<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03033810</url>
  </required_header>
  <id_info>
    <org_study_id>VFN_21_2016</org_study_id>
    <nct_id>NCT03033810</nct_id>
  </id_info>
  <brief_title>FFR Versus iFR in Assessment of Hemodynamic Lesion Significance</brief_title>
  <acronym>FiGARO</acronym>
  <official_title>FFR Versus iFR in Assessment of Hemodynamic Lesion Significance Using Gene Polymorphisms and Lesion Morphology Assessed by OCT (FiGARO Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>General University Hospital, Prague</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>General University Hospital, Prague</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study will compare two invasive methods (FFR -fractional flow reserve and&#xD;
      iFR-instantaneous wave free ratio) for assessment of hemodynamic impact of coronary stenosis&#xD;
      on myocardial perfusion. There is a very good correlation between these methods for the&#xD;
      assessment of hemodynamic significance in a broad spectrum of lesions. However, this&#xD;
      correlation decreases significantly near the cut off points for each method. The&#xD;
      investigators will try to find possible explanations for these differences by detailed&#xD;
      morphology assessment of coronary stenosis using optical coherence tomography (OCT), analysis&#xD;
      of gene polymorphisms that play a role in vasodilatation, and by shear stress analysis. The&#xD;
      head-to-head comparison between FFR and iFR is not simple, because there is no &quot;gold&#xD;
      standard&quot; for assessment of hemodynamic significance. Studies comparing these methods have&#xD;
      used hyperemic stenosis resistance (HSR). For this kind of measurement it is necessary to&#xD;
      measure the speed of blood flow. This is usually done by a Doppler analysis of flow.&#xD;
      Unfortunately, the Doppler signal can yield many artificial or erroneous indicators, and&#xD;
      obtaining a good quality signal is frequently time-consuming. These are the reasons that HSR&#xD;
      has not been used in routine practice. The investigators have developed a new console and&#xD;
      software that can provide real time analysis of the Doppler signal. It allows us to easily&#xD;
      measure HSR, and to differentiate between the FFR and iFR measures through intrabeat analysis&#xD;
      of microvascular resistance (lowest microvascular resistance is an essential condition for&#xD;
      proper pressure measurement). Using this tool, it is possible to automatically identify the&#xD;
      point of lowest microvascular resistance during each cardiac beat. The pressure gradient can&#xD;
      then be measured at that point. This approach can eliminate almost all uncertainties in&#xD;
      assessment of the pressure gradient produced by coronary stenosis. This tool can potentially&#xD;
      improve the existing methods used to precisely reveal a significant stenosis. This should&#xD;
      increase the number of hemodynamic guided procedures.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND AND RATIONALE FOR THE STUDY Coronary artery disease (CAD) is the most frequent&#xD;
      causes of death and disability in developed countries. The main diagnostic method for&#xD;
      detection of CAD is a coronary angiography (CAG. However, the correlation between CAG and&#xD;
      proven hemodynamic significance in borderline stenosis (40-70% of lumen narrowing) is only&#xD;
      about 50%. The main method for detection of flow-limiting lesions is fractional flow reserve&#xD;
      (FFR). FFR is calculated as distal pressure (Pd) divided by proximal pressure (Pa). The&#xD;
      cut-off for hemodynamic significance is 0.8 and less. The use of FFR for lesion assessment&#xD;
      has a level of recommendation of I A in European guidelines for coronary interventions from&#xD;
      2014. The FAME trail revealed that routine usage of FFR measurement decreased the costs of&#xD;
      coronary interventions over two years. The reasons are smaller quantity of implanted stents&#xD;
      and decreased number of procedures for in stent restenosis as a direct result of the lower&#xD;
      incidence of initial stent implantation. FAME-2 trial has shown lower incidence of urgent&#xD;
      revascularization in patients with FFR less than 0,8 treated by coronary intervention&#xD;
      compared to those treated conservatively. This study was preliminary halted before reaching&#xD;
      mortality endpoint for safety reasons.&#xD;
&#xD;
      Critical condition for proper FFR measurement is maximal vasodilatation. Since we do not have&#xD;
      marker for this condition based on pressure measurement only we can only presume that it was&#xD;
      reached by adenosine administration. There are a lot of limitations for this assumption.&#xD;
      Foremost, technique for proper intravenous and intracoronary adenosine administration must&#xD;
      follow strict rules and therefore can be done incorrectly and leads to wrong result in same&#xD;
      cases. Furthermore, impaired endothelial function leads to lower response to adenosine&#xD;
      administration. This situation can leads to false negative FFR result. The patients with CAD&#xD;
      have frequently significant endothelial dysfunction causing lower response to vasodilatation&#xD;
      stimuli. Endothelial dysfunction will be analyzed by a system named EndoPAT (Itamar Medical,&#xD;
      Israel) that measures ischemia induced vasodilatation on fingers. The hypothesis that has&#xD;
      never been tested is how polymorphism in genes for enzymes playing an important role in&#xD;
      proper endothelial function (HO-1, hemoxygenase-1 and ENOS, endothelial NO synthase) can&#xD;
      influences adenosine-induced vasodilatation and subsequently FFR measurement. These&#xD;
      polymorphisms are not infrequent in population with CAD (they can be found in 40-50% in such&#xD;
      patients).&#xD;
&#xD;
      Another possible limitation for FFR measurement is type of blood flow in coronary arteries.&#xD;
      In presence of coronary stenosis, plaque roughness or sharp angle of a lumen the type of flow&#xD;
      can be changed from laminar to turbulent. This type of flow is even accelerated during&#xD;
      hyperemia induced by adenosine administration. It leads to lose of energy and exaggerates&#xD;
      pressure drop behind stenosis that - for this reason- may not be proportional to stenosis&#xD;
      severity. This situation can theoretically causes false positive FFR measurement. To answer&#xD;
      this question the investigators will analyze the endothelial shear stress (ESS) that can&#xD;
      distinguish laminar and turbulent flow and morphological indices (plaque surface, plaque&#xD;
      eccentricity, lumen volume and lumen shape) by optical coherence tomography (OCT).&#xD;
&#xD;
      The new index able to identify physiologically significant stenosis has been recently&#xD;
      described. It is instantaneous wave-free ratio (iFR). This technique uses a pressure gradient&#xD;
      as well, but -unlike to FFR- iFR compares pressures (proximal and distal to stenosis) only in&#xD;
      a specific phase of diastole (so called &quot;wave free period&quot;), where microvascular resistance&#xD;
      is naturally low and stable .&#xD;
&#xD;
      The cut off point for iFR is 0.9. The correlation between FFR and iFR is between 80% and 90%&#xD;
      in all lesions. However, the correlation between FFR and iFR close to their cut-off point is&#xD;
      only 50%-60%. It is substantial caveat, because to estimate hemodynamic significance of&#xD;
      borderline lesions is the main indication for these techniques. Discrepancies between FFR and&#xD;
      iFR can be very confusing a discouraging for lesion hemodynamic assessment.&#xD;
&#xD;
      Nowadays, FFR is the only invasive method for stenosis hemodynamic assessment supported in&#xD;
      the guidelines. However, the iFR is faster, easier and cheaper, and for these reasons it can&#xD;
      be used for more lesions in more patients, which can improve the situation of poor&#xD;
      penetration of hemodynamic guidance for coronary intervention in daily practice. Moreover, an&#xD;
      increasing number of evidences implies that iFR concept can be closer to real situation in&#xD;
      coronary arteries (avoiding non-physiologic vasodilatation). It has been shown that FFR&#xD;
