uous variables are expressed as mean±SD for normally distributed variables and as median (25th–75th percen- tile) for non- normally distributed variables. Analysis was performed with the Mann–Whitney U test or Kruskal– Wallis test for variables with a non- normal distribution and with Student’s t test or analysis of variance for vari- ables with a normal distribution. Correlations between the two parameters were evaluated using linear regres- sion analysis. Receiver operating characteristic curves were analysed to assess the best cut- off values of the cQFR to predict an FFR of ≤0.80. A two- sided p- value of <0.05 indicated statistical significance. To assess reproducibility between cQFR and coronary flow reserve (CFR), or FFR and CFR, we calculated Cohen’s kappa coefficient.
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CAD: coronary artery disease; ICA: invasive coronary angiography; FFR: fractional flow reserve; FAME: fractional flow reserve versus angiography for multivessel evaluation; PCI: percutaneous coronary intervention; CCTA: coronary com- puted tomographic angiography; CFD: computational fluid dynamics; LPM: lumped parameter model; MUMPS: multi- frontal massively parallel sparse direct solver; PPV: positive predictive value; NPV: negative predictive value; +LR: positive likelihood ratio; −LR: negative likelihood ratio; AUC: area under the receiver-operator characteristics curve; SPECT: single photon emission computed tomography; cMRI: coronary magnetic resonance imaging.
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documented benefit of FFR-guided intervention over angiographic guidance, and its importance to simplify clinical decision-making in the catheterization laboratory, the clinical data supporting FFR have led interventionalists to apply FFR as a dichotomous gold-standard test for myocardial ischemia and to blindly adhere to FFR for revascular- ization decision-making in a red light/green light fashion. In contrast with this clinical application of FFR, the recent Fractional Flow Reserve Guided Percutaneous Coronary Intervention Plus Optimal Medical Therapy Versus Optimal Medical Therapy (FAME 2) trial documented that the majority of stenoses deemed hemodynamically significant by FFR do not suffer from adverse events when revascularization is deferred, whereas stenoses deemed nonsignificant by FFR are still prone to adverse cardiac events. As such, FAME 2 has shed new light on the diagnostic and prognostic characteristics of this red light/green light approach to FFR-guided revascularization in contemporary
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The presence of pulmonary arterial hypertension has also a prognostic role in advanced HF patients . When we have compared the RCA to LAD flow reserve in the pul- monary hypertension patients group, we did not find a significant difference (Table 3). Fixler et al, have found a decrease in coronary flow, and a subsequent RV failure, in setting of markedly high RV intraventricular pressure, in dogs . As a matter of fact, at initials levels of RV hyper- tension, the RCA flow even increases, corresponding to a vasomotor adaptation and reserve, including in acute con- ditions [10,43]. Only when a more extreme RV systolic pressure is reached, this vasomotor reserve exhausts, then occurring that hemodynamic consequences . Never- theless, Manohar et al. had observed experimentally in ponies that even in presence of an elevated right intraven- tricular pressure, and a consequent marked driving pres- sure reduction, the RCA flow reserve was preserved . This RCA-CFR capability to overcome hemodynamic adversities was observed experimentally by Murakami et al. as well, employing also adenosine in dogs . Cer- tainly, this evidenced capability range of CFR adaptation – added to RCA interaction to both RV and LV, as
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Little is known regarding regional atrial blood flow responses during varying hemodynamic states in both the normal and hypertrophied atria. This study was undertaken to develop a canine model of chronic atrial hypertrophy and to define in both this group and in normal dogs the regional blood flow response to acute atrial fibrillation and to measure coronary flow reserve. In the 12 dogs with atrial but not ventricular hypertrophy the mean left and right atrial weights were 75 and 47% respectively greater than in the normal group. Blood flow in the normal dogs was less in the appendage than in the non-appendage region for both atria and increased significantly during atrial fibrillation. Similar findings were noted in the
The aim of this prospective observational pilot study was to observe the impact of orbital atherectomy (OA) on the coronary microcirculation via coronary flow reserve (CFR) mea- surements. Fifteen subjects who had successful OA and stent placement with no procedural complication were enrolled at 3 hospitals in the U.S. Baseline and hyperemic velocities were 16 ± 5.2 and 36 ± 14 cm/sec, respectively. The average CFR post-procedure was within the normal range at 2.23 ± 0.33. The observation of normal CFR following OA may be attri- buted to the orbital action of the device that allows for continuous flow during treatment, minimizing a bolus embolization effect which can impact microvascular function.
