Basal Coronary Flow Research Articles

Increased basal and adenosine‐mediated coronary flow in ex vivo hearts from type I diabetic mice (1051.16)

Diabetes is known to cause morphological and functional changes in the cardiovascular system, resulting in abnormal responses to various stimuli such as adenosine. Our aim was to examine the functional changes in coronary flow (CF) to adenosine receptor (AR) agonists resulting from type I diabetes. Diabetes was induced in mice using streptozotocin (STZ, 10mg/Kg; 8 weeks) and concentration response curves to the non‐selective AR agonist NECA and to the A2A AR selective agonist (CGS‐21680; CGS) were performed in isolated perfused hearts from STZ and vehicle (C) group. Diabetes resulted in a decrease in heart weight (0.093g ± 0.002 in STZ vs. 0.117g ± 0.004 in C; p<0.05), an increase in blood glucose level (510.8mg/dL ± 22.2 in STZ vs. 140.9mg/dL ± 9.4 in C; p<0.05) and an increase in the basal coronary flow (21.6 ± 1.5 in STZ vs. 16.1 ± 0.6 in C; p<0.05). Both NECA and CGS induced a concentration‐dependent increase in CF (ml.min‐1.mg‐1) which was significantly increased in STZ compared to C (NECA: Emax 39.8 ± 1.8 in STZ vs. 28.2 ± 0.7 in C; p<0.05) (CGS; Emax 38.8 ± 1 in STZ vs. 28.3 ± 1.8 in C; p<0.05). No significant differences were observed between the groups for changes in both heart rate and left ventricular diastolic pressure to both agonists. Our data suggest that STZ‐induced diabetes resulted in an increase in basal CF as well as increased vasodilatory response to adenosine agonists, probably by upregulating A2A receptor signaling.Grant Funding Source: Supported by HL 094447 and HL 027339

A pharmacologic activator of endothelial KCa channels improves coronary function in the hearts of type 2 diabetic rats (1078.10)

Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D) who exhibit cardiovascular disease. In the present study, we have examined the effect of SKA‐31, a positive modulator of endothelial Ca2+‐activated K+ (KCa) channels, on total coronary flow in isolated hearts from Goto‐Kakizaki (GK) rats, a non‐obese model of T2D and age‐matched controls. Total coronary flow and left ventricular developed pressure were monitored simultaneously in spontaneously beating, Langendorff‐perfused hearts. Acute, bolus administrations of bradykinin (BK, 1 μg) or adenosine (ADO, 10 μg) increased coronary flow, and these responses were blunted in diabetic hearts at 10‐12 and 18‐20 weeks of age. In contrast, SKA‐31 dose‐dependently (0.01‐5 μg bolus exposures) increased coronary flow to comparable levels in both control and diabetic rat hearts at both ages. Flow responses to sodium nitroprusside were not different between control and diabetic hearts, suggesting normal coronary smooth muscle function. Importantly, continuous exposure to a sub‐threshold concentration of SKA‐31 (i.e. 0.3 μM) did not alter basal coronary flow or heart rate, but did ameliorate the blunted BK and ADO‐evoked flow responses in diabetic hearts. In summary, these data demonstrate that SKA‐31 is an effective coronary vasodilator in a rat model of T2D exhibiting endothelial dysfunction and metabolic syndrome, and further rescues impaired vasodilatory responses to BK and ADO in the coronary circulation.Grant Funding Source: Supported by CIHR

Effect of Type 2 Diabetes Mellitus on Epicardial Adipose Tissue Volume and Coronary Vasomotor Function

