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Introduction: Coronary microcirculation dysfunction can present as either a chronic coronary syndrome with angina or an acute coronary syndrome with normal coronary angiography1 . Invasive tests for microvascular disease include coronary flow reserve (CFR) and index myocardial resistance (IMR). CFR and IMR measurements are taken during routine coronary angiography using the Coroventis CoroFlow console and the PressureWire X coronary wire. A continuous adenosine infusion is used to induce stable hyperemia during the test, which causes vasodilation of the microcirculation and simulates the state of physical activity. CFR functions as a standard thermodilution method, measuring the time it takes for the saline flush to reach the thermistor. In contrast, while measuring CFR and IMR, a measurement of fractional flow reserve (FFR) is obtained, which rules out epicardial stenosis. IMR, on the other hand, is a ratio of pressure to flow velocity during maximal hyperemia. Aim: To demonstrate new diagnostic tools for determining myocardial resistance and coronary flow reserve. Results: The first CFR and IMR tests were performed in May 2022 at the University Hospital Center Zagreb’s interventional cardiology department. The tests successfully detected microvascular disease, allowing this group of patients to receive appropriate medical treatment. Conclusion: The clinical significance of CFR and IMR is to enable better treatment selection for our patients. Although these tests are minimally invasive, they can cause complications, so careful patient selection is essential. [ABSTRACT FROM AUTHOR] more...

Ischemia preconditioning (IPC) ameliorates coronary no-reflow induced by ischemia/reperfusion (I/R) injury, and pericytes play an important role in microvascular function. However, it is unclear whether IPC exerts a protective effect on coronary microcirculation and regulates the pericytes. The purpose of this study was to assess whether IPC improves coronary microvascular perfusion and reduces pericyte constriction after myocardial I/R injury. Rats were randomly divided into three groups: the sham group, the I/R group, and the IPC + I/R group. The left anterior descending artery (LAD) of rats in the I/R group were ligated for 45 min, and the rats in the IPC + I/R group received 4 episodes of 6 min occlusion followed by 6 min reperfusion before the LAD was ligated. After 24 h of reperfusion, the area of no-reflow, and area at risk were evaluated with thioflavin-S and Evens blue staining, and infarct size with triphenyl tetrazolium chloride staining, respectively. Besides, fluorescent microspheres were perfused to enable visualization of the non-obstructed coronary vessels. Cardiac pericytes and microvascular were observed by immunofluorescence, and the diameter of microvascular at the site of the pericyte somata was analyzed. The infarct size, and area of no-reflow in the IPC + I/R group were significantly reduced compared with the I/R group (infarct size, 33.5% ± 11.9% vs. 49.2% ± 9.4%, p = 0.021；no-reflow, 12.7% ± 5.2% vs. 26.6% ± 5.0%, p < 0.001). IPC improved microvascular perfusion and reduced the percentage of the blocked coronary capillary. Moreover, we found that cardiac pericytes were widely distributed around the microvascular in various regions of the heart, and expressed the contractile protein α-smooth muscle actin. The microvascular lumen diameter at pericyte somata was reduced after I/R (4.3 ± 1.0 μm vs. 6.5 ± 1.2 μm, p < 0.001), which was relieved in IPC + I/R group compared with the I/R group (5.2 ± 1.0 μm vs. 4.3 ± 1.0 μm, p < 0.001). Besides, IPC could reduce the proportion of apoptotic pericytes compared to the I/R group (22.1% ± 8.4% vs. 38.5% ± 7.5%, p < 0.001). IPC reduced no-reflow and inhibited the contraction of microvascular pericytes induced by cardiac I/R injury, suggesting that IPC might play a protective role by regulating the pericyte function. • Ischemia preconditioning improved microvascular perfusion after myocardial ischemia/reperfusion. • Cardiac pericytes might be involved in microvascular dysfunction following ischemia. • Ischemia preconditioning inhibited the constriction and apoptosis of microvascular pericytes [ABSTRACT FROM AUTHOR] more...

Abstract: We previously demonstrated that uridine adenosine tetraphosphate (Up4A) exerts a potent vasodilator effect in the healthy porcine coronary vasculature. Since the coronary microvascular effects of Up4A after myocardial infarction (MI) are unknown, the present study investigated the response to Up4A in coronary microvessels from post-MI remodeled porcine myocardium, and the involvement of purinergic receptor subtypes. Coronary small arteries (diameter ∼150μm) were dissected from the apex of Sham-operated swine and swine in which MI had been produced 5 weeks earlier by transient (2h) occlusion of the left circumflex coronary artery, and mounted on Mulvany wire myographs. Up4A (10−9–10−5 M) produced coronary vasodilation that was reduced in MI as compared to Sham-operated swine. Up4A-induced vasodilation was reduced by P1 blockade with 8-phenyltheophylline in Sham-operated swine and to a lesser extent in MI, while the attenuation by the A2A receptor blocker SCH58261 was similar in Sham-operated and MI swine. Up4A-induced vasodilation remained unaffected by non-selective P2 receptor antagonist PPADS, but was attenuated by selective P2X1 and P2Y1 receptor antagonists MRS2159 and MRS2179, albeit to a similar extent in Sham-operated and MI swine. These responses were paralleled by similar mRNA expression levels of A2A, P2X1 and P2Y1 receptors in MI compared to slaughterhouse control swine. Finally, attenuation of Up4A-induced coronary vasodilation by nitric oxide synthase inhibition was not attenuated in MI as compared to Sham-operated swine. In conclusion, blunted coronary vasodilation in response to Up4A in MI swine is most likely due to reduced activation of P1, rather than P2, receptors and does not involve a loss of NO bioavailability. [Copyright &y& Elsevier] more...

Conventionally, ischemic heart disease (IHD) is equated with large vessel coronary disease. However, recent evidence has suggested a role of compromised microvascular regulation in the etiology of IHD. Because regulation of coronary blood flow likely involves activity of specific ion channels, and key factors involved in endothelium-dependent dilation, we proposed that genetic anomalies of ion channels or specific endothelial regulators may underlie coronary microvascular disease. We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for ion channels expressed in the coronary vasculature and the possible correlation with IHD resulting from microvascular dysfunction. 242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, analyzing genetic polymorphisms relative to (1) NOS3 encoding for endothelial nitric oxide synthase (eNOS); (2) ATP2A2 encoding for the Ca 2+/H +-ATPase pump (SERCA); (3) SCN5A encoding for the voltage-dependent Na + channel (Nav1.5); (4) KCNJ8 and KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of K-ATP channels, respectively; and (5) KCN5A encoding for the voltage-gated K + channel (Kv1.5). No significant associations between clinical IHD manifestations and polymorphisms for SERCA, Kir6.1, and Kv1.5 were observed ( p > 0.05), whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with IHD and microvascular dysfunction. Interestingly, genetic polymorphisms for ion channels seem to have an important clinical impact influencing the susceptibility for microvascular dysfunction and IHD, independent of the presence of classic cardiovascular risk factors. [ABSTRACT FROM AUTHOR] more...

