Coronary Artery Endothelial Function Research Articles

Lipid Emulsions Containing Medium Chain Triacylglycerols Blunt Bradykinin-Induced Endothelium-Dependent Relaxation in Porcine Coronary Artery Rings.

Lipid emulsions for parenteral nutrition are used to provide calories and essential fatty acids for patients. They have been associated with hypertriglyceridemia, hypercholesterolemia, and metabolic stress, which may promote the development of endothelial dysfunction in patients. The aim of the present study was to determine whether five different industrial lipid emulsions may affect the endothelial function of coronary arteries. Porcine coronary artery rings were incubated with lipid emulsions 0.5, 1, or 2% (v/v) for 30min before the determination of vascular reactivity in organ chambers and the level of oxidative stress using electron paramagnetic resonance. Incubation of coronary artery rings with either Lipidem®, Medialipid® containing long- and medium-chain triacylglycerols (LCT/MCT), or SMOFlipid® containing LCT, MCT, omega-9, and -3, significantly reduced the bradykinin-induced endothelium-dependent relaxation, affecting both the nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) components, whereas, Intralipid® containing LCT (soybean oil) and ClinOleic® containing LCT (soybean and olive oil) did not have such an effect. The endothelial dysfunction induced by Lipidem® was significantly improved by indomethacin, a cyclooxygenase (COX) inhibitor, inhibitors of oxidative stress (N-acetylcysteine, superoxide dismutase, catalase) and transition metal chelating agents (neocuproine, tetrathiomolybdate, deferoxamine and L-histidine). Lipidem® significantly increased the arterial level of oxidative stress. The present findings indicate that lipid emulsions containing LCT/MCT induce endothelial dysfunction in coronary artery rings by blunting both NO- and EDH-mediated relaxations. The Lipidem®-induced endothelial dysfunction is associated with increased vascular oxidative stress and the formation of COX-derived vasoconstrictor prostanoids.

Moderate-dose atorvastatin improves arterial endothelial function in patients with angina pectoris and normal coronary angiogram: a pilot study.

IntroductionEndothelial dysfunction could contribute to the pathophysiology of angina pectoris (AP) in patients with normal coronary angiograms. Besides lipid-lowering effects, statins exert pleiotropic effects including improving endothelial function.Material and methodsOur double-blind study included 58 patients with AP, noninvasively confirmed myocardial ischemia and a normal coronary angiogram. The effect of once-daily 20 mg atorvastatin (A) was compared with placebo (P) for 6 months. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery, and microcirculation by peripheral arterial tonometry (EndoPAT) measuring the reactive hyperemia index (RHI), indicating microcirculatory endothelial function, and the augmentation index (AI), an indicator of arterial stiffness. The impact of AP on the quality of life was monitored using the Seattle Angina Questionnaire (SAQ).ResultsBrachial artery endothelial dysfunction was found in 91.4% of patients at study entry, and subnormal RHI in 41%. Group A showed an improvement of FMD compared with group P, both at 3 and 6 months (+120.8% vs. –21.2%, and +70.8% vs. –1.9%, respectively, p < 0.001). No difference was detected in the RHI. Rate-normalized AI showed an improvement (−114.49% group A vs. –30.77% group P, p = 0.077), although the differences between the groups were not significant. According to the SAQ, an improvement was found in almost all observed variables with the exception of the issue of quality of life (QoL), where patients in both groups assessed their QoL at the control study visits as poorer compared with baseline.ConclusionsModerate-dose atorvastatin therapy improves endothelial function of large conduit arteries in patients with AP and a normal coronary angiogram, which probably reflects positive effects on coronary artery endothelial function. No effect was found with vascular effects at the level of the peripheral microcirculation.

The Relationship Between Coronary Artery Shear Stress and Endothelial Progenitor Cells Number and Function

The Relationship Between Coronary Artery Shear Stress and Endothelial Progenitor Cells Number and Function

Homocysteine diminishes apolipoprotein A-I function and expression in patients with hypothyroidism: a cross-sectional study.