Patients with coronary artery disease and/or type 2 diabetes mellitus (DM) generally exhibit more epicardial adipose tissue (EAT) than healthy controls. Recently, it has been proposed that EAT affects vascular function and structure by secreting proinflammatory and vasoactive substances, thereby potentially contributing to the development of cardiovascular disease. In the present study, the interrelation of EAT, coronary vasomotor function, and coronary artery calcium was investigated in patients with and without DM, who were evaluated for coronary artery disease. Myocardial blood flow (MBF) was assessed at rest and during adenosine-induced hyperemia using [(15)O]-water positron emission tomography combined with computed tomography to quantify coronary artery calcium and EAT in 199 patients (46 with DM). In this cohort (mean age 58 ± 10 years), the patients with DM had a greater body mass index, heart rate, and systolic blood pressure at rest (all p <0.05). Coronary artery calcium and the EAT volumes were comparable between those with and without DM. Both patient groups showed comparable MBF at rest and coronary vascular resistance. A lower hyperemic MBF and coronary flow reserve (CFR) and greater hyperemic coronary vascular resistance (all p <0.05) was observed in the patients with DM. A pooled analysis showed a positive association of EAT volume with hyperemic coronary vascular resistance but not with the MBF at rest, hyperemic MBF, or coronary vascular resistance at rest. In the group analysis, the EAT volume was inversely associated with hyperemic MBF (r = -0.16, p = 0.05) and CFR (r = -0.17, p = 0.04) and positively with hyperemic coronary vascular resistance (r = 0.26, p = 0.002) only in patients without DM. Multivariate regression analysis, adjusted for age, gender, and body mass index, showed an independent association between the EAT volume and hyperemic MBF (β = -0.16, p = 0.02), CFR (β = -0.16, p = 0.04), and hyperemic coronary vascular resistance (β = 0.25, p <0.001) in the non-DM group. In conclusion, these results suggest a role for EAT in myocardial microvascular dysfunction; however, once DM has developed, other factors might be more dominant in contributing to impaired myocardial microvascular dysfunction.

Contribution of Kv7 channels to basal coronary flow and active response to ischemia.

The goal of the present study was to determine the role of KCNQ-encoded Kv channels (Kv7 channels) in the passive and active regulation of coronary flow in normotensive and hypertensive rats. In left anterior descending coronary arteries from normotensive rats, structurally different Kv7.2 to 7.5 activators produced relaxations, which were considerably less in arteries from hypertensive rats and were not mimicked by the Kv7.1-specific activator R-L3. In isolated, perfused heart preparations, coronary flow rate increased in response to the Kv7.2 to 7.5 activator (S)-1 and was diminished in the presence of a Kv7 inhibitor. The expression levels of KCNQ1-5 and their known accessory KCNE1-5 subunits in coronary arteries were similar in normotensive and hypertensive rats as measured by quantitative polymerase chain reaction. However, Kv7.4 protein expression was reduced in hypertensive rats. Application of adenosine or A2A receptor agonist CGS-21680 produced concentration-dependent relaxations of coronary arteries from normotensive rats, which were attenuated by application of Kv7 inhibitors. Kv7 blockers also attenuated the ischemia-induced increase in coronary perfusion in Langendorff studies. Overall, these data establish Kv7 channels as crucial regulators of coronary flow at resting and after hypoxic insult.

Regional Difference of Microcirculation in Patients with Asymmetric Hypertrophic Cardiomyopathy: Transthoracic Doppler Coronary Flow Velocity Reserve Analysis

To evaluate, by noninvasive coronary flow velocity reserve (CFVR), whether patients with asymmetric hypertrophic cardiomyopathy (HC), with or without left ventricular outflow tract obstruction, demonstrate significant regional differences of CFVR. We evaluated 61 patients with HC (27 men; mean age 49 ± 16 years), including 20 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 41 patients without obstruction (HCM). The control group included 20 age- and sex-matched subjects. Transthoracic Doppler echocardiography CFVR of the left anterior descending coronary artery (LAD) and the posterior descending coronary artery (PD) were performed, including calculation of relative CFVR as the ratio between CFVR LAD and CFVR PD. Compared with the controls, all the patients with HC had lower CFVR LAD (2.12 ± 0.53 vs 3.34 ± 0.67; P < .001) and CFVR PD (2.29 ± 0.49 vs 3.21 ± 0.65; P < .001). CFVR LAD in HOCM group in comparison with the HCM group was significantly lower (1.93 ± 0.42 vs 2.22 ± 0.55; P = .047), due to higher basal diastolic coronary flow velocities (0.40 ± 0.09 vs 0.33 ± 0.07 m/sec; P = .002), with similar hyperemic diastolic flow velocities (0.71 ± 0.16 vs 0.76 ± 0.19 m/sec; P = .330), respectively. There was no significant difference in CFVR PD between patients with HOCM and those with HCM (2.33 ± 0.46 vs 2.27 ± 0.50; P = .636), respectively. Relative CFVR was lower in the HOCM group compared with the HCM group (0.84 ± 0.16 vs 0.98 ± 0.14; P = .001). By multivariable regression analysis, left ventricular outflow tract gradient was the independent predictor of CFVR LAD (B = -0.24; P = .008) and relative CFVR (B = -0.34; P = .016). CFVR LAD and relative CFVR were significantly lower in patients with HOCM compared with patients with HCM. Regional differences of CFVR are present only in patients with significant left ventricular outflow tract obstruction, which suggests that obstruction per se, by increasing wall stress in basal conditions, leads to higher basal diastolic coronary flow velocities and results in lower CFVR in LAD compared with PD.