Real-time myocardial contrast echocardiography RT-MCE was performed in three apical views (apical 4-, 2-, and 3-chamber) one week following PCI using low- power continuous, power-modulation MCE in a mechani- cal index of 0.2. All subjects underwent infusion of Son- oVue (Bracco, Milan, Italy) at 50--70 mL/h with an infusion syringe-pump. The infusion rate was adjusted for each pa- tient to optimize myocardial opacification with minimal at- tenuation. Once optimized, the machine settings were main- tained throughout the study. To assess the replenishment kinetics, flash echocardiography at a high mechanical index vascular flow are also very complex. Coronary flow reserve
This review focuses on transthoracic Doppler echocardiography as noninvasive method used to assess coronary flow reserve (CFR) in a wide spectrum of clinical settings. Transthoracic Doppler echocardiography is rapidly gaining appreciation as popular tool to measure CFR both in stenosed and normal epicardial coronary arteries (predominantly in left anterior descending coronary artery). Post-stenotic CFR measurement is helpful in: functional assessment of moderate stenosis, detection of significant or critical stenosis, monitoring of restenosis after revascularization. In the absence of stenosis in the epicardial coronary artery, decreased CFR enable to detect impaired microvascular vasodilatation in: reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy. In these diseases, noninvasive transthoracic Doppler echocardiography allows for serial CFR evaluations to explore the effect of various pharmacological therapies.
16. Van Belle E, Baptista SB, Raposo L, et al. Impact of routine fractional flow reserve on management decision and 1-year clinical outcome of patients with acute coronary syndromes: PRIME-FFR (Insights From the POST-IT [Portuguese study on the evaluation of ffr-guided treatment of coronary disease] and R3F [French FFR Registry] integrated multicenter registries - implementation of FFR [Fractional Flow Reserve] in Routine Practice). Circ Cardiovasc Interv 2017;10:e004296.
Patients underwent a whole-body PET/computed tomog- raphy scanner (Discovery RX or STE LightSpeed 64, GE Healthcare, Milwaukee, WI) after at least 4 h of fasting. The study protocol for PET is similar to our previous work described elsewhere . Briefly, 13 N-ammonia was used as a flow tracer at rest and stress for PET,  and an intravenous infusion of regadenoson was given as a stressor. We quantified MBF in ml/min/g during rest and peak stress using 13 N-ammonia and calculated CFR as the ratio of stress MBF over rest MBF [28–31]. Clinically relevant cardiologic variables including heart rate, blood pressure, and 12-lead ECG were assessed at baseline and throughout the test. With commercially available software, we calculated left ventricular ejection fraction (LVEF) at rest and stress from gated myocardial perfusion images. In addition, summed rest, stress, and difference scores were computed. Higher summed stress scores reflect larger areas of myocardial scar and ischemia. In general, normal scans have the summed stress score ≤ 3 [32–34].