      itself has a factor of variability of 10%. This means that around the cut-off points the FFR&#xD;
      can be just as wrong as the iFR, perhaps even more so. Moreover, the latest study has shown&#xD;
      that iFR provides better pressure-derived diagnostic agreement with CFR (coronary flow&#xD;
      reserve) than FFR. The investigators have been developing, in close cooperation with The&#xD;
      University of Iowa, new technique that improves the quality of flow measurement. It was&#xD;
      successfully tested it in a animal trial. It is a novel way of intravascular Doppler signal&#xD;
      processing resulting in more reliable velocity curve envelope acquisition. This software&#xD;
      improvement allows instantaneous monitoring of real time microvascular resistance during any&#xD;
      phase of cardiac cycle. Detection of during instantaneous wave free period can serve as&#xD;
      verification of the proprietary iFR calculation. The system may also improve iFR measurement&#xD;
      itself, because it can measure precisely in-phase with the lowest microvascular resistance.&#xD;
      The measurement of resistance during wave free period is named iMR (instantaneous&#xD;
      microvascular resistance) and it has never been measured during previous trials. This index&#xD;
      can greatly help to distinguish which method (FFR or iFR) measures the pressure gradient&#xD;
      during lower resistance.&#xD;
&#xD;
      Further target is to develop next generation of the software that can detect lowest&#xD;
      microvascular resistance based on pressure measurement only, without necessity of using&#xD;
      Doppler. It could offer very precise and simple methods for hemodynamic assessment of&#xD;
      coronary lesions. This software must be tested and verified in a human study, which will be&#xD;
      done in the General Teaching Hospital (where both intracoronary pressure and flow will be&#xD;
      measured). Its clinical availability will be tested and verified by the international&#xD;
      cooperating centers (where only pressure indices, FFR and iFR will be measured). The foreign&#xD;
      centers will also examine coronary OCT that will be sent to corelab in The University of&#xD;
      Iowa, collect blood samples for genetic analysis that will be done in Prague and, depend on&#xD;
      their possibilities, also endothelial dysfunction by EndoPAT.&#xD;
&#xD;
      The University of Iowa, Iowa, USA will analyze OCT measurement and perform 3D vessel&#xD;
      reconstruction. This university has a world known team for the unique 3D reconstruction of&#xD;
      coronary arteries based on angiography and optical coherence tomography. This institution&#xD;
      will do an automated analysis of plaque surfaces as well.&#xD;
&#xD;
      HYPOTHESES:&#xD;
&#xD;
        1. The level of microvascular resistance can be used to distinguish which type of&#xD;
           measurement (FFR or iFR) was done during the lower and more stable stage of&#xD;
           microvascular resistance. This comparison can possibly explain discrepancies between FFR&#xD;
           and iFR measurements.&#xD;
&#xD;
        2. Based on new software, using pressure measurements only, it will be possible to&#xD;
           automatically detect the time period with the lowest microvascular resistance. This&#xD;
           could improve accuracy of both FFR and iFR measurements.&#xD;
&#xD;
        3. Plaque ruptures, erosions, irregularities of plaque geometry and plaque located near to&#xD;
           bifurcations cause turbulence in blood flow. This accelerated pressure drop can lead to&#xD;
           a false positive FFR.&#xD;
&#xD;
        4. Inadequate vasodilation caused by endothelial dysfunction can lead to false negative&#xD;
           FFR.&#xD;
&#xD;
        5. Endothelial dysfunction can be more frequently found in patients with the risk type of&#xD;
           polymorphism in genes playing an important role in vessel vasodilatation (ENOS, HO-1)&#xD;
&#xD;
      AIMS AND EXPECTED IMPACT ON CLINICAL PRACTICE&#xD;
&#xD;
        1. To use new software (developed at the author's workplace in cooperation with The&#xD;
           University of Iowa) to determine which of two methods for the functional assessment of&#xD;
           coronary stenosis (FFR and iFR) perform their measurements during a lower level of&#xD;
           microvascular resistance. This software can measure microvascular resistance in real&#xD;
           time.&#xD;
&#xD;
        2. To develop a new version of software for the detection of microvascular resistance&#xD;
           level, based only on intracoronary pressures without flow analysis. This could&#xD;
           substantially improve the accuracy of both pressure-based measurements, and potentially&#xD;
           increase the correlation between pressure based measurements and flow-based CFR.&#xD;
&#xD;
        3. To study the potential influence of endothelial dysfunction and plaque morphology on&#xD;
           discrepancies between FFR and iFR during functional assessments of coronary stenosis.&#xD;
&#xD;
        4. To study the influence of gene polymorphisms on endothelial dysfunction&#xD;
&#xD;
      METHODS Study design Patients with stable angina pectoris with suitable for coronary&#xD;
      angiography will be suitable for the study. We plan to include 250 patients to the study (50&#xD;
      from General University Hospital in Prague and 200 from cooperating centers).&#xD;
&#xD;
      Functional examinations of coronary arteries. Coronary angiography will be performed as a&#xD;
      first procedure for detection of severity and extent of coronary atherosclerosis. Stenosis&#xD;
      between 40-80% (based on CAG) will be suitable for morphological and functional examinations.&#xD;
      Combo wire (Volcano Corp., USA) for pressure and flow measurement will be introduced behind&#xD;
      the lesion and basal indices will be measured during basal flow condition: basal flow speed,&#xD;
      pressure gradient (Pd/Pa), iFR, Pd/Pa during lowest microvascular resistance proven by&#xD;
      Doppler analysis, iMR. Adenosine will be administered either intracoronary as a bolus (240&#xD;
      ug) or in continual infusion (140 μg/kg/min) based on local practice. The hyperemic indices&#xD;
      will be measured: maximal flow speed, CFR, FFR, HSR (hyperemic stenosis resistance.&#xD;
      Cooperating centers will perform pressure measurements (FFR, iFR, Pd/Pa) only and they will&#xD;
      send a raw data for further analysis (off-line calculation of iFR using the new software) in&#xD;
      General Teaching Hospital in Prague.&#xD;
&#xD;
      Morphological examinations of coronary arteries Morphological assessment of the lesions will&#xD;
      be done by OCT (St. Jude Medical, Inc). Catheter will be placed behind stenosis. Pullback&#xD;
      will be done during flushing of contrast dye. OCT measurement will help to choose optimal&#xD;
      treatment strategy by proper measuring of lumen size in a lesion and in the reference&#xD;
      segments. PCI will be done according to local practice. OCT can be use after procedure for&#xD;
      checking results, but this second examination is not part of the study.&#xD;
&#xD;
      More detail analyze will be done from 3D vessel reconstruction in The University of Iowa that&#xD;
      is well know center for 3D coronary reconstruction. Scientific team from this university have&#xD;
      received two US patents for 3D coronary reconstruction.&#xD;
&#xD;
      The methodology of 3 D reconstruction of coronary arteries The two-plane angiograms will be&#xD;
      taken immediately prior to the pullback start and cover at least one heart cycle each. They&#xD;
      will be used to extract the catheter path automatically along the expected pullback&#xD;
      trajectory by a dynamic programming approach. From the known imaging geometry, an accurate&#xD;
      3-D model of the catheter path within the respective vessel segment is generated for&#xD;
      end-diastolic heart phase. For OCT acquisition, motorized pullback ensures a constant&#xD;
      pullback speed, thus allowing to asses each OCT image frame a specific location on the 3-D&#xD;
      catheter trajectory model. The relative and absolute orientations of the OCT frames will be&#xD;
      determined using previously reported system for establishing the absolute orientation in 3-D&#xD;