Arginase inhibition improves coronary microvascular function and reduces infarct size following ischaemia–reperfusion in a rat model

Ischaemia-reperfusion injury is associated with reduced bioavailability of nitric oxide (NO) and microvascular dysfunction. One emerging mechanism behind reduced NO bioavailability is upregulation of arginase, which metabolizes the NO synthase substrate l-arginine. This study investigated the effects of arginase inhibition on coronary flow velocity and infarct size during reperfusion. Anaesthetized rats, subjected to 30-min coronary artery ligation and reperfusion up to 8 days, were treated with vehicle or the arginase inhibitor N(ω) -hydroxy-nor-l-arginine (nor-NOHA; 100 mg kg(-1) ) intravenously 15 min before ischaemia. Coronary flow velocity was determined repeatedly during reperfusion. Arginase activity in the ischaemic-reperfused myocardium was increased already at 20 min of reperfusion and maintained at 8 days. Infarct size was reduced by arginase inhibition at 2 h (39 ± 3% of the area at risk (AAR) vs. 51 ± 2% in the vehicle group, P < 0.01) and at 8 days of reperfusion (13 ± 2% of the left ventricle (LV) vs. 22 ± 2%, P < 0.05). Basal coronary flow velocity was higher during reperfusion in the group given nor-NOHA, and it correlated inversely to infarct size (P < 0.01, r = -0.60). Hyperaemic coronary flow velocity was also increased in the nor-NOHA-treated group compared to vehicle at 24 h and at day 8 (P < 0.05). It is concluded that arginase activity is increased already during early reperfusion. Arginase inhibition increases coronary flow velocity and reduces infarct size that is sustained 8 days after reperfusion. Inhibition of arginase may thus be a promising therapeutic target to prevent the development of microvascular dysfunction and myocardial injury following ischaemia-reperfusion.

106 Role of neuronal vs endothelial nitric oxide synthase in the coronary blood flow response to pacing

BackgroundEndothelial nitric oxide synthase (eNOS) has been assumed to be the major source of nitric oxide (NO) regulating human coronary blood flow (CBF). In recent first-in-human studies with a neuronal...

Cyanotic Congenital Heart Disease The Coronary Arterial Circulation

Background:The coronary circulation in cyanotic congenital heart disease (CCHD) includes the extramural coronary arteries, basal coronary blood flow, flow reserve, the coronary microcirculation, and coronary atherogenesis.Methods:Coronary arteriograms were analyzed in 59 adults with CCHD. Dilated extramural coronaries were examined histologically in six patients. Basal coronary blood flow was determined with N-13 positron emission tomography in 14 patients and in 10 controls. Hyperemic flow was induced by intravenous dipyridamole pharmacologic stress. Immunostaining against SM alpha-actin permitted microcirculatory morphometric analysis. Non-fasting total cholesterols were retrieved in 279 patients divided into four groups: Group A---143 cyanotic unoperated, Group B---47 rendered acyanotic by reparative surgery, Group C---41 acyanotic unoperated, Group D---48 acyanotic before and after operation.Results:Extramural coronary arteries were mildly or moderately dilated to ectatic in 49/59 angiograms. Histologic examination disclosed loss of medial smooth muscle, increased medial collagen, and duplication of internal elastic lamina. Basal coronary flow was appreciably increased. Hyperemic flow was comparable to controls. Remodeling of the microcirculation was based upon coronary arteriolar length, volume and surface densities. Coronary atherosclerosis was absent in both the arteriograms and the necropsy specimens.Conclusions:Extramural coronary arteries in CCHD dilate in response to endothelial vasodilator substances supplemented by mural attenuation caused by medial abnormalities. Basal coronary flow was appreciably increased, but hyperemic flow was normal. Remodeling of the microcirculation was responsible for preservation of flow reserve. The coronaries were atheroma-free because of the salutory effects of hypocholesterolemia, hypoxemia, upregulated nitric oxide, low platelet counts, and hyperbilirubinrmia.

