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.Methods:Following an overview lecture on the normal cardiac physiology, small groups of students under the guidance of a facilitator were provided with a worksheet consisting of questions related to background knowledge of cardiac physiology. Additional questions related to five valve disease and heart failure cases were also provided to promote the application of basic physiology principles to clinically relevant problems. The facilitator was provided with a guide to help facilitate the student interactions. Following the group worksheet activity, an animated slide presentation was shown to further engage student learning through active discussion of their worksheet answers.Results:Students were assessed by written examination, and were found to have a higher performance on the subset of questions related to this learning activity compared to the overall exam. Of the 175 students completing the exercise, 23 voluntarily provided feedback via a survey. Student surveys provided overwhelmingly positive feedback on the benefits of this active learning exercise.Discussion:Small group, active learning exercises benefited student learning by providing a framework for analysis, synthesis, and application of clinically relevant cardiac physiology concepts.

Basic cardiac electrophysiology is foundational to understanding normal cardiac function in terms of rate and rhythm and initiation of cardiac muscle contraction. The primary clinical tool for assessing cardiac electrical events is the electrocardiogram (ECG), which provides global and regional information on rate, rhythm, and electrical conduction as well as changes in electrical activity associated with cardiac disease, particularly ischemic heart disease. This teaching review is written at a level appropriate for first- and second-year medical students. Specific concepts discussed include ion equilibrium potentials, electrochemical forces driving ion movements across membranes, the role of ion channels in determining membrane resting potentials and action potentials, and the conduction of action potentials within the heart. The electrophysiological basis for the ECG is then described, followed by discussion on how ischemia alters cellular electrophysiology and ECG recordings, with particular emphasis on changes in T waves and ST segments of the ECG.

Exposure to acute heat or cold stress elicits numerous physiological responses aimed at maintaining body temperatures. Interestingly, many of the physiological responses, mediated by the cardiovascular and autonomic nervous systems, resemble aspects of, or responses to, certain disease states. The purpose of this Perspective is to highlight some of these areas in order to explore how they may help us better understand the pathophysiology underlying aspects of certain disease states. The benefits of using this human thermal stress approach are that (1) no adjustments for inherent comparative differences in animals are needed, (2) non-medicated healthy humans with no underlying co-morbidities can be studied in place of complex patients, and (3) more mechanistic perturbations can be safely employed without endangering potentially vulnerable populations. Cold stress can be used to induce stable elevations in blood pressure. Cold stress may also be used to model conditions where increases in myocardial oxygen demand are not met by anticipated increases in coronary blood flow, as occurs in older adults. Lower-body negative pressure has the capacity to model aspects of shock, and the further addition of heat stress improves and expands this model because passive-heat exposure lowers systemic vascular resistance at a time when central blood volume and left-ventricular filling pressure are reduced. Heat stress can model aspects of heat syncope and orthostatic intolerance as heat stress decreases cerebral blood flow and alters the Frank–Starling mechanism resulting in larger decreases in stroke volume for a given change in left-ventricular filling pressure. Combined, thermal perturbations may provide in vivo paradigms that can be employed to gain insights into pathophysiological aspects of certain disease states.

The goal of this project was to determine the effects of elevated cardiac temperature on preload-dependent and preload-independent regulation of left ventricular developed pressure (LVDP) in Langendorff-perfused, electrically paced (420bpm), Sprague-Dawley rat hearts. LVDP responses to steady-state isoproterenol infusions (10−8M) were determined at 37, 38, 39, and 40°C. Preload-dependent LVDP was determined at 37 and 40°C. Isoproterenol-induced LVDP and preload-dependent LVDP time controls were conducted in a separate group maintained at 37°C. The percent increase in LVDP during isoproterenol infusion significantly decreased at 40°C to 42±6 (SE), compared to 55±9, 55±6, and 53±7% at 37, 38, and 39°C, respectively. No significant differences were observed in the percent increase in LVDP to isoproterenol among the corresponding time controls (50±6, 47±3, 56±4, and 56±5%). Preload-dependent LVDP decreased across the experimental protocol, but there were no cardiac temperature effects. These data indicate that β-adrenergic mediated contractility is not altered by moderate heating from normothermia but is compromised at very high temperatures (40°C). Cardiac temperatures from 37 to 40°C do not alter the inherent preload-dependent LVDP, indicating that the Frank–Starling relation is not directly affected within this temperature range.