      on IVUS (intravascular ultrasound) images. Visualization will be based on automated encoding&#xD;
      of the derived contour data in VRML (Virtual Reality Modeling Language). Quantitative data&#xD;
      can be derived from the contour data, such as luminal dimensions and plaque-cap thickness,&#xD;
      actually considering the vessel curvature in contrast to conventional OCT reconstruction&#xD;
      systems. The space between adjacent contours is interpolated to form a volume element. In&#xD;
      locations of the plaque cap, integrating over an entire vessel segment or any part thereof&#xD;
      yields the total plaque cap volume enclosed by the inner and outer cap surfaces. The&#xD;
      quantification values can be included into the VRML model by color per vertex encoding, thus&#xD;
      allowing an easy and fast visual assessment of the lesion or the results of the intervention&#xD;
      by the physician.&#xD;
&#xD;
      Endothelial shear stress analysis. A steady flow computational fluid dynamics (CFD) analysis&#xD;
      will be performed in the reconstructed arterial segments in order to analyze for the local&#xD;
      fluid dynamic characteristics along the vessel segment.&#xD;
&#xD;
      Examination of endothelial dysfunction. Endothelial dysfunction will be measured by a system&#xD;
      named EndoPAT (Itamar Medical, Israel). EndoPAT uses peripheral artery tone signal (PAT) for&#xD;
      non-invasively measuring arterial tone changes in peripheral arterial beds17.&#xD;
&#xD;
      Genetic analysis of polymorphisms in gene for HO-1 and ENOS Patient's DNA will be isolated&#xD;
      from peripheral blood leukocytes using standard techniques.&#xD;
&#xD;
      Statistical analysis Data will be prospectively stored in a database and will be processed&#xD;
      using the software JMP®10.0.0, Copyright © 2012 SAS (Statistical analysis software) Institute&#xD;
      Inc. (http://www.jmp.com) in collaboration with a professional statistician.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">June 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Presence of endothelial dysfunction, plaque superficial irregularities and gene polymorphisms in patients with screpancies between FFR and iFR during functional assessments of coronary stenosis.</measure>
    <time_frame>2017-2019</time_frame>
    <description>Endothelial dysfunction measured by EndoPAT, plaque superficial irregularities measured by OCT and gene polymorphisms in ENOS and HO-1 can be different in patients with discrepancy between FFR and iFR compared to known results from patients with coronary artery disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To use a new software to determine which of two methods for the functional assessment of coronary stenosis (FFR and iFR) perform their measurements during a lower level of microvascular resistance.</measure>
    <time_frame>2017-2019</time_frame>
    <description>This software will measure microvascular resistance. It´s stable and minimal value is an essential condition for precise assessment of lesion severity by pressure measurement. Lower level of microvascular resistence during FFR or iFR measurements can help to distinguish, which of these two measurements is more relyable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To develop a new version of aforementioned software for the detection of microvascular resistance level, based only on intracoronary pressures without flow analysis</measure>
    <time_frame>2017-2019</time_frame>
    <description>For analysis of microvascular resistance is necessary to measure coronary flow. This type of measurement is time consuming and difficult. The investigators will try to find a marker of low microvascular resistance during assessment of intracoronary pressure, which is easy to measure.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Hemodynamics</condition>
  <condition>Coronary Circulation</condition>
  <condition>Tomography, Optical Coherence</condition>
  <condition>Endothelial Cells</condition>
  <condition>Polymorphism, Genetic</condition>
  <arm_group>
    <arm_group_label>Consecutive patients with FFR and iFR</arm_group_label>
    <description>Patients with stable angina pectoris with suitable for coronary angiography will be suitable for the study</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Fractional flow reserve and instantaneous wave-free ratio</intervention_name>
    <description>To explain discrepancies between FFR and iFR using demographic, morphological, genetic and functional indices.&#xD;
The development of software for the automatic detection of the lowest point of microvascular resistance.</description>
    <arm_group_label>Consecutive patients with FFR and iFR</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Genetic analysis of polymorphisms in gene for Hemoxygenase-1 and endothelial nitric oxide&#xD;
      synthase. Patient's DNA will be isolated from peripheral blood leukocytes using standard&#xD;
      techniques.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with stable angina pectoris indicated for lesion hemodynamic assessment for&#xD;
        bordeline stensois found during coronary angiography&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stable angina pectoris&#xD;
&#xD;
          -  Age 18-80 years&#xD;
&#xD;
          -  Signed inform consent&#xD;
&#xD;
          -  Coronary arteries without severe tortuosity and calcifications&#xD;
&#xD;
          -  Normal blood flow in coronary arteries (TIMI flow III)&#xD;
&#xD;
          -  Coronary artery stenosis less than 80% during CAG&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hemodynamic instability, cardio-pulmonary resuscitation in a same day&#xD;
&#xD;
          -  Thrombosis in a target coronary artery visible during angiography&#xD;
&#xD;
          -  Patients after or with planned coronary artery bypass grafting&#xD;
&#xD;
          -  Severe bronchial asthma or atrio-ventricular block higher than first degree&#xD;
             (contraindication for adenosine administration)&#xD;
&#xD;
          -  Renal insufficiency with creatinine level more than 180 umol/l&#xD;
&#xD;
          -  Known allergy to iodine contrast&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Tomas Kovarnik, MD, PhD</last_name>
    <phone>+420732210677</phone>
    <email>tomas.kovarnik@vfn.cz</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>David Zemanek, MD, PhD</last_name>
    <phone>+42022492606</phone>
    <email>david.zemanek@vfn.cz</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>II. interni klinika VFN</name>
      <address>
        <city>Praha</city>
        <zip>12808</zip>
        <country>Czech Republic</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tomas Kovarnik, MD, PhD</last_name>
      <phone>+420732210677</phone>
      <email>tomas.kovarnik@vfn.cz</email>
    </contact>
    <contact_backup>
      <last_name>David Zemanek, MD, PhD</last_name>
      <email>david.zemanek@vfn.cz</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Czech Republic</country>
  </location_countries>
  <reference>
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  <reference>
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  <reference>
    <citation>De Bruyne B, Fearon WF, Pijls NH, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nuesch E, Juni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014 Sep 25;371(13):1208-17. doi: 10.1056/NEJMoa1408758. Epub 2014 Sep 1. Erratum In: N Engl J Med. 2014 Oct 9;371(15):1465.</citation>
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  <reference>
    <citation>Kral A, Kovarnik T, Kralik L, Skalicka H, Horak J, Mintz GS, Uhrova J, Sonka M, Wahle A, Downe R, Aschermann M, Martasek P, Linhart A. Genetic variants in haem oxygenase-1 and endothelial nitric oxide synthase influence the extent and evolution of coronary artery atherosclerosis. Folia Biol (Praha). 2011;57(5):182-90.</citation>
    <PMID>22123460</PMID>
  </reference>
  <reference>
    <citation>Meuwissen M, Chamuleau SA, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, Bax M, de Jong A, Spaan JA, Piek JJ. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation. 2001 Jan 16;103(2):184-7. doi: 10.1161/01.cir.103.2.184.</citation>
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    <citation>Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, Tarkin J, Petraco R, Broyd C, Jabbour R, Sethi A, Baker CS, Bellamy M, Al-Bustami M, Hackett D, Khan M, Lefroy D, Parker KH, Hughes AD, Francis DP, Di Mario C, Mayet J, Davies JE. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol. 2012 Apr 10;59(15):1392-402. doi: 10.1016/j.jacc.2011.11.003. Epub 2011 Dec 7.</citation>
