both cell ends to evaluate stretch-induced modulation in the time course of the contraction curve and calcium transient, as well as to evaluate maximum cellular elastance, an index of cellular contractility, which is obtained from the end-systolic force-length relationship. In NOX2-/- mice, the peak calcium transient was not altered by stretch, as that in wild-type mice, but the lack of stretch-induced ROS delayed the rise of calcium transients and reduced contractility. Our mathematical modelling studies suggest that the augmented activation of ryanodine receptors by stretch-induced ROS causes a rapid and large increase in the calcium release flux, resulting in a faster rise in the calcium transient. The slight increase in the magnitude of calcium transients is offset by a decrease in sarcoplasmic reticulum calcium content as a result of ROS-induced calcium leakage, but the faster rise in calcium transients still maintains higher contractility. In conclusion, a physiological role of stretch-induced ROS is to increase contractility to counteract a given preload, that is, it contributes to the Frank-Starling law of the heart. KEY POINTS: Myocardial stretch increases the production of reactive oxygen species by NADPH oxidase 2. We used NADPH oxidase 2 knockout mice to elucidate the physiological role of stretch-induced reactive oxygen species in the heart. We showed that stretch-induced reactive oxygen species modulate the rising phase of calcium transients and increase myocardial contractility. A mathematical model simulation study demonstrated that rapid activation of ryanodine receptors by reactive oxygen species is important for increased contractility. This response is advantageous for the myocardium, which must contract against a given preload.

The role of iNOS inhibition in the mechanism of the cardioprotective effect of new GABA and glutamic acid derivatives in the model of acute alcoholic myocardial injury in rats.

The cardioprotective effects of new derivatives of glutamic acid (glufimet) and GABA (mefargin) were studied in rats exposed to acute alcohol intoxication (AAI) under conditions of selective blockade of inducible NO-synthase (iNOS). AAI induced a pronounced decrease in the contractile function of the myocardium during exercise tests (load by volume, test for adrenoreactivity, isometric exercise), caused mitochondrial dysfunction and increased processes of lipid peroxidation (LPO) in heart cells. A decrease in NO production during iNOS inhibition and AAI improved the respiratory function of mitochondria, a decreased the level of LPO products, and increased mitochondrial superoxide dismutase activity of heart cells. This led to an increase in myocardial contractility. The studied compounds, glufimet and mefargin, caused a statistically significant increase in the rates of myocardial contraction and relaxation, left ventricular pressure, and also reduced NO production. This was accompanied by a decrease in the intensity of LPO processes and an increase in the respiratory control ratio (RCR), reflecting the coupling between respiration and phosphorylation processes during activation of the respiratory chain complexes I and II. The decrease in NO concentration during selective blockade of iNOS and administration of the studied substances was less pronounced than without blockade of the enzyme. This suggests the putative effect of new derivatives of neuroactive amino acids on the NO system.

Study to relate of the coronary collareral circulation with major adverse cardiac events after percutatnenous coronary invervention in st-elevation myocardial infarction

Background: The presence of good coronary collateral circulation (CCC) can protect and preserve myocardium from ischemia, increase myocardial contractility, and reduce adverse clinical events. However, its impact on mortality is still a topic of debate, particularly in acute coronary syndrome (ACS). The aim of this study was to investigate the association of CCC with cardiac risk factors and in-hospital mortality in patients hospitalized with a diagnosis of ACS.
 Methods: The study population included 200 patients with ST – elevation myocardial infrarction who underwent coronary angiography and were found to have TIMI flow coronary 0 or 1. The CCC was graded according to the Rentrop classification. The patients were classified into a poor CCC group (Rentrop grades 0-1, n=161) or a good CCC group (Rentrop grades 2-3, n=39). Following of major adverse cardiac events about 30day after PCI.
 RESULTS: Patients with good CCC had time onset chest pains (p = 0,001), higher rate of Killip class of at least 2 at admission (p = 0,031), peak troponin T (p = 0,037), lacticemia lower (p = 0,03), multivessel lesion upper (p = 0,03) with the patients with poor CCC. MACE of patients with good CCC nosignificant with the patient with poor CCC (OR=3,9, 95%CI[0,5- to 30,5], mortality (HR 2,5, 95%CI[0,31-19,2], p=0,45), unplanned target vessel revascularisation (TVR) (HR 28,8 (0.006 to 1.4), p=0.44), comelack in-hospital by cardiovascular causes (HR 1,06, 95%CI[0,29 to 3,7]. P=0,93). Increase left ventricular ejection fraction after 30day in patients with good CCC upper patients with poor CCC (p=0,004).
 CONCLUSION: In contrast to previous studies, our study did not confirm a beneficial role of good CCC in patients with ST – elevation myocardial infarction. The presence of good CCC was even independently associated NYHA grades, Killip grades, peak troponin T, lacticemia and left ventricular ejection fraction.

