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Introduction: Impaired coronary flow reserve (CFR) to adenosine predicts adverse outcomes in women with suspected ischemia and no obstructive coronary arteries (INOCA). CFR (ratio of hyperemic to resting coronary blood flow) is a measure of coronary vasomotor dysfunction. We investigated whether resting coronary flow velocity predicts adverse outcomes among women with INOCA. Methods: As part of the WISE, we evaluated relationships between major adverse cardiac events (as first occurrence of death, myocardial infarction, stroke, or heart failure hospitalization), baseline average peak coronary blood flow velocity (bAPV), and CFR to intracoronary adenosine (hyperemic APV/bAPV) in 150 women with INOCA. Four patient groups were identified based on impaired CFR <2.32 and bAPV <22, per prior studies. Results: A total of 33 (22%) events occurred over a median follow-up of 5.9 years (Table). Among the groups, there were no significant differences in pertinent baseline characteristics (age, BMI, ethnicity, cardiac risk factors, medications, WISE coronary severity score, heart rate) except systolic blood pressure. Women with preserved CFR and low bAPV had the lowest risk of MACE (group 2, 13.2%), while women with impaired CFR and low bAPV had the highest risk (group 4, 41.2%) (Figure, log rank test p =0.0063). Women with high bAPV had intermediate risk regardless of CFR (group 1: 28.6%; group 3: 24.3%). Conclusions: Among women with INOCA, integrating CFR and resting coronary flow velocity provides unique prognostic information. These findings suggest that a high resting coronary flow velocity is associated with worse outcomes even in the setting of preserved CFR in women with INOCA. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic inactivation of coronary endothelial small conductance calcium-activated potassium channels (SK) contributes to coronary endothelial dysfunction. Hypothesis: Administration of exogenous SK channel activator protects diabetic coronary microvasculature against a period of cardioplegic hypoxia and re-oxygenation (H/R) injury. Methods: Coronary small arteries (60-100 μm in diameter) and mouse heart endothelial cells (MHECs) were dissected from the harvested heart of mice with or without type-2 diabetes (n = 6/group). The isolated microvessels and MHECs were subjected to 60 minutes of hyperkalemic cardioplegic hypoxia (15°C) and then reperfused with oxygenated Krebs-Henseleit buffer for 60 minutes. Microvessel was treated with or without the selective SK activator NS309 (10-7M) before and during cardioplegic hypoxia. At the end of 60-min re-oxygenation, all vessels was pretreated with endothelin-1 and then the response to the endothelium-dependent vasodilator ADP was examined. Results: The relaxation response to ADP (Figure) before and after cardioplegic H/R was significantly decreased in the diabetic vessels compared to that of non-diabetics (@#P<0.05,). Importantly, pretreating the diabetic and non-diabetic vessels with SK activator NS309 significantly improved the recovery of coronary endothelial function showing increased relaxation response to ADP compared with no pre-treatment alone (*P<0.05), but this protective effect is more pronounced in the non-diabetic vessels than that of diabetics (#P<0.05). The surface membrane SK-expression of MHECs after cardioplegic H/R was significantly decreased, whereas, the cytosolic SK-expression was increased compared with that of sham control group without H/R (P<0.05). Conclusions: Administration of SK activators may protect coronary microvasculature against a simulated cardioplegic ischemia/reperfusion injury, but this effect was redundant in the diabetic coronary microvasculature. SK channel internalization/redistribution may contribute to cardioplegic H/R-induced coronary microvascular dysfunction and relaxation. [ABSTRACT FROM AUTHOR]

Background: Coronary microvascular dysfunction (MVD) is diagnosed when there is impaired coronary flow reserve (CFR) in response to a vasodilator, without obstructive coronary disease. It is unclear whether this is indicative of pathophysiology on exercise. We sought to characterise in vivo coronary physiological changes during exercise in patients with MVD compared to controls. Methods: Simultaneous intracoronary pressure and flow velocity recordings were made in the left anterior descending artery of patients without obstructive epicardial disease (Fractional Flow Reserve >0.80) and normal left ventricular function. Measurements were made during rest, adenosine-mediated hyperaemia and supine bike exercise. Wave intensity analysis quantified waves that accelerated and decelerated coronary blood flow (CBF). The proportion of total waves that accelerated CBF determined the coronary perfusion efficiency. After completion of the exercise protocol, patients were classified into MVD (CFR<2.5) and control groups. Results: 60 patients were studied, 35 with MVD and 25 controls. At rest, MVD patients had significantly higher CBF (average peak velocity 22.2±6.7 vs 15.2±4.8cms-1, p<0.001) and reduced microvascular resistance (MR) (5.1±1.5 vs 7.5±2.1 mmHg.cm-1.s-1, p<0.001). On exercise, MVD patients had significantly higher peak rate-pressure product (21460±5179 vs 17879±5294bpm.mmHg, p=0.03) but similar CBF and MR. Whilst both groups had similar resting coronary perfusion efficiency, with exercise, this decreased significantly in MVD patients but remained unchanged in controls (36±11 vs 57±23%, p<0.001). Conclusions: Reduced CFR in MVD occurs because of elevated resting CBF and not abnormal minimal MR during stress. There is a greater mismatch between myocardial oxygen supply and demand and a paradoxical decrease in coronary perfusion with exercise in these patients. Each pathophysiological process represents a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies indicate that vasodilation and enhanced blood flow to the heart following increases in myocardial O2demand are mediated by voltage-gated Kv1 channels in coronary smooth muscle cells (CVSM). Periods of high O2demand alter the intracellular pyridine nucleotide (PN) redox (e.g., elevated NADH:NAD+), which, in heterologous systems, differentially modulates the gating properties of Kv1 channels by binding to intracellular Kvβ subunits. Hypothesis: Elevated levels of reduced PNs increase Kv1 channel activity in CVSM via the Kvβ complex. Methods: We performed patch clamp electrophysiology on CVSM freshly isolated from the left anterior descending coronary arteries (1stand 2ndorder) of wild type and Kvβ2-null (Kvβ2-/-) mice. In the conventional whole cell configuration, we measured outward K+current density and the voltage-dependence of activation and inactivation (V0.5, act,V0.5,inact, respectively) in the absence and presence of extracellular lactate or pyruvate (10 mM), which alter intracellular PN levels. In inside-out membrane patches, we measured the open probability (nPo) of single K+-permeable channels that are sensitive to the Kv1 channel inhibitors 4-aminopyridine (4-AP; 1 mM) and psora-4 (500 nM), in the absence and presence of NADH (1 mM). Results: Treatment of wild type CVSM with lactate to elevate [NADH]Isignificantly increased whole cell Kv current density and shifted V0.5, actto more negative membrane potentials (n=4, P<0.05). This response was effectively reversed upon increasing [NAD+]iby treatment with pyruvate. Recordings performed in the inside-out configuration revealed K+currents that were sensitive to inhibition by psora-4 and 4-AP and had a unitary conductance of 70.2 ± 2.4 pS. Perfusion with a bath solution that contained 1 mM NADH lead to a significant increase (~2-fold) in the nPo of 4-AP-sensitive channels (n=25-30 cells, P<0.05). However, this effect was largely attenuated in membrane patches from Kvβ2-/-CVSM. Conclusions: Native Kv1 channels in CVSM are functionally regulated by the intracellular NADH:NAD+ratio via their auxiliary Kvβ subunit complex. [ABSTRACT FROM AUTHOR]