Abstract: Uridine adenosine tetraphosphate (Up4A) has been identified as an endothelium-derived contracting factor, which acts through purinergic P2X and P2Y receptors. Since the coronary vascular actions of Up4A are unknown, we investigated the vasoactive profile of Up4A in coronary microvessels, and studied the involvement of purinergic receptor subtypes. Studies were performed in isolated porcine coronary small arteries (diameter∼250μm), with and without endothelial denudation, mounted on a Mulvany wire myograph. Purinergic receptor expression was assessed by real-time PCR. Up4A (10−9–10−5 M) failed to induce contraction at basal tone, but produced concentration-dependent vasorelaxation in precontracted microvessels. Up4A was slightly less potent than adenosine, ATP, and ADP in producing vasorelaxation, but significantly more potent than UTP and UDP. mRNA expression of P2X4, P2Y1, P2Y2, P2Y4, P2Y6 and A2A, but not P2X1, receptors was observed. Up4A-induced vasodilation was unaffected by non-selective P2 receptor antagonist PPADS, P2X1 antagonist MRS2159, P2Y1 antagonist MRS2179 and P2Y6 antagonist MRS2578, but was markedly attenuated by non-selective P1 receptor antagonist 8PT and A2A antagonist SCH58261. Up4A-induced vasodilation was not affected by ectonucleotidase inhibitor ARL67156, suggesting that A2A stimulation was not the result of Up4A breakdown to adenosine. Up4A-induced vasodilation was blunted in denuded vessels; additional A2A receptor blockade further attenuated Up4A-induced vasodilation, suggesting that A2A receptor-mediated vasodilation is only partly endothelium-dependent. In conclusion, Up4A exerts a vasodilator rather than a vasoconstrictor influence in coronary microvessels, which is mediated via A2A receptors and is partly endothelium-dependent. [Copyright &y& Elsevier] more...

Background: One out of 5 patients undergoing coronary angiography has angiographically normal coronary arteries (ANCA). Some of them have abnormally slow coronary flow (SCF). The prevalence and causes of SCF in these patients are not clear. Methods: We studied 114 consecutive patients with ANCA. Each angiogram was independently evaluated by 2 physicians unaware of all other clinical features of the case. Coronary flow (CF) was graded using the corrected TIMI Frame Count (cTFC) and Coronary Clearance Frame Count (CCFC) methodologies. SCF was defined as a cTFC exceeding the reported normal (mean cTFC + 2 SD) in each of the three major coronary arteries. The association between SCF and various clinical, inflammatory, and metabolic variables was tested using a multivariable analysis model. Results: Thirty-nine (34%) patients had SCF. Inter-individual CF varied substantially among them (range 10-143 frames/sec, mean: 37 ± 22 frames/sec). The intra-individual CF did not vary: CF correlated well in the three major epicardial coronary arteries of a given individual (r = 0.7, p = 0.0001). Multivariable analysis revealed that current smoking was the most significant variable related to SCF (odds ratio = 4.7, p = 0.006, CI 95% 1.6-13.3). The SCF group included significantly more smokers (41% versus 15%, p = 0.002). Conclusions: SCF is a common finding (34%) among patients with angiographically normal coronary arteries. In these patients, slow flow is a systemic phenomenon that involves all three coronary arteries rather than a local event and is associated with current smoking. [ABSTRACT FROM AUTHOR] more...

Background: The whole body periodic acceleration (WBPA) system was recently developed as a passive exercise device by providing increased pulsatile shear stress for improvement of endothelial function. This study aimed to investigate the acute effects of WBPA on coronary microcirculation and glucose tolerance in patients with type 2 diabetes (T2D). Methods: The study subjects were 8 patients with T2D who underwent transthoracic Doppler echocardiography for the assessment of coronary flow reserve (CFR) before and immediately after a 45-min session of WBPA. The flow velocity in the distal portion of the left anterior descending coronary artery was measured at baseline and during adenosine infusion. The CFR represented the ratio of hyperemic to basal mean diastolic flow velocity. Results: WBPA increased CFR from 2.3 ±0.3 to 2.6±0.4 (p = 0.02). WBPA decreased serum insulin level from 26 ± 19 μg/ml to 19 ± 15 μg/ml (p = 0.01) and increased total adiponectin from 11.6 ± 7.3 μg/ml to 12.5 ± 8.0 μg/ml (p = 0.02) and high molecular weight adiponectin from 4.9 ± 3.6 μg/ml to 5.3 ±3.9 μg/ml (p = 0.03), whereas the serum glucose level was stable from 207 ± 66 mg/dl to 203 ±56 mg/dl (p = 0.8). Conclusions: This study demonstrates that a single session of WBPA treatment simultaneously improved coronary microcirculation and glucose tolerance in patients with T2D. [ABSTRACT FROM AUTHOR] more...

Abstract: Backgrounds and objectives: The aim of this study was to evaluate relationships between the degree of resolution of the ST-segment elevation (ST segment resolution; STR) and the extent of microcirculatory dysfunction in infarct-related area (IRA) in patients with ST-segment elevation myocardial infarction (STEMI) using 13N-ammonia positron emission tomography (N-PET). Methods: The subjects comprised 33 patients with STEMI who underwent successful reperfusion. Serial 12-lead electrocardiography (ECG) was performed at the baseline and at 100min after reperfusion to calculate STR. The myocardial flow reserve (MFR) was assessed quantitatively using N-PET at 2weeks after the onset. The summed defect score (SDS) of 99mTc-tetrofosmin myocardial perfusion imaging was used as an index of the severity of myocardial infarction. To assess the extent of post-infarct left ventricular remodeling, the changes in the LVEDVI (ΔEDVI) were also calculated. Results: A significant correlation of the STR to the MFR in IRA (r=0.68, p<0.0001) was observed. A significant correlation was also identified between the SDS and the baseline sum ST-segment elevation (r=0.65, p<0.0001), while no correlation was observed between the SDS and the STR. Furthermore, a significant inverse correlation of the STR with the ΔEDVI was also recognized (r=−0.58, p<0.01). Conclusions: These data indicate that STR after successful reperfusion in STEMI is closely related to the extent of microcirculatory disturbance; in other words, incomplete STR may be a marker of persistent microcirculatory dysfunction after reperfusion therapy. [Copyright &y& Elsevier] more...

Abstract: The beneficial effects of statin pretreatment as well as of staccato reperfusion (SR) on myocardium have been demonstrated in patients undergoing cardiac interventions. In this study, we compared the effects of the acute statin administration prior to percutaneous coronary intervention (PCI) with the effects of staccato or abrupt reperfusion on coronary microcirculation in patients with myocardial infarction (MI). Methods: We randomly assigned 47 patients who had ST-elevation or non-ST-elevation MI 48 h prior to PCI, into three groups: staccato reperfusion (consisting of 6 periods of 10-s balloon inflation/deflation) plus statin therapy (SRSG), statin therapy plus abrupt reperfusion (SG), and abrupt reperfusion alone (ARG). Myocardial contrast echocardiography (MCE) was performed to assess the blood volume (A), velocity (β) and flow (A × β) of the segments associated with the PCI-treated artery the day following intervention and 30 days after. LV end-diastolic (EDV) and systolic volumes (ESVs), wall motion score index (WMSI) were evaluated. Results: Compared to ARG, SRSG and SG resulted in a greater improvement in A, β and A × β (F = 20.6, p < 0.001 for A, F = 3.5, p = 0.03 for β and F = 11.3, p < 0.001 for A × β for the overall effect of intervention) as well as a greater decrease of WMSI, EDV and ESV (p < 0.01) one month post-PCI. The changes of all echocardiography markers were greater in SRSG than SG (p < 0.01). The % changes in ESV correlated with the corresponding % changes in MCE indices in SRSG and SG (p < 0.05). Conclusion: The acute statin administration prior to reperfusion either alone or in synergy with staccato reperfusion ameliorates coronary microcirculatory dysfunction in patients with myocardial infarction [Copyright &y& Elsevier] more...

