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

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

Characteristics of coronary vasodilation reserve in partial restriction and subsequent recovery of the coronary blood flow

The studies were performed on anesthetized dogs using the model of partial controlled blood flow restriction in the left circumflex coronary artery with intact thorax. 70% of blood flow restriction were compensated by coronary vasodilation reserve, evaluated in hyperemia reaction. No rapid reperfusion hyperemia reaction was observed in reperfusion period, while moderate reduction in heart contractility was maintained. Alterations in coronary vessel reactivity could have a certain depressing effect on reperfusion hyperemia reaction. The observed changes were reversible, as coronary vessels retained their dilatation ability in response to an additional ischemic stimulus.     

Slackness between vessel and myocardium is necessary for coronary flow reserve

Tone regulation in coronary microvessels has largely been studied in isolated vessels in the absence of myocardial tethering. Here, the potential effect of radial tethering and interstitial space connective tissue (ISCT) between coronary microvessels and the surrounding myocardium was studied. We hypothesized that rigid tethering between microvessels and the myocardium would constrain the active contraction of arterioles and is not compatible with the observed tone regulation. The ISCT between coronary microvessels and myocardium in five swine was found to increase exponentially from 0.22 ± 0.02 μm in capillaries (modified Strahler order 0) of the endocardium to 34.9 ± 7.1 μm in epicardial vessels (order 10). Microvessels with both soft tethering and ISCT gap were capable of significant changes in vessel resistance (up to an ～1,600% increase), consistent with experimental measurements of high coronary flow reserve. Additionally, the mechanical energy required for myogenic contraction was estimated. The results indicate that rigid tethering requires up to four times more mechanical energy than soft tethering in the absence of a gap. Hence, the experimental measurements and model predictions suggest that effectiveness and efficiency in tone regulation can be achieved only if the vessel is both softly tethered to and separated from the myocardium in accordance with the experimental findings of ISCT gap. These results have fundamental implications on future simulations of coronary circulation.     

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.     

Relationship between beta-adrenoceptors and coronary blood flow heterogeneity

The purpose of this study was to investigate the hypothesis that the heterogeneous distribution of beta adrenoceptors contributes to the control of flow heterogeneity in the canine myocardium. beta adrenoceptor density and affinity were measured simultaneously with coronary blood flow in multiple sections of the left ventricle of 14 anesthetized open chest dogs. Radioactive microspheres were used for the measurement of blood flow. The left ventricle was cut into 15 subepicardial (EPI) and 15 subendocardial (ENDO) sections. Receptor density (Bmax) and dissociation constant (Kd) were measured using [125I]-iodopindolol. The average control myocardial blood flow (MBF) was 86 +/- 15 ml/min/100 g. Isoproterenol (0.5 micrograms/kg/min) increased MBF by 82%, whereas propranolol (2 mg/kg) reduced MBF by 13%. The mean value for Bmax was unaltered by either treatment. Under control conditions, a significant positive correlation (r = 0.26, p less than 0.0001) was observed between Bmax and blood flow. In the isoproterenol treatment group, this correlation was enhanced (r = 0.49, p less than 0.0001). Beta adrenoceptor blockade led to a negative correlation. Kd showed no overall correlation with blood flow. Kd but not Bmax was significantly higher in the EPI than in the ENDO and in the base compared to the apex. There appears to be a direct linear relationship between the distribution of beta adrenoceptors and MBF distribution which is enhanced under conditions of high beta adrenergic activity. There is a correlation between beta adrenoceptor activity and blood flow distribution in the canine myocardium.     

New method to measure coronary velocity and coronary flow reserve

Coronary flow reserve (CFR) is an important index of coronary microcirculatory function. The objective of this study was to validate the reproducibility and accuracy of intravascular conductance catheter-based method for measurements of baseline and hyperemic coronary flow velocity (and hence CFR). The absolute coronary blood velocity was determined by measuring the time of transit of a saline injection between two pairs of electrodes (known distance) on a conductance catheter during a routine saline injection without the need for reference flow. In vitro validation was made in the velocity range of 5 to 70 cm/s in reference to the volume collection method. In 10 swine, velocity measurements were compared with those from a flow probe in coronary arteries at different CFR attained by microsphere embolization. In vitro, the mean difference between the proposed method and volume collection was 0.7 ± 1.34 cm/s for steady flow and -0.77 ± 2.22 cm/s for pulsatile flow. The mean difference between duplicate measurements was 0 ± 1.4 cm/s. In in vivo experiments, the flow (product of velocity and lumen cross-sectional area that is also measured by the conductance catheter) was determined in both normal and stenotic vessels and the mean difference between the proposed method and flow probe was -1 ± 12 ml/min (flow ranged from 10 to 130 ml/min). For CFR, the mean difference between the two methods was 0.06 ± 0.28 (range of 1 to 3). Our results demonstrate the reproducibility and accuracy of velocity and CFR measurements with a conductance catheter by use of a standard saline injection. The ability of the combined measurement of coronary lumen area (as previously validated) and current velocity and CFR measurements provides an integrative diagnostic tool for interventional cardiology.     