Вплив L-аргініну на клінічний перебіг і параметри гемодинаміки у хворих на ішемічну хворобу серця на тлі анемічного синдрому у пацієнтів середнього і старшого віку

The purpose of the study was to evaluate hemodynamic changes in middle-aged and older patients with coronary artery disease and anemia, against the background of standard therapy, as well as in combination with L-arginine. Materials and methods. 53 patients (35 women and 18 men) with stable ischemic heart disease and mild to moderate anemia (mean age 73.1 ± 1.2 years old) were examined. Among them, there were 24 (45.3%) patients with HF I, 21 (39.6%) patients with HF 2A, and 8 (15.1%) patients with HF 2B. The control subgroup (subgroup 1) consisted of 24 patients who received standard therapy for coronary artery disease and anemia. The remaining 29 people, in addition to standard therapy, additionally received L-arginine according to the scheme and made up the 2nd subgroup of the study. The follow-up period for patients was 6 months. An anamnesis was collected from all patients, the clinical picture of the disease was assessed, blood pressure and heart rate were measured, clinical and biochemical blood tests were studied, ECG and ECHO-CG were recorded. The effect of treatment with iron preparations was assessed by the dynamics of iron metabolism parameters. In the course of the ECHO-CG study, the main structural-geometric and functional parameters of the left ventricle were determined. Results and discussion. Under the influence of standard therapy and an increase in hemoglobin levels to normal levels (from 114.8 ± 1.4 g/l to 131.9 ± 1.1 g/l in the first subgroup; from 112.3 ± 2.1 g/l to 140.0 ± 1.3 g/l in the second subgroup (p<0.001 between subgroups after treatment) [17], complaints of general weakness, shortness of breath and palpitations decreased and the general condition of patients improved (blood pressure, heart rate, respiratory rate parameters normalized; there was a decrease or elimination of edema) in both clinical groups. But in patients who additionally received L-arginine, the intensity of manifestations of general weakness and palpitations were significantly less (p<0.001 and p<0.05 between subgroups). Against the background of standard therapy, symptoms such as dyspnea, edema, and pain in the heart area also decreased in both subgroups, but the effect of L-arginine on these symptoms was more noticeable. According to the results of the ECHO-CG study, in patients with coronary artery disease and anemia, a statistically significant recovery of structural and geometric parameters of the myocardium was observed: a decrease in end-diastolic and end-systolic volume and an increase in myocardial contractility in both subgroups, however, against the background of additional intake of L-arginine, the dynamics of indicators was more expressed; regression of signs of left ventricle hypertrophy. Conclusion. The results of the study showed the positive effect of L-arginine on cardiac remodeling and the clinical condition of middle-aged and older patients. Treatment with L-arginine did not cause side effects and did not require discontinuation of the drug

