Local Coronary Flow Research Articles

Abstract 15802: Chemogenetic Activation of Intracardiac Cholinergic Ganglia Neurons Reduces the Incidence of Arrhythmias After an Acute Myocardial Infarction

Intracardiac cholinergic ganglia (ICG) neurons receive excitatory input from vagal pre-ganglionic fibers and are critical for the transmission of parasympathetic drive throughout the heart. During disease, electronic vagal stimulation improves cardiac function and reduces arrhythmias. However, vagal stimulation is not selective for efferent or cholinergic fibers and implanting an electronic device before unanticipated episodes of cardiac infarction is not clinically feasible. We addressed these limitations by testing the hypothesis that chemogenetic ICG activation immediately after an infarction would reduce arrhythmia incidence and improve ventricular function. Floxed DREADDs (AAV2-hSyn-DIOhM3D(Gq)-mcherry) were injected into the pericardial sac of neonatal rats that selectively express Cre recombinase in cholinergic neurons. At 8 weeks, hearts were excised for ex-vivo studies and excitatory hM3Dq DREADDs expressed in ICG cholinergic neurons were activated by clozapine-N-oxide (CNO). Heart rate (HR), LV developed pressure, and overall arrhythmia incidence were measured. In healthy hearts, CNO decreased HR for the duration of the experiment (247 ±10.56 to 189.35± 3.46 beats per minute, p<0.0001, n=5). To study ICG activation after infarction, hearts received CNO or saline after complete ligation of the left anterior descending coronary artery or partial obstruction of the left coronary artery. The ECG was analyzed to assess PR interval and arrhythmia incidence, including non-sustained and sustained VT and fibrillation. ICG activation increased PR interval from 39.13 ± 2.75 to 42.46 ± 3.07 ms (p=0.0097, n=5). ICG activation also reduced arrhythmia incidence after coronary artery ligation from 1.65 to 0.6467 arrhythmias per min (p=0.042, n=5), an outcome that is likely motivated by ICG neuron inhibition of adrenergic activity in addition to vasodilation and increased coronary flow. These studies demonstrate that cardiac cholinergic ICG activation following an MI quickly elevates cardiac parasympathetic drive, protecting against arrhythmias. Future studies will focus on measuring the inhibition of adrenergic activity by chemogenetic activation of cholinergic ICG neurons and local coronary flow increases.

Three-Dimensional Fluid Dynamical Features of Coronary Plaque Rupture Provoking Acute Coronary Syndrome.

Aim: Coronary plaque rupture is the main cause of acute coronary syndrome (ACS), but the role of blood flow features around plaque rupture for ACS is still unknown. The present study aimed to assess the relationship between the geometric configuration of ruptured plaque and ACS occurrence using computational fluid dynamics (CFD) by moving particle method in patients with coronary artery disease. Methods: In this study, 45 patients with coronary artery disease who underwent three-dimensional intravascular ultrasound (IVUS) and had a coronary ruptured plaque (24 plaques with provoked ACS, 21 without) were included. To compare the difference in blood flow profile around ruptured plaque between the patients with and without ACS, the IVUS images were analyzed via the novel CFD analysis. Results: There were no significant differences in localized flow profile around ruptured plaque between the two groups when the initial particle velocity was 10.0 cm/s corresponded to a higher coronary flow velocity at ventricular diastole. However, when it was 1.0 cm/s corresponded to lower coronary flow velocity at ventricular systole, particles with lower velocity (0 ≤ V ≤ 5 cm/s) were more prevalent around ACS-PR ( p =0.035), whereas particles with higher velocity (10 ≤ V ≤ 20 cm/s) were more often detected in silent plaque ruptures ( p =0.018). Conclusions: Three-dimensional IVUS revealed that coronary plaque rupture was a complex one with a wide variety of its stereoscopic configuration, leading to various patterns of the local coronary flow profile. A novel CFD analysis suggested that the local flow was more stagnant around ACS-provoked ruptures than in silent ones.

