Functional Adaptations in Coronary Reactivity following Healthy Pregnancy in Swine.

Introduction: This study was designed to test the hypothesis that coronary artery adaptations during the postpartum period are related to underlying reductions in endothelium-dependent relaxation and/or augmented smooth muscle vasoconstrictor responsiveness.

Methods: In vivo experiments were performed in control (nonpregnant) and postpartum swine 35-45 days of postdelivery, with isometric tension experiments performed in isolated coronary arteries from those animals.

Results: Coronary artery rings demonstrated increases in active tension generation following incremental increases in passive stretch with no differences between groups.

Impaired balance between coronary blood flow and myocardial metabolism in postpartum swine.

Understanding of the mechanisms contributing to the increased maternal susceptibility for major adverse cardiovascular events in the postpartum period remains poor. Accordingly, this study tested the hypothesis that the balance between coronary blood flow and myocardial metabolism is compromised during the puerperium period (35-45 days post-delivery) in swine. Systemic and coronary hemodynamic responses were assessed in anesthetized, open-chest control (nonpregnant) and puerperium/postpartum swine at baseline and in response to intravenous infusion of dobutamine (1-30 μg/kg/min).

Integrated modeling and simulation of recruitment of myocardial perfusion and oxygen delivery in exercise.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport.

Unraveling the Gordian knot of coronary pressure-flow autoregulation.

The coronary circulation has the inherent ability to maintain myocardial perfusion constant over a wide range of perfusion pressures. The phenomenon of pressure-flow autoregulation is crucial in response to flow-limiting atherosclerotic lesions which diminish coronary driving pressure and increase risk of myocardial ischemia and infarction. Despite well over half a century of devoted research, understanding of the mechanisms responsible for autoregulation remains one of the most fundamental and contested questions in the field today.

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response.

Chronic high-rate pacing induces heart failure with preserved ejection fraction-like phenotype in Ossabaw swine.

The lack of pre-clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. We examined whether chronic cardiometabolic stress in Ossabaw swine, which possess a genetic propensity for obesity and cardiovascular complications, produces an HFpEF-like phenotype. Swine were fed standard chow (lean; n = 13) or an excess calorie, high-fat, high-fructose diet (obese; n = 16) for ~ 18 weeks with lean (n = 5) and obese (n = 8) swine subjected to right ventricular pacing (180 beats/min for ~ 4 weeks) to induce heart failure (HF).

Acute SGLT-2i treatment improves cardiac efficiency during myocardial ischemia independent of Na/H exchanger-1.

Aims: Sodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ischemia. Sodium‑hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition.

Higher heart rate variability predicts better affective interaction quality in non-intimate social interactions.

Adaptive emotional responding is crucial for psychological well-being and the quality of social interactions. Resting heart rate variability (HRV), a measure of autonomic nervous system activity, has been suggested to index individual differences in emotion regulation (ER). As non-intimate social interactions require more regulatory efforts than intimate social interactions, we predicted that the association between HRV and affective interaction quality is moderated by the perceived intimacy of the exchange.

Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms.

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo.

Bioengineering Systems for Modulating Notch Signaling in Cardiovascular Development, Disease, and Regeneration.

The Notch intercellular signaling pathways play significant roles in cardiovascular development, disease, and regeneration through modulating cardiovascular cell specification, proliferation, differentiation, and morphogenesis. The dysregulation of Notch signaling leads to malfunction and maldevelopment of the cardiovascular system. Currently, most findings on Notch signaling rely on animal models and a few clinical studies, which significantly bottleneck the understanding of Notch signaling-associated human cardiovascular development and disease.

Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in K channels.

Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood.

Distinct hemodynamic responses to (pyr)apelin-13 in large animal models.

This study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure ( = 0.

Experimental animal models of coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed 'ischaemia and no obstructive coronary artery disease' (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive.

Disentangling the Gordian knot of local metabolic control of coronary blood flow.

Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation.

Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization.