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    <citation>Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve). Circ Cardiovasc Interv. 2014 Aug;7(4):492-502. doi: 10.1161/CIRCINTERVENTIONS.113.000926. Epub 2014 Jul 1.</citation>
    <PMID>24987048</PMID>
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    <citation>van de Hoef TP, Nolte F, EchavarrIa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014 Jun;100(12):951-9. doi: 10.1136/heartjnl-2013-305124. Epub 2014 Apr 11.</citation>
    <PMID>24727867</PMID>
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    <citation>Wahle A, Prause GP, von Birgelen C, Erbel R, Sonka M. Fusion of angiography and intravascular ultrasound in vivo: establishing the absolute 3-D frame orientation. IEEE Trans Biomed Eng. 1999 Oct;46(10):1176-80. doi: 10.1109/10.790492.</citation>
    <PMID>10513120</PMID>
  </reference>
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    <citation>Wahle A, Prause PM, DeJong SC, Sonka M. Geometrically correct 3-D reconstruction of intravascular ultrasound images by fusion with biplane angiography--methods and validation. IEEE Trans Med Imaging. 1999 Aug;18(8):686-99. doi: 10.1109/42.796282.</citation>
    <PMID>10534051</PMID>
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    <citation>Perktold K, Hofer M, Rappitsch G, Loew M, Kuban BD, Friedman MH. Validated computation of physiologic flow in a realistic coronary artery branch. J Biomech. 1998 Mar;31(3):217-28. doi: 10.1016/s0021-9290(97)00118-8.</citation>
    <PMID>9645536</PMID>
  </reference>
  <reference>
    <citation>Ethier CR. Computational modeling of mass transfer and links to atherosclerosis. Ann Biomed Eng. 2002 Apr;30(4):461-71. doi: 10.1114/1.1468890.</citation>
    <PMID>12085998</PMID>
  </reference>
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    <citation>Weydahl ES, Moore JE. Dynamic curvature strongly affects wall shear rates in a coronary artery bifurcation model. J Biomech. 2001 Sep;34(9):1189-96. doi: 10.1016/s0021-9290(01)00051-3.</citation>
    <PMID>11506789</PMID>
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    <citation>Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41. doi: 10.1016/j.jacc.2004.08.062.</citation>
    <PMID>15582310</PMID>
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  <reference>
    <citation>Jeremias A, Maehara A, Genereux P, Asrress KN, Berry C, De Bruyne B, Davies JE, Escaned J, Fearon WF, Gould KL, Johnson NP, Kirtane AJ, Koo BK, Marques KM, Nijjer S, Oldroyd KG, Petraco R, Piek JJ, Pijls NH, Redwood S, Siebes M, Spaan JAE, van 't Veer M, Mintz GS, Stone GW. Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study. J Am Coll Cardiol. 2014 Apr 8;63(13):1253-1261. doi: 10.1016/j.jacc.2013.09.060. Epub 2013 Nov 6.</citation>
    <PMID>24211503</PMID>
  </reference>
  <reference>
    <citation>Eshtehardi P, McDaniel MC, Suo J, Dhawan SS, Timmins LH, Binongo JN, Golub LJ, Corban MT, Finn AV, Oshinski JN, Quyyumi AA, Giddens DP, Samady H. Association of coronary wall shear stress with atherosclerotic plaque burden, composition, and distribution in patients with coronary artery disease. J Am Heart Assoc. 2012 Aug;1(4):e002543. doi: 10.1161/JAHA.112.002543. Epub 2012 Aug 24.</citation>
    <PMID>23130168</PMID>
  </reference>
  <reference>
    <citation>Campbell IC, Timmins LH, Giddens DP, Virmani R, Veneziani A, Rab ST, Samady H, McDaniel MC, Finn AV, Taylor WR, Oshinski JN. Computational Fluid Dynamics Simulations of Hemodynamics in Plaque Erosion. Cardiovasc Eng Technol. 2013 Dec;4(4):10.1007/s13239-013-0165-3. doi: 10.1007/s13239-013-0165-3.</citation>
    <PMID>24223678</PMID>
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  <reference>
    <citation>Finet G, Huo Y, Rioufol G, Ohayon J, Guerin P, Kassab GS. Structure-function relation in the coronary artery tree: from fluid dynamics to arterial bifurcations. EuroIntervention. 2010 Dec;6 Suppl J:J10-5. doi: 10.4244/EIJV6SUPJA3. No abstract available.</citation>
    <PMID>21930472</PMID>
  </reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 8, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <last_update_submitted>January 24, 2017</last_update_submitted>
  <last_update_submitted_qc>January 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>General University Hospital, Prague</investigator_affiliation>
    <investigator_full_name>Tomas Kovarnik</investigator_full_name>
    <investigator_title>The Head of Invasive Cardiology Dpt.</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03033810
org study id: VFN_21_2016
nct id: NCT03033810
lead sponsor: 
collaborator: 
has dmc: No
The study will compare two invasive methods (FFR -fractional flow reserve and
      iFR-instantaneous wave free ratio) for assessment of hemodynamic impact of coronary stenosis
      on myocardial perfusion. There is a very good correlation between these methods for the
      assessment of hemodynamic significance in a broad spectrum of lesions. However, this
      correlation decreases significantly near the cut off points for each method. The
      investigators will try to find possible explanations for these differences by detailed
      morphology assessment of coronary stenosis using optical coherence tomography (OCT), analysis
      of gene polymorphisms that play a role in vasodilatation, and by shear stress analysis. The
      head-to-head comparison between FFR and iFR is not simple, because there is no "gold
      standard" for assessment of hemodynamic significance. Studies comparing these methods have
      used hyperemic stenosis resistance (HSR). For this kind of measurement it is necessary to
      measure the speed of blood flow. This is usually done by a Doppler analysis of flow.
      Unfortunately, the Doppler signal can yield many artificial or erroneous indicators, and
      obtaining a good quality signal is frequently time-consuming. These are the reasons that HSR
      has not been used in routine practice. The investigators have developed a new console and
      software that can provide real time analysis of the Doppler signal. It allows us to easily
      measure HSR, and to differentiate between the FFR and iFR measures through intrabeat analysis
      of microvascular resistance (lowest microvascular resistance is an essential condition for
      proper pressure measurement). Using this tool, it is possible to automatically identify the
      point of lowest microvascular resistance during each cardiac beat. The pressure gradient can
      then be measured at that point. This approach can eliminate almost all uncertainties in
      assessment of the pressure gradient produced by coronary stenosis. This tool can potentially
      improve the existing methods used to precisely reveal a significant stenosis. This should
      increase the number of hemodynamic guided procedures.
BACKGROUND AND RATIONALE FOR THE STUDY Coronary artery disease (CAD) is the most frequent
      causes of death and disability in developed countries. The main diagnostic method for
      detection of CAD is a coronary angiography (CAG. However, the correlation between CAG and
      proven hemodynamic significance in borderline stenosis (40-70% of lumen narrowing) is only
      about 50%. The main method for detection of flow-limiting lesions is fractional flow reserve
      (FFR). FFR is calculated as distal pressure (Pd) divided by proximal pressure (Pa). The
      cut-off for hemodynamic significance is 0.8 and less. The use of FFR for lesion assessment
      has a level of recommendation of I A in European guidelines for coronary interventions from
      2014. The FAME trail revealed that routine usage of FFR measurement decreased the costs of
      coronary interventions over two years. The reasons are smaller quantity of implanted stents
      and decreased number of procedures for in stent restenosis as a direct result of the lower
      incidence of initial stent implantation. FAME-2 trial has shown lower incidence of urgent
      revascularization in patients with FFR less than 0,8 treated by coronary intervention
      compared to those treated conservatively. This study was preliminary halted before reaching
      mortality endpoint for safety reasons.