Acute hemodynamic effect of ketone bodies in patients with decompensated heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Chronically failing heart increases utilization of ketone bodies as an energy substrate. Purpose This study investigated feasibility, safety and acute hemodynamic effect of exogenous ketosis induced by administration of beta-hydroxybutyrate (OHB) in patients with decompensated heart failure and low cardiac output syndrome. Methods Patients with acutely decompensated heart failure with reduced ejection fraction (HFrEF), who were on inotropic support for at least 24 hours (milrinone 0.5±0.1 ug/kg/min), were given oral solution of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) in 3-hour intervals up to a total dose of 75g. Serum concentration of OHB and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were measured repeatedly before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 8 patients with decompensated HFrEF (male/female gender: 6/2; age: 58 ± 6 years; left ventricular ejection fraction: 19 ± 5%; non-ischemic/ischemic cardiomyopathy: 7/1). The baseline OHB concentration was 0.4 ± 0.2 mmol/L (normal range: 0 - 0.6 mmol/L). Mild ketosis (1.8 ± 0.6 mmol/L) was induced in all patients within one hour after administration of OHB. The maximum OHB concentration (2.5 ± 0.8 mmol/L) was reached after a median of 5 hours (IQR, 2 to 7 hours). No complications occurred except of temporary dyspepsia in one patient. Within 3 hours after administration of OHB, the CI increased from the baseline by 39 ± 25% (CI 3.4 ± 0.8 vs. 2.5 ± 0.5 L/min/m2; absolute increase of 1.0 ± 0.6 L/min/m2, p = 0.003). The maximum increase of CI reached 52 ± 20% (1.2 ± 0.4 L/min/m2 from the baseline, p <0.001) and it was observed after a median of 5 hours (IQR 3 to 8 hours). After 24 hours, CI returned to the baseline values (p = 0.4). The increase of CI was nor related to changes in the heart rate (at baseline vs. at the maximum CI: 101 ± 5 vs. 103 ± 6 beats/min, p = 0.5). Conclusion Induction of mild ketosis by administration of OHB on top of established inotropic therapy caused a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to the inotropic support in patients with decompensated HFrEF.

Regional Left Ventricular Myocardial Injury and Function Characterisation by Cardiac Magnetic Resonance Imaging in a Sheep Model of Myocardial Infarction

Left ventricular (LV) remodelling following a myocardial infarction(MI) elicits different responses in infarct and remote LV, with prior studies reporting increased contractility in the latter. We explored the relationship between myocardial injury and its functional consequences using a combination of 3D late gadolinium enhancement (LGE), feature tracking (FT) cardiac magnetic resonance (CMR) and autopsy findings in a sheep model of MI. MI was induced in sheep (n=11) by coronary artery ligation under general anaesthesia. Baseline (pre-MI) and follow-up (15d post-MI) CMR exams were performed for cine imaging. LGE imaging was performed using a 3D inversion recovery fast low angle shot (IR-FLASH) sequence in the follow-up examination. MI size was confirmed at post-mortem. Regions of MI identified by imaging were compared with post-mortem findings using AHA LV segmentation. The sensitivity and specificity of the LGE imaging was calculated and compared to post-mortem using McNemar’s test. FT was applied to the cine imaging to quantify regional circumferential strain (CS). The percentage change in regional CS was calculated for each segment (Data: mean±SD; *p<0.05). LGE detected MI with a sensitivity of 90.6% and specificity of 96.4% (p=0.7). LV ejection fraction (EF) was 55.7±5.6% post-MI. Percentage changes in regional CS were -34.3±13.8% and -17.4±30.7% in AHA segments 13 and 16, respectively, while other segments exhibited increased CS (range=+0.1% to +28.7%). Our novel application of 3D IR-FLASH and FT provided comprehensive visualisation of LV injury and function in the setting of MI. Our data reproduces prior descriptions of compensatory increases in myocardial contractility in remote regions in STEMI patients with ≥50% EF [[1]Leung S.W. Ratajczak T.M. Abo-Aly M. Shokri E. Abdel-Latif A. Wenk J.F. Regional end-systolic circumferential strain demonstrates compensatory segmental contractile function in patients with ST-segment elevation myocardial infarction.J Biomech. 2021; 129 (110794)Crossref PubMed Scopus (1) Google Scholar] and a canine model of MI [[2]Lew W.Y. Chen Z.Y. Guth B. Covell J.W. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle.Circ Res. 1985; 56: 351-358Crossref PubMed Scopus (112) Google Scholar].

Non-invasive Systemic Hemodynamic Index in Vascular Risk Stratification Tailored for Hypertensives.