BackgroundHypothyroidism (HO) can significantly impair lipid metabolism and increase cardiovascular disease risk. Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Our previous study demonstrated that HHcy significantly induced insulin resistance and impaired coronary artery endothelial function in patients with either hypertension or HO. In the present study, we studied whether plasma levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) were altered in patients with HO, and if so, whether this change was mediated by HHcy.MethodsA total of 258 subjects were enrolled and divided into the following three groups: control group (n = 94), HO group (n = 73), and subclinical hypothyroidism (SHO) group (n = 91). Additionally, all groups were subdivided based on the subjects’ Hcy levels into HHcy (plasma Hcy level over 15 μmol/l) and normal Hcy subgroups. The plasma levels of lipid indexes were measured. Statistical analyses were performed to evaluate the correlations between groups.ResultsThe plasma Hcy levels were significantly higher in the HO group than in the SHO or control groups (all p < 0.05). Moreover, levels of Apo A-I and HDL-C were markedly reduced in the HHcy subgroup compared with the normal Hcy subgroup for patients with either HO (Apo A-I: p < 0.05; HDL-C: p < 0.01) or SHO (Apo A-I: p < 0.05; HDL-C: p < 0.01). In addition, the plasma Hcy levels were negatively correlated with levels of Apo A-I in all three groups (HO group: r = − 0.320, SHO group: r = − 0.337 and control group: r = − 0.317; all p < 0.01).ConclusionsHcy levels were significantly increased in patients with HO or SHO. These increased Hcy levels may impair cardiovascular function via the inhibition of Apo A-1 expression and impairment of its antioxidant capacity. Our findings provide new insights into the pathogenesis of hypothyroidism-induced metabolic disorders.

Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function.

Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE. Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (R=0.91) and blood flow (R=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-l-arginine (P<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (P=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease. MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health.

Functional Tuning of Intrinsic Endothelial Ca2+ Dynamics in Swine Coronary Arteries.

Recent data from mesenteric and cerebral beds have revealed spatially restricted Ca(2+) transients occurring along the vascular intima that control effector recruitment and vasodilation. Although Ca(2+) is pivotal for coronary artery endothelial function, spatial and temporal regulation of functional Ca(2+) signals in the coronary endothelium is poorly understood. We aimed to determine whether a discrete spatial and temporal profile of Ca(2+) dynamics underlies endothelium-dependent relaxation of swine coronary arteries. Using confocal imaging, custom automated image analysis, and myography, we show that the swine coronary artery endothelium generates discrete basal Ca(2+) dynamics, including isolated transients and whole-cell propagating waves. These events are suppressed by depletion of internal stores or inhibition of inositol 1,4,5-trisphosphate receptors but not by inhibition of ryanodine receptors or removal of extracellular Ca(2+). In vessel rings, inhibition of specific Ca(2+)-dependent endothelial effectors, namely, small and intermediate conductance K(+) channels (K(Ca)3.1 and K(Ca)2.3) and endothelial nitric oxide synthase, produces additive tone, which is blunted by internal store depletion or inositol 1,4,5-trisphosphate receptor blockade. Stimulation of endothelial inositol 1,4,5-trisphosphate-dependent signaling with substance P causes idiosyncratic changes in dynamic Ca(2+) signal parameters (active sites, event frequency, amplitude, duration, and spatial spread). Overall, substance P-induced vasorelaxation corresponded poorly with whole-field endothelial Ca(2+) measurements but corresponded precisely with the concentration-dependent change in Ca(2+) dynamics (linearly translated composite of dynamic parameters). Our findings show that endothelium-dependent control of swine coronary artery tone is determined by spatial and temporal titration of inherent endothelial Ca(2+) dynamics that are not represented by tissue-level averaged Ca(2+) changes.

Progression and reversal of coronary and mesenteric vascular dysfunction associated with obesity.