Myocardial dysfunction and coronary macro/microvascular alterations are the hallmarks of diabetic cardiomyopathy and are ascribed to increased oxidative stress and altered nitric oxide synthase (NOS) activity. We hypothesize that pre-treatment by cobalt-protoporphyrin IX (CoPP) ameliorates both myocardial function and coronary circulation in streptozotocin (STZ)-induced diabetic rats. Isolated hearts from diabetic rats in Langendorff configuration displayed lower left ventricular function and higher coronary resistance (CR) compared to hearts from control animals. CoPP treatment of diabetic animals (0.3 mg/100g body weight i.p., once a week for 3 weeks) significantly increased all the contractile/relaxation indexes (p <0.01), while decreasing CR (p <0.01). CoPP enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the significant (p <0.05) decrease in heart % GSSG, O-2 , and malondialdehyde (MDA) levels. CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS/iNOS expression imbalance observed in the untreated diabetic heart. Furthermore, after CoPP treatment, a rise in malonyl-CoA as well as a decrease in acetyl-CoA was observed in diabetic hearts. In this experimental model of diabetic cardiomyopathy, CoPP treatment improved both cardiac function and coronary flow by blunting oxidative stress, restoring eNOS/iNOS expression balance and increasing HO-1 levels, thereby favoring improvement in both endothelial function and insulin sensitivity. [ABSTRACT FROM AUTHOR] more...

Abstract: Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α1-adrenoceptors; the constriction of the resistive microcirculation largely by α2-adrenoceptors, but also by α1-adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α1- and α2-adrenoceptors improves coronary blood flow, myocardial function and metabolism. This article is part of a Special Issue entitled “Coronary Blood Flow”. [Copyright &y& Elsevier] more...

This review will briefly describe the principles of myocardial contrast echocardiography, and then discuss the clinical and experimental observations that led to the use of this approach to investigate the pathophysiological basis of coronary blood flow reserve. The insights offered by myocardial contrast echocardiography are unique and novel, and highlight the importance of the myocardial capillaries in determining coronary blood flow reserve in health and disease. [ABSTRACT FROM AUTHOR] more...

We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity (LP) was registered. LP of SC-PAO remained low under all conditions (3.24 ± 0.52∙10-8cm∙s-1∙cmH2O-1). In contrast, in the venular wall model, PGE2, plateletactivating factor (PAF), leukotriene B4 (LTB4), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in LP with synergistic support when combined. PAF and LTB4 released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6 - 8 h by the presence of 50 μM quercetin glucuronide (QG). LTB4 synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention. [ABSTRACT FROM AUTHOR] more...

Background: Positron emission tomography (PET) enables robust and reproducible measurements of myocardial blood flow (MBF). However, the relatively limited resolution of PET till recently prohibited distinction between the subendocardial and the subepicardial layers in non-hypertrophied myocardium. Recent developments in hard- and software, however, have enabled to identify a transmural gradient difference in animal experiments. The aim of this study is to determine the feasibility of subendocardial and subepicardial MBF in normal human hearts assessed with O-labeled water PET. Methods: Twenty-seven healthy subjects (mean age 41 ± 13 years; 11 men) were studied with O-labeled water PET to quantify resting and hyperaemic (adenosine) MBF at a subendocardial and subepicardial level. In addition, cardiac magnetic resonance imaging was performed to determine left ventricular (LV) volumes and function. Results: Mean rest MBF was 1.46 ± 0.49 in the subendocardium, and 1.14 ± 0.342 mL · min · g in the subepicardium ( P < .001). MBF during vasodilation was augmented to a greater extent at the subepicardial level (subendocardium vs subepicardium: 3.88 ± 0.86 vs 4.14 ± 0.88 mL · min · g, P = .013). The endocardial-to-epicardial MBF ratio decreased significantly during hyperaemia (1.35 ± 0.23 to 1.12 ± 0.20, P < .001). Hyperaemic transmural MBF was inversely correlated with left ventricular end-diastolic volume index (LVEDVI) ( r = 0.41, P = .0003), with greater impact however at the subendocardial level. Conclusions: O-labeled water PET enables MBF measurements with distinction of the subendocardial and subepicardial layers in the normal human heart and correlates with LVEDVI. This PET technique may prove useful in evaluating patients with signs of ischaemia due to coronary artery disease or microvascular dysfunction. [ABSTRACT FROM AUTHOR] more...

This study investigated the effects of alcohol septal ablation (ASA) on microcirculatory function and myocardial energetics in patients with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction. In 15 HCM patients who underwent ASA, echocardiography was performed before and 6 mo after the procedure to assess the LVOT gradient (LVOTG). Additionally, [15O]water PET was performed to obtain resting myocardial blood flow (MBF) and coronary vasodilator reserve (CVR). Changes in LV mass (LVM) and volumes were assessed by cardiovascular magnetic resonance imaging. Myocardial oxygen consumption (MVo2) was evaluated by [11C]acetate PET in a subset of seven patients to calculate myocardial external efficiency (MEE). After ASA, peak LVOTG decreased from 41 ± 32 to 23 ± 19 mmHg (P = 0.04), as well as LVM (215 ± 74 to 169 ± 63 g; P < 0.001). MBF remained unchanged (0.94 ± 0.23 to 0.98 ± 0.15 ml·min-1·g-1; P = 0.45), whereas CVR increased (2.55 ± 1.23 to 3.05 ± 1.24; P = 0.05). Preoperatively, the endo-to-epicardial MBF ratio was lower during hyperemia compared with rest (0.80 ± 0.18 vs. 1.18 ± 0.15; P < 0.001). After ASA, the endo-to-epicardial hyperemic (h)MBF ratio increased to 1.03 ± 0.26 (P = 0.02). ΔCVR was correlated to ΔLVOTG (r = -0.82; P < 0.001) and ΔLVM (r = -0.54; P = 0.04). MEE increased from 15 ± 6 to 20 ± 9% (P = 0.04). Coronary microvascular dysfunction in obstructive HCM is at least in part reversible by relief of LVOT obstruction. After ASA, hMBF and CVR increased predominantly in the subendocardium. The improvement in CVR was closely correlated to the absolute reduction in peak LVOTG, suggesting a pronounced effect of LV loading conditions on microvascular function of the subendocardium. Furthermore, ASA has favorable effects on myocardial energetics. [ABSTRACT FROM AUTHOR] more...

Abstract: Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α1-adrenoceptors; the constriction of the resistive microcirculation largely by α2-adrenoceptors, but also by α1-adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α1- and α2-adrenoceptors improves coronary blood flow, myocardial function and metabolism. [Copyright &y& Elsevier] more...

Protease-activated receptor-2 (PAR2) is expressed in endothelial cells and mediates endothelium-dependent vasodilation. We hypothesized that PAR2 regulates tumor necrosis factor-alpha (TNF-α)-induced coronary arteriolar dysfunction in type 2 diabetic (db/db) mice. To test this, coronary arterioles from WT control, db/db, db/db mice treated with PAR2 antagonist FSLLRY-NH (db/db+FSLLRY-NH) and db/db mice null for TNF (db/db) were isolated and pressurized (60 cmHO) without flow. Although vasodilation to the endothelium-independent vasodilator sodium nitroprusside (SNP) was not different among WT, db/db, db/db+FSLLRY-NH and db/db, endothelium-dependent acetylcholine (ACh)- and flow-mediated vasodilation were impaired in db/db mice but were enhanced in db/db mice and db/db mice treated with PAR2 antagonist. NOS inhibitor N-nitro- l-arginine-methyl ester ( l-NAME) significantly reduced ACh-induced dilation in WT, db/db and db/db+FSLLRY-NH, but did not alter the vasodilation in db/db mice. In contrast, cyclooxygenase (COX) inhibitor indomethacin (Indo) did not alter ACh-induced vasodilation in these four groups of mice. PAR2-activating peptide (PAR2-AP, 2-Furoyl-LIGRLO-am)-induced dilation was higher in db/db mice than that in WT, db/db and db/db mice treated with PAR2 antagonist. These effects were abolished by denudation, or in the presence of l-NAME or Indo. Protein expressions of TNF-α, PAR2, gp91 and p47 in the heart and isolated coronary arterioles were higher in db/db mice compared to WT mice. Administration of PAR2 antagonist to db/db mice reduced protein expression of TNF-α, gp91 and PAR2. Protein expression of gp91 and p47 was lower in db/db compared to db/db mice. These results indicate that PAR2 plays a pivotal role in endothelial dysfunction in type 2 diabetes by up-regulating the expression/production of TNF-α and activating NAD(P)H oxidase subunit p47. [ABSTRACT FROM AUTHOR] more...