Effects of N-3 Polyunsaturated Fatty Acids on Left Ventricular Function and Coronary Flow in Children with Type 1 Diabetes Mellitus

Purposes: It has earlier been suggested that dietary supplementation with N-3 Polyunsaturated Fatty Acids (n-3 PUFAs) could have beneficial effects on cardio- vascular system patients with type 1 diabetes mellitus (DM1). Whether the benefit also extends to coronary circulation has not been yet investigated. Methods: In a double-blind placebo controlled cross-over study, 33 children with DM1 duration of more than one year were randomly and equally assigned to either n-3 PUFAs (2 gm/day, Nycoplus® Omega-3) or placebo treatment for 4 weeks. Following a 4-week period recovery, the groups were crossovered with above treatments for another 4 weeks. Transthoracic Doppler echocardiography (TTDE) study was done on each visit; pre treatment, post treatment with n-3 PU- FAs on one occasion and with placebo on another and after one month recovery to assess left ventricular function and flow in the left anterior descending coronary artery (LAD). All data are mean±SD. Results: Of 33 recruited children, 28 (85%) completed the study. n-3 PUFAs treatment was associated with increase in both mean cardiac index (CI; from 2.7±0.4 to 3.7±0.8 l/min/m2, p<0.0001) and left ventricular fractional shortening (FS; from 31±2.5 to 39±3%, p<0.0001). In placebo treated groups there were no significant changes in these parameters. Also N-3 PUFAs treatment was as- sociated to decrease of both LAD peak flow velocity (PFVd; from 96±17 to 68±12 cm/s, p<0.0001) and LADs CF (from 105±31 to 66±15 ml/min, p<0.0001). Stop- ping n-3 PUFAs treatment and after one month recovery led to decrease of CI from 3.7±0.8 to 2.6±0.5 l/min/m2, p<0.0001 and mean FS from 39±3 to 32±2, p<0.0001. Mean PFVd increased from 68±12 to 90±12 cm/s, p<0.0001 and CF from 66±15 to 108±30 ml/min, p<0.0001. Conclusions: In patients with DM1, basal coronary flow parameters are in- creased, which could contribute to reduced coronary flow reserve. Treatment with n-3 PUFAs increases the cardiac index and LV systolic function and reverses the increased basal coronary flow, thereby improving the circumstances for better coronary flow reserve.

Double-Edged Role of the CXCL12/CXCR4 Axis in Experimental Myocardial Infarction

Here we assess the intrinsic functions of the chemokine receptor CXCR4 in remodeling after myocardial infarction (MI) using Cxcr4 heterozygous (Cxcr4(+/-)) mice. Myocardial necrosis triggers complex remodeling and inflammatory changes. The chemokine CXCL12 has been implicated in protection and therapeutic regeneration after MI through recruiting angiogenic outgrowth cells, improving neovascularization and cardiac function, but the endogenous role of its receptor CXCR4 is unknown. MI was induced by ligation of the left descending artery. Langendoff perfusion, echocardiography, quantitative immunohistochemistry, flow cytometry, angiogenesis assays, and cardiomyocyte analysis were performed. After 4 weeks, infarct size was reduced in Cxcr4(+/-) mice compared with wild-type mice and in respective bone marrow chimeras compared with controls. This was associated with altered inflammatory cell recruitment, decreased neutrophil content, delayed monocyte infiltration, and a predominance of Gr1(low) over classic Gr1(high) monocytes. Basal coronary flow and its recovery after MI were impaired in Cxcr4(+/-)mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4(+/-)mice compared with wild-type mice. Despite defective angiogenesis, Cxcr4(+/-) mouse hearts showed no difference in CXCL12, vascular endothelial growth factor or apoptosis-related gene expression. Electron microscopy revealed lipofuscin-like lipid accumulation in Cxcr4(+/-) mouse hearts and analysis of lipid extracts detected high levels of phosphatidylserine, which protect cardiomyocytes from hypoxic stress in vitro. CXCR4 plays a crucial role in endogenous remodeling processes after MI, contributing to inflammatory/progenitor cell recruitment and neovascularization, whereas its deficiency limits infarct size and causes adaptation to hypoxic stress. This should be carefully scrutinized when devising therapeutic strategies involving the CXCL12/CXCR4 axis.