A mathematical model for hemoglobin oxygen saturation (StO 2 ) in skeletal muscle was derived from Poiseuille's equation, the Fick principle, and from published data on skeletal muscle hemodynamics and oxygen consumption (VO 2 ). The model shows that StO 2 is about 85% under resting conditions of blood flow, arterial oxygen content and VO 2 . A 40% reduction in flow caused either by reducing perfusion pressure or increasing vascular resistance reduces StO 2 from 85 to 75%. Flow reductions greater than 40% cause large, disproportionate decreases in StO 2 . At any given flow, a change in oxygen consumption (VO 2 ) causes a reciprocal change in StO 2 . If VO 2 decreases as flow decreases, which occurs in low flow states, a paradoxical increase in StO 2 may result. At a given perfusion pressure, increasing hematocrit (Hct) from 40 to 60% has no effect on StO 2 ; however, increasing the Hct to 80% reduces StO 2 because blood viscosity increases more than blood O 2 carrying capacity. Reducing Hct from 40 to 20% decreases StO 2 because O 2 carrying capacity decreases more than blood viscosity. The predictions of the model closely parallel clinical observations of thenar muscle StO 2 when monitored in normal subjects and trauma patients. Therefore, the model helps to explain how changes in patient status before and during resuscitation alter StO 2 .

The pathologies of both obesity and type 2 diabetes (T2DM) involve inflammatory processes that, especially in the coronary vasculature, lead to atherosclerotic lesion formation. The purpose of this study was to examine lesion formation and endothelial adhesion molecule expression in the coronary vasculature of control and type 2 diabetic mice. T2DM was induced in C57BL/6J mice by ad libitum high-fat, high-carbohydrate feeding for 15 weeks. Coronary lesion formation and VCAM-1, ICAM-1 and E-selectin adhesion molecule expression was determined by immunostaining of myocardial sections from both groups. Blood lipid profiles (total cholesterol, triglycerides, HDL and LDL) and glucose tolerance were also determined. Diabetogenic diet fed mice developed obesity, hyperglycemia and hyperinsulinemia characteristic of T2DM. T2DM mice were glucose intolerant with elevated blood glucose levels two hours post challenge (492 ± 43 vs 193 ± 23 mg/dl). All measured blood lipids were elevated in T2DM mice; however, no significant coronary lesions were found in either group. Immunostaining for VCAM-1, but not ICAM-1 or E-selectin, was increased in T2DM coronary vessels. Our results suggest that dyslipidemic type 2 diabetes in this mouse model is characterized by the initial steps of vascular inflammation that may lead to monocyte emigration and atherosclerotic lesion formation. Funded by Ohio Univ. and NIH AR048523-04.