Introduction: Endothelial independent microvascular function is measured by coronary flow reserve (CFR) to intracoronary adenosine and low CFR predicts adverse outcomes in women with ischemia with no obstructive coronary artery disease (INOCA). Coronary flow capacity (CFC) interprets CFR in relation to hyperemic average peak velocity (hAPV). CFC is known to predict major adverse cardiac events (MACE) in CAD but has not been evaluated in INOCA. We evaluated whether CFC improves risk prediction for MACE in INOCA patients. Methods: Using data from the WISE study, 150 women with signs and symptoms of ischemia underwent coronary reactivity testing to diagnose INOCA. As previously described CFR < 2.32 was defined as abnormal. Mean hAPV of 55 was used to define low and high hAPV. Impaired CFC was defined as CFR < 2.32 and hAPV < 55, preserved CFC was defined as CFR ≥2.32 or hAPV ≥55. Women were followed annually for 8-years and MACE was defined as patients with death, or first occurrence of nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Results: Mean age was 54.4 years ± 10.3 (± SD), CFR 2.57 ± 0.69, hAPV 54.4 ± 18.7, median follow up was 5.9 years. A total of 33 (22%) events occurred during follow up. CFR < 2.32 predicted longer-term MACE (Figure 1, p=0.043). Although, hAPV alone did not predict MACE (data not shown, p=0.70), poor CFC did predict MACE in women with INOCA (Figure 2, p=0.033). Conclusions: Our results confirm prognostic value of CFR <2.32 as an important long-term predictor of MACE in women with INOCA. While CFR appears to be a more powerful predictor of MACE than hAPV in women with INOCA, those who have low CFC are at particularly high risk. [ABSTRACT FROM AUTHOR]

Background: Larger epicardial plaque burden (PB) and coronary microvascular endothelial dysfunction (CMED) have both been associated with major adverse cardiovascular events (MACE). However, the relationship between PB and CMED remains unknown. Methods: 148 patients with chest pain, referred for evaluation of coronary vasomotion and found to have angiographically normal coronary arteries or mild coronary artery disease (CAD) [<40% stenosis], underwent acetylcholine (Ach) assessment of CMED (defined as coronary blood flow [CBF] change <50% post ACh) and gray-scale intravascular ultrasound (IVUS) imaging of the left anterior descending artery for evaluation of vessel-averaged epicardial plaque area (PA) and PB (PB: PA/vessel area x 100). Results: Baseline clinical characteristics were not significantly different between patients with (n=87, 58.8%) vs. those without CMED (n=61, 41.2%). We observed a significant inverse linear relationship between both IVUS segment-level PA and PB with CBF (Figure). Patients with CMED had significantly higher averaged epicardial PA and PB (Figure). Hypertension (β=0.179, p=0.027 for PA and β=0.166, p=0.036 for PB), hyperlipidemia (β=0.26, p=0.001 for PA and β=0.311, p<0.001 for PB), and CMED (β=0.189, p=0.017 for PA and β=0.20, p=0.01 for PB) were independent predictors of larger PA and higher PB after adjusting for age, sex, hypertension, hyperlipidemia, diabetes mellitus, smoking and CMED. Conclusion: Coronary microvascular endothelial dysfunction is an independent predictor of larger epicardial PA and higher PB in patients with non-obstructive CAD. [ABSTRACT FROM AUTHOR]