Vascular dysfunction is a key hallmark of hypertension and related cardiovascular outcomes. As a well-known hemodynamic disease, hypertension is characterized by abnormal ventricular-vascular interactions. Complementing non-invasive systemic hemodynamics in hypertensive vascular risk assessment is of promising significance. We aimed to investigate the effects of abnormal hemodynamic states other than elevated blood pressure on vascular damage and establish a united index of systemic hemodynamics for generalized vascular risk evaluation. Non-invasive systemic hemodynamics, assessed by impedance cardiography, was compared among blood pressure stages. Vascular function was evaluated by flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV). Systemic hemodynamics was obtained from a total of 88 enrollees with a mean (±SD) systolic blood pressure 140 (±17) mm Hg, and aged 17 to 91 years. Both stroke systemic vascular resistance index and left stroke work index exhibited a significant alteration among blood pressure stages (p < 0.001; p = 0.01, respectively), whereas heterogeneous hemodynamic and vascular function subsets existed within similar blood pressure. In addition, blood pressure categories failed to recognize between-group differences in endothelial dysfunction (p = 0.88) and arterial stiffness (p = 0.26). An increase in myocardial contractility and a parallel decrease in afterload was associated with the decline of vascular dysfunction. Systemic Hemodynamic Index (SHI), as a surrogate marker, demonstrated a significantly negative correlation with vascular damage index (VDI, r = −0.49, p < 0.001). These findings illustrate that systemic hemodynamics underlying hypertensives provides more vascular information. The SHI/VDI score may be a feasible tool for cardiovascular function assessment.

Hypertonic saline for goal-directed therapy guided by Capstesia in gastrointestinal surgery: arandomized controlled study.

Goal-directed fluid therapy (GDT) aims to increase stroke volume and cardiac output and improve gut perfusion. Hypertonic saline (HS) can restore the macro-and micro-circulation, increase myocardial contractility, and reduce tissue edema. Therefore, we aimed to investigate the efficacy of intraoperative HS administration in GDT during gastrointestinal (GI) surgery. Forty patients who underwent GI surgery under general anesthesia were enrolled in this randomized controlled study. Patients received boluses of either lactated Ringer's (LR) solution, or 3% HS solution guided by an algorithm dependent on asmartphone application for estimations of pulse pressure variation (PPV). The primary outcome was the total amount of administered intraoperative crystalloid fluids in both groups. Serum sodium and time to first bowel movement after surgery were also recorded. In the HS group, patients received 1262.50 ± 318.25 mL of crystalloids compared to 2667.50 ± 670.29 mL received by patients in the LR group (P 0.05. The use of HS solution for GDT in GI surgery resulted in abeneficial reduction in positive fluid balance and possibly earlier resumption of bowel movements.

Stymulacja modulująca kurczliwość mięśnia sercowego — opis przypadku i przegląd piśmiennictwa

Cardiac contractility modulation (CCM) is a new implantable device that transmits electrical impulse to the heart during the absolute refractory period, which leads to an increase in myocardial contractility. This pacemaker works on several molecular levels and is dedicated to patients with heart failure (HF). The therapeutic effect is mainly due to the improvement in the circulation of calcium ions inside the cardiomyocytes. The final CCM effect leads to improved exercise capacity, increased quality of life, decreased symptoms and the number of hospitalizations as the results of HF. Device is an important alternative for patients with ineffective pharmacological therapy, who are not eligible for CRT implantation due to the narrow QRS complex, have a decreased ejection fraction, and in the New York Heart Association scale they were classified on the II–III degree. Previous studies have not demonstrated the impact of CCM on life expectancy. The effect of cardiac contractility modulation device on the improvement of everyday functioning and the reduction of hospitalization has been proven, which is important in the long-term perspective for both individual patients and the entire health care system. The case report shows an example of a patient for whom CCM was an addition to treatment.

The use of methods of spatial displacement of the myocardial structure (speckle tracking) to determine the indications for coronary angiography in patients suffering from coronary heart disease

The indicators of global and segmental longitudinal deformation of the left ventricular myocardium are presented and analyzed in patients suffering from coronary heart disease. The latter, as before, remains one of the urgent diseases of the circulatory system. To verify and determine management tactics for patients suffering from coronary heart disease, coronary angiography is performed. Indications for its implementation are based on the results of exercise tests, in particular, stress echocardiography. However, its implementation can be difficult due to poor visualization of the walls of the left ventricle, and the conclusion is not without subjectivity. One of the modern methods for assessing the contractility of the left ventricular myocardium, both global and segmental, is the spatial displacement of the myocardial structure (speckle-tracking- echocardiography). The technique automatically calculates the longitudinal deformation of the myocardium, expressed as a percentage of the initial values. It was found that the global and segmental longitudinal deformation of the left ventricular myocardium in the majority of the evaluated segments in the examined patients did not differ before loading. When conducting a stress test, the exact opposite dynamics of changes in the parameters of the global and segmental longitudinal deformation of the left ventricular myocardium is observed. So, in patients with a high risk of complications of coronary heart disease, a decrease in these indicators was observed, in patients without a risk of complications, on the contrary, their increase was observed, which indicates an increase in myocardial contractility during physical exertion. It was revealed that the indicator of global longitudinal deformation of the left ventricular myocardium is highly informative. The lower value of the decrease in the global longitudinal deformation of the left ventricular myocardium was calculated, which can serve as an additional indication for coronary angiography.

