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To evaluate the first experience of real-time instantaneous wave–free ratio (iFR) measurement by clinicians. The iFR is a new vasodilator-free index of coronary stenosis severity, calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, when distal resistance is lowest and stable. Because all previous studies have calculated iFR offline, the feasibility of real-time iFR measurement has never been assessed. Three hundred ninety-two stenoses with angiographically intermediate stenoses were included in this multicenter international analysis. Instantaneous wave–free ratio and fractional flow reserve (FFR) were performed in real time on commercially available consoles. The classification agreement of coronary stenoses between iFR and FFR was calculated. Instantaneous wave–free ratio and FFR maintain a close level of diagnostic agreement when both are measured by clinicians in real time (for a clinical 0.80 FFR cutoff: area under the receiver operating characteristic curve [ROCAUC] 0.87, classification match 80%, and optimal iFR cutoff 0.90; for a ischemic 0.75 FFR cutoff: iFR ROCAUC 0.90, classification match 88%, and optimal iFR cutoff 0.85; if the FFR 0.75-0.80 gray zone is accounted for: ROCAUC 0.93, classification match 92%). When iFR and FFR are evaluated together in a hybrid decision-making strategy, 61% of the population is spared from vasodilator while maintaining a 94% overall agreement with FFR lesion classification. When measured in real time, iFR maintains the close relationship to FFR reported in offline studies. These findings confirm the feasibility and reliability of real-time iFR calculation by clinicians. [Display omitted]

Conventional lumped parameter models (LPMs) simulate coronary flow incorporating intramyocardial pressure and vascular compliance, but assuming constant resistance despite its dynamic changes during myocardial contraction. We developed a coronary LPM incorporating time-varying resistance, intramyocardial pressure and vascular compliance to simulate phasic flow, critically evaluating key contributing factors. A closed-loop LPM with coronary tree was constructed. For each of Left Anterior Descending (LAD), left circumflex and Right Coronary (RCA) territories, time-varying microvascular resistanceRmicrot and intramyocardial pressure (IMP)Pimt were defined additionally to standard components. Scenarios of normal physiology and Pulmonary Hypertension (PH) were studied. Model output was assessed against in vivo measurement in the literature. The mean diastolic-systolic flow ratio (mDSFR) in LAD was underestimated by the conventional model only considering IMP (mDSFR = 1.70, vs 1.95 for in vivo measurement). Inclusion of time-varying resistance in the LPM raised mDSFR to 2.65. In the RCA, mDSFR was raised from 1.00 to 1.50 by introduction of time-varying resistance, markedly closer to 1.76 that was measured in vivo. In PH, modelled RCA flow became more diastolic dominant, represented by mDSFR of 5.35 that is closer to in vivo value of 5.83 than 2.17 which was obtained by the conventional model. The intramyocardial pressure component remained essential for regional arterial phasic changes and venous systolic-dominant flow. The simple-to-implement method of time-varying vascular resistance, developed in this study to better reflect the myocardial contraction in coronary flow analysis, facilitated an improved physiological representation compared to conventional methods, notably in the RCA especially in PH.

BackgroundDespite restoration of epicardial blood flow in acute ST-elevation myocardial infarction (STEMI), inadequate microcirculatory perfusion is common and portends a poor prognosis. Intracoronary (IC) thrombolytic therapy can reduce microvascular thrombotic burden; however, contemporary studies have produced conflicting outcomes.ObjectivesThis meta-analysis aims to evaluate the efficacy and safety of adjunctive IC thrombolytic therapy at the time of primary percutaneous coronary intervention (PCI) among patients with STEMI.MethodsComprehensive literature search of six electronic databases identified relevant randomised controlled trials. The primary outcome was major adverse cardiac events (MACE). The pooled risk ratio (RR) and weighted mean difference (WMD) with a 95% CI were calculated.Results12 studies with 1915 patients were included. IC thrombolysis was associated with a significantly lower incidence of MACE (RR=0.65, 95% CI 0.51 to 0.82, I2=0%, p<0.0004) and improved left ventricular ejection fraction (WMD=1.87; 95% CI 1.07 to 2.67; I2=25%; p<0.0001). Subgroup analysis demonstrated a significant reduction in MACE for trials using non-fibrin (RR=0.39, 95% CI 0.20 to 0.78, I2=0%, p=0.007) and moderately fibrin-specific thrombolytic agents (RR=0.62, 95% CI 0.47 to 0.83, I2=0%, p=0.001). No significant reduction was observed in studies using highly fibrin-specific thrombolytic agents (RR=1.10, 95% CI 0.62 to 1.96, I2=0%, p=0.75). Furthermore, there were no significant differences in mortality (RR=0.91; 95% CI 0.48 to 1.71; I2=0%; p=0.77) or bleeding events (major bleeding, RR=1.24; 95% CI 0.47 to 3.28; I2=0%; p=0.67; minor bleeding, RR=1.47; 95% CI 0.90 to 2.40; I2=0%; p=0.12).ConclusionAdjunctive IC thrombolysis at the time of primary PCI in patients with STEMI improves clinical and myocardial perfusion parameters without an increased rate of bleeding. Further research is needed to optimise the selection of thrombolytic agents and treatment protocols.