The purpose of this study was to examine progression and reversal of microvascular complications when rats were fed a high fat diet. Sprague-Dawley rats 10 weeks of age were fed a diet containing 45% kcal fat for up to 32 weeks. Blood pressure and heart rate was measured by telemetry. Vascular reactivity of aorta and small coronary and mesenteric vessels was determined after 8, 16, 24, and 32 weeks on diet. There was a modest increase in weight and blood pressure in high fat fed rats. Sodium nitroprusside (SNP)-induced relaxation of coronary arteries was potentiated after 8 weeks on high fat diet, however, this enhanced response was not observed after 16, 24, or 32 weeks of diet. Acetylcholine (Ach) mediated relaxation was attenuated after 16, 24, and 32 weeks of high fat diet in coronary arteries; however, in aorta and mesenteric arteries, Ach-mediated response was not altered until 32 weeks on high fat diet. Reversing the high fat diet for 8 weeks resulted in partial recovery of metabolic parameters; however endothelial function in coronary arteries remained impaired. These studies indicate that high fat diet promotes progressive impairment of coronary vascular function that is difficult to reverse.

0051: Lipid emulsions used in parenteral nutrition induce endothelial dysfunction in porcine coronary artery rings: role of oxidative stress and cyclooxygenase-derived vasoconstrictors

Lipid emulsions are used to provide a source of calories and essential fatty acids for patients requiring parenteral nutrition. They have been associated with hypertriglyceridemia, hypercholesterolemia and metabolic stress, which may promote the development of endothelial dysfunction. The aim of the present study was to determine the possibility that five different commercial lipid emulsions affect the endothelial function of coronary arteries, and, if so, to investigate the underlying mechanism. Porcine coronary arteries were incubated with lipid emulsions for 30 minutes before the determination of vascular reactivity in organ chambers and the level of oxidative stress using the redox-sensitive fluorescent dye dihydroethidium (DHE). Incubation of coronary artery rings with either Lipidem ® , Medialipid ® or Smoflipid ® (medium-chain triglycerides), but not with Intralipid ® or Clinoleic ® (long-chain triglycerides), significantly reduced the bradykinin- induced endothelium-dependent relaxations mediated by both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH). In contrast, Lipidem ® did not affect endothelium-independent relaxations to sodium nitroprusside. The endothelial dysfunction induced by Lipidem ® was significantly improved by indomethacin, a cyclooxygenase (COX) inhibitor, and by inhibitors of oxidative stress (N-acetylcysteine, superoxide dismutase, catalase) and transition metal chelating agents (neocuproine, L-histidine, desferoxamine). Lipidem ® markedly increased the vascular oxidative stress as indicated by increased DHE signal throughout the arterial wall. The present findings indicate that several but not all lipid emulsions induce an endothelial dysfunction in coronary artery rings, involving both blunted NO- and EDH-mediated relaxations. The Lipidem ® -induced endothelial dysfunction is associated with increased vascular oxidative stress and the formation of COX-derived vasoconstrictor prostanoids.

Effects of maternal exercise during pregnancy on coronary artery vascular function in high fat fed swine offspring (886.2)

The purpose of this study was to test the hypothesis that maternal exercise during pregnancy would enhance coronary artery endothelial function in swine offspring that were fed a high fat diet. Pubertal gilts were divided into exercise (n =8) and sedentary (n =8) groups. Pregnant gilts in the exercise group performed treadmill exercise 5 days per week. Offspring were fed a high fat diet and endothelial (bradykinin; BK) and vascular smooth muscle (sodium nitroprusside; SNP) function were measured at 4 and 8 months of age in the left anterior descending (LAD) artery using in vitro wire myography. Exercise sows had a significantly lower resting heart rate at week 15 of pregnancy compared to their sedentary counterparts (EX: 94.43 ± 4.0; SED: 107.13 ± 3.6 bpm). There were no significant differences in litter characteristics at birth (i.e., number of piglets alive and litter weight). There were no significant differences in vasorelaxation dose response or maximal response to BK or SNP from offspring of exercise or sedentary sows at 4 months of age (BK: EX: 94.35 ± 3.8; SED: 104.1 ± 7.7 % relaxation; SNP: EX: 101.45 ± 2.3; SED: 100.44 ± 3.4 % relaxation) or 8 months of age (BK: EX: 82.75 ± 8.5; SED: 93.92 ± 7.4 % relaxation; SNP: EX: 95.44 ± 2.7; SED: 96.51 ± 1.5 % relaxation) for the LAD artery. Therefore, maternal exercise during pregnancy does not significantly alter LAD artery function at 4 or 8 months of age in swine offspring fed a high fat diet.Grant Funding Source: Supported by the American Heart Association Grant # 12FDG8540001 (S.C.N.)

