Posts Tagged ‘Fractional Flow Reserve’

Emerging Clinical Applications for Cardiac CT: Plaque Characterization, SPECT Functionality, Angiogram’s and Non-Invasive FFR

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC


Article Curator: Aviva Lev-Ari, PhD, RN


UPDATED on 7/25, 2018


VIDEO: Using FFR-CT in Everyday Practice

Kavitha Chinnaiyan, M.D., FACC, FSCCT, associate professor, Oakland University, William Beaumont School of Medicine, Royal Oak, Mich. She presented at the Society of Cardiovascular Computed Tomography (SCCT) 2018 meeting.


Related FFR-CT Content:

Clinical Applications of FFR-CT

VIDEO: Implementation and the Science Behind FFR-CT — interview with James Min, M.D.

VIDEO: Early U.S. Experience With FFR-CT in Evaluating ED Chest Pain Presentation — interview with Simon Dixon, M.D.

VIDEO: Status of FFR-CT Adoption in the United States — interview with Campbell Rogers, M.D.

Clinical studies of coronary anatomy by computed tomography use equipment with various numbers of concurrent slices through the heart: 1, 4, 16, 32, 64, 128, and recently 256 or more. Like interventional catheterization, iodine is injected to make the inside of the coronary arteries opaque to xray transmission, to create contrast (otherwise the xray of the coronary tree would be like a photograph of a white polar bear in a snow storm; the contrast acts like spray paint). Computed tomographic angiography (CTA) uses a similar or higher dye load than catheterization, and provides generally lower imaging quality than catheterization but with 3-dimensional reconstruction instead of flat projection (hundreds of linear views at different angles versus one or two image planes at a time). The results from CTA are generally deemed qualitative: whther or not there are potentially flow-limiting lesions in the major branch arteries that supply the heart (with exception: the posterior descending artery to the inferior wall of the heart is not reliably seen). Catheter-based projection coronary angiography sees smaller branches with finer ability to measure the degree of lumen narrowing. However, other imaging methods show greater promise in identifying plaque character. The following examines initial enthusiasm for improvements in CTA which offer better results compared to current clinical CTA and hope to offer advantages over catheter-based methods beyond the avoidance of catheters.

I. Cardiac CT Challenging Functionality of SPECT and Angiogram

Noninvasive computed tomography (CT) perfusion imaging added to CT angiography accurately identifies flow-limiting coronary lesions that need to be treated, results of the CORE320 trial show.

Dr João AC Lima (Johns Hopkins University, Baltimore, MD) presented results of the 381-patient, 16-center trial, which showed that stress CT myocardial perfusion analysis (CTP) significantly improves the diagnostic power of rest CT angiography (CTA) alone. The study also showed that the CTA+CTP strategy has about the same power to identify patients who need revascularization within 30 days as the current standard strategy of invasive angiography plus a single photon-emission computed tomography (SPECT) myocardial perfusion imaging (MPI) test.

Lima explained that the potential advantage of the CT-based approach is that it can obtain information on myocardial perfusion and coronary flow in two scans about 10 minutes apart and is noninvasive.

All patients in the study had been referred for an invasive angiogram to investigate suspected or known coronary artery disease (CAD), but all patients underwent a rest CTA, stress CTP, and SPECT-MPI test in addition to the invasive angiogram. Invasive angiography alone identified apparently obstructive coronary disease in 59% of patients, but adding the SPECT-MPI information reduced that number to 38%.

The accuracy of the CTA+CTP approach was measured as the area under the receiver-operating-characteristic curve. When 50% greater stenosis on invasive angiography was set as the reference standard for a flow-limiting stenosis, the accuracy of the CTA+CTP approach for detecting flow-limiting CAD was 0.87 on a per-patient basis. When the standard was >70% stenosis, the accuracy of the CTA+CTP approach was 0.89.


 VIEW VIDEO on CORE320 with Dr João Lima
Flow Limiting Lesion (low perfusion) vs. Anatomic Stenosis Severity


Results of the Diagnosis of Ischemia-Causing Stenoses Obtained via Noninvasive Fractional Flow Reserve (DISCOVER FLOW) study show that the coronary stenoses that cause ischemia can be identified noninvasively with computer analysis of coronary computed tomography angiograms (CCTAs) [1].

