Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Finally, GPR39 knockout mice are protected from myocardial ischemia compared to wild-type littermates. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease. One Sentence Summary: GPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.One Sentence SummaryGPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.

Geschlechts spezifische Unterschiede in der absoluten myokardialen Perfusion

Summary Aim: To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2 15O-PET). Results: Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml-1*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml-1*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml-1*min*ml; p = ns) showed sex-related differences. Conclusion: Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

Abstract 15436: Remote Ischemic Conditioning Modulates Myocardial Perfusion and Coronary Vascular Resistance in Ischemic and Non-ischemic Myocardial Territories in Humans

Purpose: Remote ischemic conditioning (RIC) confers protection against myocardial ischemia-reperfusion injury through cellular protective pathways but may also involve modulation of the myocardial perfusion (MP). We investigated whether RIC modulates MP and coronary vascular resistance (CVR) in ischemic and non-ischemic myocardial territories in humans. Methods: In a prospective, single blinded study, we studied 49 patients with suspected stable coronary artery disease. MP was quantified by 82 Rb-PET before and after RIC, and CVR was calculated as mean arterial pressure divided by MP. RIC was conducted as 4 cycles of 5 min upper arm ischemia followed by 5 min of reperfusion. A subsequent adenosine 82 Rb-PET stress scanning identified non-ischemic, reversibly and irreversibly ischemic myocardial segments by summed difference scores, and quantified coronary flow reserve (CFR). Results: Stress 82 Rb-PET data were available for 47 patients and identified 682 non-ischemic, 38 reversibly ischemic, and 37 irreversibly ischemic myocardial segments. Mean CFR was decreased in reversibly ischemic myocardial segments. Global MP and CVR were not affected by RIC (p=0.64 and p=0.53). RIC decreased MP and increased CVR in reversibly ischemic myocardial segments but not in non-ischemic or irreversibly ischemic myocardial segments (Table). Overall, CFR correlated with a change in MP and CVR by RIC (r 2 =0.08, p<0.001 and r 2 =0.10, p<0.001), and allowed identification of a cut-off of CFR<2.3 for a decrease in MP by RIC. Conclusion: RIC modulated MP and CVR dependent on the ischemic status of the myocardium and the vasodilatative capacity of the microcirculation. These findings support the assumption that gentle perfusion may be involved in the cardioprotective mechanisms underlying RIC.

Assessment of donor heart viability during ex vivo heart perfusion

Ex vivo heart perfusion (EVHP) may facilitate resuscitation of discarded donor hearts and expand the donor pool; however, a reliable means of demonstrating organ viability prior to transplantation is required. Therefore, we sought to identify metabolic and functional parameters that predict myocardial performance during EVHP. To evaluate the parameters over a broad spectrum of organ function, we obtained hearts from 9 normal pigs and 37 donation after circulatory death pigs and perfused them ex vivo. Functional parameters obtained from a left ventricular conductance catheter, oxygen consumption, coronary vascular resistance, and lactate concentration were measured, and linear regression analyses were performed to identify which parameters best correlated with myocardial performance (cardiac index: mL·min–1·g–1). Functional parameters exhibited excellent correlation with myocardial performance and demonstrated high sensitivity and specificity for identifying hearts at risk of poor post-transplant function (ejection fraction: R2 = 0.80, sensitivity = 1.00, specificity = 0.85; stroke work: R2 = 0.76, sensitivity = 1.00, specificity = 0.77; minimum dP/dt: R2 = 0.74, sensitivity = 1.00, specificity = 0.54; tau: R2 = 0.51, sensitivity = 1.00, specificity = 0.92), whereas metabolic parameters were limited in their ability to predict myocardial performance (oxygen consumption: R2 = 0.28; coronary vascular resistance: R2 = 0.20; lactate concentration: R2 = 0.02). We concluded that evaluation of functional parameters provides the best assessment of myocardial performance during EVHP, which highlights the need for an EVHP device capable of assessing the donor heart in a physiologic working mode.