Introduction: The effect of aortic stenosis on coronary pressure and flow has not been studied. Methods: 30 patients with severe AS and CAD were included. Intracoronary pressure and flow was measured, pre and post TAVI. Results: Flow during the wave-free period of diastole (iFR-flow) did not change post-TAVI (29.78±14.9 cm/s versus 30.81±19.6 cm/s, p=0.64). Whole cycle hyperaemic flow (FFR-flow) increased significantly post-TAVI (33.44±13.4 cm/s pre-TAVI versus 40.33±17.4 cm/s post-TAVI, p=0.006); this was secondary to significant increases in systolic hyperaemic flow post-TAVI (27.67±12.1cm/s pre-TAVI versus 34.15±17.5cm/s post-TAVI, p=0.02). iFR values did not change post-TAVI (0.88±0.09 pre-TAVI versus 0.88±0.09 post-TAVI, p=0.73); whereas FFR decreased significantly post-TAVI (0.87±0.08 pre-TAVI versus 0.85±0.09 post-TAVI, p=0.001 Conclusions: Systolic and hyperaemic coronary flow increased significantly post-TAVI; consequently, hyperaemic indices that include systole underestimated coronary stenosis severity in patients with severe aortic stenosis. Flow during the wave-free period of diastole did not change post-TAVI; suggesting that indices calculated during this period are not vulnerable to the confounding effect of the stenotic aortic valve. [ABSTRACT FROM AUTHOR]

Introduction: Coronary microvascular dysfunction (CMD) is a potential cause of myocardial ischemia and may affect myocardial function at rest and during stress. CMD can be identified, in patients with non-obstructive coronary artery disease (CAD), by a reduced transthoracic Doppler-derived coronary flow reserve (CFR), which is an index of coronary arterial reactivity. Left ventricular contractile reserve (LVCR), assessed by dipyridamole stress echocardiography, reflects contractile reserve independently from preload and afterload changes, and have demonstrated to be prognostically powerful in identifying patients at higher risk. Hypothesis: The aim of our study was to assess LVCR in patients with CMD, and the effect of ivabradine on this parameter, as it was never investigated. Methods: 158 patients (94 M, 64 F; mean age 66±5 years) without obstructive CAD, assessed by invasive coronary angiogram, underwent Doppler-derived CFR. 41 of them (25 M, 16 F; mean age 62±2 years), with CMD (defined as CFR < 2) were enrolled in the study. Coronary flow was assessed in the left anterior descending coronary artery and CFR was determined as the ratio of hyperaemic, induced by intravenous dipyridamole administration, to baseline diastolic coronary flow velocity. LVCR was defined as the stress/rest ratio of force, calculated as the ratio between systolic pressure and left ventricular end-systolic volume index. A control group without CMD was used to compare LVCR. Patients were randomly assigned to ivabradine or placebo for one month (after up-titration phase). Doppler echocardiography, CFR and LVCR assessment were performed again at the end of treatment period. Results: There were no significant differences in baseline characteristics between control and study group and ivabradine and placebo group. LVCR was significantly lower in patients with CMD (1.18±0.24 vs. 1.28±0.32 - p<0.01). Baseline CFR and LVCR were not significantly different in ivabradine and placebo group. After treatment, in ivabradine group both CFR and LVCR significantly increased (2.78±0.36 vs. 1.84±0.12 - p<0.01 and 1.34±0.33 vs. 1.18±0.24 - p<0.01), while in placebo group they did not significantly changed. There was a weak correlation between CFR and LVCR in study group. Conclusions: Patients with CMD showed a lower LVCR compared with control group. Ivabradine showed to be able to improve both CFR and LVCR. Improvement of both parameters suggest a significant effect on the prognosis of these patients. Larger studies could confirm our data. [ABSTRACT FROM AUTHOR]

Introduction: Multiple comorbidities, such as diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) cause inflammation and alterations in coronary microvascular NO bioavailability, leading to impaired myocardial perfusion. Hypothesis: Increased production of reactive oxygen species (ROS) due to DM, CKD and high fat diet (HFD) results in loss of coronary microvascular NO bioavailability in exercising swine. Methods: In 6 female swine, DM (streptozotocin 3x50mg/kg iv) and CKD (renal embolization) were induced, and HFD was given for 6 months (DM+HFD+CKD). 8 female healthy swine on normal pig chow served as controls (CON). Coronary flow regulation and the role of ROS-NO balance herein, was studied at rest and during treadmill exercise with/without eNOS inhibition (nitro-L-arginine), and ROS scavengers (MPG+Tempol). Results: DM+HFD+CKD had hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min), hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l) and sustained inflammation (TNF 51.6±5.1 vs 24.6±5.5pg/ml, all P<0.05). Myocardial superoxide production was increased in DM+HFD+CKD animals and was associated with a lower NO myocardial production, (P<0.5). Myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, resulting in reduced coronary venous oxygen saturation (cvSaO2) compared to CON, (P<0.05). eNOS-inhibition resulted in coronary microvascular constriction in CON, reflected by reduced cvSaO2, but had no effect in DM+HFD+CKD (Fig. A, B, *P<0.05). Interestingly, scavenging of ROS resulted in decreased cvSaO2 in DM+HFD+CKD and had no effect in CON (Fig. C, D), suggesting that the increased oxidative stress resulted in increased production of the vasodilator hydrogen peroxide. Conclusions: In swine with multiple co-morbidities, altered NO bioavailability was associated with increased oxidative stress. This was partially compensated by increased hydrogen peroxide-mediated vasodilation. [ABSTRACT FROM AUTHOR]