Increased basal coronary blood flow as a cause of reduced coronary flow reserve in diabetic patients

A reduced coronary flow reserve (CFR) has been demonstrated in diabetes, but the underlying mechanisms are unknown. We assessed thermodilution-derived CFR after 5-min intravenous adenosine infusion through a pressure-temperature sensor-tipped wire in 30 coronary arteries without significant lumen reduction in 30 patients: 13 with and 17 without a history of diabetes. We determined CFR as the ratio of basal and hyperemic mean transit times (T(mn)); fractional flow reserve (FFR) as the ratio of distal and proximal pressures at maximal hyperemia to exclude local macrovascular disease; and an index of microvascular resistance (IMR) as the distal coronary pressure at maximal hyperemia divided by the inverse of the hyperemic T(mn). We also assessed insulin resistance by the homeostasis model assessment (HOMA) index. FFR was normal in all investigated arteries. CFR was significantly lower in diabetic vs. nondiabetic patients [median (interquartile range): 2.2 (1.4-3.2) vs. 4.1 (2.7-4.4); P = 0.02]. Basal T(mn) was lower in diabetic vs. nondiabetic subjects [median (interquartile range): 0.53 (0.25-0.71) vs. 0.64 (0.50-1.17); P = 0.04], while hyperemic T(mn) and IMR were similar. We found significant correlations at linear regression analysis between logCFR and the HOMA index (r(2) = 0.35; P = 0.0005) and between basal T(mn) and the HOMA index (r(2) = 0.44; P < 0.0001). In conclusion, compared with nondiabetic subjects, CFR is lower in patients with diabetes and epicardial coronary arteries free of severe stenosis, because of increased basal coronary flow, while hyperemic coronary flow is similar. Basal coronary flow relates to insulin resistance, suggesting a key role of cellular metabolism in the regulation of coronary blood flow.

Coronary blood flow in patients with stable coronary artery disease treated long term with folic acid and vitamin B12

Plasma concentration of total homocysteine is associated with risk of cardiovascular disease in epidemiological studies. We wanted to examine the effects of B-vitamin therapy, which may lower total homocysteine, on coronary flow and vascular function in patients with established coronary artery disease (CAD). Forty patients with stable CAD, mean (standard deviation) aged 57.8 (9.0) years, recruited into the Western Norway B-Vitamin Intervention Trial, were randomly assigned to daily oral treatment with 0.8 mg of folic acid and 0.4 mg of vitamin B12 or placebo, and 40 mg of vitamin B6 or placebo, using a 2 × 2 factorial design. At baseline, and after 9 and 24 months, coronary blood flow was assessed by coronary angiography and Doppler flow-wire measurements during intracoronary infusion of saline (basal), incremental doses of acetylcholine, adenosine, and nitroglycerin. We found a significant increase in basal (P < 0.02) and adenosine-induced (P < 0.05) coronary blood flow in patients who received folic acid/vitamin B12 for 24 months, compared with placebo or vitamin B6 alone. Folic acid/vitamin B12 or vitamin B6 treatment did not change endothelial-dependent response after acetylcholine infusion or flow-dependent proximal dilatation in response to adenosine-induced maximal hyperemia (P ≥ 0.45). Long-term treatment with a combination of folic acid and vitamin B12 increase basal and adenosine-induced maximal coronary blood flow. This may reflect improved microvascular function in patients with stable CAD.