Coronary flow velocity reserve is impaired in hypertensive patients with hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) is an independent risk factor for coronary artery disease. Chronic HHcy induces coronary endothelial injury, and homocysteine (Hcy) inhibits insulin sensitivity by inducing endoplasmic reticulum stress in adipose tissue. However, the combined effects of chronic HHcy and hypertension on coronary artery endothelial function have still remained unclear. Fifty-one patients with essential hypertension (HT) were recruited, and were divided into nHT group (without HHcy) and H-type HT group (with HHcy). Forty healthy subjects were enrolled as controls. We assessed coronary artery endothelial function by coronary flow velocity reserve (CFVR). Hcy levels were significantly higher (15.60±6.58 vs 13.08±4.13 μmol l(-1), P<0.05), whereas CFVR values were significantly lower in the HT patients than in the control group (2.88±0.70 vs 3.23±0.54, P<0.05). Hcy levels were negatively correlated with CFVR value (r=-0.578, P<0.01, 95% confidence interval -0.085 to -0.046). The homeostasis model assessment-insulin resistance values were significantly higher (3.92±2.16 vs 2.72±1.50, P<0.05) , whereas CFVR values were significantly lower in H-type HT group than in nHT group (2.31±0.31 vs 3.25±0.62, P<0.01). Coronary artery endothelial function may be impaired in essential hypertensive patients with HHcy, and insulin resistance induced by HHcy may contribute to this damage.

Impact of Darunavir, Atazanavir and Lopinavir Boosted with Ritonavir on Cultured Human Endothelial Cells: Beneficial Effect of Pravastatin

HIV-infected patients administered long-term ritonavir-boosted protease inhibitors (PIs) are at a greater risk for developing cardiovascular diseases. Endothelial dysfunction is an initiating event in HIV-associated atherosclerosis. Cultured endothelial cells can be used as a model to compare the endothelial toxicity of different PIs. We compared the effect of darunavir (DRV), darunavir/ritonavir (DRV/r), lopinavir/ritonavir (LPV/r) and atazanavir/ritonavir (ATV/r), used at clinically relevant concentrations, on human coronary artery endothelial cell vascular function, oxidative stress, inflammation and senescence, and studied the effect of pravastatin on PI-induced alterations. Vascular endothelial cell function, evaluated by the expression of endothelial nitric oxide synthase and the production of nitric oxide and endothelin-1, was unaffected by DRV or DRV/r, but altered by LPV/r or ATV/r. DRV or DRV/r did not alter, or mildly induced oxidative stress and inflammation (phosphorylation of p65/RelA-NFκB, secretion of IL-6 and IL-8), while ATV/r and LPV/r induced a marked increase. Secretion of sICAM or sVCAM, indicative of altered cell integrity, was not or weakly altered by DRV or DRV/r, but increased by 2-3-fold by LPV/r or ATV/r. Similar results were observed regarding senescence markers: SA-β-galactosidase activation and overexpression of phospho-p53, p16(ink4), p21(WAF-1) and prelamin A. Pravastatin could, in part, reverse PI-induced adverse effects. Ritonavir-boosted PIs differentially induced vascular endothelial cell dysfunction, reactive oxygen species production, inflammation and senescence with no effect or a mild effect of DRV/r, an intermediate effect of ATV/r, and a stronger effect of LPV/r. Statins could, in part, protect the cells from PI-induced endothelial dysfunction.