Diagnostic accuracy of on-site coronary computed tomography-derived fractional flow reserve in the diagnosis of stable coronary artery disease

Purpose

Invasive fractional flow reserve (FFR), the reference standard for identifying significant coronary artery disease (CAD), can be estimated non-invasively by computed tomography-derived fractional flow reserve (CT-FFR). Commercially available off-site CT-FFR showed improved diagnostic accuracy compared to coronary computed tomography angiography (CCTA) alone. However, the diagnostic performance of this lumped-parameter on-site method is unknown. The aim of this cross-sectional study was to determine the diagnostic accuracy of on-site CT-FFR in patients with suspected CAD.

Methods

A total of 61 patients underwent CCTA and invasive coronary angiography with FFR measured in 88 vessels. Significant CAD was defined as FFR and CT-FFR below 0.80. CCTA with stenosis above 50% was regarded as significant CAD. The diagnostic performance of both CT-FFR and CCTA was assessed using invasive FFR as the reference standard.

Results

Of the 88 vessels included in the analysis, 34 had an FFR of ≤?0.80. On a per-vessel basis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 91.2%, 81.4%, 93.6%, 75.6% and 85.2% for CT-FFR and were 94.1%, 68.5%, 94.9%, 65.3% and 78.4% for CCTA. The area under the receiver operating characteristic curve was 0.91 and 0.85 for CT-FFR and CCTA, respectively, on a per-vessel basis.

Conclusion

On-site non-invasive FFR derived from CCTA improves diagnostic accuracy compared to CCTA without additional testing and has the potential to be integrated in the current clinical work-up for diagnosing stable CAD.

     

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI(2)) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.     

Coronary flow measurements on the isolated rat heart following experimental coronary artery stenosis]

A stenosing proliferation of the vascular wall was produced by exposing the Ramus descendens of the rat's left coronary artery to continued mechanical stimulation. Two weeks after the operation the hearts were perfused according to a modified Langendorff method, and the flow rate was measured under aerobic conditions and following short-time anoxia. Under either experimental conditions, the flow rate proved to be significantly decreased.     

Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.     

Effect of statins on coronary blood flow after percutaneous coronary intervention in patients with stable coronary artery disease

Aims

Statins have favourable effects on the vascular system. However, few data are available regarding the effect of these drugs on patients undergoing percutaneous coronary intervention (PCI). We sought to determine the impact of prior statin use on coronary blood flow after PCI in patients with stable coronary artery disease (CAD) by using the corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC).

Methods

A total of 80 consecutive eligible patients (mean age: 60 ± 7 years, 65?% male) with the diagnosis of stable CAD who were hospitalised for elective PCI were retrospectively enrolled in our study. The study population was divided into two groups according to statin use at least 6 months before PCI. Group 1 comprised of 51 patients (67?% male; mean age: 58 ± 4 years) taking statins and group 2 comprised of 29 patients (62?% male; mean age: 60 ± 3 years) not taking statins. PCI was applied to de novo type A lesions. CTFC was calculated for the treated vessels at baseline and after PCI.

Results

The two groups had similar characteristics in terms of age, sex, concomitant medications, lesion characteristics, pre-procedural CTFC, lipid parameters, and risk factors for CAD. Post-PCI CTFC (16 ± 3 vs. 22 ± 5, p = 0.01) and hs-CRP (2.1 ± 0.7 mg/l vs. 6.1 ± 2 mg/l, p = 0.01) in patients receiving statins before PCI were significantly lower than in patients without statin therapy. Multiple logistic regression analysis showed that statin pre-treatment (OR 2.5, 95?% CI 1.2 to 3.8, p < 0.001) and hs-CRP level (OR 1.8, 95?% CI 1.2 to 2.4, p = 0.001) were independent predictors of post-PCI CTFC.

Conclusions

In patients with stable CAD undergoing PCI, receipt of long-term statin therapy was associated with improvement in epicardial perfusion after PCI.

     

Microsphere maps of regional blood flow and regional ventilation.