Overfeeding During Lactation in Rats is Associated with Cardiovascular Insulin Resistance in the Short-Term.

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

Development of basic criteria for assessing the adaptation level of athletes-mountaineers’ organism to a mountain climate

Introduction. Mountain climbers’ activity is constantly accompanied by harsh ambient conditions. Changeable exogenous factors joint by reduced oxygen pressure considerably complicate athletes’ medical support and demand objective appraisal elaboration for the purpose of adaptation level timely correction. Aim. To develop the athletes’ body adaptation level’s criteria under extreme conditions of sport work. Materials and methods . Mathematical-statistical analysis of results of examenation of 62 climbers at the age of 30.5±3.6 years old was carried out using volumetric compression oscillometry method before, during and after sporting event. Results. As a result of the obtained data of volumetric compression oscillometry indicators’ analysis, mountain climbers were divided into three groups of kinetic blood circulation types, which were hypokinetic, eukinetic and hyperkinetic. Climbers with hyperkinetic blood type were not admitted to take part in sporting event. Statistically significant (p&lt;0.05) signs allowing to determine athlete’s organism adaptation level to external environment exogenous factors were specified. These features are diastolic blood pressure, lateral systolic blood pressure, average hemodynamic arterial pressure, arterial pulse pressure, energy consumption indicators for the movement of one liter of blood, total peripheral vascular resistance, specific peripheral vascular resistance, systolic pressure and linear circulation time. Conclusion. The analysis of volumetric compression oscillometry revealed significant (p&lt;0.05) criteria for evaluating the level of adaptation, where the change of adaptation level from the optimum condition to the violation of the regulation mechanisms of the organism was accompanied by an increase in myocardial contractility, heart rate, blood pressure, minute volume of blood flow and a decrease in stroke volume. These changes were confirmed by the transition to a more energy-intensive type of regulation of blood circulation at rest. Correlation between the increased intensity of the training process in the conditions of mountain climate and the increase of long-term hemodynamics was found, and the lack of timely correction of the adaptation level of organism contributed to the increase in infectious morbidity.

P2575Excess and deficiency of serotonin in embryogenesis affects the contractility of the right ventricle myocardium

Abstract Background Congenital heart disease (CHD) is one of the most common pathologies among congenital malformations in children. The incidence of CHD is currently more than 30% of all malformations. The most frequent and severe complication of CHD is pulmonary hypertension (PH). PH worsens the CHD prognosis, affects the survival rate of children, and increases the risk of disability and mortality. Experimental studies demonstrate a high correlation between the PH degree, concentrations of serotonin and its metabolites in the blood. The purpose of our study was to investigate the effect of excess and lack of serotonin in the embryonic period on the functioning of the heart in early postnatal ontogenesis. Methods Study was conducted according to “Principles of laboratory animal care”. The study was carried out on pregnant female Wistar rats and their offspring at the age of 14 days. Myocardial contractility in vitro was studied on myocardial strips of right ventricle. The amplitude-time characteristics of the contraction were calculated by the method of S. Laer 1998. The following series of experiments were conducted: 1. Pregnant females, starting from the 11th day of pregnancy for 10 days were injected intraperitoneally: group 1 - serotonin synthesis inhibitor (p-chlorophenylalanine) at a dose of 100 mg/kg; group 2 - selective serotonin reuptake inhibitor (fluoxetine) at a dose of 50 mg/kg; group 3 - (control group) - saline solution. Inotropic myocardial function was studied in the offsprings of each group at the age of 14 days. The reactions of the contraction of myocardial stripes of rat pups were evaluated in 2 batches: first on epinephrine and then on the calcium channel inhibitor (verapamil) at concentrations of 2.5 μM and in the reverse order. Results Our experiment demonstrates that the reaction of inotropic function of the right ventricle on epinephrine in 2 weeks of age rats is not affected by changes in serotonin metabolism in the embryonic period of development. Against the background of a pronounced positive effect from the use of epinephrine, verapamil was used to inhibit calcium channels. We observed a significant reduction in the force of contraction by 83.41±3.14% in the control group, by 71.42±2.95% in the group with an excess of serotonin and by 63.97±7.93% in group with serotonin deficiency. In the next series of experiments, verapamil was first applied, resulting the decrease of contraction strength by 78.58±1.71% in the control group, by 80.81±7.33% in the myocardium of rats with an excess of serotonin and by 67.70±4, 66% in the group with serotonin deficiency. Subsequent exposure of epinephrine led to an increase in myocardial contractility equally in all groups at 132–135%. Conclusion Violation of serotonin metabolism during embryogenesis affects the regulation of contractility (force of contraction) of the right ventricle. Acknowledgement/Funding This work was supported by the Ministry of Science and Education of Republic of Kazakhstan [grant number AP05136034]