“I think it’s a potential game-changer, because for the first time you have the ability to look at coronary stenosis and ischemia simultaneously, [and] you have the ability to pinpoint the lesion that is causing the ischemia,” DISCOVER FLOW senior investigator Dr James Min (Cedars-Sinai Medical Center, Los Angeles, CA) told heartwire. “You can imagine a scenario where somebody has an abnormal stress test and then you go in and you do an angiogram and see four or five stenoses, but you don’t really know which one caused the ischemia.” But this new “virtual fractional flow reserve” process—or FFRCT—can quantify the fractional flow reserve for each lesion with the data taken from a CCTA, thereby revealing which stenoses are causing ischemia and ought to be treated, as well as which stenoses do not need to be treated. “We’ve never before had this one-stop shop to . . . pinpoint the lesions that cause the ischemia noninvasively.”

As reported by heartwire at EuroPCR 2011, in DISCOVER FLOW, Dr Bon-Kwon Koo (Seoul National University Hospital, Korea) and colleagues used computation of FFRCT to assess 159 vessels in 103 patients undergoing CCTA. Results of the study are published in the November 1, 2011 issue of the Journal of the American College of Cardiology.

All of the patients also underwent invasive CCTA and invasive catheter FFR imaging. Ischemia was defined as an FFR of <0.80 and anatomically obstructive coronary disease was defined as stenosis >50% as measured on the CCTA scan. The diagnostic performance of FFRCT and CCTA were assessed against invasive FFR as the reference standard. Of the patients in the study, 56% had at least one vessel with an FFR of <0.80.

Because only about half of stenoses over 50% actually cause ischemia, the specificity of traditional assessment of a stenosis by CCTA is below 50%. “The concern there is that you identify some high-grade stenoses that are angiographically confirmed, but the lesions don’t actually cause ischemia.” Fractional flow reserve measures how much of the blood flow is being blocked by a lesion, so it is about 25% more accurate than traditional CCTA at picking out lesions that cause ischemia, Min explained.

Per vessel diagnostic accuracy FFRCT and CCTA (reference for both was invasive FFR) 

Imaging technology Accuracy(%) Sensitivity(%) Specificity(%) Positive predictive value (%) Negative predictive value (%)
FFRCTa  84.3 87.9 82.2 73.9 92.2
CCTAb 58.5 91.4 39.6 46.5 88.9

a. Ischemic defined as <0.80

b. Ischemia defined as stenosis >50%

FFRCT can assess stenoses from any CCTA scan—prospectively gated or retrospectively gated—without any additional imaging techniques or changes to the acquisition parameters. Just as computational fluid dynamics can predict the behavior of an airplane wing under different environmental parameters, FFRCT can measure the flow of blood through a stenotic coronary based on the specific geometry of the patient’s coronaries and myocardium.

At the American Heart Association meeting in Orlando next month, Min will present results of a substudy from DISCOVER FLOW looking specifically at intermediate-grade stenoses (40%-69%), which present the most difficult treatment decisions. “If somebody sees a 90% stenosis or 10% stenosis, they are comfortable with what to do with that. But when you hit that 40% to 70% range—it’s possible that those lesions are ischemic, but you don’t know until you actually assess them,” Min said.

DISCOVER FLOW was designed to evaluate the accuracy of FFRCT on a per-vessel basis, but the more important demonstration of its value will be its ability to guide treatment decisions for each patient. TheDEFACTO trial, which finished enrollment at 17 centers about three weeks ago, is evaluating FFRCT per patient. “That’s the big one,” Min said. “DEFACTO will be the pivotal trial.” Specifically, the 285-patient DEFACTO trial is assessing the ability of CCTA plus FFRCT to determine the presence or absence of at least one hemodynamically significant coronary stenosis in each trial subject. Invasive catheter FFR is the reference standard. Min expects that study to be completed in the first quarter of 2012.