Purpose: The mechanisms underlying increased cardiovascular risk in primary hyperparathyroidism (pHPT) have not been fully defined. Recently, this issue has become the subject of renewed interest due to the increasing evidence that the endothelium and vascular wall are targets for parathyroid hormone (PTH). The aim of this study was to measure regional coronary flow reserve (CFR) to determine whether the vascular damage induced by pHPT extends to affect the coronary microvascular function. Methods: A total of 22 pHPT patients without a history of coronary artery disease and 7 age-matched control subjects were recruited. Dipyridamole myocardial blood flow (MBF) was assessed using Tc-sestamibi by measuring first-transit counts in the pulmonary artery and myocardial count rate from G-SPECT images. Baseline MBF was estimated 2 h later according to the same procedure. Regional CFR was defined as the ratio between dipyridamole and baseline MBF using a 17-segment left ventricular model. Results: Three pHPT patients showed reversible perfusion defects and were excluded from the analysis. In the remaining 19, CFR was significantly lower with respect to the control subjects (1.88 ± 0.64 vs. 3.36 ± 0.66, respectively; p < 0.01). Moreover, patients studied for more than 28 months from pHPT diagnosis showed lower CFR values than the others (1.42 ± 0.18 vs. 2.25 ± 0.64, respectively; p < 0.01). Consequently, the time from diagnosis to the nuclear study showed a reasonable correlation with the degree of CFR impairment (Spearman's rho −0.667, p < 0.02). Conclusion: pHPT is associated with a significant dysfunction of the coronary microcirculation. This disorder might contribute to the high cardiovascular risk of conditions characterized by chronic elevations in serum PTH levels. [ABSTRACT FROM AUTHOR] more...

We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) plays an important role in the canine coronary microcirculation as an endothelium-derived hyperpolarizing factor in vivo. However, it remains to be examined whether endogenous H2O2 is involved in the dilatation of coronary collaterals during myocardial ischemia in vivo and, if so, whether erythropoietin (EPO) enhances the responses. Canine subepicardial native collateral small arteries (CSA; ≥ 100 μm) and arterioles (CA; <100 μm) were observed using an intravital microscope. Experiments were performed after left anterior descending coronary artery ischemia (90 min) under the following eight conditions (n = 5 each): control, EPO, EPO+catalase, EPO+N-monomethyl-l-arginine (l-NMMA), EPO+l-NMMA+catalase, EPO+l-NMMA+iberiotoxin [Ca2+-activated K+ (KCa) channel blocker], EPO+l-NMMA+apamin+charybdotoxin (KCa channel blocker), and EPO+wortmannin (phosphatidylinositol 3-kinase inhibitor). Myocardial ischemia caused significant vasodilatation in CA but not in CSA under control conditions, which was significantly decreased by catalase in CA. After EPO, the vasodilatation was significantly increased in both sizes of arteries and was significantly decreased by catalase. The enhancing effect of EPO was reduced by l-NMMA but not by catalase in CSA and was reduced by l-NMMA+catalase in CA, where the greater inhibitory effects were noted with l-NMMA+catalase, l-NMMA+iberiotoxin, L-NMMA+apamin+charybdotoxin, or wortmannin. EPO significantly ameliorated ischemia-induced impairment of myocardial Akt phosphorylation, which was abolished by l-NMMA+catalase or wortmannin. EPO also ameliorated oxidative stress and myocardial injury, as assessed by plasma 8-hydroxydeoxyguanosine and troponin-T, respectively. These results indicate that EPO enhances H2O2-mediated dilatation of coronary collateral arterioles during myocardial ischemia in dogs in vivo. [ABSTRACT FROM AUTHOR] more...

Abstract: Background and aim: Abnormal coronary microvascular circulation has been demonstrated in diabetes and is associated with increased rate of cardiovascular events. Our objective was to evaluate coronary vasoreactivity in young people with type 1 diabetes with and without microvascular complications. Methods and results: Twenty-five type 1 diabetic patients without microvascular complications (DC–), 23 with microvascular complications (DC+), and 18 control subjects (C) were studied. Coronary vasoreactivity was assessed by means of coronary flow reserve (CFR). Blood flow velocity in the left anterior descending coronary artery was measured at rest and after high-dose dipyridamole using transthoracic color-guided pulsed Doppler echocardiography. CFR was defined as the ratio of hyperaemic to resting diastolic peak flow velocities. The three groups had similar cardiac function parameters, and also systolic and diastolic blood pressure at rest, which remained unchanged during dipyridamole infusion. Resting coronary flow velocity was comparable in C, DC–, and DC+ (p =ns). Dipyridamole infusion produced a threefold increase in coronary diastolic peak velocity, which reached similar values in C (0.69±0.16m/s), DC– (0.69±0.18m/s), and DC+ (0.66±0.11m/s). Mean CFR ratio was similar in C (3.33±0.66), DC– (3.30±0.51), and DC+ (3.24±0.60). At multiple linear regression analysis, no association was found between CFR and age, sex, HbA1c, duration of diabetes, and complications. Conclusion: Coronary vasodilatory function is preserved in young D patients, even those with early microvascular complications, suggesting that coronary vasoreactivity deteriorates at more advanced stages of microvascular complications and/or in the presence of other cardiovascular risk factors. [ABSTRACT FROM AUTHOR] more...

Abstract: It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies. [ABSTRACT FROM AUTHOR] more...

Background: Takotsubo cardiomyopathy was described for the first time in Japan in the 1990s. It is very similar to the ischemic cardiopathy both for clinical and instrumental characteristics. His peculiarity is an alteration of the ventricular contraction mechanism with hypo-akinesis of the apex and lateral segments of the left ventricle, associated with hyper-kinesis of the heart base which is responsible for the typical echocardiographic aspect of a cruet during the systole. However, the etiology of this cardiomyopathy is still unknown despite the fact that numerous hypothesis have been made. A single study of 16 patients proved multivasal damage by a BLASH SCORE analysis of the coronary radiography. In our study, performed on 24 patients, we intended to assess the actual implication of the microcirculation by analyzing the TIMI frame count (TFC), so as reporting correlations between alterations of each single artery and its respective myocardial area. Methods and results: Six Cardiology Centres performed an International multi-centre collection of a consecutive series of 24 patients, of which 20 were women and four men. The average age was 67.4 years. All patients admitted to one of the Cardiology divisions were previously listed for symptoms and signs of Takotsubo cardiomyopathy. An electrocardiographic (ECG), echocardio-gram and a hemodynamic study were carried out on each patient. The patients were evaluated with a follow up lasting 7 weeks. On the coronary radiography film, the microcirculation was examined by an analysis of the TFC according to the Gibson technique. The value obtained was considered pathological if it was >30 frames. The evaluation of the microcirculation by the TFC analysis showed that in 23 of the 24 patients there was a pathological slow down of the flow in the coronary micro- circulation. By analysing the number of involved vessels it was noted that nine patients had a slowdown of the general flow in all three vessels, six patients in only two vessels and the remaining nine in one vessel. In particular: in 14 patients there was an abnormal TFC in left anterior descending coronary artery (LAD), 16 in the right coronary artery (RCA) and 18 in the left circumflex coronary artery (LCX), while in one patient the picture quality in the acute phase did not allow an evaluation of the score in the RCA and in another patient in the LDA. None of the explored vessels that was responsible for the disorder of the microcirculation showed any stenosis. Conclusion: From the data evaluated by us, microcirculatory dysfunction seems to be present very often during acute phases of Takotsubo illness, but it is not the only determining factor of the illness. [ABSTRACT FROM AUTHOR] more...