Introduction: Epicardial coronary artery spasm, both diffuse or focal, can cause myocardial infarction with no obstructive coronary artery disease (MINOCA) in women. Evidence of myocardial scar, as detected by late gadolinium enhancement (LGE) using cardiac magnetic resonance imaging (CMRI), is of prognostic value, however its prevalence in patients with epicardial coronary spasm is unknown. Methods: Women with no obstructive coronary artery disease undergoing clinically indicated invasive coronary reactivity testing were enrolled in the WISE-CVD Continuation Study. History of prior MINOCA was determined by chart review. Functional capacity at baseline was estimated using the Duke Activity Status Index questionnaire. Coronary flow reserve (CFR) to intracoronary (IC) adenosine, coronary blood flow and diameter response to IC acetylcholine 36.4 mcg, spasm testing with IC acetylcholine 108 mcg and coronary artery diameter response to IC nitroglycerin were evaluated. Women were considered to have epicardial spasm if either diffuse or focal coronary artery spasm (≥ 75% artery diameter reduction) developed following spasm testing. Presence and type of LGE pattern were assessed qualitatively and semi-quantitative measure of myocardial perfusion reserve index (MPRI) were determined by CMRI performed subsequently to coronary reactivity testing. Results: 51 women (mean age 55.3 ± 11.1 years) were enrolled of whom 19 (38%) had hypertension, 10 (20.4%) had hyperlipidemia, 27 (52.9%) had a family history of CAD, 11 (21.6%) were smokers, 4 (7.8%) had diabetes and 13 (25.5%) had history of MINOCA. LGE was detected in 5 patients (10%). Epicardial spasm was present in 13 women (Table), of whom three had LGE (23%), one of which did not have a history of MINOCA. Those with epicardial spasm had a trend towards reduced CFR and lower functional capacity compared to patients without spasm but a similar prevalence of LGE. Conclusions: Among women with signs and symptoms of ischemia but no obstructive CAD, almost a quarter of women with epicardial spasm have LGE, including women without a prior history of MINOCA. Considering the established prognostic significance of LGE, these findings may be useful in the risk stratification of these women. [ABSTRACT FROM AUTHOR]

Coronary artery disease and coronary microvascular disease are a leading cause of death in diabetic patients. However, the molecular mechanisms by which diabetes causes coronary microvascular dysfunction is not well understood. Protein O -GlcNAcylation is one of the posttranslational modifications and regulated by two enzymes; O -GlcNAc transferase catalyzes the addition of O -GlcNAc to the proteins and O -GlcNAcase (OGA) removes O -GlcNAc. We recently reported that increased protein O -GlcNAcylation attenuated endothelium-dependent vascular relaxation in type 1 diabetic mice. In this study, we investigate whether and how excessive protein O -GlcNAcylation leads to coronary microvascular dysfunction in type 2 diabetic (T2D) mice. We used endothelium-specific tetracycline-inducible OGA transgenic mice. T2D mice were generated by a single injection of low dose streptozotocin (75mg/kg, i.p.) with a high fat diet (60 % kcal from fat). Six weeks after T2D induction, doxycycline was administered in drinking water (0.2 mg/ml) for 6 weeks. T2D mice exhibited decreased coronary flow velocity reserve (CFVR, a marker of coronary microvascular dysfunction), increased EC apoptosis and decreased capillary density in the left ventricle (LV) compared to the control. OGA overexpression in T2D mice restored the level of EC apoptosis, capillary density, and CFVR toward control levels. T2D mice also exhibited attenuated cardiac contractility evidenced by decreased left ventricular systolic pressure, ejection fraction, and dp/dt. These parameters were increased by OGA overexpression in T2D mice. To investigate the target genes influenced by protein O -GlcNAcylation, we isolated mouse coronary ECs and performed a PCR Array. We revealed that Sp1 and Mapk1 were decreased in T2D mice and increased by OGA overexpression in T2D. Our results suggest that increased protein O -GlcNAcylation leads to coronary microvascular disease via increasing EC apoptosis. Overexpression of OGA in ECs not only restores coronary microvascular function, but also improves cardiac function. Further study on the role of Sp1 and Mapk1 in coronary microvascular disease might help develop novel treatment for coronary microvascular disease and cardiac dysfunction in type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

Pericytes (PCs) are mural cells that envelop the endothelial cells (ECs) of microvessels throughout the body. As per studies in the brain, PCs are known to have multiple functions which include vessel development and maturation as well as maintenance of endothelial barrier integrity. However, little is relatively known about their tissue-specific function in the heart. Recently, others have shown that cardiac PCs constrict coronary capillaries and decrease reperfusion in an ischemic heart. However, their response to hypoxia and their ability to contract at a cellular level have yet to be elucidated. Using FACS, we have isolated and purified a population of murine cardiac pericytes (MPCs) that are characterized by NG2+ PDGFRβ+ CD146+ CD34- CD31- CD45-. Functionally, we provide evidence that these MPCs increase endothelial barrier integrity. Comparing mono and coculture models, MPCs increased EC TEER by 2.3-fold and decreased EC permeability by 1.29-fold. When MPCs were subjected to hypoxic conditions, the HIF-1α pathway was activated (Fig. 1), there was a significant increase in secretion of angiogenic factors (VEGF and PDGFbb), and they became apoptotic. Here we show for the first time that this population of MPCs express contractile machinery (MLC2/P-MLC2, actin filaments, adrenergic receptors), have an increase in intracellular calcium upon phenylephrine stimulation (Fig. 2), and finally, their changes in electrical resistance to different stimuli represent contraction. Our in vitro study further supports the current in vivo findings in the literature that suggests MPCs are sensitive to hypoxia and are vasoconstrictive in an ischemic heart. [ABSTRACT FROM AUTHOR]