      Critical condition for proper FFR measurement is maximal vasodilatation. Since we do not have
      marker for this condition based on pressure measurement only we can only presume that it was
      reached by adenosine administration. There are a lot of limitations for this assumption.
      Foremost, technique for proper intravenous and intracoronary adenosine administration must
      follow strict rules and therefore can be done incorrectly and leads to wrong result in same
      cases. Furthermore, impaired endothelial function leads to lower response to adenosine
      administration. This situation can leads to false negative FFR result. The patients with CAD
      have frequently significant endothelial dysfunction causing lower response to vasodilatation
      stimuli. Endothelial dysfunction will be analyzed by a system named EndoPAT (Itamar Medical,
      Israel) that measures ischemia induced vasodilatation on fingers. The hypothesis that has
      never been tested is how polymorphism in genes for enzymes playing an important role in
      proper endothelial function (HO-1, hemoxygenase-1 and ENOS, endothelial NO synthase) can
      influences adenosine-induced vasodilatation and subsequently FFR measurement. These
      polymorphisms are not infrequent in population with CAD (they can be found in 40-50% in such
      patients).

      Another possible limitation for FFR measurement is type of blood flow in coronary arteries.
      In presence of coronary stenosis, plaque roughness or sharp angle of a lumen the type of flow
      can be changed from laminar to turbulent. This type of flow is even accelerated during
      hyperemia induced by adenosine administration. It leads to lose of energy and exaggerates
      pressure drop behind stenosis that - for this reason- may not be proportional to stenosis
      severity. This situation can theoretically causes false positive FFR measurement. To answer
      this question the investigators will analyze the endothelial shear stress (ESS) that can
      distinguish laminar and turbulent flow and morphological indices (plaque surface, plaque
      eccentricity, lumen volume and lumen shape) by optical coherence tomography (OCT).