Quantification of disturbed coronary flow by disturbed vorticity index and relation with fractional flow reserve

Background and aimsThe relation between FFR and local coronary flow patterns is incompletely understood. We aimed at developing a novel hemodynamic index to quantify disturbed coronary flow, and to investigate its relationship with lesion-associated pressure-drop, and fractional flow reserve (FFR). MethodsThree-dimensional angiographic reconstruction and computational fluid dynamics were applied to simulate pulsatile coronary flow. Disturbed vorticity index (DVI) was derived to quantify the stenosis-induced flow disturbance. The relation between DVI and pressure-drop was assessed in 9 virtual obstruction models. Furthermore, we evaluated the correlation between DVI, FFR, hyperemic flow velocity, and anatomic parameters in 84 intermediate lesions from 73 patients. ResultsIn virtual models, DVI increased with increasing flow rate, stenosis severity, and lesion complexity. The correlation between DVI and pressure-drop across all models was excellent (determination coefficient R2 = 0.85, p < 0.001). In vivo, DVI showed a correlation with FFR (rho (ρ) = -0.74, p < 0.001) that was stronger than the relations of FFR with hyperemic flow velocity (ρ = -0.27, p=0.015), lesion length (ρ = -0.36, p=0.001) and percent diameter stenosis (ρ = -0.40, p < 0.001). ConclusionsDVI, a novel index to quantify disturbed flow, was related to pressure-drop in virtual obstruction models and showed a strong inverse relation with FFR in intermediate lesions in vivo. It supports the prognostic value of FFR and may provide additional information about sources of energy loss when measuring FFR.

TCT-453 Quantification of Disturbed Coronary Blood Flow: Disturbed Vorticity Index and its Relation With Fractional Flow Reserve

Disturbed flow patterns are associated with the localization of atherosclerotic lesion, where recirculation and secondary flows are usually present. However, there is no metric to quantify the extent of flow disturbance. And the relation between fractional flow reserve (FFR) and local coronary flow

Strut protrusion and shape impact on endothelial shear stress: insights from pre-clinical study comparing Mirage and Absorb bioresorbable scaffolds

Protrusion of scaffold struts is related with local coronary flow dynamics that can promote scaffold restenosis and thrombosis. That fact has prompted us to investigate in vivo the protrusion status of different types of scaffolds and their relationship with endothelial shear stress (ESS) distributions. Six Absorb everolimus-eluting Bioresorbable Vascular Scaffolds (Absorb, Abbott Vascular) and 11 Mirage sirolimus-eluting Bioresorbable Microfiber Scaffolds (Mirage, Manli Cardiology) were implanted in coronaries of eight mini pigs. Optical coherence tomography (OCT) was performed post-scaffold implantation and obtained images were fused with angiographic data to reconstruct the three dimensional coronary anatomy. Blood flow simulation was performed and ESS distribution was estimated for each scaffold. Protrusion distance was estimated using a dedicated software. Correlation between OCT-derived protrusion and ESS distribution was assessed for both scaffold groups. A significant difference was observed in the protrusion distances (156 ± 137 µm for Absorb, 139 ± 153 µm for Mirage; p = 0.035), whereas difference remained after adjusting the protrusion distances according to the luminal areas. Strut protrusion of Absorb is inversely correlated with ESS (r = −0.369, p < 0.0001), whereas in Mirage protrusion was positively correlated with EES (r = 0.192, p < 0.0001). Protrusion distance was higher in Absorb than in Mirage. The protrusion of the thick quadratic struts of Absorb has a tendency to lower shear stress in the close vicinity of struts. However, circular shape of the less thick struts of Mirage didn’t show this trend in creating zone of recirculation around the struts. Strut geometry has different effect on the relationship between protrusion and shear stress in Absorb and Mirage scaffolds.