Studies assessing the treatment of refractory no-reflow in patients with ST-elevation myocardial infarction (STEMI) are limited to clinical cases and pilot studies. This study aimed to evaluate the efficacy and safety of intracoronary adrenaline administration in such patients. Ninety consecutive patients with refractory coronary no-reflow during percutaneous coronary intervention (PCI) were prospectively included after the initial failure of conventional treatment. They were randomized into 2 groups: 45 patients in Group 1 received adrenaline, and 45 patients in Group 2 (control) received conventional treatments alone. After intracoronary drug administration, the adrenaline group demonstrated significantly higher rates of coronary flow restoration in the infarct-related artery to the level of thrombolysis in myocardial infarction grade 3 (56% vs 29% [p = 0.01]) and resolution of STEMI >50% after PCI (78% vs 36% [p <0.001]). Additionally, the adrenaline group showed a lower indexed microvascular obstruction (MVO) volume compared with the control group (0.9 [0.3; 3.1] % vs 1.9 [0.6; 7.9] % [p = 0.048]). A significant improvement in ejection fraction (EF) was observed in the adrenaline group (p = 0.025). Intracoronary adrenaline administration during PCI in patients with STEMI with refractory no-reflow is more effective compared with conventional treatments. This approach improves coronary flow in the infarct-related artery, facilitates a faster resolution of STEMI, enhances EF, and reduces MVO volume. Intracoronary adrenaline administration demonstrates a comparable safety profile to conventional treatment strategies in terms of life-threatening arrhythmias occurrence. The study suggests that intracoronary adrenaline administration during PCI could be an effective treatment strategy for patients with STEMI with refractory no-reflow. [Display omitted]

The PLEIO (comParison of ticagreLor and clopidogrEl on mIcrocirculation in patients with acute cOronary syndrome) study showed that 6 months of ticagrelor therapy significantly improved microvascular dysfunction in acute coronary syndrome (ACS) patients with stent implantation compared to clopidogrel. Improved microvascular function may affect myocardial blood flow (MBF). We compared the effects of ticagrelor and clopidogrel on MBF over a 6-month follow-up period among patients diagnosed with ACS treated with percutaneous coronary intervention (PCI). In the PLEIO trial, 120 participants were randomized to receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily after at least 6 months. 13 N-ammonia positron emission tomography (PET) imaging was performed in 94 patients to measure MBF at the 6-month follow-up visit. On a per-patient level, MBF (1.88 ± 0.52 versus 1.67 ± 0.64 mL/min per gram, P = .01) was significantly higher with ticagrelor compared with clopidogrel in the hyperemic state, but not under resting state (0.75 ± 0.24 versus 0.75 ± 0.19 mL/min per gram, P = .84). On a culprit-vessel analysis, the resting MBF was similar (0.69 ± 0.20 versus 0.70 ± 0.21, P = .89) between the two groups. However, the hyperemic MBF and myocardial flow reserve in the ticagrelor group were significantly higher compared with clopidogrel (1.75 ± 0.46 versus 1.52 ± 0.59, P = .03 and 2.71 ± 0.89 versus 2.20 ± 0.81, P = .02, respectively). These differences were not observed in non-culprit vessels. Maintenance treatment of ticagrelor increased the hyperemic MBF and myocardial flow reserve compared with clopidogrel. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02618733

Background The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear. Methods With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO). Results Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation. Conclusions T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM.

Limited data are available regarding the influence of percutaneous coronary intervention (PCI) of non-totally occluded lesions (non-CTO) on the coronary flow of non-target vessels. We sought to investigate the short-term impact of the non-left anterior descending artery (non-LAD) PCI on the coronary flow physiology of LAD using transthoracic Doppler echocardiography (TDE). We consecutively studied 50 patients who underwent successful PCI of non-LAD and non-CTO lesions and a coronary flow velocity assessment of LAD at rest and maximal hyperemia before and at 2 days after the procedure by TDE. Coronary flow velocity reserve (CFVR) was calculated as the ratio of hyperemic to resting diastolic peak velocity (hDPV/bDPV). We evaluated the changes in LAD coronary flow characteristics after PCI of non-LAD and explored the determinants of the change in LAD-CFVR. The median fractional flow reserve (FFR) of the culprit lesion and the LAD quantitative flow ratio (QFR) were 0.67 and 0.88, respectively. After non-LAD PCI, LAD-CFVR was decreased in 33 patients (66.0%). LAD-CFVR significantly decreased (pre-PCI: 2.41, post-PCI: 2.03, p = 0.001) due to a significant decrease in LAD-hDPV (P = 0.007). The prevalence of impaired LAD-CFVR (≤2.0) significantly increased (pre: 30%, post: 48%, P = 0.027). Multivariable linear regression analysis showed that pre-PCI LAD-CFVR was independent predictor of the change in LAD-CFVR after PCI. LAD-CFVR significantly decreased after successful non-LAD PCI due to the postprocedural reduction of coronary flow assessed by LAD-hDPV.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5–7). Hypoxemia (PaO2 < 40 mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60 mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25 mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD. ClinicalTrials.gov Identifier: NCT01039389.

Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H 2 O 2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H 2 O 2 . In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.