Systematically mapped samples cut from lungs previously labeled with intravascular and aerosol microspheres can be used to create high-resolution maps of regional perfusion and regional ventilation. With multiple radioactive or fluorescent microsphere labels available, this methodology can compare regional flow responses to different interventions without partial volume effects or registration errors that complicate interpretation of in vivo imaging measurements. Microsphere blood flow maps examined at different levels of spatial resolution have revealed that regional flow heterogeneity increases progressively down to an acinar level of scale. This pattern of scale-dependent heterogeneity is characteristic of a fractal distribution network, and it suggests that the anatomic configuration of the pulmonary vascular tree is the primary determinant of high-resolution regional flow heterogeneity. At approximately 2-cm(3) resolution, the large-scale gravitational gradients of blood flow per unit weight of alveolar tissue account for <5% of the overall flow heterogeneity. Furthermore, regional blood flow per gram of alveolar tissue remains relatively constant with different body positions, gravitational stresses, and exercise. Regional alveolar ventilation is accurately represented by the deposition of inhaled 1.0-microm fluorescent microsphere aerosols, at least down to the approximately 2-cm(3) level of scale. Analysis of these ventilation maps has revealed the same scale-dependent property of regional alveolar ventilation heterogeneity, with a strong correlation between ventilation and blood flow maintained at all levels of scale. The ventilation-perfusion (VA/Q) distributions obtained from microsphere flow maps of normal animals agree with simultaneously acquired multiple inert-gas elimination technique VA/Q distributions, but they underestimate gas-exchange impairment in diffuse lung injury.     

Quantification of absolute coronary flow reserve and relative fractional flow reserve in a swine animal model using angiographic image data

Coronary flow reserve (CFR) and fractional flow reserve (FFR) are important physiological indexes for coronary disease. The purpose of this study was to validate the CFR and FFR measurement techniques using only angiographic image data. Fifteen swine were instrumented with an ultrasound flow probe on the left anterior descending artery (LAD). Microspheres were gradually injected into the LAD to create microvascular disruption. An occluder was used to produce stenosis. Contrast material injections were made into the left coronary artery during image acquisition. Volumetric blood flow from the flow probe (Q(q)) was continuously recorded. Angiography-based blood flow (Q(a)) was calculated by using a time-density curve based on the first-pass analysis technique. Flow probe-based CFR (CFR(q)) and angiography-based CFR (CFR(a)) were calculated as the ratio of hyperemic to baseline flow using Q(q) and Q(a), respectively. Relative angiographic FFR (relative FFR(a)) was calculated as the ratio of the normalized Q(a) in LAD to the left circumflex artery (LC(X)) during hyperemia. Flow probe-based FFR (FFR(q)) was measured from the ratio of hyperemic flow with and without disease. CFR(a) showed a strong correlation with the gold standard CFR(q) (CFR(a) = 0.91 CFR(q) + 0.30; r = 0.90; P < 0.0001). Relative FFR(a) correlated linearly with FFR(q) (relative FFR(a) = 0.86 FFR(q) + 0.05; r = 0.90; P < 0.0001). The quantification of CFR and relative FFR(a) using angiographic image data was validated in a swine model. This angiographic technique can potentially be used for coronary physiological assessment during routine cardiac catheterization.     

Determinants of coronary flow velocity reserve in healthy young men

The objective of this study was to identify risk markers for attenuated coronary flow velocity reserve (CFVR) that exist in healthy young men without evident atherosclerotic risk factors. Coronary blood flow velocity was measured with transthoracic Doppler echocardiography at baseline and during adenosine infusion in 37 healthy nonsmoking men [mean age, 27 yr (SD 4.0)]. Body composition and distribution of fat tissue were assessed with anthropometric measures and regulation of fat metabolism by determination of adiponectin and leptin levels. Physical performance capacity was tested with ergospirometry. The mean body mass index was 23 kg/m2 (SD 1.9), waist-to-hip ratio was 0.84 (SD 0.04), and CFVR was 3.5 (SD 0.61). Obesity indexes at study outset, leptin, adiponectin, maximal load (Max load in W/kg) and maximal oxygen consumption (Vo2 peak in ml x kg(-1) x min(-1)) in ergospirometry, rate-pressure product, and heart rate at rest were significantly associated with CFVR. In multivariate analysis, Max load (in W/kg) and waist-to-hip ratio were the only independent predictors of CFVR. We found no relationship between CFVR and serum lipids or body mass index. We conclude that abdominal fat accumulation and low aerobic fitness are independently associated with CFVR in men.