      The new index able to identify physiologically significant stenosis has been recently
      described. It is instantaneous wave-free ratio (iFR). This technique uses a pressure gradient
      as well, but -unlike to FFR- iFR compares pressures (proximal and distal to stenosis) only in
      a specific phase of diastole (so called "wave free period"), where microvascular resistance
      is naturally low and stable .

      The cut off point for iFR is 0.9. The correlation between FFR and iFR is between 80% and 90%
      in all lesions. However, the correlation between FFR and iFR close to their cut-off point is
      only 50%-60%. It is substantial caveat, because to estimate hemodynamic significance of
      borderline lesions is the main indication for these techniques. Discrepancies between FFR and
      iFR can be very confusing a discouraging for lesion hemodynamic assessment.

      Nowadays, FFR is the only invasive method for stenosis hemodynamic assessment supported in
      the guidelines. However, the iFR is faster, easier and cheaper, and for these reasons it can
      be used for more lesions in more patients, which can improve the situation of poor
      penetration of hemodynamic guidance for coronary intervention in daily practice. Moreover, an
      increasing number of evidences implies that iFR concept can be closer to real situation in
      coronary arteries (avoiding non-physiologic vasodilatation). It has been shown that FFR
      itself has a factor of variability of 10%. This means that around the cut-off points the FFR
      can be just as wrong as the iFR, perhaps even more so. Moreover, the latest study has shown
      that iFR provides better pressure-derived diagnostic agreement with CFR (coronary flow
      reserve) than FFR. The investigators have been developing, in close cooperation with The
      University of Iowa, new technique that improves the quality of flow measurement. It was
      successfully tested it in a animal trial. It is a novel way of intravascular Doppler signal
      processing resulting in more reliable velocity curve envelope acquisition. This software
      improvement allows instantaneous monitoring of real time microvascular resistance during any
      phase of cardiac cycle. Detection of during instantaneous wave free period can serve as
      verification of the proprietary iFR calculation. The system may also improve iFR measurement
      itself, because it can measure precisely in-phase with the lowest microvascular resistance.
      The measurement of resistance during wave free period is named iMR (instantaneous
      microvascular resistance) and it has never been measured during previous trials. This index
      can greatly help to distinguish which method (FFR or iFR) measures the pressure gradient
      during lower resistance.

      Further target is to develop next generation of the software that can detect lowest
      microvascular resistance based on pressure measurement only, without necessity of using
      Doppler. It could offer very precise and simple methods for hemodynamic assessment of
      coronary lesions. This software must be tested and verified in a human study, which will be
      done in the General Teaching Hospital (where both intracoronary pressure and flow will be
      measured). Its clinical availability will be tested and verified by the international
      cooperating centers (where only pressure indices, FFR and iFR will be measured). The foreign
      centers will also examine coronary OCT that will be sent to corelab in The University of
      Iowa, collect blood samples for genetic analysis that will be done in Prague and, depend on
      their possibilities, also endothelial dysfunction by EndoPAT.

      The University of Iowa, Iowa, USA will analyze OCT measurement and perform 3D vessel
      reconstruction. This university has a world known team for the unique 3D reconstruction of
      coronary arteries based on angiography and optical coherence tomography. This institution
      will do an automated analysis of plaque surfaces as well.

      HYPOTHESES:

        1. The level of microvascular resistance can be used to distinguish which type of
           measurement (FFR or iFR) was done during the lower and more stable stage of
           microvascular resistance. This comparison can possibly explain discrepancies between FFR
           and iFR measurements.