Exercise prevents Western diet-associated erectile dysfunction and coronary artery endothelial dysfunction: response to acute apocynin and sepiapterin treatment

The aim of this study was to investigate aerobic exercise training as a means to prevent erectile dysfunction (ED) and coronary artery disease (CAD) development associated with inactivity and diet-induced obesity. Male Sprague-Dawley rats were fed a Western diet (WD) or a control diet (CD) for 12 wk. Subgroups within each diet remained sedentary (Sed) or participated in aerobic interval treadmill running throughout the dietary intervention. Erectile function was evaluated under anesthesia by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, in the absence or presence of either apocynin, an NADPH oxidase inhibitor, or sepiapterin, a tetrahydrobiopterin precursor. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of ACh applied to preconstricted segments of the left anterior descending coronary artery. CAEF was assessed in the absence or presence of apocynin or sepiapterin. Erectile function (P < 0.0001) and CAEF (P < 0.001) were attenuated in WD-Sed. Exercise preserved erectile function (P < 0.0001) and CAEF (P < 0.05) within the WD. Erectile function (P < 0.01) and CAEF (P < 0.05) were augmented by apocynin only in WD-Sed, while sepiapterin (P < 0.05) only augmented erectile function in WD-Sed. These data demonstrate that a chronic WD induces impairment in erectile function and CAEF that are commonly partially reversible by apocynin, whereas sepiapterin treatment exerted differential functional effects between the two vascular beds. Furthermore, exercise training may be a practical means of preventing diet-induced ED and CAD development.

Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes.

ObjectivesTo evaluate the association of coronary artery endothelial function and plasma levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in patients with Type 2 Diabetes Mellitus (DM).MethodsWe investigated 90 participants from our institution between October 2007 to March 2010: non-DM (n = 60) and DM (n = 30). As an indicator of coronary endothelial dysfunction, we used non-invasive Doppler echocardiography to quantify coronary flow velocity reserve (CFVR) in the distal part of the left descending artery after rest and after intravenous adenosine administration.ResultsPlasma level of LDL-C was significantly higher in patients with DM than in non-DM (3.21 ± 0.64 vs. 2.86 ± 0.72 mmo/L, P < 0.05), but HDL-C level did not differ between the groups (1.01 ± 0.17 vs. 1.05 ± 0.19 mmo/L). Furthermore, the CFVR value was lower in DM patients than non-diabetics (2.45 ± 0.62 vs. 2.98 ± 0.68, P < 0.001). Plasma levels of LDL-C were negatively correlated with CFVR in all subjects (r = −0.35, P < 0.001; 95% confidence interval (CI): −0.52 – −0.15) and in the non-DM (r = −0.29, P < 0.05; 95% CI: −0.51– −0.05), with an even stronger negative correlation in the DM group (r = −0.42, P < 0.05; 95% CI: −0.68 – −0.06). Age (β = −0.019, s = 0.007, sβ = −0.435, 95% CI: −0.033 – −0.005, P = 0.008), LDL-C (β = −0.217, s = 0.105, sβ = −0.282, 95% CI: −0.428 – −0.005, P = 0.045) remained independently correlated with CFVR in the DM group. However, we found no correlation between HDL-C level and CFVR in any group.ConclusionsDiabetes may contribute to coronary artery disease (CAD) by inducing dysfunction of the coronary artery endothelium. Increased LDL-C level may adversely impair coronary endothelial function in DM. HDL-C may lose its endothelial-protective effects, in part as a result of pathological conditions, especially under abnormal glucose metabolism.

Exercise prevents Western‐diet associated erectile and coronary artery endothelial dysfunction mediated by NADPH oxidase