Background: We have previously reported that sympathetic nerve stimulation by cold exposure dilates coronary arteries in the normal rat, and constricts in the diabetic rat, but it was evaluated only morphologically by measuring the caliber change of the coronary artery. The purpose of this study is to confirm by functional evaluation method that coronary reaction is induced by cold exposure. Conventional coronary angiography cannot visualize small arteries of less than 300 μm in diameter, such as the rat coronary artery. We have developed a system of synchrotron radiation coronary microangiography (SRCA) in the in vivo rat. SRCA can visualize vessels as small as 50 μm in diameter, thus enabling us to evaluate the coronary artery reaction in the in vivo rat. Method: The advantages of synchrotron radiation-derived X-rays are their high spatial resolution (9 μm/pixel) obtained as a result of the increased photon density and straightness of the beam. High density resolution is obtained with the high-gain avalanche rushing amorphous photoconductor camera tube using a fiber-optic plate. Diabetes was induced in rats by administration of 65 mg/kg streptozotocin. A polyethylene tube for angiography was inserted into the carotid artery of anesthetized rat. SRCA was performed before and after cold exposure. We compared the time-dependent changes in the contrast agent density of the left coronary artery between the normal rats (n = 9) and diabetic rat (n= 7) using Hitachi micro-angio tracking program. Results: High spatial and density resolution images were obtained. The time-dependent changes in the contrast agent density of the left coronary were plotted in a line graph (Figure). The inclination of the graph was considered as velocity. The initial velocity increased from 0.015 (baseline) to 0.024 (after cold exposure) in normal rat. Decreased from 0.021 to 0.016 in diabetic rat. This result supports our previous report that sympathetic nerve stimulation dilates coronary arteries in the normal rat and constricts in the diabetic. Conclusion: The coronary reaction that induced by sympathetic nerve stimulation was confirmed using the SRCA system and Hitachi micro-angio tracking program. This system was useful for functional evaluation of micro artery. [ABSTRACT FROM AUTHOR]

Introduction: Quantitative flow ratio (QFR) is a novel non-invasive technique to calculate fractional flow reserve (FFR), without hyperaemia induction or an invasive pressure-wire. The diagnostic performance of QFR was recently demonstrated to be reduced in the presence of coronary microvascular dysfunction (CMD). QFR has not yet been validated in diabetic patients, which are known to have an increased risk of CMD. Hypothesis: We assessed the hypothesis that the diagnostic performance of QFR is reduced in diabetic patients. Methods: Patients who underwent invasive coronary angiography and subsequent invasive FFR measurement within 6 months were included. QFR was determined in all coronary arteries in which invasive FFR was performed, using a dedicated software package. Diagnostic accuracy and the area under the receiver operating characteristic (ROC) curve were determined for QFR, using FFR as the reference standard. QFR and invasive FFR values of ≤0.80 were considered significant. Results: In total, 320 coronary arteries from 66 (25.5%) diabetic and 193 (74.5%) non-diabetic patients were analysed. On a vessel-based analysis, diagnostic accuracy, sensitivity and specificity showed no significant difference between diabetic and non-diabetic patients, 87.8% (95% confidence interval (CI) 78.7%-94.0%) vs. 84.5% (95% CI 79.2%-88.8%) (P = 0.47), 70.8% (95% CI 48.9%-87.4%) vs. 68.7% (95% CI 56.2%-79.4%) (P = 0.72) and 94.8% (95% CI 85.6%-98.9%) vs. 90.6% (95% CI 85.3%-94.6%) (P = 0.24). Moreover, the area under the ROC curve was not significantly different between diabetic and non-diabetic patients, 0.91 (95% CI 0.84-0.99) vs. 0.93 (95% CI 0.89-0.96) (P = 0.74). Conclusions: In our study, we showed a good diagnostic performance of QFR which was independent of the presence of diabetes. [ABSTRACT FROM AUTHOR]

Background: Thermodilution through continuous infusion of saline is a novel technique to selectively quantify absolute coronary flow. Together with distal coronary pressure, this technique allows for assessment of microvascular resistance (MVR). Of note, intracoronary infusion of room-temperature saline is observed to induce maximal hyperemia, obviating the need for adenosine. The goal of the present study was to compare coronary flow measurements with this novel technique to [15O]H2O positron emission tomography (PET), the current gold standard for quantification of myocardial perfusion. Additionally, we investigated whether absolute hyperemic flow and minimal MVR can be reliably quantified without the use of adenosine. Methods: Twenty-five patients with a focal lesion in either the left anterior descending artery or left circumflex artery underwent [15O]H2O PET followed by invasive coronary angiography. A dedicated microcatheter was used to selectively infuse saline into the coronary artery. Distal coronary pressure and temperature were recorded using a temperature/pressure tipped guidewire. Measurements were performed with and without intravenous administration of adenosine. Results: Invasive and non-invasive measurements of hyperemic flow and MVR, obtained during intravenous administration of adenosine showed strong correlation (r =0.91; p<0.001 for hyperemic flow and r =0.85; p<0.001 for MVR) and good agreement (intraclass correlation coefficient [ICC]=0.90; p<0.001 for hyperemic flow and ICC=0.79; p<0.001 for MVR). Bland-Altman plots showed an overall bias of 3.1 ± 23% for hyperemic flow and -1.9 ± 28% for MVR. Hyperemic flow and MVR also correlated well between measurements with and without adenosine (r =0.97; p<0.001 for hyperemic flow and r =0.98; p<0.001 for MVR) and showed good agreement (ICC=0.96; p<0.001 for hyperemic flow and ICC=0.98; p<0.001 for MVR) with a mean relative difference of 5.9% ± 10% (ICC=0.96; p<0.001) for hyperemic flow and 1.9% ± 9% for MVR. Conclusions: Thermodilution through continuous infusion of saline is a highly accurate method to measure absolute hyperemic coronary flow and minimal MVR, which is evidenced by a strong correlation with [15O]H2O PET derived flow and resistance. This technique can be reliably performed without the use of adenosine. [ABSTRACT FROM AUTHOR]