P621Variation of global longitudinal strain (2D STE) with passive leg lifting maneuver: a marker of myocardial functional reserve?

Abstract Introduction In a normal heart, the passive leg lifting maneuver (LLM) will result in an increase in myocardial contractility, according to the mechanistic concept of the Frank-Starling law. With the progression of myocardial disease this ability is impaired and the myocardial functional reserve (mFR) is reduced (Figure1 – Panel A). The variation of left ventricular global longitudinal strain (as an index of contractile function) with LLM may thus represent a marker of left ventricular mFR. Purpose To assess the variation of left ventricular global longitudinal strain (LV GLS) with LLM as a marker of mFR in a healthy population and in patients with myocardial disease (hypertrophic myocardiopathy - HCM and systolic dysfunction patients – SystDysf. Methods and results We evaluated the variation of LV GLS by 2-dimensional Speckle Tracking Echocardiography (2D-STE), in response to passive LLM, in a population of 103 individuals (54 healthy individuals, 28 HCM patients and 21 left ventricular SystDysf patients). Clinical, demographic and echocardiographic parameters (including LV longitudinal mechanics obtained with 2D-STE before and after LLM) were described. The population had a mean age of 46±18 years and 55% were women. Increased venous return to the heart during LLM was confirmed by an increase in the maximal diameter of the inferior vena cava (15,1±3,6 vs 20,6±3,8 mm, p&lt;0.001). There was a significant variation of LV GLS in healthy individuals submitted to LLM (−20,58±3,0 vs −21,5±2,6%, p=0,02, Δ 0,6%, 95% CI 0,1–1,1%). Regarding the HCM and SystDysf groups, no significant change in LV GLS was observed with LLM (−13,2±2,8 vs −12,3±2,9%, p=0,12, Δ +0,6%, 95% CI −1,4 to 0,18% and −10,2±2,5 vs 10,2±2,7%, p=0,79, Δ 0,08%, 95% CI −0,7 to 0,5%, respectively). Figure 1 (Panel B) Conclusion To our knowledge, this is the first report describing the use of LV GLS and LLM to assess mFR in this clinical setting. The absolute increase of LV GLS in the healthy population suggests that this may be a reliable method and a sensitive marker to assess the mFR. Conversely, patients with HCM and with SystDysf show poor or no response to the LLM, suggesting, as expected, a low myocardial functional reserve. Given the non-invasiveness and cost-effectiveness nature of this technique, we suggest that this maneuver could pose a feasible way to assess mFR. Further studies are needed to validate this technique and to assess the role of mFR by 2D-STE as a prognostic marker.

3077Load dependency of left ventricular longitudinal strain by 2D-speckle tracking echocardiography: myth or reality?