The purpose of this study was to investigate NADPH oxidase as a common mechanism underlying both erectile dysfunction (ED) and coronary artery disease (CAD) in inactivity and diet‐induced obesity. Male Sprague‐Dawley rats were fed a Western diet (WD) or Control diet (CD) for 12 weeks. Subgroups within each diet remained sedentary (Sed) or engaged in treadmill exercise (Ex) throughout the dietary intervention. Erectile function was evaluated by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, prior to and following an intracavernosal injection of apocynin (Apo; an NADPH oxidase inhibitor). Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of acetylcholine (ACh) applied to coronary artery segments pre‐constricted with serotonin. CAEF was assessed in the presence and absence of Apo. Erectile function (p &lt; 0.0001) and CAEF (p &lt; 0.001) were attenuated in WD‐Sed rats. Erectile function (p &lt; 0.01) and CAEF (p &lt; 0.05) were augmented by Apo only in WD‐Sed rats. Ex preserved erectile function (p &lt; 0.0001) and CAEF (p &lt; 0.05) within the WD. This study suggests that erectile function and CAEF are impaired by NADPH oxidase in chronic WD‐fed rats, while Ex training may be a practical means of preventing WD‐induced ED and CAD.Supported by the Sexual Medicine Society of North America.

Effects of local mechanical stimulation on coronary artery endothelial function and angiotensin II type 1 receptor in pressure or flow-overload

This study investigates the effect of local mechanical stimulation induced by pressure or flow-overload in right coronary artery (RCA) angiotensin II type 1 (AT1) receptor-mediated endothelial dysfunction in swine models of aortic or pulmonary artery banding. A total of 36 pigs (37 ± 7 kg) were studied. The RCA was exposed to pressure-overload by aortic banding (n = 6) or blood flow-overload by pulmonary artery banding (n = 6) for 4 weeks, and sham-operated animals served as controls (n = 6). The RCA of 18 pigs were exposed to acute ex-vivo pressure-overload. The effects of local mechanical stimuli on AT1 receptor were determined by external cuff. Aortic banding caused RCA pressure-overload of 118 ± 11 mmHg in comparison with 79 ± 9 mmHg for sham controls. The cross-sectional area of the RCA lumen increased 27.9% (from 8.09 ± 0.89 to 10.3 ± 0.96 mm) when the blood flow increased by 80% (from 23.8 ± 4.3 to 44.3 ± 7.2 ml/min) in the 4-week pulmonary artery banding period. Both pressure and flow-overload resulted in the up-regulation of expression and activation of AT1 receptor. An increased production of reactive oxygen species (ROS) and endothelium dysfunction were observed in the RCA. The acute inhibition of AT1 receptor and NADPH oxidase partially restored the endothelial function. The endothelial dysfunction and activation of AT1 receptor was also realized in ex-vivo pressure-overload of normal RCA. An external cuff inhibited the increase in activation of AT1 receptor and preserved endothelial function in ex-vivo pressure-overload which implicates local wall mechanical stimulation as opposed to pressure. Local mechanical stimulation activates the AT1 receptor which likely mediates ROS production and endothelial dysfunction in RCA.

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

ObjectivesOur objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.BackgroundCoronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).MethodsTwenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.ResultsIn healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).ConclusionMRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.

Erectile Dysfunction Precedes Coronary Artery Endothelial Dysfunction in Rats Fed a High-Fat, High-Sucrose, Western Pattern Diet

Introduction. It is suggested that erectile dysfunction (ED) may be an early risk factor for cardiovascular disease. Aim. The goal of this study was to determine whether development of ED precedes the onset of coronary artery endothelial dysfunction in response to a Western diet (WD), thereby establishing whether the WD differentially impacts the endothelium in a time-dependent manner. Additionally, a goal was to determine if diet-induced ED is reversible with intracavernosal sepiapterin treatment. Methods. Male Sprague-Dawley rats were fed a WD for 4, 8, or 12 weeks, or a control diet for 8 weeks. Erectile function was evaluated by measuring the mean arterial pressure (MAP) and intracavernosal pressure (ICP) in response to electrical field stimulation of the cavernosal nerve near the major pelvic ganglion, in the absence and presence of sepiapterin. Coronary artery endothelial function was evaluated ex vivo with cumulative doses of acetylcholine (ACh) applied to segments of the left anterior descending coronary artery preconstricted with serotonin. Main Outcome Measures. Erectile function was assessed as the ICP response to electrical field stimulation (EFS), normalized to MAP. Coronary artery endothelial function was assessed as the effective concentration producing 50% of a maximal response (EC50 ) of the ACh response. Results. The ICP/MAP response to EFS was significantly attenuated following both 8 and 12 weeks of the WD compared with the control diet (P < 0.05). Sepiapterin treatment augmented the ICP/MAP response in all WD groups (P < 0.05). The coronary artery EC50 of the ACh response was not different from control following 4 or 8 weeks but was significantly elevated following 12 weeks of the WD (P < 0.01). Conclusions. These data suggest that erectile function is reduced prior to coronary artery endothelial function in response to the WD. Improvement of erectile function with sepiapterin in WD rats indicates that nitric oxide synthase uncoupling is a key mechanism in diet-induced ED. La Favor JD, Anderson EJ, Hickner RC, and Wingard CJ. Erectile dysfunction precedes coronary artery endothelial dysfunction in rats fed a high-fat, high-sucrose, Western pattern diet. J Sex Med 2013;10:694-703.