The assessment of MCE with intracoronary or venous injection of ultrasound contrast agents composed of microbubbles has been shown to provide information on perfusion territories, collateral flow, infarct size, myocar- dial viability, and success of reperfusion therapy [9-12]. Recent advances in both of the contrast agents and ultra- sound technology have enabled the improvement of detection of myocardial perfusion using intravenous con- trast application. The evaluation of myocardial perfusion is an important component of the risk stratification of patients with ischemic heart diseases. Harmonic power Doppler imaging (HPDI) has emerged as a promising tool to detect myocardial perfusion after intravenous injection of contrast agents. MCE may be more versatile than per-
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A total of 75 patients (58 men = 77.3 %) were studied with an average age of 59.5 ± 11.2 years. The baseline characteristics, and the results of the flow velocity meas- urements of the study patients are summarized in Table 2. The flow velocity was measured in 23 patients (31 %) in the right coronary artery (RCA), in 18 patients (35 %) in the circumflex artery, and in 34 patients (65 %) in the left anterior descending artery. A PCI was necessary in 42 patients (56 %). In these patients the CFVR increased from 1.6 ± 0.40 to 2.7 ± 0.35 after PCI. Only 12 patients received a stent due to an angiographically unsatisfying result of the balloon inflation. We measured the maxi- mum hyperemic APV value in 43 patients before, and in 32 patients after an angioplasty. Among those 43 patients were 33 patients (77 %) in whom the angioplasty was deferred due to an initially recorded CFVR above 2.0. Peak APV values were measured in 32 patients (76 %) post angioplasty. In 10 patients (24%) the recording of the APV reached its maximum before the intervention. How- ever, the highest individual APV value of each patient was used for further analysis. Figure 3 summarizes the maxi- mum values of the hyperemic APV of all patients. Peak values of APV varied between 14 cm/s and 154 cm/ s. In 15 patients (20 %) the maximum APV exceeded the velocity of the CRN. In 7 patients (9.3 %) the maximum APV in the RCA, and in 8 patients (10.7 %) the maximum Maximum value of the average peak velocity APV in 43
A basic transthoracic echocardiography protocol was per- formed according to recommendations from the European Association of Echocardiography. 10 We used the Sequoia C256 (Acuson Siemens, Mountain View, CA) ultrasound system with a 4-MHz probe. Detailed protocol and valida- tion of Doppler ﬂ ow measurements in LAD have been previously described. 11,12 Brie ﬂ y, the mid to distal part of the LAD was identi ﬁ ed using 3.5-MHz color Doppler in the interventricular sulcus in a modi ﬁ ed 2-chamber view. Flow velocity signals at rest and during adenosine infusion (140 μ g/min/kg) over 5 mins was recorded with pulsed Doppler. We monitored blood pressure and ECG during the whole procedure. All studies were digitally stored for off-line measurements. CFR was analyzed off- line using the ultrasound software Image-Arena (Tomtec, Unterschlissheim, Germany). Mean diastolic ﬂ ow velocity at baseline and during peak hyperemia was measured by manual tracing of the diastolic Doppler ﬂ ow signals. CFR was calculated as the ratio between the hyperemic and baseline ﬂ ow velocity values. All evaluation CFR was performed by one experienced sonographer at the core lab (Sahlgrenska University Hospital) blinded to the infor- mation about patients ’ characteristics. We divided patients into two groups based on the cut-off value for CFR of 2.5. This cut-off value has previously been demonstrated to be associated with worse prognosis. 13,14
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In CAD, common physiological findings are included in planning a revascularization strategy for non-severe stenosis. We routinely employ stress tests for coronary blood flow through exercise or pharmacologic stimulation, and coronary pressure measurements are commonly used for assessment of the ischemic potential of a stenosis in our daily practice. Recent large clinical trials have established fractional flow reserve (FFR) measured using a pressure wire as a standard diagnostic tool in patients with non-severe stenosis. 10,11 In
Fractional flow reserve (FFR) is increasingly used to guide myocardial revascularisation. However, supporting evidence regarding its use originates from studies that have enrolled mainly patients with stable angina, while patients with acute coronary syndromes (ACS) have not been included. Notably, multifactorial microvascular dysfunction and an increased sympathetic tone in patients with ACS may lead to blunted response to adenosine and false-negative results of FFR due to submaximal hyperaemia. This may raise the possibility of deferring treatment of stenosis that instead would have needed dilatation, thus leaving a residual risk of preventable cardiac events. In this literature review, we aim at summarising laboratory and clinical investigations concerning the use of FFR in culprit and non-culprit lesions in ACS. Furthermore, we will report recent data on instantaneous wave-free ratio, an adenosine-free index of functional stenosis severity, in stable coronary artery disease and in patients with ACS.