Local Coronary Flow Is Associated With an Unsuccessful Complete Block Line at the Mitral Isthmus in Patients With Atrial Fibrillation

The addition of a mitral isthmus (MI) block line after pulmonary vein isolation could lead to a favorable outcome of catheter ablation in patients with atrial fibrillation (AF). However, it is sometimes tough to create a complete MI block line, and the cooling effect because of the local coronary flow may prevent the creation of a successful MI block line. This study enrolled 81 AF patients in whom the creation of an MI block line was attempted in those with persistent or pacing-inducible AF after pulmonary vein isolation. A local coronary artery (LCA) across the MI block line was observed in 43 (53%) of 81 patients, and a bidirectional MI block was successfully accomplished in 53 (65%) of 81 patients, at the estimated MI line. The ratio of a successful MI block line was significantly lower in the patients with an LCA than in those without an LCA (42% versus 92%; P<0.001). The mean diameter of the coronary sinus (0.59 ± 0.18 versus 0.82 ± 0.22 cm; P<0.001) and length of the estimated MI line (33.4 ± 9.9 versus 29.4 ± 7.1 mm; P=0.032) were significantly shorter in the patients with a successful MI block line than in those without a successful MI block line. In the multivariable analysis, an LCA at the MI and a larger coronary sinus diameter were independent risk factors for an unsuccessful MI block line. Local coronary flow at the MI is associated with an increased incidence of an unsuccessful MI block line.

Myocardial ischemia-reperfusion and cardioprotection: a study with microdialysis in a porcine model

The studies in this thesis are based on questions raised in the clinical setting. Perioperative myocardial ischemia occurs more often than recognized. This may lead to myocardial infarction, increased morbidity, mortality, and health care costs. In the first study, myocardial metabolism was investigated before, during, and after 30 min of regional coronary artery occlusion, utilizing the microdialysis technique, concomitantly with the monitoring of global circulation and local coronary artery flow in an open chest pig model. Myocardial interstitial metabolites demonstrated characteristic, significant, and reproducible changes as decreased glucose, increased glycerol, and increased lactate/pyruvate ratio during ischemia, normalizing after reperfusion. Of special interest was found that myocardial glycerol concentrations remained high initially at reperfusion, raising the hypothesis of this release corresponding to reperfusion injury. This model was used for the next two studies. In cardiac surgery, episodes of myocardial ischemia or decreased myocardial performance are highly expected to occur. Patients with poor cardiac function will have a double benefit of an inotropic drug with anti-ischemic properties. Levosimendan may have this potential. In the second study, it was demonstrated that an infusion of levosimendan started before the coronary artery occlusion, as compared to start during the ischemia, reduced the effect of ischemia on the myocardial metabolism, improved, and preserved cardiac performance during this period. In recent years, concerns with the use of perioperative beta-blockers have been debated. Beta-blockers may inhibit the pharmacological preconditioning elicited by volatile anaesthetics. In the third study, it was demonstrated that levosimendan, in the presence of beta-blockade, was still able to induce a cardioprotective effect on the myocardial ischemic metabolism. During cold cardioplegic storage, or in the future during preservation of donor hearts by perfusion, monitoring of the donor heart before transplantation may be of benefit. We hypothesized, that myocardial microdialysate glycerol will reflect progressive damage. As the first step in pursuing this, in the fourth study, the course of myocardial metabolites was investigated during ten hours of cold cardioplegic storage. An accelerating myocardial glycerol accumulation was demonstrated during storage, after an initial stable period, probably reflecting the acceptable storage time. (Less)

Significance of Local Coronary Artery Flow as a Complete Block Line at the Mitral Isthmus in Patients with Atrial Fibrillation

Significance of Local Coronary Artery Flow as a Complete Block Line at the Mitral Isthmus in Patients with Atrial Fibrillation

Myocardial glycerol release, arrhythmias and hemodynamic instability during regional ischemia‐reperfusion in an open chest pig model