Coronary Flow Velocity Reserve is Improved by PPAR‐α Agonist Fenofibrate in Patients with Hypertriglyceridemia

Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPAR-α), has a vascular protective effect. We investigated the effect of the PPAR-α agonist on coronary artery endothelial function in patients with hypertriglyceridemia. Fifty-eight patients with hypertriglyceridemia were divided into two groups: control (no treatment; n = 23) and fenofibrate treatment (n = 35), 200 mg/d, for 6 months. The patients had undergone rest and adenosine treatment to induce hyperemia for quantification of coronary flow velocity reserve (CFVR) by noninvasive Doppler echocardiography before treatment and at 6-month follow-up. Pulse wave velocity (PWV) was measured before treatment and at 6-month follow-up. CFVR was significantly improved with fenofibrate treatment as compared with baseline level and control group (3.14 ± 0.36 vs. 2.80 ± 0.58 and 2.79 ± 0.65, P < 0.01 and 0.05, respectively), with no difference between baseline levels and untreated controls. In addition, at 6 months, plasma level of homocysteine was significantly increased with fenofibrate treatment as compared with at baseline and control group (median 18.13 [range 14.46-22.02]μmol/L vs. 14.09 [12.01-18.81] and 13.34 [9.69-17.06]μmol/L, P < 0.001 and 0.01, respectively). Furthermore, at 6 months, PWV was significantly decreased with fenofibrate treatment as compared with control group (1446 ± 136 cm/s vs. 1570 ± 203 cm/s, P < 0.05). Treatment with PPAR-α agonist fenofibrate significantly improved CFVR and arterial stiffness in patients with hypertriglyceridemia. This endothelial protective effect may be reduced in part by the side effect of increasing homocysteine.

Reply to letter to the editor: coronary flow velocity reserve was impaired in chronic hyperhomocysteinemic patients: why?

to the editor: Hyperhomocysteinemia (HHcy) is considered a potentially modifiable risk factor for coronary artery disease (CAD) and atherosclerosis. The possible mechanisms of accelerated CAD in HHcy include endothelial dysfunction and enhanced oxidative stress ([13][1]). However, the precise

Coronary Artery Endothelial Dysfunction Associated With Sleep Apnea

There is little information about coronary artery endothelial dysfunction in patients with sleep apnea. We evaluated relation between severity of sleep apnea and coronary artery endothelial dysfunction. In all, 26 patients without significant coronary stenoses were enrolled. Endothelial function was estimated by measuring coronary vasoreactivity in response to acetylcholine infusion (10(-7) mol/L) into coronary arteries. Vasoconstriction rate was defined as ([lumen diameter after isosorbide dinitrate injection - lumen diameter after acetylcholine injection]/lumen diameter after isosorbide dinitrate injection × 100). Vasoconstriction rate was calculated at each major coronary artery and the highest value was used for that patient. Overnight sleep study was performed and the apnea-hypopnea index (AHI) was calculated as the mean number of apneas and hypopneas per hour of sleep. There was significant correlation between AHI and vasoconstriction rate (P = .04). There is significant correlation between severity of sleep apnea and endothelial function of coronary arteries.