The aim of this current study is to assess the association of F-FDG PET/CT combined with biomarkers in con- firming the diagnosis of CMVD. Coronary flow reserve (CFR) is a non-invasive measure of coronary vasomo- tor function that integrates the hemodynamic effects of epicardial coronary stenosis, diffuse atherosclerosis and microvascular dysfunction on myocardial tissue perfu- sion . CFR can be measured non-invasively by PET, Transthoracic Doppler echocardiography and cardiac MRI. We chose PET because dynamic PET imaging affords robust and reproducible measurements of abso- lute myocardial blood flow (MBF) in ml/min/g at rest and during pharmacological stress which allows the calcula- tion of CFR (defined as a ratio between MBF at stress and MBF at rest [10, 11].
Another area for the clinical use of a non-invasive cor- onary US by TTE may be the evaluation of fractional flow reserve (FFR). As recently reported by Renker et al.  by using CT scan and a dedicated algorithm, one can cal- culate FFR without the need of coronary catheterization. Additive pronostic value of FFR evaluation was shown Rigo and Picano [24, 25] this is of special value for pa- tients with normal or near normal ECG. Full achievement of this goal will, of course, require full length visualization of each coronary artery. A recent overview on the cardiac imaging approach to the athlete’s heart suggested that echocardiography, also with the objective of assessing anomalous coronary origins, should be tested in all com- petitive athletes . According to these Authors, coron- ary origins can be visualized in >90 % of the athletes using TTE.
In a European cohort, 82 % of the patients diagnosed with coronary artery disease (CAD) were overweight or obese , and two thirds of the US population are esti- mated to be overweight or obese . Despite this, CFVR by TTE Doppler of LAD has previously only been validated against myocardial flow reserve (MFR) by posi- tron emission tomography (PET), the non-invasive gold standard method of myocardial perfusion, in ten healthy, young, male subjects . Thus with reference to the obes- ity epidemic and an increasing interest in CFR as a measure of coronary microvascular function in CAD [2, 4], valid- ation of CFVR in overweight and obese patients is needed.
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All patients underwent a series of three 82 Rb cardiac PET/CT (Discovery LS, GE Healthcare, Milwaukee, WI, USA) studies. After a rest study, a cold pressor test [CPT] was carried out to assess myocardial blood flow [MBF] variations mainly due to endothelium-dependent vasomotion. CPT was done by a 2-min immersion of the left lower limb on ice water starting 1 min before the administration of 82 Rb. Ten minutes afterwards, a pharmacological hyperemic stress was performed by adenosine infusion (140 μ g/kg/min) over 6 min to mea- sure a myocardial blood flow increase (stress-MBF) mainly due to endothelium-independent vasomotion and myocardial flow reserve (MFR = stress-MBF/rest- MBF), which also helped to exclude any underlying cor- onary artery disease. For each study, after a 10-s infu- sion of 82 Rb (1450 MBq), a 6-min dynamic cardiac PET was acquired. Cardiac CT scans were also performed to correct for photon attenuation by soft tissues (before the rest study and just after the stress study). The good alignments between the PET and CT series were checked to avoid attenuation correction mistakes.
There are several non-invasive diagnostic modalities, which can be helpful in assessing LM lesion severity and all these methods can provide important prognostic information, as well. For instance, Dragu et al. found that multidetector computed tomography assessment of LM correlated well with LM IVUS assessed plaque bur- den . Jasti et. al. found significant correlation between IVUS assessed plaque burden and FFR in cases of ambiguous left main stenosis . Inducible ischemia, detected either during stress perfusion scintigraphy [14,15] or stress echocardiography  is also an impor- tant factor in the determination of the physiologic sever- ity of LM disease. Coronary flow reserve, assessed by transthoracic Doppler echocardiography has been also extensively studied and proposed as a valuable adjunct in ambiguous cases following coronary angiography . Recently, Anjaneyulu et al. reported that LM stenosis could be assessed by transthoracic echocardiography with an acceptable degree of sensitivity and specificity . Furthermore, Caiati et al  have found that the entire LAD can be visualized by the use of contrast-