Introduction: Although the association between obstructive atherosclerosis of the epicardial coronary arteries and adverse clinical outcomes is well-established, there are few studies on the impact of coronary microvascular dysfunction (CMD) on mortality and major adverse cardiovascular events (MACE). Coronary flow reserve (CFR), measured either invasively or non-invasively, can be used to assess for CMD. We conducted a meta-analysis of the impact of abnormal CFR in patients being assessed for myocardial ischemia on mortality and cardiovascular MACE. Methods: Electronic databases were searched for studies where CFR was measured either invasively or non-invasively and clinical events, including mortality, were recorded and compared between patients with normal and abnormal CFR. Only data on patients who had a negative stress test for myocardial ischemia or non-obstructive coronary artery disease and studies where the cut-off for abnormal CFR was prospectively defined were included in the analysis. Data were extracted and summary odds ratios (ORs) were obtained using a random effects model. Results: Six studies that reported mortality (6,047 patients, mean follow-up 53 months) and five studies that reported major adverse cardiovascular events (2,745 patients, mean follow-up 36 months) were identified. The percentage of females in the studies ranged from 31% to 64%. Abnormal CFR was associated with increased mortality (OR 4.17; 95% CI, 3.27-5.31) and increased MACE (OR 2.85; 95% CI, 2.12-3.82). Conclusion: The presence of isolated coronary microvascular dysfunction in patients presenting with suspected myocardial ischemia is associated with increased mortality and MACE. Future studies are needed to investigate therapies aiming at treatment of CMD as a target for intervention to improve cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The central nervous system autonomic network (CAN) is the functional net of autonomic control during cognitive, affective and motor tasks. The CAN comprises sympathetic (sCAN) and parasympathetic (pCAN) subnetworks. Resting state functional magnetic resonance imaging (RS-fMRI) can evaluate the CAN activity by the changes of oxygen level in the blood. Hypothesis: To investigate potential differences in the functional organization of the CAN by RS-fMRI in patients with Cardiac Syndrome X (CSX), previous Tako-Tsubo Cardiomyopathy (TTC) and previous acute myocardial infarction (AMI). Methods: We prospectively enrolled patients with CSX, TTC and previous AMI. Patients underwent RS-fMRI examination on a 3.0T scanner. We evaluated commonly activated regions of interest (ROIs) identified in the CAN, sCAN and pCAN according to a previous meta-analysis by Beissner. We calculated resting state functional connectivity (RS-FC) (expressed as Pearson's correlations) in the whole network, between the two subnetworks, within each network and ROIs pairs. Pre-processing and analysis were performed by CONN v13 functional connectivity toolbox software. Results: We included 39 subjects (35 women): 15 CSX, 12 TTC, and 12 AMI matched patients. We found no significant difference in the degree of average connectivity within the whole CAN, sCAN and pCAN subnetworks. In the explorative ROI-to-ROI analysis, the RS-FC between the sCAN Midcingulate Cortex (sCAN-MCC) and pCAN Primary Motor area (pCAN-PM) differed between groups (F=6.25, p< 0.01 FDR-corr). After correction for multiple comparisons, TTC exhibited stronger connectivity than AMI (p=0.02 corr), but similar to CSX (p=0.05 unc). Conclusions: TTC patients exhibited increased RS-FC than CSX and AMI between sympathetic specific CAN areas involved in interoceptive pain awareness and negative emotional statuses (sCAN-MCC) and visceral regulation of both sympathetic (sCAN-MCC) and parasympathetic (pCAN-PM). This difference may be associated with subjective pain perception expression and suggests a possible intriguing pathophysiologic pathway in patients with TTC. This is the first study investigating RS-fMRI in CSX and comparing it to TTC and AMI. [ABSTRACT FROM AUTHOR]

Introduction: Little evidence suggests a role of psychosocial and psychiatric mechanisms in Cardiac Syndrome X (CSX) and Tako-Tsubo Cardiomyopathy (TTC). However, no studies have performed a complete psychosocial evaluation in these patients. Hypothesis: To investigate by detailed validated questionnaires, whether CSX and TTC patients may present specific psychosocial profiles as compared to patients with previous acute myocardial infarction (AMI). Methods: We prospectively enrolled patients with CSX, previous (at least 6 months) TTC and previous (at least 6 months) AMI. Patients underwent the following extensively validated psychosocial investigation administered by a psychologist and confirmed by a psychiatrist: Millon Clinical Multiaxial Inventory-III (MCMI-III), State-Trait Anxiety Inventory form Y (STAI-Y), Short Form(36) Health Survey (SF-36) related to quality of life questionnaire (higher score indicates better health state). Results: We evaluated 50 patients (46 women): 16 CSX, 17 TTC and 17 AMI patients, which were age-sex-cardiovascular risk factor matched. No differences in psychotropic medications prescribed were appreciated. CSX showed significant lower SF-36 Body Pain score (means higher level of pain) than AMI (52.69 vs 69.47; p 0.046), but higher SF-36 Mental Health score (means higher level of mental health) (76.75 vs 63.76; p 0.039). The latter, was higher than the age-sex-matched score in the general population in a significantly greater proportion of CSX patients as compared to TTC and AMI (93.8 vs 76.5% vs 64.7%; chi2 p 0.056). No significant differences were appreciated in either MCMI-III and STAI-Y. Conclusions: Our study suggests that no specific psychosocial patterns characterize either CSX or TTC in comparison to AMI patients. CSX patients had the highest level of self-reported body pain, conceivably subsequently to insufficient symptoms control by the current empiric treatments. Backwards, CSX patients showed the best self-reported mental health, possibly due to somatization mechanisms. Further studies are required to confirm these hypothesises. [ABSTRACT FROM AUTHOR]