Abstract 12899: A New Prognostic Marker for Functional Deterioration in Heart Failure: Coronary Vascular Resistance

Introduction: Heart failure (HF) is a challenging clinical syndrome with complex pathophysiology. Previous studies demonstrated that coronary flow reserve assessed by PET technique was impaired in HF. Transthoracic echocardiography (TTE) can provide reliable data for myocardial blood flow (MBF) which can be measured from coronary sinus (CS). In relation with MBF, coronary vascular resistance (CVR) can be evaluated. In this study, we aimed to evaluate the association of MBF and CVR with clinical data in HF. Methods: The MBF was measured in 100 patients (80 patients with HF (LVEF<30%) and 20 healthy control subjects. MBF was measured from anterograde CS flow TVI at PLAX RV inflow view and CS diameter at A2C view (2Πr2*TVI*heart rate) and indexed to left ventricular mass index. Patient group was categorized based on NYHA functional classes (NYHA FCs). Results: There was an incremental trend for MBF with advancing NYHA FCs (β=0.253, p=0.015). MBF was similar among HF patients due to NYHA FCs. However, MBF was higher in NYHA FC 4 group compared to healthy subjects (p=0.029). Also, CVR was lower in HF patients than the control group (11.15±6.54 vs.24.84±7.29, p<0.001). In the subgroup analysis, CVR was not statistically different between non-ischemic and ischemic etiology of HF (6.91±1.38 vs. 6.31±0.89, p=0.249). Additionally, CVR was significantly lower in NYHA FC 4 compared to other study groups. CVR was positively correlated with peak VO2 (β=0.596, p<0.001), and Seattle Heart Failure Model derived life expectancy (β=0.476, p<0.001) and negatively correlated with serum BNP level (β=-0.450, p=0.001), troponin I (β=-0.366, p=0.001) and serum uric acid level (β=-0.503, p<0.001). In multivariate analysis, CVR is an independent predictor of mortality (HR:0.763 95%CI:0.624-0.933 P=0.008). In ROC analysis, a cut of value 6.73 for CVR has a 74% sensitivity and 66.7 % specifity for prediction of mortality in HF(AUC 0.825 P<0.001). Conclusion: Our results showed that CVR was reduced with advancing FC in HF patients, despite MBF was similar among different FCs. In addition, CVR was significantly correlated with various prognostic markers in HF patients. Therefore, evaluation of MBF hemodynamics, particularly CVR, with TTE may utilize prognostic assessment of HF patients.

Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats

Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial β1- and β3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood-perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a β1-integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the β1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the β3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the β1-integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the β1- and β3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of β1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart.

Glutathione enhances endothelium-mediated control of coronary vascular resistance via a ROS- and NO intermediate-dependent mechanism

The purpose of this investigation was to determine the effects of acute physiological GSH administration on endothelium-mediated reduction in coronary vascular resistance (CVR) using isolated perfused Sprague-Dawley rat hearts. A dose-response curve to GSH was conducted to determine a threshold concentration of GSH. We demonstrate that 30 μM GSH was sufficient to reduce CVR, and maximal dilation was achieved with 1 mM. In subsequent experiments, GSH was administered at concentrations of 0 [control (CON)], 1 μM, or 10 μM (GSH10), and dose-response curves to the endothelial agonist bradykinin (BK) were constructed. These GSH concentrations were chosen because of the physiological relevance and because the effects of GSH on BK action could be assessed independent of baseline differences in CVR. Sensitivity to BK (EC50) was enhanced in GSH10 vs. CON ( P < 0.05). This enhancement remained in the presence of nitric oxide (NO) synthase inhibition l-ωnitro-l-arginine (lNAME) and/or soluble guanylate cyclase (sGC) inhibition. Treatment with 4-hydroxy (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPOL) enhanced the sensitivity to BK in CON, similar to the effects of GSH10 and GSH10 + TEMPOL. However, the GSH10-dependent enhancement of EC50 observed in the presence of lNAME did not occur in the presence of lNAME + TEMPOL or in the presence of lNAME + sGC inhibition and NO scavenging. Collectively, these results suggest that GSH enhances BK-mediated dilation and reduction in CVR through an antioxidant-dependent mechanism that involves a NO intermediate but is unrelated to acute production of NO and GC-dependent effects of NO. These results suggest a mechanism whereby physiologically relevant levels of GSH modulate the endogenous reactive oxygen species and NO control of endothelium-dependent coronary vascular function.