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

73 Heritability of coronary flow reserve

Introduction Coronary flow reserve (CRF) is the ratio of peak coronary flow during maximal coronary artery dilatation to basal coronary flow and is an important predictor of coronary microvascular function. A variety of environmental stimuli have been shown to affect CFR but little is known about the genetic component of CFR. To characterise the genetics of CFR we initially measured in vivo blood pressure (BP) and ex vivo cardiac phenotypes including CFR in two inbred rat strains, Brown Norway (BN) and Spontaneously Hypertensive Rat (SHR) which is a genetic model for hypertension and microvascular dysfunction. We then studied BP and coronary flow (CF) phenotypes in F 1 and F 2 crosses derived from BN and SHR to estimate the heritability of CFR and its relationship with BP. Methods Animals were anaesthetized using a mixture of Oxygen and Isoflurane. BP was measured invasively by cannulation of carotid artery. Following BP measurement hearts were excised and rapidly transferred to the ex vivo perfusion apparatus where retrograde perfusion was established using the Langendorff technique. Hearts were perfused with Carbogen buffered Kreb′s solution and paced constantly at 360 bpm. A fluid filled balloon was placed in the left ventricular (LV) cavity to measure the pressure indices. CF, LV developed pressure, myocardial contractility (LV dP/dt max ) and myocardial relaxation (LV dP/dt min ) were recorded at baseline, during peak hyperaemia, regional ischaemia (induced by ligation of the proximal left anterior descending artery) and reperfusion. Results 1) CFR differs significantly between the two inbred parental rat strains. (BN=2.1 ± 0.32, SHR=1.5 ± 0.18, p=2.6×10 −7 , n=16 each). 2) Heritability of CFR: Broad sense heritability (the proportion of total phenotypic variance attributable to total genetic variance) for CFR is 62% indicating a large and previously unrecognised genetic component of CFR. 3) Relationship between CFR and BP: We did not find statistically significant correlation between CFR and BP in the F 2 intercross (r=0.11, p=0.11, n=176). 4) Relationship between CF and myocardial relaxation (LV dP/dt min ): LV dP/dt min correlated strongly with CF during all stages of the experiment (baseline CF, r=−0.36, p Conclusions Our results demonstrate that CFR has a significant genetic component and is largely independent of BP effects. Furthermore we demonstrate a very significant relationship between CF and LV dP/dt min indicating a link between LV diastolic dysfunction and impaired CF. Using 768 SNP genotyping assay for linkage mapping and gene expression analysis with Affymetrix rat gene chip, we will determine the quantitative trait loci and transcripts associated with CFR to improve our understanding of the genomic architecture of CFR.

Prediction of Myocardial Functional Recovery by Noninvasive Evaluation of Basal and Hyperemic Coronary Flow in Patients with Previous Myocardial Infarction

The aim of this study was to evaluate the relation of basal and hyperemic coronary flow with myocardial functional improvement in patients with previous myocardial infarction undergoing elective percutaneous coronary intervention (PCI). Coronary flow was measured using transthoracic Doppler echocardiography in 50 patients (41 men; mean age, 53 ± 8 years) with previous myocardial infarction before, 24 hours, and 3 months after elective PCI. Diastolic deceleration time (DDT) was measured from the peak diastolic velocity to the point of intercept of initial decay slope with baseline. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to basal peak diastolic flow velocities. In comparison with patients without improvements in left ventricular function, patients with recovered left ventricular function had longer DDTs before angioplasty (841 ± 286 vs. 435 ± 80 msec, P < .001). CFR was significantly higher in recovered compared with nonrecovered patients (2.60 ± 0.70 vs. 2.16 ± 0.34, P = .034) 24 hours after PCI. Global and regional wall motion scores before PCI, end-diastolic and end-systolic volumes, and CFR 24 hours after PCI and DDT before PCI were univariate predictors of left ventricular functional recovery. By multivariate analysis, DDT and regional wall motion score before PCI were independent predictors of left ventricular recovery in the follow-up period (P = .003 and P = .007, respectively). In patients with previous myocardial infarction undergoing elective PCI, evaluation of basal coronary flow pattern and measurement of DDT before angioplasty may predict functional improvement of myocardium in the follow-up period and could be useful quantitative parameters in the evaluation of potential improvement in myocardial function.