        2. Based on new software, using pressure measurements only, it will be possible to
           automatically detect the time period with the lowest microvascular resistance. This
           could improve accuracy of both FFR and iFR measurements.

        3. Plaque ruptures, erosions, irregularities of plaque geometry and plaque located near to
           bifurcations cause turbulence in blood flow. This accelerated pressure drop can lead to
           a false positive FFR.

        4. Inadequate vasodilation caused by endothelial dysfunction can lead to false negative
           FFR.

        5. Endothelial dysfunction can be more frequently found in patients with the risk type of
           polymorphism in genes playing an important role in vessel vasodilatation (ENOS, HO-1)

      AIMS AND EXPECTED IMPACT ON CLINICAL PRACTICE

        1. To use new software (developed at the author's workplace in cooperation with The
           University of Iowa) to determine which of two methods for the functional assessment of
           coronary stenosis (FFR and iFR) perform their measurements during a lower level of
           microvascular resistance. This software can measure microvascular resistance in real
           time.

        2. To develop a new version of software for the detection of microvascular resistance
           level, based only on intracoronary pressures without flow analysis. This could
           substantially improve the accuracy of both pressure-based measurements, and potentially
           increase the correlation between pressure based measurements and flow-based CFR.

        3. To study the potential influence of endothelial dysfunction and plaque morphology on
           discrepancies between FFR and iFR during functional assessments of coronary stenosis.

        4. To study the influence of gene polymorphisms on endothelial dysfunction

      METHODS Study design Patients with stable angina pectoris with suitable for coronary
      angiography will be suitable for the study. We plan to include 250 patients to the study (50
      from General University Hospital in Prague and 200 from cooperating centers).

      Functional examinations of coronary arteries. Coronary angiography will be performed as a
      first procedure for detection of severity and extent of coronary atherosclerosis. Stenosis
      between 40-80% (based on CAG) will be suitable for morphological and functional examinations.
      Combo wire (Volcano Corp., USA) for pressure and flow measurement will be introduced behind
      the lesion and basal indices will be measured during basal flow condition: basal flow speed,
      pressure gradient (Pd/Pa), iFR, Pd/Pa during lowest microvascular resistance proven by
      Doppler analysis, iMR. Adenosine will be administered either intracoronary as a bolus (240
      ug) or in continual infusion (140 μg/kg/min) based on local practice. The hyperemic indices
      will be measured: maximal flow speed, CFR, FFR, HSR (hyperemic stenosis resistance.
      Cooperating centers will perform pressure measurements (FFR, iFR, Pd/Pa) only and they will
      send a raw data for further analysis (off-line calculation of iFR using the new software) in
      General Teaching Hospital in Prague.

      Morphological examinations of coronary arteries Morphological assessment of the lesions will
      be done by OCT (St. Jude Medical, Inc). Catheter will be placed behind stenosis. Pullback
      will be done during flushing of contrast dye. OCT measurement will help to choose optimal
      treatment strategy by proper measuring of lumen size in a lesion and in the reference
      segments. PCI will be done according to local practice. OCT can be use after procedure for
      checking results, but this second examination is not part of the study.

      More detail analyze will be done from 3D vessel reconstruction in The University of Iowa that
      is well know center for 3D coronary reconstruction. Scientific team from this university have
      received two US patents for 3D coronary reconstruction.

      The methodology of 3 D reconstruction of coronary arteries The two-plane angiograms will be
      taken immediately prior to the pullback start and cover at least one heart cycle each. They
      will be used to extract the catheter path automatically along the expected pullback
      trajectory by a dynamic programming approach. From the known imaging geometry, an accurate
      3-D model of the catheter path within the respective vessel segment is generated for
      end-diastolic heart phase. For OCT acquisition, motorized pullback ensures a constant
      pullback speed, thus allowing to asses each OCT image frame a specific location on the 3-D
      catheter trajectory model. The relative and absolute orientations of the OCT frames will be
      determined using previously reported system for establishing the absolute orientation in 3-D
      on IVUS (intravascular ultrasound) images. Visualization will be based on automated encoding
      of the derived contour data in VRML (Virtual Reality Modeling Language). Quantitative data
      can be derived from the contour data, such as luminal dimensions and plaque-cap thickness,
      actually considering the vessel curvature in contrast to conventional OCT reconstruction
      systems. The space between adjacent contours is interpolated to form a volume element. In
      locations of the plaque cap, integrating over an entire vessel segment or any part thereof
      yields the total plaque cap volume enclosed by the inner and outer cap surfaces. The
      quantification values can be included into the VRML model by color per vertex encoding, thus
      allowing an easy and fast visual assessment of the lesion or the results of the intervention
      by the physician.

      Endothelial shear stress analysis. A steady flow computational fluid dynamics (CFD) analysis
      will be performed in the reconstructed arterial segments in order to analyze for the local
      fluid dynamic characteristics along the vessel segment.

      Examination of endothelial dysfunction. Endothelial dysfunction will be measured by a system
      named EndoPAT (Itamar Medical, Israel). EndoPAT uses peripheral artery tone signal (PAT) for
      non-invasively measuring arterial tone changes in peripheral arterial beds17.

      Genetic analysis of polymorphisms in gene for HO-1 and ENOS Patient's DNA will be isolated
      from peripheral blood leukocytes using standard techniques.