Aim: The purpose of this study was to evaluate the hypothesis that acute hyperglycaemia in hearts of rats without diabetes alters coronary vascular responses to nitric oxide (NO), adenosine (ADO) and phenylephrine (PHE).Methods: Coronary function was studied in isolated, Langendorff-perfused, non-beating rat hearts that were perfused with an oxygenated Krebs-Henseleit solution containing 40 mM KCl to arrest the hearts. Changes in coronary vascular resistance were assessed by measuring changes in coronary perfusion pressure under constant flow conditions. Coronary responses to ADO, sodium nitroprusside (SNP), PHE and L-NAME (inhibitor of NO synthase) were studied either under normoglycaemic conditions (100 mg/dl D-glucose) or after 60 min of hyperglycaemic perfusion (500 mg/dl D-glucose). D-mannitol was used as a hyperosmotic control.Results: Hyperglycaemia did not alter vasodilator responses to ADO or SNP in the presence or absence of L-NAME. Furthermore, hyperglycaemia, compared with normoglycaemia, did not alter vasoconstrictor responses induced by L-NAME or PHE.Conclusions: Sixty minutes of exposure to 500 mg/dl of D-glucose in an isolated, non-beating, buffer-perfused rat heart did not significantly affect coronary vascular smooth muscle vasodilator responses to NO and ADO or alter alpha(1)-adrenoceptor-mediated vasoconstrictor responses to PHE. Furthermore, an unchanged vasoconstrictor response to L-NAME suggests that acute hyperglycaemia did not alter NO bioavailability.

Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ET(A)) and type B (ET(B)) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ET(A) and ET(B) receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary alpha(1)-AR function has not been examined. Therefore, we examined the effect of ET(A) and ET(B) receptor inhibition on coronary vasoconstriction to ET-1 and alpha(1)-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective alpha(1)-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with selective ET(A) or ET(B) receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET(B), but not ET(A), receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ET(A) receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET(B) inhibition abolished this response only in control hearts. In addition, ET(A) inhibition enhanced alpha(1)-AR-mediated vasoconstriction in T2D, but not control, hearts following l-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ET(B) receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ET(A) receptor subtype.

Aim: The aim of the present study was to examine nitric oxide (NO)- mediated coronary vascular responses in a mouse model of obesity and diabetes induced by a high-fat, high-carbohydrate diet. We hypothesized that endogenous NO bioavailability would be reduced in obese/diabetic mouse hearts due to enhanced superoxide anion production, and that coronary smooth muscle responses to exogenous NO would be reduced.Methods: Age-matched, male C57BL/6J mice were fed either a control diet or a high-fat, high-carbohydrate diet. After 15 weeks, the mice were anesthetized and their hearts were removed and perfused by the Langendorff method under constant flow conditions with an oxygenated buffer solution, and changes in coronary vascular resistance were quantified.Results: Mice fed the high-fat, high-carbohydrate diet became obese, hyperglycaemic and hyperinsulinaemic. Coronary vasoconstrictor responses to NO synthase inhibition by N-omega-nitro-L-arginine methyl ester were reduced in obese/diabetic mice; normal responses were restored by pretreatment with the superoxide dismutase mimetic 2,2,6,6tetramethyl-1-piperidinyloxy (Tempol). Coronary endothelium-independent vasodilation to the NO donor (+/-)S-nitroso-N-acetylpenicillamine (SNAP) was reduced; however, 8-bromo-cyclic guanosine monophosphate (cGMP)induced vasodilation was unchanged in obese/diabetic hearts.Conclusions: These findings suggest that in a diet-induced mouse model of obesity and diabetes, NO bioavailability is reduced by increased superoxide NO scavenging leading to impaired NO-mediated vasodilation. Furthermore, the attenuation of SNAP-induced vasodilation may be due to increased reactive oxygen species scavenging of exogenous NO because normal vascular smooth muscle NO signalling is maintained as indicated by similar 8-bromo-cGMP responses in control and obese/diabetic hearts.

Women generally exhibit angina rather than myocardial infarction as the first manifestation of heart disease. Postmenopausal use of hormone replacement therapy, specifically estrogens, is associated with reduced incidence of major cardiac events suggesting estrogen may protect the heart during ischemia. We recently showed that acute administration of conjugated equine estrogens prior to ischemia attenuated the ventricular arrhythmias of ischemia as well as those of reperfusion. This study looks at basal effects of estrogen on coronary blood flow and the effects of estrogen on regional blood flow during ischemia to determine if estrogen exerts its antiarrhythmic effects during ischemia by altering blood flow.