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The article reports on research on whether Tumor necrosis factor α and the monocyte chemoattractant protein-1 (MCP-1) contribute to vascular inflammation and endothelial dysfunction in type 2 diabetes. Researchers used anti-MCP-1 to block MCP-1 signaling in genetically modified mice with type 2 diabetes. They found that the expression of MCP1 is colocalized with endothelial cells and that the endothelial dysfunction in type 2 diabetes results from TNF-α and TNF-α-related signaling. more...

Objectives: The purpose of this study was to investigate the reflections of the improvement in microvascular perfusion provided by adjuvant intracoronary streptokinase (ICSK) on late-phase infarct size and left ventricular volumes and functions. Background: It has been shown that ICSK given immediately after primary percutaneous coronary intervention (PCI) improves myocardial perfusion in the early days of ST-segment elevation acute myocardial infarction. Methods: Ninety-five patients undergoing primary PCI were randomized to ICSK 250 kU (n = 51) or no additional therapy (n = 44). Two days later, coronary hemodynamic indexes were measured to evaluate tissue-level perfusion. After 6 months, angiography, echocardiography, and technetium-99m single-photon emission computed tomography (SPECT) were performed. Results: At 2 days, all indexes of microvascular function were significantly better in the ICSK group than in the control group, including coronary flow reserve (2.5 vs. 1.7, p < 0.001) and index of microvascular resistance (20.2 vs. 34.2, p < 0.001). At 6 months, infarct size (22.7% vs. 32.9%; p = 0.003) and left ventricular end-systolic (41.1 ml vs. 60.9 ml; p = 0.009) and end-diastolic volumes (95.5 ml vs. 118.3 ml; p = 0.006) were significantly smaller, and the ejection fraction was significantly higher (57.2% vs. 51.8%; p = 0.018) in the ICSK group compared with the control group. Conclusions: In this study, it has been demonstrated that low-dose ICSK given immediately after primary PCI significantly limits long-term infarct size and preserves left ventricular volumes and functions. (Effect of Complementary Intracoronary Streptokinase Administration Immediately After Primary Percutaneous Coronary Intervention on Microvascular Perfusion and Late Term Infarct Size in Patients With Acute Myocardial Infarction; NCT00302419) [Copyright &y& Elsevier] more...

Background/Aims: Exercise training enhances vasodilatation to vascular endothelial growth factor (VEGF165) in collateral-dependent coronary arterioles. Interaction of VEGF receptor 2 (VEGFR-2) and the non-tyrosine-kinase receptor, neuropilin-1 has been reported to potentiate VEGF165-mediated signaling. In the current study, we tested the hypotheses that neuropilin-1 mediates the exercise-enhanced VEGF165-mediated vasodilatation in collateral-dependent arterioles and that neuropilin-1 and/or VEGFR-2 protein levels are increased in these arterioles. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Eight weeks after surgery, the animals were randomized into sedentary or exercise training (treadmill run; 5 days/week; 14 weeks) protocols. Coronary arterioles (∼100 μm diameter) were isolated from both collateral-dependent and control (left anterior descending) myocardial regions and studied by in vitro videomicroscopy or frozen for immunoblot analysis. Results: Exercise-enhanced VEGF165-mediated vasodilatation in collateral-dependent arterioles was reversed by inhibition of the VEGF165-neuropilin-1 interaction. VEGF121, which does not interact with neuropilin-1, induced similar vasodilatation in arterioles from all treatment groups. Immunoblot revealed significantly elevated VEGFR-1, VEGFR-2 and neuropilin-1 protein levels in collateral-dependent arterioles of exercise-trained pigs. Conclusions: Neuropilin-1 plays a vital role in the exercise-enhanced VEGF165-mediated vasodilatation of collateral-dependent coronary arterioles and is associated with increased neuropilin-1 receptor protein levels. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR] more...

We hypothesized that maturation-induced vascular inflammation produces endothelial dysfunction in type II diabetes and TNFα plays a key role in triggering inflammation in the development of diabetes. In control (Db/db) mice aged 6, 12, 18 and 24 weeks, sodium nitroprusside (SNP) and acetylcholine (ACh) induced dose-dependent vasodilation, and dilation to ACh was blocked by the NO synthase inhibitor N G-monomethyl- l-arginine. In type II diabetic (db/db) mice at age of 12, 18 and 24 weeks, ACh or flow-induced dilation was blunted compared to Db/db; endothelial function is normal at 6 weeks of age in db/db Vs. control mice, but SNP produced comparable dilation at age of 6, 12, 18 and 24 weeks. Decrements in endothelial function in db/db mice progressively increased from 6–12 to 18–24 weeks. Administration of neutralizing antibodies to TNFα ameliorated endothelial dysfunction in db/db mice aged 12, 18 and 24 weeks. The effect was most prominent in the younger animals. Plasma concentration, expression of TNFα and TNFα receptor 1 (TNFR1) were elevated in coronary arterioles, even at the age of 6 weeks before the development of diabetes in db/db mice compared to control mice. Superoxide production was lower in Db/db mice compared to db/db mice and increments in superoxide production in db/db mice progressively increased from 6–12 to 18–24 weeks. NAD(P)H oxidase inhibitor apocynin attenuated superoxide production in db/db mice at 12 weeks of age, mitochondria respiratory chain inhibitor rotenone attenuated superoxide production at 24 weeks in db/db and Db/db mice, but the combination of apocynin and rotenone reduced superoxide production at 18 weeks for db/db and Db/db mice. The expression of TNFα and its receptors increase progressively with maturation in concert with the development of diabetes. Incremental increases in TNFα/TNFR1 expression induces activation and production of superoxide via NAD(P)H oxidase and/or mitochondria respiratory chain, leading to endothelial dysfunction progressing to the development of type II diabetes. [ABSTRACT FROM AUTHOR] more...

We hypothesized that impaired nitric oxide (NO)-dependent dilation (endothelial dysfunction) in Type 2 diabetes results, in part, from elevated production of superoxide (02) induced by the interaction of advanced glycation end products (AGE)/receptor for AGE (RAGE) and TNF-ot signaling. We assessed the role of AGE/RAGE and TNF-a signaling in endothelial dysfunction in Type 2 diabetic (Leprdlb) mice by evaluation of endothelial function in isolated coronary resistance vessels of normal control (nondiabetic, m Lepr~) and diabetic mice. Although dilation of vessels to the endothelium-independent vasodilator sodium nitroprusside (SNP) was not different between diabetic and control mice, dilation to the endothelium-dependent agonist acetylcholine (ACh) was reduced in diabetic vs. control mice. The activation of RAGE with RAGE agonist Si OOb eliminated SNP- potentiated dilation to ACh in Lepr~' mice. Administration of a soluble form of RAGE (5RAGE) partially restored dilation in diabetic mice but did not affect dilation in control mice. The expression of RAGE in coronary arterioles was markedly increased in diabetic vs. control mice. We also observed in diabetic mice that augmented RAGE signaling augmented expression of TNF-a, because this increase was attenuated by sRAGE or NF-KB inhibitor MG132. Protein and mRNA expression of NAD(P)H oxidase subunits including NOX-2, p22Ph0~~, and p4OP~~0~~ increased in diabetic compared with control mice. sRAGE significantly inhibited the expression of NAD(P)H oxidase in diabetic mice. These results indicate that AGE! RAGE signaling plays a pivotal role in regulating the productionl expression of TNF-a, oxidative stress, and endothelial dysfunction in Type 2 diabetes. [ABSTRACT FROM AUTHOR] more...