III. Ten Emerging Uses for Cardiac CT from SCCT 2013

July 11-14, 2013
Palais des congrès
Montréal, Québec, Canada

JULY 16, 2013  – heartwire

Dr Matthew Budoff (Los Angeles Biomedical Research Institute, CA), a longtime researcher in the use of cardiac CT, described what he believes to be the most important uses for CT today [1].

First, CT angiography is emerging as “a single tool that gives us [information about] function and anatomy,” he told the audience.

Second, it is now known that patients are more likely to have a cardiovascular event if they have low-attenuation plaque (soft plaque), positive remodeling, and spotty calcification, he explained. If a clinician were limited to looking only at plaque or stenosis, he would advise him or her to “just read the CTA for plaque and plaque characteristics and [don’t] read it for stenosis severity, and you’ll probably serve your patients better in predicting risk” of a cardiovascular event. “I think in future we’re going to be using plaque characterization in every case,” he added. “I certainly don’t advocate stenting these patients [who have vulnerable plaque] yet, but . . . I do treat these patients more aggressively.”

Third, coronary CT angiography is a noninvasive way to identify complex aortic-valve geometry and guide TAVR.

“With perfusion imaging, TAVR, and plaque assessment leading the way, the increased utilization of CTA is certain,” Budoff concluded. “However, more validation work is needed to ensure that industry and payers accept these applications.”

Speaking to heartwire, Budoff singled out TAVR as “an easy launching point for doctors to get familiar with” CT angiography. He also believes that using CT for “heart-failure assessment or even plaque assessment . . . will really add value to their practice.” CT also allows clinicians to “start getting a handle on what’s causing stenosis [in a patient], what it looks like, and . . . how severe the stenosis is.”

In a separate presentation [2], Dr James K Min (Cedars-Sinai, Los Angeles, CA) identified the same three clinical applications as Budoff in his “top 10 things to watch” in coronary CT in the coming year. He identified his “up-and-coming areas to watch” in the following order:

  • Dual-energy CT scanners. This hardware, when combined with new software, is producing enhanced image quality that allows, for example, a “plaque biopsy,” which provides detailed information about plaque characteristics.
  • Myocardial CT perfusion. “We’ve looked at this for seven years, and I think it’s starting to become ready for prime time,” said Min. In the next year, he expects investigators to figure out exactly how to use CT to look at coronary flow reserve.
  • Computational fluid dynamics. Exciting work is being done, for example, using a virtual stent to see how a real stent would potentially resolve a patient’s ischemia.
  • PlaqueCoronary CT can do more than identify how many vessels are blocked, he said, echoing Budoff’s words. It is enabling investigators to study the pathogenesis of atherosclerosis. “We’re going to be able to identify plaque characteristics beyond stenosis for the prediction of acute MI,” Min said.
  • Structural heart disease. CT is already being used to help guide TAVR to reduce postsurgery complications.
  • Radiation-dose reduction. Min weighed in and said, “I think it’s becoming a nonissue.” He noted that during the past year, investigators reported how coronary CT angiography can be used with radiation doses as low as 0.01 mSv, (should be 1mSv) whereas a screening mammogram exposes a woman to 0.05 mSv of radiation. (1/5 of mammography)
  • Contrast-agent reduction.”I think we will see improvements—we will get to the 10-cc scan,” Min predicted.
  • Appropriate-use criteria. Physicians are continuing to identify which patients benefit from cardiac CT, as the technology is advancing.
  • Two trialsAmong the many ongoing trials in the field, Min identified two to watch. The PROMISEstudy is comparing functional vs anatomic testing to identify heart disease. The Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization (CONSERVE) trial is looking at using CT as a “gatekeeper” to the cath lab, to identify which patients should be sent for invasive coronary angiography and which ones have only have mild stenosis and could be sent home and treated with medical therapy .
  • Worldwide growth in CT. Collaboration with investigators around the world is growing, and the SCCT meetings next year in Hawaii and China will offer more opportunities for this.
Budoff has received research/grant support from HeartFlow, study funding from Wakunaga of America and GE Healthcare and has been a consultant and speaker for GE Healthcare. Min has received research/grant support fromGE Healthcare, Phillips Healthcare, and Vital Images and study funding from Astellas. He has been a consultant for GE Healthcare and Arineta and on the speaker’s bureau for GE Healthcare. He holds equity interest in TC3 and MDXX.