Introduction: Trans-radial access (TRA) for PCI has been consistently shown to reduce mortality and bleeding complications compared with trans-femoral access (TFA) in pts with STEMI. On the contrary the efficacy and the safety of TRA in NSTE-ACS is still matter of debate Hypothesis: The purpose of this study was to determine the potential clinical benefits of TRA in the NSTE-ACS patient population Methods: We compared outcomes of TRA versus TFA in a real world population of patients with NSTE-ACS drawn from the ISACS-TC registry (NCT01218776) The primary outcome was the incidence of all cause death and stroke at 30 days. The secondary outcome was the combined endpoint of periprocedural major complications (MI type 4, abrupt closure, loss of side branches, distal embolization and postPCI TIMI flow≤2). The incidence of nonCABG related major bleeding (TIMI definition) was also noted Results: Of 3127 NSTE ACS patients undergoing PCI 2047 (65.5%) underwent TRA, which was more likely to be employed among male sex and patients with lower-risk characteristics: patients were younger with a lower burden of risk factors. Patients undergoing TRA had significantly more periprocedural complications than those who received TFA (24.4% vs 8.6% p<0.001). The combined endpoint was driven mainly by the rate of noreflow phenomenon (24.4% vs 9.7%). After adjustment for baseline variables, the risk of periprocedural complications was attenuated but still remained significant between the radial and femoral groups (OR 3.63 CI: 2.52-5.22). There were significant differences in center experience: 1651 of the 2047 TRA procedures were performed by centers with high volume characteristics. There was heterogeneity in treatment effect in patients receiving TRA in centers with high versus medium/low volume characteristics. The risk of periprocedural complications was no longer significant after adjustment for center characteristics (OR 0.94 CI 0.52-1.68). The rate of the primary outcome was 1.6% in the TRA group compared with 2.2% in the TFA (adjusted OR 0.65 CI 0.33-1.29). The rate of nonCABG-related major bleeding at 30 days was 1.5% in the TRA group compared with 0.5% in the TFA group. Yet this rate was substantially lower in centers with high volume characteristics. (Adjusted for age and sex OR 0.25 CI 0.03-2.06). Conclusions: No significant differences in the combined outcome of 30 day mortality and ischemic stroke were seen between TRA and TFA approach in patients with NSTE-ACS undergoing PCI. TRA may be preferred in these patients only in centers with considerable experience. [ABSTRACT FROM AUTHOR]

Introduction: Although the importance of coronary vasomotor abnormalities, including epicardial coronary artery spasm and coronary microvascular dysfunction, has been emerging, no study has ever examined both disorders in the same cohort. We thus examined the prognostic impacts of the 2 disorders together in patients with angina and unobstructive coronary arteries. Methods and Results: We enrolled 187 consecutive patients with angina and unobstructive coronary arteries (M/F 113/74, 63.2±12.3 [SD] year-old). To assess coronary vasoconstricting responses, we performed acetylcholine provocation tests. Then, to evaluate coronary microvascular function, we measured coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) during hyperemic state induced by intravenous adenosine. For the analysis, we divided the patients into 4 groups according to CFR (<2.0) and IMR (>20) levels; high CFR and low IMR (Group 1, n=84), high CFR and high IMR (Group 2, n=37), low CFR and low IMR (Group 3, n=39), and low CFR and high IMR (Group 4, n=27). Among the 4 groups, there was no significant difference in baseline characteristics. Compared with other 3 groups, Group 4 had the highest incidence of epicardial coronary spasm (P=0.02). Moreover, we analyzed the incidence of major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, hospitalization for unstable angina pectoris, during the median follow-up period of 618 days (IQR 373, 814). Kaplan-Meier survival analysis showed a significantly worse prognosis in Group 4 compared with other 3 groups (HR 9.14, 95%CI 1.17-184.75, P=0.03). Multivariable logistic regression analysis showed that epicardial coronary spasm (OR 2.96, 95%CI, 0.789-11.075 P=0.11) was an independent predictor for Group 4. Importantly, intracoronary administration of fasudil, a selective Rho-kinase inhibitor, significantly ameliorated CFR and IMR in Group 4 as compared with other 3 groups (both P<0.001). Conclusions: These results provide the first evidence that a combination of epicardial spasm and coronary microvascular dysfunction, both of which are caused by Rho-kinase activation, is associated with a poor prognosis in patients without coronary stenosis. [ABSTRACT FROM AUTHOR]

Introduction: In patients with stable angina, confirming whether symptoms are due to epicardial coronary artery disease (CAD) or coronary microvascular dysfunction (MVD) remains challenging. Recent advances in fully automated in-line CMR myocardial perfusion mapping now enables quantification of myocardial blood flow (MBF) to be performed rapidly within a clinical workflow. Aims: To assess the performance of perfusion mapping against invasive coronary physiology reference standards for detecting CAD (fractional flow reserve (FFR) < 0.80), MVD (defined by index of microcirculatory resistance (IMR > 25) and the ability to differentiate between the two. Methods: Fifty patients (40 male, mean age 63±8 years) with stable angina and 15 healthy volunteers underwent adenosine stress CMR at 1.5T. MBF and myocardial perfusion reserve (stress/rest MBF) were measured on stress and rest perfusion maps (Panel A). During subsequent angiography, 27 patients had CAD (14 single vessel, 5 two vessel, 8 three vessel disease (3VD)) and 23 had non-obstructed arteries (7 normal IMR, 16 abnormal IMR). A multi-tiered detection strategy was used to objectively classify normal, MVD, 3VD, and 1 or 2 vessel CAD. Results: FFR-positive (epicardial stenosis) areas had significantly lower stress MBF (1.47±0.48ml/g/min) and MPR (1.75±0.60) than FFR-negative IMR-positive (MVD) areas (stress MBF 2.10±0.35ml/g/min, MPR 2.41±0.79) and normal areas (stress MBF 2.47±0.50ml/g/min, MPR 2.94±0.81). Stress MBF < 1.94ml/g/min accurately detected obstructive CAD on a regional basis (AUC 0.90, p<0.001) (Panel B). In subjects without regional perfusion defects, stress MBF >2.28ml/g/min differentiated normal from abnormal (3VD or MVD) subjects (AUC 0.94, p<0.001). Furthermore, stress MBF <1.82ml/g/min was able to accurately discriminate between obstructive 3VD and MVD (AUC 0.94 p<0.001) (Panel C). Conclusions: Myocardial perfusion mapping by CMR is able to accurately detect and differentiate physiologically significant CAD defined by FFR from MVD defined by IMR. [ABSTRACT FROM AUTHOR]