Non-nuclear Estrogen Receptor Signaling in the Endothelium

In addition to the classical function of estrogen receptors (ER) as transcription factors, evidence continues to accumulate that they mediate non-nuclear processes in numerous cell types, including the endothelium, in which they activate endothelial NO synthase. Non-nuclear ER signaling entails unique post-translational modifications and protein-protein interactions of the receptor with adaptor molecules, kinases, and G proteins. Recent in vitro and in vivo studies in mice using an estrogen-dendrimer conjugate that is excluded from the nucleus indicate that non-nuclear ER activation underlies the migration and growth responses of endothelial cells to estrogen but not the growth responses of endometrial or breast cancer cells to the hormone. In this minireview, the features of ERα and protein-protein interactions that enable it to invoke extranuclear signaling in the endothelium and the consequences of that signaling are discussed.

The Indirect Alloimmune Response Causes Microvascular Endothelial Dysfunction—A Possible Role for Alloantibody

The causes of endothelial dysfunction after cardiac transplantation are unknown. Here, we have investigated whether the indirect alloimmune response mediates endothelial dysfunction in a major histocompatibility complex class I mismatch model. PVG.RT1 rat hearts were transplanted into thymectomized CD8 T-cell-depleted allogeneic (PVG.R8) or syngeneic (PVG.RT1) recipients. Alloantibody was assessed at 2, 4, and 8 weeks. Cardiac allograft vasculopathy, the nature of the inflammatory infiltrate, and origin of endothelial cells were examined at 1, 2, 4, and 8 weeks. Endothelial function was assessed by Langendorff preparations at 1, 2, and 4 weeks. Recipients produced alloantibody and showed luminal occlusion at 1 (17.7%±8.0%), 2 (23.2%±4.9%), 4 (34.3%±5.0%), and 8 weeks (58.1%±1.8%) posttransplantation. The major inflammatory features of the allografts consisted of CD11b monocytes, CD4 T cells, and C4d deposition. At 1 week, the basal coronary flow and the vasodilator response to 5-hydroxytrytamine of syngeneic and allografted hearts were inhibited compared with normal hearts. At 4 weeks, the basal coronary flow of allografts was 54% lower than syngrafts (P<0.01), and 5- hydroxytrytamine and sodium nitroprusside did not evoke an increase in coronary flow in the allograft heart compared with syngeneic controls (P<0.01). Culture of aortic rings with antibody to major histocompatibility complex class I inhibited endothelium-dependent vasodilation to acetylcholine. Transient microvascular endothelial dysfunction occurred in syngeneic and allogeneic cardiac grafts after transplantation. Syngeneic but not allogeneic grafts recovered, suggesting the indirect immune response, consisting of CD4 T cells, monocytes, and antibody, mediates endothelial dysfunction. A possible role for alloantibody in endothelial dysfunction is discussed.

Mechanism of coronary flow reserve reduction in systemic sclerosis: insight from intracoronary pressure wire studies

Functional impairment of coronary microcirculation is thought to be a major pathway in the development of primary cardiac involvement in SSc; however, the underlying mechanism is not fully understood. We aimed to investigate the mechanisms of coronary flow reserve (CFR) reduction in patients with SSc. Seventeen SSc patients and 17 gender- and age-matched controls were enrolled. Coronary angiography and determination of coronary flow parameters including index of myocardial resistance (IMR) using intracoronary pressure wire at basal conditions and during vasodilator-induced maximal hyperaemia were performed. Transit times of repeated intracoronary saline injection were measured to evaluate the role of cold exposure. SSc patients with decreased CFR had accelerated basal coronary flow velocity (P < 0.05), and their IMR in hyperaemia (IMR(hyp)) did not differ from either SSc patients with normal CFR or from the controls (P = 0.292 and P = 0.308). The coronary flow velocity of SSc patients correlated with the IMR at baseline (IMR(bas)) (r = 0.56, P = 0.019). Injection of room temperature saline did not provoke changes in coronary transit times. The lack of decrease in the maximal vasodilatation response indicates that there is no irreversible functional damage at the level of the coronary arterioles. In patients with reduced CFR, the decreased basal IMR and higher velocity reflect compensatory vasodilatory mechanisms probably triggered by ischaemic signals deriving from abnormal myocardial microcirculation.