  1. Budoff MJ. Emerging Clinical applications for cardiac CT. Society of Cardiovascular Computed Tomography 2013 Annual Scientific Meeting; July 12, 2013; Montreal, QC.
  2. Min JK. The future of cardiac CT. What will the next 12 months bring? Society of Cardiovascular Computed Tomography 2013 Annual Scientific Meeting; July 12, 2013; Montreal, QC.

Related links


IV. Stress CT Perfusion matches SPECT for detecting Myocardial Ischemia

Montreal, QC – In stress testing using regadenoson (Lexiscan, Astellas), detection rates of myocardial ischemia were similar with less invasive computed-tomography (CT) perfusion imaging compared with the reference method, single-photon-emission CT (SPECT) imaging, in a phase 2 trial [1].

JULY 18, 2013 

Regadenoson, a selective adenosine-receptor agonist that produces coronary vasodilation in patients unable to undergo exercise stress testing, is the most common agent used to induce pharmaceutical stress in SPECT tests in the US; it was used off-label for the CT imaging.

Dr Ricardo C Cury (Baptist Hospital of Miami, FL) presented the trial results here at a late-breaking clinical-trials session at the Society of Cardiovascular Computed Tomography (SCCT) 2013 Scientific Meeting.

To heartwire, Cury noted that this trial established noninferiority of regadenoson stress CT perfusion to the reference method, regadenoson SPECT, to detect or exclude myocardial ischemia, which was the primary study outcome.

“This is the second multicenter trial validating [regadenoson] stress CT perfusion, which [builds on the accumulating supporting data from] many single-center studies,” he said, adding that it is still too early, however, to implement these findings into clinical practice.

To heartwire, session moderator Dr John Hoe (Parkway Health Radiology, Singapore) commented that “this is quite an important multicenter trial . . . and the results look very good.” Echoing Cury, he added that “this [research] is slowly [progressing] along the path to validate [regadenoson] CT perfusion as a technique to assess myocardial ischemia.”

In study, 39% of patients had suspected CAD

This was a crossover study conducted at 11 sites in the US, using six types of CT scanners, including 64-, 128-, 256-, and 320-slice machines.

A total of 124 individuals with known (39%) or suspected CAD were randomized to either rest and stress SPECT using regadenoson on day 1, followed by rest and combined stress CT perfusion using regadenoson and coronary CT angiography on day 2; or the same tests in the reverse order.

At baseline, the subjects had a mean age of about 62 and an average body-mass index (BMI) of close to 30. Their average heart rate increased from 64 to 84 beats per minute with the stress-CT perfusion test.

Myocardial ischemia was defined as having two or more reversible defects.

High agreement, specificity, and sensitivity

When it came to detecting myocardial ischemia, CT perfusion imaging agreed with the findings of the reference method, SPECT, 87% of the time (95% CI 0.77-0.97).

“This was well above the specified primary end point for the agreement rate between SPECT and CT perfusion for the detection of ischemia,” Cury said.

Stress CT perfusion imaging also had a high specificity (84%) and sensitivity (90%) for detecting or excluding myocardial ischemia.

Similarly, when it came to detecting the presence or absence of one or more fixed myocardial defects, CT perfusion imaging agreed with the results of the reference method, SPECT, 86% of the time (95% CI 0.74-0.98).

Again, stress CT perfusion imaging had a high specificity (95%) and sensitivity (77%) for detecting or excluding fixed defects.

Used alone, compared with the reference standard of SPECT, stress CT perfusion diagnosed or excluded ischemia accurately in 85% of cases, whereas CT angiography alone made the correct diagnosis in 69% of cases. Thus, “stress CT perfusion may add significant [diagnostic] value to CT angiography alone,” Cury noted.

Regadenoson was well tolerated, and the most common adverse events were flushing or headache.

The study was funded by Astellas. Cury is a consultant for Astellas and has received research grants from Astellas and GE Healthcare. Hoe has received grant and research support and travel funding from Toshiba Medical Systems and is on its speaker’s bureau. 