Introduction: Coronary microvascular dysfunction results in impaired global coronary flow reserve (CFR) and is implicated in the development of atherosclerosis and heart failure. Although assessment of CFR using positron emission tomography provides independent prognostic information, the prognostic value of cardiac magnetic resonance (CMR) derived CFR remains unclear. Hypothesis: Global CFR derived from coronary sinus (CS) flow measurements may provide prognostic value in patients with known or suspected CAD undergoing stress CMR. Methods: Consecutive patients undergoing regadenoson stress perfusion CMR were prospectively enrolled (n=507). CS flow was measured using phase contrast imaging at baseline and immediately after stress perfusion. CFR was calculated as the ratio of stress:baseline flow. Patients were followed for major adverse cardiac events (MACE) - death, non-fatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia and late revascularization. Cox proportional hazards regression modeling was used to examine the association between CFR and MACE. Results: Over a median follow-up of 2.1 years, 80 patients experienced MACE. By Kaplan-Meier analysis, risk of MACE was significantly higher in patients with CFR

Background: Epicardial coronary endothelial dysfunction is associated with development and progression of local coronary atherosclerotic lesion. However, the role of coronary microvascular endothelial function in the development of coronary atherosclerosis is largely unknown. The aim of the present study was to test the hypothesis that coronary microvascular endothelial dysfunction (CMED) is associated with epicardial atherosclerotic coronary artery disease (CAD). Methods and Results: 148 patients with chest pain, referred for the evaluation of coronary vasomotion and found to have angiographically normal coronary arteries or mild CAD (<40% stenosis), underwent invasive coronary endothelial function testing and virtual-histology intravascular ultrasound (VH-IVUS) of the left anterior descending coronary artery. Endothelium-dependent coronary vascular reactivity was evaluated by graded administration of intracoronary acetylcholine. CMED was defined as percent increase in coronary blood flow of ≤50% in response to a maximum dose of acetylcholine. Patients with CMED (n=87), as compared to those with normal microvascular endothelial function (n=61), had higher averaged epicardial plaque necrotic core area [0.07 (0.01-0.34) vs. 0.03 (0.00-0.17) mm2, p=0.016] and higher frequency of imaged arteries containing at least one VH-IVUS-derived thin-cap fibroatheroma (TCFA) [n=22 (25.3%) vs. 5 (8.2%), p=0.008] (Figure). After adjusting for age, gender and CAD risk factors, CMED was an independent predictor of VH-IVUS-derived larger averaged necrotic core area (β=0.176, p=0.033) and TCFA frequency (β=0.180, p=0.028). Conclusions: CMED is an independent predictor of larger necrotic core plaque area and higher TCFA frequency, both of which are characteristics of rupture-prone plaques. [ABSTRACT FROM AUTHOR]

Introduction: Coronary microvascular dysfunction (MVD) is diagnosed when there is impaired coronary flow reserve (CFR), with no obstructive coronary artery disease (NOCAD). It is not known whether this is a manifestation of a generalized disorder of endothelial, smooth muscle function and nitric oxide metabolism, as previous studies of NOCAD have not been restricted to MVD cohorts, confirmed on coronary reactivity testing. Methods: Simultaneous intracoronary pressure and flow velocity recordings were made in the left anterior descending artery of patients referred for elective diagnostic angiography who had no obstructive epicardial disease (Fractional Flow Reserve >0.80) and normal left ventricular (LV) function. Measurements were made during rest and adenosine-mediated hyperaemia with subsequent classification into MVD (CFR<2.5) and control groups. Thereafter, forearm blood flow (FBF) was measured by venous occlusion plethysmography in response to low and high dose intra-arterial infusions of acetylcholine, adenosine and NG-monomethyl-L-arginine (L-NMMA) with saline washouts between agents. Data are mean+/-SD with between group responses compared by ANOVA. Results: 47 patients (87% female, age 57±11) were enrolled. CFR was 2±0.3 in the MVD group (n=31) and 3±0.4 in controls (n=16) with significantly higher resting coronary blood flow (CBF) in the MVD group. Augmentation of FBF with acetylcholine was significantly reduced in patients with MVD compared to controls (P=0.01) but was similar in response to adenosine (P=0.08). L-NMMA caused significantly greater reduction in FBF in patients with MVD (P<0.001). Conclusion: Impaired CFR is associated with impaired endothelium-dependent peripheral vascular function, which may represent a non-invasive means of defining coronary MVD and emphasises the systemic nature of this disorder. Patients with MVD have elevated basal nitric oxide synthase tone, which may also be the basis of elevated resting CBF. [ABSTRACT FROM AUTHOR]