Synthesis and Biological Activity of the Pyridine-Hexacyclic-Steroid Derivative on a Heart Failure Model

Background: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. Objective: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. Methods: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. Results: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. Conclusion: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

Methodology of asystolic donor heart’s condition study in an experiment using small laboratory animals

In transplantation, there has always been an acute problem of the discrepancy between the number of donor organs and the number of recipients, including donor hearts. There are various ways to increase the pool of donor organs, one of them is the use of asystolic or non-heart-beating donors. Due to poor myocardial tolerance of ischemia during the asystole period, as well as because of the difficulties in diagnosing cardiac diseases of the asystolic donor, which can be contraindication to transplantation. Therefore, an in-depth study of the state of the myocardium in asystolic donors is required. Currently, there is no generally accepted protocol for working with asystolic heart donors. This protocol should include methods of heart conditioning and assessing of myocardium state. For its development we need more experimental and preclinical studies. A protocol for such a study is proposed. The modeling of an asystolic donor using rats is described on the basis of experimental work carried out by a team of authors. The article describes the following technical aspects: anesthetic guidance, asystole detection criterion, maintaining the rat body temperature in accordance with the human body temperature during cardiac arrest, surgical aspects of performing the main experimental model. The Langendorff model of isolated cardiac perfusion was chosen as the main model for assessing the state of the myocardium of a small laboratory animal. Intra-left ventricular pressure, volume of coronary blood flow, heart rate and the presence of post-reperfusion arrhythmias were selected as criteria for assessing the state of donor hearts. Assessment of the volume of damage to the donor heart is carried out using triphenyltetrazolium chloride staining of the donor organ.

PV Loops and REBOA During Hemorrhage and Resuscitation

Retrograde Endovascular Balloon Occlusion of the Aorta (REBOA) is frequently used in hemorrhagic shock to facilitate resuscitation. In theory, aortic occlusion increases afterload and focuses perfusion to the coronary arteries and great vessels; also to focus perfusion to the brain. It is, however, unknown exactly how and to what extent REBOA impacts cardiovascular parameters such as preload, afterload and contractility, or coronary artery blood flow. It is also not known how these parameters evolve over time during REBOA as it is shifted from fully to partially occlusive, or weaned down entirely. We aim to use left ventricular Pressure-Volume (PV) loop analysis and directly measure coronary flow in swine as they descend into hemorrhagic shock, are resuscitated with full aortic occlusion with REBOA, transitioned to partial aortic occlusion with REBOA, and then weaned completely off of the REBOA and are resuscitated. We will examine, specifically, measures of preload, afterload, contractility and coronary blood flow during each study time period (baseline, hemorrhagic shock, full aortic occlusion, partial aortic occlusion, and post-occlusion during resuscitation).

Quantitative Analysis of Myocardial Work by Non-invasive Left Ventricular Pressure-Strain Loop in Patients With Type 2 Diabetes Mellitus

Background: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular diseases. The aims of this study were to evaluate the changes in the left ventricular myocardial work in T2DM patients using the left ventricular pressure-strain loop (PSL) technique, and to explore the risk factors for the left ventricular myocardial work impairment.Methods: Fifty patients with T2DM and 50 normal controls (NCs) were included in the study. In addition to conventional echocardiography and two-dimensional speckle tracking echocardiography, the left ventricular myocardial work parameters were measured using PSL technology.Results: The absolute value for global longitudinal strain (GLS), global work index (GWI) and, global constructive work (GCW) were significantly decreased in the T2DM group (P < 0.05), while the left ventricular ejection fraction (LVEF) was not significantly different between the T2DM and NC groups. Multivariable linear regression analysis showed that hemoglobin A1c (HbA1c) was independently related to GWI (β = −0.452, P < 0.05), while HbA1c and the diabetes duration were independently related to GCW (β = −0.393, P < 0.05 and β = −0.298, P < 0.05, respectively).Conclusions: Changes in the left ventricular myocardial systolic function in T2DM patients were identified using PSL technology. HbA1c was shown to be an independent risk factor affecting GWI, while HbA1c and diabetes duration were demonstrated to be independent risk factors affecting GCW.

Clinical Assessment of Ventricular Wall Stress in Understanding Compensatory Hypertrophic Response and Maladaptive Ventricular Remodeling

Ventricular wall stress (WS) is an important hemodynamic parameter to represent myocardial oxygen demand and ventricular workload. The normalization of WS is regarded as a physiological feedback signal that regulates the rate and extent of ventricular hypertrophy to maintain myocardial homeostasis. Although hypertrophy is an adaptive response to increased biomechanical stress, persistent hypertrophic stimulation forces the stressed myocardium into a progressive maladaptive process called ventricular remodeling, consisting of ventricular dilatation and dysfunction in conjunction with the development of myocyte hypertrophy, apoptosis, and fibrosis. The critical determinant of this pathological transition is not fully understood, but an energetic mismatch due to uncontrolled WS is thought to be a central mechanism. Despite extensive basic investigations conducted to understand the complex signaling pathways involved in this maladaptive process, clinical diagnostic studies that translate these molecular and cellular changes are relatively limited. Echocardiographic assessment with or without direct measurement of left ventricular pressure used to be a mainstay in estimating ventricular WS in clinical medicine, but in recent years more and more noninvasive applications with magnetic resonance imaging have been studied. In this review article, basic clinical applications of WS assessment are discussed to help understand the progression of ventricular remodeling.