V. New Protocol Limits Use Of SPECT MPI For Angina

Article Date: 07 May 2013 – 1:00 PDT

A new stress test protocol that investigates reducing the use of perfusion imaging in low risk patients undergoing SPECT myocardial perfusion imaging for possible anginasymptoms was found to be diagnostically safe, revealed a US retrospective analysis. The study, reported as an abstract¹ at the International Conference on Nuclear Cardiology and Cardiac CT (ICNC11) May 5 to May 8 in Berlin, Germany, predicted that using exercise ECG stress testing alone in patients with high exercise capacity would have had no adverse effects on their prognosis at five years.

“Our results are reassuring in that there are few patients whose diagnosis of coronary artery disease (CAD) would be missed,” said Milena Henzlova, the first author of the study. “Not only would widespread adoption of this approach reduce radiation exposure, it would also save considerable amounts of time and money.”

Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) has been used for over 30 years to detect ischemia in patients with suspected CAD. In SPECT MPI patients are injected with radioactive agents (such as Tc-99m or Thallium 201) whose passage through the heart is viewed with a SPECT camera. By comparing the heart’s blood flow at rest and during stress (patients exercise on a treadmill, cycle ergometers or undergo pharmacological stress with vasodilators or dobutamine), cardiologists can determine if the myocardium receives sufficient blood supply, as well as the location and extent of underlying CAD.

“Because it’s non invasive and many patients with a chest pain syndrome don’t have coronary disease, SPECT MPI is often viewed as a ‘gate keeper’ to coronary angiography,” explained Lane Duvall, an investigator in the study.

While SPECT MPI represents a well established technique, the main disadvantage is that patients are exposed to diagnostic levels of radiation. In recent years intensive efforts have been made to reduce ionizing radiation associated with cardiac imaging due to concerns that it damages DNA in cells and may ultimately give rise to cancer. Indeed, extrapolating data from the survivors of the Hiroshima and Nagasaki atomic bombs, Andrew Einstein, from Columbia University Medical Center, New York, has estimated that the low levels of radiation encountered during medical imaging might lead to a 2% excess relative risk for future cancers.

Other studies have suggested that exercise treadmill testing alone may be sufficient to predict CVD outcome without use of SPECT MPI in low risk patients. In 2011, Bourque and colleagues from the University of Virginia, Charlottesville, reported that patients who exercise at >10 metabolic equivalents (METS), [the unit used to estimate the amount of oxygen used by the body during physical activity] during stress testing had a very low prevalence of significant ischemia and very low rates of cardiac events during follow-up².

The advantage of exercise treadmill testing is that it offers a quicker study that involves no radiation exposure, with prognostic information provided via a variety of treadmill scores, most notably the Duke Treadmill score. “This has led to investigators questioning the added value of SPECT MPI over exercise testing alone. There’s growing recognition that patients need to be treated as individuals and that those in whom the CVD risks are considered negligible shouldn’t be undergoing the risks of radiation exposure,” said Duvall.

In the current abstract, Henzlova, Duvall and colleagues, from the Mount Sinai School of Medicine, New York, US, set out to investigate retrospectively if a provisional injection protocol in which patients where they met certain criteria were converted to exercise treadmill tests without imaging maintained diagnostic accuracy and prognostic ability. For the retrospective study, data was reviewed from a total of 24,689 patients who had undergone SPECT MPI between February 2004 and June 2010. After exclusion of patients older than 65 years of age, who had known CAD and uninterruptable resting ECGs, 5,352 subjects were identified for analysis.

Subjects were divided into those who would have met all the criteria for not undergoing SPECT MPI (the No injection group n= 1,561 [29.2%]) and those who met the criteria for undergoing SPECT MPI (the Yes injection group, n=3,791, [70.8%]). For the study the criteria laid down for patients considered eligible for not undergoing SPECT MPI included achieving a maximal predicted heart rate >85%, > 10 METs of exercise, no symptoms of chest pain or significant shortness of breath during stress, and no ECG changes (ST depression or arrhythmia). Outcomes for the two groups at five years were then compared based on their actual myocardial perfusion imaging results and all-cause mortality that had been retrospectively identified from the National Death Index.