Abstract: Background and purpose: To evaluate intramyocardial coronary flow velocity pattern by transthoracic Doppler echocardiography and its clinical significance in patients with hypertrophic cardiomyopathy (HCM). Methods and results: In 48 patients with HCM who had angiographically normal coronary artery, coronary flow velocity in the left anterior descending coronary artery (LAD) and intramyocardial coronary artery (IMCA) derived from LAD were evaluated using transthoracic Doppler echocardiography. Two clearly different flow patterns in the IMCA were observed in patients with HCM. Twenty-seven HCM patients (group A) had slow deceleration slope in the IMCA flow (average diastolic deceleration time, 989±338; range, 585–1680) and the remaining 21 patients (group B) had steep deceleration slope with diastolic deceleration time <300ms, resulting in a no reflow-like pattern in the IMCA flow (average diastolic deceleration time, 166±67; range, 55–280). There were no significant differences in the clinical characteristics and LAD flow velocity profiles between the two groups. The incidence of cardiovascular symptoms (chest pain or syncope) was significantly higher in group B than in group A (67% vs. 26%, p <0.01). Additionally, exercise-induced ischemia as detected by thallium-201 scintigraphy was significantly more frequent in group B than in group A (6 of 9 (67%) vs. 0 of 9 (0%), p <0.01). Conclusions: Two different intramyocardial coronary flow velocity patterns are observed in patients with HCM using transthoracic Doppler echocardiography. No reflow-like pattern in the IMCA is strongly related to myocardial ischemia in the absence of epicardial coronary artery stenosis, suggesting that coronary microvascular dysfunction may be a causative mechanism. [Copyright &y& Elsevier] more...

The regulation of the coronary circulation is a complex paradigm in which many inputs that influence vasomotor tone have to be integrated to provide the coronary vasomotor adjustments to cardiac metabolism and to perfusion pressure. We hypothesized that the integration of many disparate signals that influence membrane potential of smooth muscle cells, calcium sensitivity of contractile filaments, receptor trafficking result in complex non-linear characteristics of coronary vasomotion. To test this hypothesis, we measured an index of vasomotion, flowmotion, the periodic fluctuations of flow that reflect dynamic changes in resistances in the microcirculation. Flowmotion was continuously measured in periods ranging from 15 to 40 min under baseline conditions, during antagonism of NO synthesis, and during combined purinergic and NOS antagonism in the beating heart of anesthetized open-chest dogs. Flowmotion was measured in arterioles ranging from 80 to 135 μm in diameter. The signals from the flowmotion measurements were used to derive quantitative indices of non-linear behavior: power spectra, chaotic attractors, correlation dimensions, and the sum of the Lyapunov exponents (Kolmogorov–Sinai entropy), which reflects the total chaos and unpredictability of flowmotion. Under basal conditions, the coronary circulation demonstrated chaotic non-linear behavior with a power spectra showing three principal frequencies in flowmotion. Blockade of nitric oxide synthase or antagonism of purinergic receptors did not affect the correlation dimensions, but significantly increased the Kolmogorov–Sinai entropy, altered the power spectra of flowmotion, and changed the nature of the chaotic attractor. These changes are consistent with the view that certain endogenous controls, nitric oxide and various purines (AMP, ADP, ATP, adenosine) make the coronary circulation more predictable, and that blockade of these controls makes the control of flow less predictable and more chaotic. [ABSTRACT FROM AUTHOR] more...

Mitochondrial H2O2 contributes to flow-mediated dilation (FMD) in human coronary arterioles (HCA). We examined the hypothesis that the endothelial cytoskeleton plays a critical role in transducing endothelial wall shear stress into a stimulus for releasing mitochondrial ROS. Phallacidin together with α-, β-tubulin antibodies and Mito-Tracker Red showed the proximity of F-actin, microtubules and mitochondria in endothelial cells. Cytochalasin D (CytoD) and nocodazole (Noc) disrupted endothelial F-actin and microtubules in HCA, respectively, concurrent with a reduction in the generation of cytosolic O2 •− and H2O2 (hydroethidine and dichlorodihydrofluorescein fluorescence) and mitochondrial superoxide (mitoSox) during flow (control: 3.5 ± 1.6, Cyto D: 0.51 ± 0.2, Noc: 0.81 ± 0.6). FMD, but not the dilation to bradykinin or papaverine, was reduced by Cyto D (26 ± 10% vs. 56 ± 3%) or Noc (26 ± 11% vs. 58 ± 7%). These results suggest that cytoskeletal elements are a critical component of the signaling mechanism linking endothelial shear stress and mitochondrial release of ROS in the human coronary microcirculation. [ABSTRACT FROM AUTHOR] more...

Impaired hyperemic myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM), despite normal epicardial coronary arteries, results in microvascular dysfunction. The aim of the present study was to determine the relative contribution of extravascular compressive forces to microvascular dysfunction in HCM. Eighteen patients with symptomatic HCM and normal coronary arteries and 10 age-matched healthy volunteers were studied with PET to quantify resting and hyperemic MBF at a subendocardial and subepicardial level. In HCM patients, MRI was performed to determine left ventricular (LV) mass index (LVMI) and volumes, echocardiography to assess diastolic perfusion time, heart catheterization to measure LV outflow tract gradient (LVOTG) and LV pressures, and serum NH2-terminal pro-brain natriuretic peptide (NT-proBNP) as a biochemical marker of LV wall stress. Hyperemic MBF was blunted in HCM vs. controls (2.26 ± 0.97 vs. 2.93 ± 0.64 ml·min-1·g-1, P < 0.05). In contrast to controls (1.38 ± 0.15 to 1.25 ± 0.19, P = not significant), the endocardial-to-epicardial MBF ratio decreased significantly in HCM during hyperemia (1.20 ± 0.11 to 0.88 ± 0.18, P < 0.01). This pattern was similar for hypertrophied septum and lateral wall. Hyperemic MBF was inversely correlated with LVOTG, NT-proBNP, left atrial volume index, and LVMI (all P < 0.01). Multivariate regression analysis, however, revealed that only LVMI and NT-proBNP were independently related to hyperemic MBF, with greater impact at the subendocardial myocardial layer. Hyperemic MBF is more severely impaired at the subendocardial level in HCM patients. The level of impairment is related to markers of increased hemodynamic LV loading conditions and LV mass. These observations suggest that, in addition to reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to microvascular dysfunction in HCM patients. [ABSTRACT FROM AUTHOR] more...