      Statistical analysis Data will be prospectively stored in a database and will be processed
      using the software JMP®10.0.0, Copyright © 2012 SAS (Statistical analysis software) Institute
      Inc. (http://www.jmp.com) in collaboration with a professional statistician.
observational model: Cohort
time perspective: Prospective
measure: Presence of endothelial dysfunction, plaque superficial irregularities and gene polymorphisms in patients with screpancies between FFR and iFR during functional assessments of coronary stenosis.
time frame: 2017-2019
description: Endothelial dysfunction measured by EndoPAT, plaque superficial irregularities measured by OCT and gene polymorphisms in ENOS and HO-1 can be different in patients with discrepancy between FFR and iFR compared to known results from patients with coronary artery disease.
measure: To use a new software to determine which of two methods for the functional assessment of coronary stenosis (FFR and iFR) perform their measurements during a lower level of microvascular resistance.
time frame: 2017-2019
description: This software will measure microvascular resistance. It´s stable and minimal value is an essential condition for precise assessment of lesion severity by pressure measurement. Lower level of microvascular resistence during FFR or iFR measurements can help to distinguish, which of these two measurements is more relyable.
measure: To develop a new version of aforementioned software for the detection of microvascular resistance level, based only on intracoronary pressures without flow analysis
time frame: 2017-2019
description: For analysis of microvascular resistance is necessary to measure coronary flow. This type of measurement is time consuming and difficult. The investigators will try to find a marker of low microvascular resistance during assessment of intracoronary pressure, which is easy to measure.
arm group label: Consecutive patients with FFR and iFR
description: Patients with stable angina pectoris with suitable for coronary angiography will be suitable for the study
intervention type: Device
intervention name: Fractional flow reserve and instantaneous wave-free ratio
description: To explain discrepancies between FFR and iFR using demographic, morphological, genetic and functional indices.
The development of software for the automatic detection of the lowest point of microvascular resistance.
arm group label: Consecutive patients with FFR and iFR
Genetic analysis of polymorphisms in gene for Hemoxygenase-1 and endothelial nitric oxide
      synthase. Patient's DNA will be isolated from peripheral blood leukocytes using standard
      techniques.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Tomas Kovarnik, MD, PhD
phone: +420732210677
email: tomas.kovarnik@vfn.cz
last name: David Zemanek, MD, PhD
phone: +42022492606
email: david.zemanek@vfn.cz
facility: 
status: Recruiting
contact: 
contact backup: 
country: Czech Republic
citation: Park SJ, Kang SJ, Ahn JM, Shim EB, Kim YT, Yun SC, Song H, Lee JY, Kim WJ, Park DW, Lee SW, Kim YH, Lee CW, Mintz GS, Park SW. Visual-functional mismatch between coronary angiography and fractional flow reserve. JACC Cardiovasc Interv. 2012 Oct;5(10):1029-36. doi: 10.1016/j.jcin.2012.07.007.
PMID: 23078732
citation: Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, Higano ST, Lim MJ, Meuwissen M, Piek JJ, Pijls NH, Siebes M, Spaan JA; American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation. 2006 Sep 19;114(12):1321-41. doi: 10.1161/CIRCULATIONAHA.106.177276. Epub 2006 Aug 28.
PMID: 16940193
citation: Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009 Jan 15;360(3):213-24. doi: 10.1056/NEJMoa0807611.
PMID: 19144937
citation: De Bruyne B, Fearon WF, Pijls NH, Barbato E, Tonino P, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd K, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Limacher A, Nuesch E, Juni P; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014 Sep 25;371(13):1208-17. doi: 10.1056/NEJMoa1408758. Epub 2014 Sep 1. Erratum In: N Engl J Med. 2014 Oct 9;371(15):1465.
PMID: 25176289
citation: Kral A, Kovarnik T, Kralik L, Skalicka H, Horak J, Mintz GS, Uhrova J, Sonka M, Wahle A, Downe R, Aschermann M, Martasek P, Linhart A. Genetic variants in haem oxygenase-1 and endothelial nitric oxide synthase influence the extent and evolution of coronary artery atherosclerosis. Folia Biol (Praha). 2011;57(5):182-90.
PMID: 22123460
citation: Meuwissen M, Chamuleau SA, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, Bax M, de Jong A, Spaan JA, Piek JJ. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation. 2001 Jan 16;103(2):184-7. doi: 10.1161/01.cir.103.2.184.
PMID: 11208673
citation: Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007 Jun 26;49(25):2379-93. doi: 10.1016/j.jacc.2007.02.059. Epub 2007 Jun 8.
PMID: 17599600
citation: Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, Tarkin J, Petraco R, Broyd C, Jabbour R, Sethi A, Baker CS, Bellamy M, Al-Bustami M, Hackett D, Khan M, Lefroy D, Parker KH, Hughes AD, Francis DP, Di Mario C, Mayet J, Davies JE. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol. 2012 Apr 10;59(15):1392-402. doi: 10.1016/j.jacc.2011.11.003. Epub 2011 Dec 7.
PMID: 22154731
citation: Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve). Circ Cardiovasc Interv. 2014 Aug;7(4):492-502. doi: 10.1161/CIRCINTERVENTIONS.113.000926. Epub 2014 Jul 1.
PMID: 24987048
citation: van de Hoef TP, Nolte F, EchavarrIa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014 Jun;100(12):951-9. doi: 10.1136/heartjnl-2013-305124. Epub 2014 Apr 11.
PMID: 24727867
citation: Wahle A, Prause GP, von Birgelen C, Erbel R, Sonka M. Fusion of angiography and intravascular ultrasound in vivo: establishing the absolute 3-D frame orientation. IEEE Trans Biomed Eng. 1999 Oct;46(10):1176-80. doi: 10.1109/10.790492.
PMID: 10513120
citation: Wahle A, Prause PM, DeJong SC, Sonka M. Geometrically correct 3-D reconstruction of intravascular ultrasound images by fusion with biplane angiography--methods and validation. IEEE Trans Med Imaging. 1999 Aug;18(8):686-99. doi: 10.1109/42.796282.
PMID: 10534051
citation: Perktold K, Hofer M, Rappitsch G, Loew M, Kuban BD, Friedman MH. Validated computation of physiologic flow in a realistic coronary artery branch. J Biomech. 1998 Mar;31(3):217-28. doi: 10.1016/s0021-9290(97)00118-8.
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responsible party type: Principal Investigator
investigator affiliation: General University Hospital, Prague
investigator full name: Tomas Kovarnik
investigator title: The Head of Invasive Cardiology Dpt.
sharing ipd: No