Abstract Background 2D-speckle tracking echocardiography (2D-STE) derived strain measurements has been proposed as a non-invasive measure of myocardial deformation and function. However, the effects of left ventricular (LV) loading conditions on 2D-STE derived LV longitudinal strain (GLS) have not been totally elucidated and the results of some studies regarding the load dependency of GLS are controversial. Purpose To characterize the effects of acute load change (preload increase) on LV GLS. Methods and results We evaluated the variation of LV GLS by 2D-STE, in response to a preload increasing maneuver (leg lifting maneuver – LLM), in a population of 30 healthy individuals. Clinical, demographic and echocardiographic parameters (including LV longitudinal mechanics obtained with 2D-STE before and after LLM) were described. The population had a mean age of 27±4 years and 73% were women. Increased preload to the heart with LLM was confirmed by an increase in the maximal diameter of the inferior vena cava (16±3.5 vs 22±3.3 mm, p&lt;0.01). No significant changes in left atrial volume, LV ejection volume and LV ejection fraction were observed in response to the LLM. There was a significant variation of global LV GLS (−21.9±2.3 vs −23.2±1.6%, p&lt;0.001, Δ 1.25%, 95% CI 0.5–1.91) – figure. An increase in right ventricular longitudinal function with LLM (TAPSE 22.5±5.4 vs 25.5±0.5 mm, p=0.005, Δ 2.9, 95% CI 0.9–4.8) was also observed. Conclusion To our knowledge this is the first study performed to assess the effect of preload increase in GLS using the LLM in healthy individuals. In this study, the absolute LV GLS value increased significantly in response to preload increase (LLM). The dependence of GLS on preload is in accordance with the Frank-Starling Law, in which an increase in preload in a healthy individual lead to an increase in myocardial contractility. These findings suggest that LV GLS is a sensitive parameter for detecting subtle changes in LV longitudinal function.

3071Peptidomimetic targeting of CavBeta2 improves contractility in models of senescence- or genetically (MYBPC3 KI)-induced heart failure

Abstract Background L-type calcium channel (LTCC) trafficking controls LTCC density at T-tubule levels for optimal Excitation-Coupling (EC) and resultant adaptive heart work. In some forms of heart failure (HF), abnormalities in calcium-induced calcium-release have been proposed to arise from alteration of T-tubular dyad architecture (LTCC-RyRs) associated with impaired LTCC density. Recently, the R7W-MP peptide, working as a binder of the LTCC Cavβ2 chaperone, was shown to restore the altered density of LTCC current by both promoting forward and reducing reverse trafficking, which consequently improved cellular calcium homeostasis. Accordingly, R7W-MP improved the impaired cardiomyocyte calcium current density and the reduced Ejection Fraction (EF%) in a pharmacologically-induced diabetes model (STZ mice). We aimed to investigate further the benefit to improve LTCC trafficking pathway with R7W-MP in a more physiological model of HF (senescent mice) and in a Dilated Cardiomyopathy (DCM) model (HO MYBPC3 targeted KI mutant). Methods Senescent male C57Bl/6J mice (26 months) or HO MYBPC3 KI male mice (2 months) were treated with R7W-MP (3 mg/kg/d IP for 3 days). Echocardiographies (echo) were conducted before treatment and 4-hours after the last injection. When applied, Pressure-Volume (PV)-loop investigations were conducted one day post-echo 4 hours following an additional R7W-MP injection. Results In senescent mice population, HF was characterized by a midrange ejection fraction (EF%= 43±2 vs 55±1 for young adult mice) associated with enlarged ventricles and decreased cardiac contractility. In contrast to a scrambled peptide (scrP), R7W-MP markedly increased EF% monitored by echo (+38%, 63±3 vs 45±1 for scrP, p≤0.001, n=6–7) without modification of heart rate. EF% improvement was confirmed by PV-loop analysis (78±3 vs 51±4 for scrP (+54%), p≤0.001, n=5), associated with a marked, although not significant, 2.5-fold increase in myocardial contractility [end systolic pressure volume relationship (ESPVR) = 12.1±3.6 vs 4.9±1.3 for scrP, p=0.10, n=4]. Stroke volume, cardiac output and end diastolic volume tended to decrease suggesting an impaired LV filling at this dose regimen. In the DCM model, HF was more severe with a dramatically low EF% (26±1, n=8), impaired myocardial contractility and a pronounced left ventricle enlargement. R7W-MP significantly increased EF% (+17%, reaching 31±1, p≤0.01, n=8) without altering heart rate. Stroke volume was significantly increased by 36% (32±3 vs 24±3 mL at baseline, p≤0.01), without any impairment of diastolic function. All parameters returned to baseline after a 2 week-washout period. Conclusions R7W-MP displays potent positive inotrope properties in senescent or DCM mice models. Although further asses tsments of diastolic function are needed (different dosing and duration), these data underline the potential benefit brought by LTCC trafficking modulation to treat severe dilated cardiomyopathy.