At a mean follow-up of 60.6 months, 1.1% of patients had died in the No-injection cohort compared to 2.2% Yes injection cohort (P=.01). Furthermore perfusion results were abnormal in 5.9% of the No injection group compared to 14.4% in the Yes injection group (P<.0001). The risk adjusted survival at the end of the follow up was 98.8% in the No injection group compared to 97.2% for patients found to have normal perfusion in the Yes injection group (P=0.009).

“Withholding isotope injections in these selected patients was found to be diagnostically safe with a small percentage of ‘missed’ abnormal perfusion studies, a very low rate of significant stress perfusion defects and left ventricular ischemia, and a prognosis which was better than their counterparts who were injected with the isotope,” said Duvall.

Eliminating the need for imaging in 6% of the 9 million SPECT MPI studies performed annually in the US, the authors added, would result in significant cost savings and the total test time would be halved from three hours to roughly one hour. “There’s a need to accept that less can be more. By individualizing therapy we can reduce radiation exposure and costs without jeopardizing the quality, the diagnostic utility or missing something important,” said Henzlova. 

1. M Henzlova, EJ Levine, S Moonthungal, et al. A protocol for the provisional use of perfusion imaging with exercise stress testing. Abstract no 70123.
2. Bourque JM, Charlton GT, Holland BH, et al. Prognosis in patients achieving >10 METS on exercise stress testing: was SPECT imaging useful? J Nucl Cardiol 2011, 2 230-7.
European Society of Cardiology

VI. Contemporary Stress Echo good for Risk Stratification in Chest-Pain Units

12/20/2012, Lisa Nainggolan

London, UK – Doctors in a London chest-pain unit have shown that employing contemporary stress echocardiography in patients with suspected acute coronary syndrome (ACS) but normal ECG and negative troponin is a successful approach for risk stratification [1].

Stress echo is feasible and safe and allows early triage and rapid discharge of patients, plus it is a good predictor of hard events, say Dr Benoy N Shah (Royal Brompton Hospital, London, UK) and colleagues in their paper published online December 18, 2012 in Circulation: Cardiovascular Imaging. Those with an abnormal stress echo had a 13- to15-fold increased risk of MI or death compared with those who had a normal stress echo, they report.

“Stress echo is a very effective gatekeeper for patients undergoing further risk stratification,” senior author Dr Roxy Senior (Royal Brompton Hospital) told heartwire. “It helps select patients for coronary angiography [those with a positive stress echo] and allows immediate discharge of those patients with a negative result.”

Stress echo is perceived to be a technique that is difficult, but that is a misconception.

But Senior says his chest-pain unit is the only one in the UK using this approach. “It is perceived to be a technique that is difficult, but that is a misconception. We have nine stress-echo operators, and it’s easy to train people. With contemporary techniques, which employ contrast in around 50% of cases, the images are quite clear and quick and easy to interpret. It’s very user-friendly. We want to show people around the world that it’s a very doable technique, so why don’t you use it?”

Stress echo also compares favorably with other tests used or proposed for risk stratification of such patients, he says. Exercise ECG is perhaps the most basic technique, “and we have shown that the downstream costs are lower with stress echo than with exercise ECG,” given that the latter provides such equivocal results [2], he explained. And with regard to other imaging modalities that have been employed in this way, computed tomography coronary angiography (CTCA) and single-photon-emission computed tomography (SPECT) require the use of ionizing radiation and have other drawbacks, he notes.

Nevertheless, he and his colleagues say that further, multicenter studies comparing stress echo with CTCA, SPECT, and other imaging techniques for this purpose “will help determine the most cost-effective means of investigating this acute patient population.”

Stress echo performed within 24 hours of admission

Shah and colleagues say that after they showed in 2007 that stress echo was more cost-effective than exercise ECG, they have been employing the former in day-to-day practice in their unit to assess patients who come in with severe chest pain, but whose troponin is negative at 12 hours and whose ECG is “nondiagnostic” (ie, does not suggest any abnormality or shows only minor changes).