To develop cardioprotection against peri-operative myocardial ischemia-reperfusion injury, we need animal models where the local metabolism and blood flow are studied concomitantly with the global circulatory consequences during regional coronary occlusion. In six anesthetized domestic pigs, the largest branch of the circumflex artery was occluded for 30 min. Microdialysate was sampled from the ischemic and non-ischemic myocardium along with continuous measurements of local coronary artery flow, global hemodynamics and registration of arrhythmias, from baseline through to 30 min of ischemia and 180 min of reperfusion. During ischemia, the microdialysate glucose concentration decreased, the glycerol concentration increased and the lactate/pyruvate ratio increased significantly. For glycerol, there was a further increase at reperfusion. During ischemia, cardiac output was unchanged; however, during reperfusion there was a significant drop lasting for several minutes, longer than the period in which an increased number of arrhythmias were registered. The present study demonstrates deranged circulation and arrhythmias corresponding to ischemic metabolism after regional myocardial ischemia and reperfusion. Reperfusion induced more pronounced circulatory changes than the actual ischemia. A substantial increase in myocardial glycerol release seems to be a marker of ischemic metabolism and may prove to be an indicator of reperfusion injury.

Does local coronary flow control metabolic flux rates? A 13C-NMR study.

Coronary flow; NMR; Metabolic flux Left ventricular perfusion is inhomogeneous even under resting conditions. While at a resolution of 6 x 6 x 6 mm 3 local coronary flow in 1/2 of the my- ocardium is within 20% of the normalized mean, 1/10 of the myocardium receives less than 50% and another 1/10 more than 150% of mean flow [1]. There is thus at least a 3-fold difference in local perfusion and conse- quently oxygen and substrate supply between low and high flow areas. A correlation of fatty acid and glucose uptake and local flow has been demonstrated [1 3]. It is however unclear, whether there is in fact spatial heterogeneity of tricarboxylic acid cycle turnover (VTcA) and thus MVO2 and whether local perfusion influences other metabolic flux rates, e.g. anaplerosis. In the open chest dog, radioactive microspheres were applied for the determination of local coronary flow and MVO 2 measured. [3-13C]pyruvate (2 raM) was in- fused into the left anterior descending artery (LAD) for a defined period of time. Immediately thereafter the left ventricular free wall was excised and rapidly frozen. Lyophyllized tissue was cut into 40 mg pieces following a standardized scheme (256 samples/heart), r-radioac- tivity was counted and local flow determined. In each dog, a similar number of low ( 150%) flow samples were extracted. [3JgC]lactate and alanine as well as [4-~3C] and [3-~3C]glutamate were measured by ~3C-NMR spectroscopy. Glutamate and TCA cycle intermediates were determined by classical biochemical techniques in each individual sample. * Corresponding author. After [3-~3C]pyruvate infusion for 12 rain, glutamate

Does local coronary flow control metabolic flux rates? A 13C-NMR study

Does local coronary flow control metabolic flux rates? A 13C-NMR study

18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium. Evidence for transmural variations in chronic hibernating myocardium.

Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of 18F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall. We chronically instrumented pigs (n = 18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an over-night fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80 +/- 0.06 versus 1.07 +/- 0.06 mL.min-1.g-1, P < .001; full-thickness: 0.87 +/- 0.04 versus 0.99 +/- 0.06 mL.min-1.g-1, P < .01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8 +/- 0.2 by positron emission tomography versus 1.9 +/- 0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5 +/- 0.2 in the subendocardium, 1.9 +/- 0.2 in the midmyocardium, and 1.4 +/- 0.1 in the subepicardium. These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.