We have observed that hydrogen peroxide (H2O2), the dismutated product of superoxide, is a coronary metabolic dilator and couples myocardial oxygen consumption to coronary blood flow. Because the chemical activity of H2O2 favors its role as an oxidant, and thiol groups are susceptible to oxidation, we hypothesized that coronary metabolic dilation occurs via a redox mechanism involving thiol oxidation. To test this hypothesis, we studied the mechanisms of dilation of isolated coronary arterioles to metabolites released by metabolically active (paced at 400 mm) isolated cardiac myocytes and directly compared these responses with authentic H2O2. Studies were performed under control conditions and using interventions designed to reduce oxidized thiols [0.1 μM dithiothreitol (DTT) and 10 mM N-acetyl-L-cysteine (NAC)]. Aliquots of the conditioned buffer from paced myocytes produced vasodilation of isolated arterioles (peak response, 71% ± 6% of maximal dilation), whereas H2O2 produced complete dilation (92% ± 7%). Dilation to either the conditioned buffer or to H2O2 was significantly reduced by the administration of either NAC or DTT. The location of the thiols oxidized by the conditioned buffer or of H2O2 was determined by the administration of the fluorochromes monochlorobimane (20 μM) or monobromotrimethylammoniobimane (20 μM), which covalently label the reduced total or extracellular-reduced thiols, respectively. H2O2 or the conditioned buffer predominately oxidized intracellular thiols since the fluorescent signal from monochiorobimane was reduced more than that of monobromotrimethylammoniobimane. To determine whether one of the intracellular targets of thiol oxidation that leads to dilation is the redox- sensitive kinase p38 mitogen-activated protein (MAP) kinase, we evaluated dilation following the administration of the p38 inhibitor SB-203580 (10 μM). The inhibition of p38 attenuated dilation to either H2O2 or to the conditioned buffer from stimulated myocytes by a similar degree, but SB-203580 did not attenuate dilation to nitroprusside. Western blot analysis for the activated form of p38 (phospho-p38) in the isolated aortae revealed robust activation of this enzyme by H2O2. Taken together, our results show that an active component of cardiac metabolic dilation, like that of H2O2, produces dilation by the oxidation of thiols, which are predominately intracellular and dependent activation on the p38 MAP kinase. Thus coronary metabolic dilation appears to be mediated by redox-dependent signals. [ABSTRACT FROM AUTHOR] more...

Abstract: Aldosterone is involved in many cardiovascular diseases with increased oxidative stress. Aldosterone-induced cardiac fibrosis is abolished by blockade of angiotensin II Type-1 (AT1) receptor. Recently, non-genomic vasoconstrictor effects of aldosterone were reported in various vascular beds. We tested the hypothesis that aldosterone stimulates angiotensin AT1 receptor, and causes vasoconstriction by increasing oxidative stress in coronary microcirculation. Coronary arterioles (60–120 μm) were isolated from spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, aged 23–26 weeks. They were cannulated, and pressurized at 60 cm H2O. Effect of aldosterone (10−15 to 10−6 M) on coronary arteriolar diameter was examined. Aldosterone rapidly and dose-dependently decreased coronary arteriolar diameter in WKY rats and SHR (diameter changes, 8.4±0.7% vs 13.9±0.8%, P <0.05). Aldosterone-induced vasoconstriction was enhanced by 1.6-folds in SHR compared to WKY rats (P <0.05). Mineralocorticoid receptor antagonist spironolactone (10−6 M) did not influence aldosterone-induced vasoconstriction. Selective angiotensin AT1 receptor blocker valsartan (10−4 M) or candesartan (10−7 M) abolished aldosterone-induced vasoconstriction. Similarly, superoxide dismutase (SOD, 300 U/ml), and NADPH oxidase inhibitor apocynin (10−4 M) abolished it. Moreover, the vasoconstrictor effect of aldosterone disappeared in denuded vessels. Real-time quantitative RT-PCR revealed that angiotensin AT1 receptor mRNA level in coronary arterioles of SHR was upregulated by 1.5-folds compared to that in WKY rats (P <0.05). Aldosterone causes vasoconstriction in coronary arterioles, and this vasoconstrictor effect is enhanced by genetically defined hypertension. Aldosterone-induced vasoconstriction is mediated by angiotensin AT1 receptor presumably via oxidative stress. [Copyright &y& Elsevier] more...

Abstract: Objectives: We sought to investigate the differences of pressure waveforms at a distal point of an epicardial coronary artery comparatively to the ostium and to assess the effect of microcirculatory vasodilation on them. Background: Pressure waveforms in the systematic circulation and their alterations along the aorta due to wave reflections from the periphery have been extensively studied. However, similar data regarding intracoronary pressure waveforms and the effects of coronary microcirculation on them are limited. Methods: In 18 patients who underwent diagnostic coronary angiogram or percutaneous coronary intervention in the left circumflex or the right coronary artery, we studied pressure waveforms recorded by a high-fidelity pressure wire, which was advanced to the ostium and to a distal site of the free of significant lesions left anterior descending coronary artery. Pressure recording was performed both at rest and at hyperemia induced by intravenous infusion of adenosine. Analysis of pressure waveforms at the frequency domain was performed with Fast Fourier Transform. Results: At baseline conditions, distal pressure waveforms were characterized by higher pulsatility, higher presystolic wave and higher amplitude of the 11th to the 15th harmonics. Hyperemia increased the pulsatility, compressed the notch and decreased the amplitude of higher than the 10th harmonics of distal waveforms. Conclusions: This study identifies differences of pressure waveforms between proximal and distal sites of free of significant lesions coronary arteries, which are affected by the status of coronary microcirculation and may therefore facilitate assessment of microvascular disease. [Copyright &y& Elsevier] more...

Abstract: Background: Our objective were to know whether coronary flow velocity reserve measured by transthoracic Doppler echocardiography, as marker of microvascular integrity, affects the recovery of global systolic function. Secondly, we intended to define the best cut-off point of coronary flow velocity reserve to predict recovery of global systolic function. Methods: We studied 57 patients with coronary flow recorded by transthoracic Doppler echocardiography, after suffering a first anterior acute myocardial infarction and undergoing a successful primary percutaneous coronary intervention (TIMI 3 flow). We measured, at discharge and at 1 month: ejection fraction, volume indexes and anterior wall motion score index. Coronary flow in left anterior descending artery was detected by transthoracic Doppler echocardiography and coronary flow velocity reserve was calculated. Results: After applying ROC curves, 1.54 was the best cut-off value of coronary flow velocity reserve for detection of recovery of global systolic function. Ejection fraction only increased significantly in patients with normal coronary flow velocity reserve. Only end-systolic volume index increased significantly at 1 month in patients with impaired coronary flow velocity reserve. Conclusion: We showed that coronary flow velocity reserve, measured by transthoracic Doppler echocardiography, influence the recovery of global systolic function, mainly by ventricular dilation. Furthermore, a quite lower value of coronary flow velocity reserve than that used for diagnostic purpose should be used to predict improvement of systolic function. [Copyright &y& Elsevier] more...

Abstract: Background:: Scleroderma-related cardiac involvement primarily affects coronary microvascular structures and function. The microvasculature disorder is responsible for impairment of coronary flow velocity reserve (CFVR), which has been reported in studies of patients with systemic sclerosis (SSc). l-Propionylcarnitine (L-PC) is a metabolic substance that is associated with a beneficial effect on both microcirculation and myocyte function. Objective:: The objective of this study was to determine whether or not CFVR was acutely improved or restored in patients with SSc after a single administration of IV L-PC. Methods:: In this pilot study, we screened volunteers with SSc who had no clinical evidence of ischemic heart disease. CFVR was determined by a blinded investigator by evaluating the left anterior descending coronary artery (LADCA) by transthoracic echocardiography during adenosine infusion (140 μg/kg · min−1 for 5 minutes), 30 minutes before and 15 minutes after administration of L-PC (300 mg IV in 5-minute bolus). Results:: Thirty-three patients were screened for this study. Fourteen patients (mean [SD] age, 54.3 [11.2] years; mean [SD] weight, 63.8 [14.5] kg; mean [SD] height, 156.3 [8.7] cm) with SSc and no evidence of coronary heart disease were included in the study; 13 women and 1 man (4 with the diffuse cutaneous form of SSc and 10 with the limited cutaneous form). After administration of L-PC to patients with SSc, median CFVR was significantly increased from 2.60 to 3.23 (P < 0.001), whereas peak diastolic velocity in the LADCA decreased significantly at the basal evaluation (30.0 vs 26.0, P = 0.009) and significantly increased (80.0 vs 87.5, P = 0.005) during adenosine infusion. No adverse events occurred before, during, or after L-PC infusion. Conclusions:: Acute administration of L-PC was associated with a short-term beneficial effect on CFVR in this pilot study of patients with SSc. These results suggest that further, randomized, controlled, double-blind evaluation of longer-term administration to patients with SSc should be considered. [Copyright &y& Elsevier] more...