The Investigation of Combined Na+/Ca2+ Exchanger and the L-type Ca2+- Channel Inhibition in Langendorff Perfused Isolated Guinea Pig Hearts

Objective: The sodium/calcium exchanger (NCX) and the L-type Ca2+-channel (LTCC) are nowadays considered the major transmembrane transport mechanisms that control Ca2+ homeostasis. In pathophysiological conditions the altered function of these currents may influence the Ca2+ homeostasis and cardiac contractility and thereby, may enhance the development of severe tachyarrhythmias. The blockade of NCX current has been proposed as possible approach in the prevention and/or suppression of arrhythmias; however, this mechanism is not always favourable because the inhibition of both modes of NCX may induce Ca2+ overload. The decrease of the Ca2+ level by partial LTCC inhibition may be beneficial in increasing the antiarrhythmic efficacy. Therefore, the aim of our study was to investigate the antiarrhythmic effects of combined NCX and LTCC blockade in the ex vivo guinea pig arrhythmia model. Methods: We have performed Langendorff experiments in isolated guinea pig hearts. We have recorded electrocardiograms (ECG) and left ventricle pressure. We have applied 1 μM ORM-10962 (ORM), a compound that block NCX current and 30 nM nisoldipine for the inhibition of LTCC. Arrhythmias have been provoked by decreasing the activity of the sodium/potassium pump with 5 μM ouabain. Results: We found that neither LTCC nor NCX blockade alone increased, while the combined inhibition of the two currents significantly delayed (p<0.05) the mean time of appearance of ouabain-induced ventricular fibrillation. The heart f equency was affected by none of the drugs, only the left ventricular pressure (end-systolic and diastolic difference) was significantly elevated by ORM (p<0.001). Conclusion: In the Langendorff-perfused guinea pig heart, specific, combined NCX and LTCC blockade may be favourable than the inhibition of NCX or LTCC alone. However, further investigations are necessary to identify the pathological settings in which this combined cardiac drug therapy may be a potential new approach.

Abstract P471: Mechanisms Controlling Regression Of Cardiac Fibrosis By Removal Of Pressure Overload

Background: Antecedent conditions, like aortic stenosis, can induce left ventricular pressure overload (LVPO), that can lead to Heart Failure with Preserved Ejection Fraction (HFpEF). Myocardial fibrosis and stiffness are key characteristics of HFpEF. Cardiac fibroblasts are the primary cell type regulating ECM production and deposition. In previous studies, biopsies isolated at the time of SAVR surgery, to correct stenosis, and then at 1-year and 5-years post-SAVR showed reductions in hypertrophy and fibrosis demonstrating these processes can regress. However, cellular mechanisms, including fibroblast activity, are poorly defined. Objective: Define mechanisms that contribute to remodeling of ECM before and after LVPO. Methods: LVPO was induced using transverse aortic constriction (TAC). LVPO was relieved by removal of the band (unTAC) at 4 wks. Cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), and protein production was measured by histology and immunoblot for five time points: nonTAC, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, and 4wk TAC+4wk unTAC. Results: In response to LVPO, myocyte CSA increased by 23% at 2wk TAC and by 47% at 4wk. CVF increased by 64% and 204% at 2wk and 4wk TAC, respectively, versus nonTAC. In 2wk TAC hearts, SMA, a marker of fibroblast activation was increased as was production of two collagen cross-linking enzymes, lysyl oxidase (LOX) and LOXL2, in the absence of significant increases in markers of ECM degradation. After unloading, myocyte CSA decreased by 20% in 2wk unTAC versus 4wk TAC and CVF decreased by 38% in 4wk unTAC versus 4wk TAC. Coincident with decreases in CVF, levels of pro-MMP2 increased at 2wk unTAC as did levels of degraded collagen measured by collagen hybridizing peptide reactivity. Whereas markers of ECM deposition, LOX and LOXL2, were not increased in unTAC myocardium, a resurgence of SMA production occurred in 2wk unTAC. Conclusions: In LVPO hearts, hypertrophy was characterized by increases in myocyte CSA, greater CVF, and fibroblast activation with increased production of pro-fibrotic ECM. After unloading, hypertrophy and fibrosis significantly decreased accompanied by increases in ECM degrading activity and reductions in proteins that contribute to collagen assembly.

Impact of Arrhythmia on Myocardial Perfusion: A Computational Model-Based Study

(1) Background: Arrhythmia, which is an umbrella term for various types of abnormal rhythms of heartbeat, has a high prevalence in both the general population and patients with coronary artery disease. So far, it remains unclear how different types of arrhythmia would affect myocardial perfusion and the risk/severity of myocardial ischemia. (2) Methods: A computational model of the coronary circulation coupled to the global cardiovascular system was employed to quantify the impacts of arrhythmia and its combination with coronary artery disease on myocardial perfusion. Furthermore, a myocardial supply–demand balance index (MSDBx) was proposed to quantitatively evaluate the severity of myocardial ischemia under various arrhythmic conditions. (3) Results: Tachycardia and severe irregularity of heart rates (HRs) depressed myocardial perfusion and increased the risk of subendocardial ischemia (evaluated by MSDBx), whereas lowering HR improved myocardial perfusion. The presence of a moderate to severe coronary artery stenosis considerably augmented the sensitivity of MSDBx to arrhythmia. Further data analyses revealed that arrhythmia induced myocardial ischemia mainly via reducing the amount of coronary artery blood flow in each individual cardiac cycle rather than increasing the metabolic demand of the myocardium (measured by the left ventricular pressure-volume area). (4) Conclusions: Both tachycardia and irregular heartbeat tend to increase the risk of myocardial ischemia, especially in the subendocardium, and the effects can be further enhanced by concomitant existence of coronary artery disease. In contrast, properly lowering HR using drugs like β-blockers may improve myocardial perfusion, thereby preventing or relieving myocardial ischemia in patients with coronary artery disease.