Myocardial protection by simple systemic hypothermia without aortic occlusion

Systemic hypothermia at 25 degrees-28 degrees C without chemical cardioplegia was used in 908 patients undergoing coronary artery bypass grafting. Local coronary artery flow was interrupted only during grafting of a distal anastomosis. Systemic perfusion pressure was maintained at 80-100 mmHg, hematocrit at 20%-25%, and pCO2 and pH were monitored during hypothermia according to the alpha-stat principle, while the left ventricle was vented routinely. Proximal anastomoses were performed just before extracorporeal circulation was started by only partially occluding the ascending aorta. Preoperatively 61.9% of the patients had had a myocardial infarction, and 44% had unstable angina. In 14% a severe lesion of the main stem of the left coronary artery was present. Left ventricular function was moderately depressed in 25% and severely depressed in 8% of the patients. Forty-eight patients (5.3%) were aged 70 years or older. The mean number of grafts placed per patient was 3.3. Perioperative myocardial infarction occurred in 3%. Death due to left ventricular failure occurred in 0.4%. No left ventricular assist devices were needed; an intra-aortic balloon pump was used in 1%; positive inotropic support was required in 3.8% of the patients. These results indicate that systemic hypothermia alone provides safe myocardial protection and in certain cases may be the method of choice, particularly if aortic cross clamping or administration of cardioplegic solution is contraindicated. In addition, this method provides rapid revascularization of a severely ischemic zone, as present after unsuccessful PTCA procedures.

Quantification of O2 consumption and arterial pressure as independent determinants of coronary flow.

The steady-state relationship between coronary arterial blood flow (CBF) and both myocardial O2 consumption (MVO2) and coronary arterial pressure (P) was explored in anesthetized dogs and goats. Both species were subjected to constant pressure perfusion of the left main coronary artery by an external pressure-controlling circuit. In addition a group of goats was studied with normal aortic perfusion using an occluder around the left main coronary artery to vary coronary arterial pressure. The statistical analysis revealed that despite the direct effect of P on MVO2 (the Gregg effect) the effects of both variables on CBF were independent and linear over a wide range of P and MVO2 so that multiple regression analysis with a linear equation (CBF = a X P + b X MVO2 + c) gave an excellent fit which was not improved by the introduction of an addition interactive term b3MVO2 X P. The mean correlation coefficient for all animals was greater than 0.9. From these data we conclude that any factor regulating coronary arterial flow would be influenced by both MVO2 and perfusion pressure in an independent way. This study characterizes the stationary behavior of local coronary flow control. Hence, it specifies quantitatively the relations to be predicted by hypotheses aiming to explain this control mechanism.

Coronary driving pressure and vasomotor tonus as determinants of coronary blood flow.

A method is described that measures the contribution of coronary vasomotor tonus and extracoronary factors in the regulation of coronary blood flow. Coronary flow was measured from the bypassed right heart when the left ventricle pumped the entire systemic flow (method "A") and when a heart-lung machine generated systemic pressure (method "B"). In method "B," the mechanical activity and the oxygen consumption of the heart could be dissociated from systemic pres sure by the use of a balloon in the ventricle. Control measurements were performed in "uninjured" hearts; when a balloon was inflated to a left ventricular diastolic pressure of 15 mm. Hg or more, a state of "cardiac injury" supervened. The arterial oxygen content was kept above 20 to 21 vol. per cent, but the cardiac oxygen consumption varied over a wide range. Whenever hemodynamic factors changed, coronary flow was a highly correlated, straight-line function of the difference between the aortic pressure and the left ventricular pressure, which we call the "coronary driving pressure." In "injured" hearts this linearity and high correlation persisted, but the slope of the regression line increased. We conclude that coronary flow is determined by the integrated difference between the propulsive force (the fluctuating pressure head at the coronary ostia) and opposing forces (intramyocardial pressure, which is known to oppose local coronary flow whenever and wherever it exceeds intravascular pressures). Cardiac oxygen consumption and coronary blood flow were not significantly related and were, therefore, coordinated by purely mechanical pressure differentials and not by changes of coronary vasomotor tonus. However, coronary vasomotor tonus decreased markedly during arterial anoxia or after various types of cardiac injury; it increased after Pitressin.