Tune JD, Sturek M, Basile DP. Flipped classroom model improves graduate student performance in cardiovascular, respiratory, and renal physiology. The purpose of this study was to assess the effectiveness of a traditional lecture-based curriculum versus a modified "flipped classroom" curriculum of cardiovascular, respiratory, and renal physiology delivered to first-year graduate students. Students in both courses were provided the same notes and recorded lectures. Students in the modified flipped classroom were required to watch the prerecorded lectures before class and then attend class, where they received a quiz or homework covering material in each lecture (valued at 25% of the final grade) followed by a question and answer/problem-solving period. In the traditional curriculum, attending lectures was optional and there were no quizzes. Evaluation of effectiveness and student performance was achieved by having students in both courses take the same multiple-choice exams. Within a comparable group of graduate students, participants in the flipped course scored significantly higher (P Յ 0.05) on the cardiovascular, respiratory, and weighted cumulative sections by an average of Ͼ12 percentage points. Exam averages for students in the flipped course also tended to be higher on the renal section by ϳ11 percentage points (P ϭ 0.06). Based on our experience and responses obtained in blinded student surveys, we propose that the use of homework and in-class quizzes were critical motivating factors that likely contributed to the increase in student exam performance. Taken together, our findings support that the flipped classroom model is a highly effective means in which to disseminate key physiological concepts to graduate students. flipped classroom; didactic lectures; student performance AS ADVANCEMENTS in our understanding of key physiological mechanisms continue to expand, the challenge for educators to effectively disseminate increasing volumes of complex material to students is readily apparent. Along with the expansion of course content are studies that indicate that comprehension is enhanced when students are actively engaged in the learning process (1,3,8). This active engagement of students typically involves problem-based learning (PBL) modules with or without traditional didactic lectures to promote critical thinking and self-directed learning skills (2, 3, 7, 10). Although previous investigations have suggested that students' perceived understanding and performance can be improved by promoting active learning (3,4,9), the overall effectiveness of these approaches continues to be debated. In fact, a systematic review of PBL learning in preclinical medical education by Hartling et al. (5) in 2010 concluded that 22 yr of research does not unequivocally support that PBL enhances learning or impacts knowledge acquisition, although there are notable exceptions showing benefit (6). Therefore, research to elucidate the most effective methods to facilitate student learning and performance is greatly needed to guide...

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiologic mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review we highlight current knowledge regarding the pathophysiologic consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiologic and molecular mechanisms that may contribute to these adverse outcomes.

At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.

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. The purpose of this series of Comprehensive Physiology is to highlight current knowledge regarding the physiologic regulation of coronary blood flow, with emphasis on functional anatomy and the interplay between the physical and biological determinants of myocardial oxygen delivery.

Objective Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of eNOS by PKC-β. However, our understanding of how PVAT potentially contributes to coronary disease as a complication of obesity/metabolic syndrome (MetS) remains limited. The current study investigated whether PVAT derived leptin impairs coronary vascular function via PKC-β in MetS. Methods and Results Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw miniature swine for isometric tension studies. Endothelial-dependent vasodilation to bradykinin was significantly reduced in MetS. PVAT did not affect bradykinin-mediated dilation in arteries from lean swine, but significantly exacerbated endothelial dysfunction in arteries from MetS swine. PVAT-induced impairment was reversed by inhibition of either PKC-β with ruboxistaurin or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western and immunohistochemical analysis demonstrated increased PVAT-derived leptin and coronary leptin receptor (ObR) density with MetS. Coronary PKC-β activity was increased in both MetS arteries exposed to PVAT and lean arteries exposed to leptin. Finally, leptin-induced endothelial dysfunction was reversed by ruboxistaurin. Conclusions Increases in epicardial PVAT leptin exacerbate coronary endothelial dysfunction in MetS via a PKC-β-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.

Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 microm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1-3.0 microg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3-30.0 microg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 micromol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.

Background This investigation examined the mechanisms by which coronary perivascular adipose tissue (PVAT)-derived factors influence vasomotor tone and the PVAT proteome in lean vs. obese swine. Methods and Results Coronary arteries from Ossabaw swine were isolated for isometric tension studies. We found that coronary (P=0.03) and mesenteric (P=0.04), but not subcutaneous adipose tissue, augmented coronary contractions to KCl (20 mM). Inhibition of CaV1.2 channels with nifedipine (0.1 μM) or diltiazem (10 μM) abolished this effect. Coronary PVAT increased baseline tension and potentiated constriction of isolated arteries to PGF2α in proportion to the amount of PVAT present (0.1–1.0 g). These effects were elevated in tissues obtained from obese swine and were observed in intact and endothelium denuded arteries. Coronary PVAT also diminished H2O2-mediated vasodilation in lean, and to a lesser extent in obese arteries. These effects were associated with alterations in the obese coronary PVAT proteome (detected 186 alterations) and elevated voltage-dependent increases in intracellular [Ca2+] in obese smooth muscle cells. Further studies revealed that a Rho-kinase inhibitor fasudil (1 μM) significantly blunted artery contractions to KCl and PVAT in lean, but not obese swine. Calpastatin (10 μM) also augmented contractions to levels similar to that observed in the presence of PVAT. Conclusions Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (e.g. calpastatin), Rho-dependent signaling, and the functional contribution of K+ and CaV1.2 channels to smooth muscle tone.

The hypothesis that exercise-induced coronary vasodilation is a result of sympathetic activation of coronary smooth muscle beta-adrenoceptors was tested. Ten dogs were chronically instrumented with a flow transducer on the circumflex coronary artery and catheters in the aorta and coronary sinus. During treadmill exercise, coronary venous oxygen tension decreased with increasing myocardial oxygen consumption, indicating an imperfect match between myocardial blood flow and oxygen consumption. This match was improved after alpha-adrenoceptor blockade with phentolamine but was significantly worse than control after alpha + beta-adrenoceptor blockade with phentolamine plus propranolol. The response after alpha-adrenoceptor blockade included local metabolic vasodilation plus a beta-adrenoceptor vasodilator component, whereas the response after alpha + beta-adrenoceptor blockade contained only the local metabolic vasodilator component. The large difference in coronary venous oxygen tensions during exercise between alpha-adrenoceptor blockade and alpha + beta-adrenoceptor blockade indicates that there is significant feedforward beta-adrenoceptor coronary vasodilation in exercising dogs. Coronary venous and estimated myocardial interstitial adenosine concentrations did not increase during exercise before or after alpha + beta-adrenoceptor blockade, indicating that adenosine levels did not increase to compensate for the loss of feedforward beta-adrenoceptor-mediated coronary vasodilation. These results indicate a meaningful role for feedforward beta-receptor-mediated sympathetic coronary vasodilation during exercise.