632 Cardiac Evaluation of Neonates with Impaired Intrauterine Growth

Background and aims. We investigated the relationship between the cardiac function and coronary flow in neonates with impaired intrauterine growth.Methods. Fetal growth was assessed by fetometry and Doppler velocimetry of the umbilical artery blood flow. Impaired fetal growth was defined as an estimated fetal weight less than mean -2SD from the normal gestational age related fetal weight. Cardiac function and left anterior descending artery (LAD) flow parameters were measured by transthoracic Doppler echocardiography in 14 newborns at one week of age when the ductus arteriosus was closed. Gestational age- and age-matched healthy newborns, appropriate for gestational age (N=15) served as controls.Results. The mean pulsatility index was 0.97 and the mean birth weight 2.2 (range 2.1 to 2.4) kg. The left ventricular shortening fraction was normal 39±4.3%. Aortic velocity time integral/minute as a measure of systolic LV function correlated to LAD PFVd, r=0.54, p< 0.0001. LAD peak flow velocity in diastole (PFVd) correlated to left ventricular mass (r=0.46, p=0.0001). The mean LAD diameter was 0.99±0.09 mm. Impaired intrauterine growth was associated with an increase of PFVd (mean 34.5±4, controls 19±6 mm/s, p=0.0001) and coronary flow (7.3±2, and 4.8±2 ml/min respectively, p=0.04). LAD velocity time integral per minute correlated to mitral peak E-wave (r=0.74, p< 0.01).Conclusions. Basal coronary flow and peak flow velocity appear to be significantly increased in these neonates with intrauterine growth impairment, which leads to decreased coronary flow reserve. LAD flow parameters were linearly related to LV systolic and diastolic functions and to LV mass.

Non-Invasive Coronary Flow Reserve After Successful Primary Angioplasty for Acute Anterior Myocardial Infarction Is an Independent Predictor of Left Ventricular Recovery and In-Hospital Cardiac Events

The prediction of left ventricular (LV) recovery and adverse cardiac events after reperfused acute myocardial infarction (AMI) is challenging. The aim of this study was to assess the usefulness of noninvasive coronary flow reserve (CFR) to predict LV recovery and in-hospital adverse cardiac events after AMI by comparison with other available tools. Fifty-five consecutive patients (mean age, 59 +/- 13 years; 33% women) with first reperfused ST-elevation anterior AMIs and sustained Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow underwent prospectively, < 24 hours after successful primary coronary angioplasty, standard echocardiography and noninvasive CFR assessment in the distal part of the left anterior descending coronary artery, using intravenous adenosine infusion, while in a stable hemodynamic situation. CFR was defined as peak hyperemic left anterior descending coronary artery flow velocity divided by baseline flow velocity. LV ejection fraction (LVEF) was measured using the biplane Simpson's rule. A no-reflow pattern was defined as diastolic deceleration time of basal diastolic coronary flow velocity < 600 ms and/or systolic flow reversal and recovery of LV function as an absolute increase of LVEF >or= 10% at 3-month follow-up. Adverse events were defined as the composite of death, recurrent AMI, and acute heart failure. In the whole population, the mean LVEF was 46 +/- 5% at baseline and 55 +/- 9% at follow-up. Patients without LV recovery had more severely impaired CFR compared with those with LV recovery (2.1 +/- 0.55 vs 1.46 +/- 0.2, P < .001), as did patients with adverse events compared with those without events (P = .01). Furthermore, CFR was significantly correlated with 3-month LVEF and regional wall motion score (both P values < .01). On multivariate analysis, CFR was an independent predictor of global and regional LV function at follow-up (both P values <or= .01) and of in-hospital cardiac events (P = .02). Receiver-operating characteristic curve analysis demonstrated that a cutoff value of 1.7 for CFR yielded sensitivity of 76% and specificity of 96% to predict LV recovery at follow-up (P < .01). Noninvasive CFR determined < 24 hours after AMI was an independent predictor of LV recovery at 3-month follow-up and of in-hospital adverse cardiac events.