The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300 mg PO) 24 h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period.

Small-Group Activity to Reinforce the Impact of Valvular Defects and Heart Failure on Cardiac Pressure-Volume Relationships.

Introduction: An important topic in cardiac physiology is the relationship between changes in intracardiac pressures and volumes during the cardiac cycle. This topic lends itself well to utilizing active learning principles to facilitate student understanding of pressure and volume changes in normal cardiac physiology and in the pathophysiology of valve disease and heart failure. We describe an active learning exercise regarding this topic that engages and facilitates student learning in a small-group setting.

Local metabolic hypothesis is not sufficient to explain coronary autoregulatory behavior.

The local metabolic hypothesis proposes that myocardial oxygen tension determines the degree of autoregulation by increasing the production of vasodilator metabolites as perfusion pressure is reduced. Thus, normal physiologic levels of coronary venous PO, an index of myocardial oxygenation, are proposed to be required for effective autoregulation. The present study challenged this hypothesis through determination of coronary responses to changes in coronary perfusion pressure (CPP 140-40 mmHg) in open-chest swine in the absence (n = 7) and presence of euvolemic hemodilution (~ 50% reduction in hematocrit), with (n = 5) and without (n = 6) infusion of dobutamine to augment MVO.

Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection vs. Insulin Alone in Type 2 Diabetes.

Context: It is unclear if effects of glucagon-like peptide-1 (GLP-1) and clinically available GLP-1 agonists on the heart occur at clinical doses in humans, possibly contributing to reduced cardiovascular disease risk.

Objective: To determine whether liraglutide, at clinical dosing, augments myocardial glucose uptake (MGU) alone or combined with insulin compared with insulin alone in metformin-treated type 2 diabetes mellitus (T2D).

Design: In a randomized clinical trial of patients with T2D treated with metformin plus oral agents or basal insulin, myocardial fuel use was compared after 3 months of treatment with insulin detemir, liraglutide, or combination detemir plus liraglutide added to background metformin.

Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K channels.

This study was designed to identify mechanisms responsible for coronary vasodilation in response to progressive decreases in hematocrit. Isovolemic hemodilution was produced in open-chest, anesthetized swine via concurrent removal of 500 ml of arterial blood and the addition of 500 ml of 37 °C saline or synthetic plasma expander (Hespan, 6% hetastarch in 0.9% sodium chloride).

Glucagon-Like Peptide 1 Receptor Activation Augments Cardiac Output and Improves Cardiac Efficiency in Obese Swine After Myocardial Infarction.

This study tested the hypothesis that glucagon-like peptide 1 (GLP-1) therapies improve cardiac contractile function at rest and in response to adrenergic stimulation in obese swine after myocardial infarction. Obese Ossabaw swine were subjected to gradually developing regional coronary occlusion using an ameroid occluder placed around the left anterior descending coronary artery. Animals received subcutaneous injections of saline or liraglutide (0.

Regulation of Coronary Blood Flow.

The heart is uniquely responsible for providing its own blood supply through the coronary circulation. Regulation of coronary blood flow is quite complex and, after over 100 years of dedicated research, is understood to be dictated through multiple mechanisms that include extravascular compressive forces (tissue pressure), coronary perfusion pressure, myogenic, local metabolic, endothelial as well as neural and hormonal influences. While each of these determinants can have profound influence over myocardial perfusion, largely through effects on end-effector ion channels, these mechanisms collectively modulate coronary vascular resistance and act to ensure that the myocardial requirements for oxygen and substrates are adequately provided by the coronary circulation.

Mutual reinforcement of pathophysiological host-microbe interactions in intestinal stasis models.

Chronic diseases arise when there is mutual reinforcement of pathophysiological processes that cause an aberrant steady state. Such a sequence of events may underlie chronic constipation, which has been associated with dysbiosis of the gut. In this study we hypothesized that assemblage of microbial communities, directed by slow gastrointestinal transit, affects host function in a way that reinforces constipation and further maintains selection on microbial communities.