Myogenetic tone is intrinsic to vascular tissue and plays an important role in determining basal coronary resistance. However, the effect of the beating heart on myogenic tone is unknown. We investigated the effects of myocardium-derived vasoactive factors on the myogenic tone of coronary microvessels in the resting condition and during increased metabolism. Pressurized isolated coronary vessels (detector vessel, DV) of rabbits (n = 33, maximal inner diameter 201 ± 8 µm) were gently placed on beating hearts of anesthetized dogs and observed with an intravital microscope equipped with a floating objective. To shut off the myocardiurn-derived vasoactive signals, we placed plastic film between DV and the heart. The intravascular pressure was changed from 120 to 60 cmH2O, and pressure-diameter curves were obtained with and without the contact of DV and the myocardium. The direct contact shifted the pressure-diameter curve upward (P < 0.05 vs. without contact), and myogenic tone was reduced by ~40%. When endothelium of DV was denuded, the shift persisted, but the degree of shift was reduced to 10% (P < 0.05 vs. with endothelium). The shift was abolished by glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. A similar upward shift was induced by rapid pacing, but the shift was not blocked by glibenclamide. We conclude that the beating myocardium counteracts myogenic tone by releasing transferable vasoactive signals that affect the endothelium and the vascular smooth muscle, and that the signals are solely mediated by the activation of KATP channels, unlike the rapid pacing-induced vasoactive factors. [ABSTRACT FROM AUTHOR] more...

Objectives: We sought to evaluate the effect of acute hyperglycemia on coronary microcirculation by noninvasive measurement of coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography (TTDE). Research Design and Methods: Measurements of CFVR using TTDE and levels of plasma glucose and serum insulin and lipids were determined before and 1 hour after loading with oral glucose (75-g glucose) in 10 young healthy males (mean age, 30 ± 2 years) or an artificial sweetener in five of the 10 subjects without coronary risk factors. Results: In all subjects, the levels of plasma glucose and serum insulin significantly increased after glucose loading compared with baseline (5.1 ± 0.6 vs 7.6 ± 1.2 mM/l, 6 ± 3 vs 49 ± 13 μU/ml, respectively; P < 0.0001). CFVR was significantly decreased 1 hour after acute oral glucose loading (4.4 ± 0.7–3.8 ± 0.7, respectively; P < 0.01). There was no significant change in CFVR after loading with an artificial sweetener (4.4 ± 0.6–4.4 ± 0.5 cm/sec). Conclusions: TTDE revealed that acute hyperglycemia induced by oral glucose loading suppresses CFVR in healthy young male subjects. This result suggests that acute hyperglycemia may have adverse effects on coronary microcirculation. [ABSTRACT FROM AUTHOR] more...

Aims During severe coronary stenosis, capillary resistance increases. Drag-reducing polymers (DRPs) are blood-soluble macromolecules that reduce vascular resistance, possibly by altering blood hydrodynamics and rheology. Thus, we hypothesized that DRPs would enhance myocardial perfusion distal to a severe coronary stenosis. [ABSTRACT FROM PUBLISHER] more...

Abstract: Background: Erectile dysfunction is associated with, and may be the first sign of coronary artery disease. We aimed to assess whether men with erectile dysfunction but without cardiovascular disease have reduced coronary flow reserve, as a sign of early coronary atherosclerosis. Methods: We investigated 12 men aged 68–73 years with erectile dysfunction, and 12 age-matched controls. Erectile function was evaluated using the validated IIEF-5 questionnaire. A score ≤18 (of 25) was defined as erectile dysfunction and ≥21 was considered normal. Patients with neurological or psychological reasons for erectile dysfunction were excluded, as were patients with symptoms of or prescribed medication for cardiovascular disease, hypertension or diabetes. Coronary flow velocity reserve was measured non-invasively by Doppler in the left anterior descending artery, before and during adenosine infusion. Results: Coronary flow velocity reserve was significantly reduced in subjects with erectile dysfunction: 2.36 versus 3.19; P =0.024. In logistic regression analysis, compared to control subjects, men with erectile dysfunction had significantly increased risk of reduced coronary flow velocity reserve (≤3.0): odds ratio 15.4, P =0.02. In multivariate analysis, adjusting for age, tobacco use, systolic blood pressure, heart rate and body mass index, erectile dysfunction was the only significant predictor of reduced coronary flow velocity reserve, P =0.016. Conclusions: Men with erectile dysfunction but without diabetes or clinical cardiovascular disease have early signs of coronary artery disease. Our findings suggest that a cardiac risk evaluation may be indicated in men with suspected vasculogenic erectile dysfunction, and these individuals should be considered for primary prevention measures regarding cardiovascular disease risk factors. [Copyright &y& Elsevier] more...

The objective of this study was to apply transthoracic Doppler echocardiography (TTDE) in mice to study coronary flow reserve (CFR), an index of coronary microvascular function, in mild and severe forms of experimental viral myocarditis. Regarding methodology, BALB/c mice were infected with cardiotropic coxsackieviruses causing either a mild (Nancy strain) or a severe (Woodruff strain) myocarditis. Left ventricular dimensions, fractional shortening, and CFR (ratio of left coronary artery flow velocity during maximal adenosine-induced vasodilatation to rest) were measured by TTDE before infection and again 1 or 2 wk after infection. As a result, the resting flow velocity did not change after infection. In contrast, CFR reduced significantly 1 wk after infection with either virus variant [from 2.5 (SD 0.3) to 1.4 (SD 0.1) in severe and from 2.4 (SD 0.4) to 2.1 (SD 0.3) in mild myocarditis], being significantly lower in the severe than mild myocarditis. CFR remained low in severe myocarditis 2 wk after infection. Fractional shortening decreased to the same levels 1 wk after infection with either virus variant [from 0.54 (SD 0.02) to 0.43 (SD 0.03) in severe and from 0.51 (SD 0.03) to 0.44 (SD 0.02) in mild myocarditis, P < 0.05]. However, 2 wk after infection, mice with severe myocarditis had enlarged left ventricles and lower fractional shortening [0.31 (SD 0.03)] than mice with mild myocarditis [0.47 (SD 0.02), P < 0.01]. In conclusion, CFR measured with TTDE is reduced in coxsackievirus myocarditis in mice. Low CFR is associated with progressive heart failure, indicating that dysfunction of coronary microcirculation is a determinant of poor outcome in viral myocarditis. [ABSTRACT FROM AUTHOR] more...

Presents several studies about cardiovascular imaging and hypertension detection. "Coronary Artery Calcium and Hypertension as Predictors of Coronary Artery Disease: A Real-World Experience," by George S. Chrysant et al; "Prognostic Implication of Changes in Wall Motion Abnormalities in Patients With Left Ventricular Hypertrophy: The Life Study," by Silvana Cicala et al; "Covariates of Aortic Root Size in Patients With Asymptomatic Aortic Stenosis," by Erlend Eriksen et al. more...