The current study is a retrospective look at the patients they have seen so far and is the first evaluation of the clinical impact of incorporating stress echo in a real-world chest-pain unit for the assessment of both short- and long-term prediction of hard events, they say.

“This was sort of an audit; we wanted to know, ‘Is this right? Or are we overcalling it?’ ” Senior explains.

He says the stress echos are performed, for the most part, “within 24 hours” of admission to the chest-pain unit, from 9 am-5 pm Monday to Friday. Those admitted on a weekend will wait slightly longer for a stress echo, he acknowledged. The stress echo is performed on a treadmill if the patient is capable of exercise; if not, a pharmacological stress test is performed using dobutamine. Approximately 30% of the patients in this study performed the test on a treadmill, Senior noted.

Results of the stress echo are available quickly and, if negative, the patient is discharged immediately. If they are positive, the patient is investigated further.

Event rate much higher for those with a positive stress echo

In the study, 839 consecutive patients were assessed; 802 were available for follow-up. Approximately 75% of them had a normal stress echo and were discharged.

“The 30-day readmission rate for all patients was extremely low,” Senior notes, but for those with a negative stress echo it was exceedingly low (at 0.3% compared with 1.1% for those with an abnormal stress echo).

A normal stress echo carried a 99.7% event-free survival for death and 99.5% event-free survival for all hard events in the first year of follow-up; these event rates increased 15-fold and 13-fold respectively if the stress echo was abnormal.

There were 15 “hard” events, 0.5% in the normal stress echo group and 6.6% in the abnormal stress echo group in the first year. At two years, 2.3% of those in the normal stress echo group had died or had a nonfatal MI compared with 9.6% in the stress echo abnormal group, and at three years these figures were 5.1% and 21.1%, respectively. The median follow-up for the study was 27 months.

“For the patients who had a positive stress echo, the event rate was much higher,” Senior notes. Of these 184 patients, 98 had ischemia and most of these underwent coronary angiography, with 57 demonstrating flow-limiting coronary artery disease and 30 subsequently undergoing revascularization.

Among all prognostic variables, only abnormal stress echo (hazard ratio 4.08) and advancing age (HR 1.78) predicted hard events in multivariable regression analysis.

Stress echo should be much more widely used in chest-pain units

“This study demonstrates the excellent feasibility and safety of stress echo in a real-world chest-pain-unit setting, with rapid early triaging and discharge and accurate risk stratification,” the researchers say.

“The two most important outcomes for patients reassured and discharged from the emergency department are that they do not suffer early mortality or early readmission with the same complaint. Our study highlights the excellent negative predictive value of stress echo and very low 30-day readmission rate.”

In addition, the results show that stress echo “appropriately influences the use of coronary angiography and subsequent revascularization” and overall support the wider use of this technique in chest-pain units, they conclude.

Senior has previously received consultancy fees from Lantheus Medical. The coauthors report they have no conflicts of interest.


  1. Shah BN, Balaji G, Alhajiri A, et al. The incremental diagnostic and prognostic value of contemporary stress echo in a chest pain unit: mortality and morbidity outcomes from a real-world setting. Circ Cardiovasc Imaging 2012; DOI:10.1161/CIRCIMAGING.112.980797. Available at:
  2. Jeetley P, Burden L, Stoykova B, Senior R. Clinical and economic impact of stress echocardiography compared with exercise electrocardiography in patients with suspected acute coronary syndrome but negative troponin: a prospective randomized controlled study. Eur Heart J. 2007; 28:204-211.

VII. PET Perfusion Imaging Improves Risk Estimates

12/5/2012 Reed Miller

Boston, MA – New data from a large multicenter registry suggest that positron-emission-tomography (PET) myocardial perfusion imaging (MPI) can greatly improve the accuracy of risk estimation in coronary disease patients compared with a model based on traditional risk factors [1].

Only small single-center studies have demonstrated the prognostic value of PET MPI in predicting which patients are at greatest risk for coronary disease events. So Dr Sharmila Dorbala (Brigham and Women’s Hospital, Boston) and colleagues analyzed outcomes from 7061 patients from four centers who underwent a clinically indicated rest/stress rubidium-82 PET MPI test.

Results of the study are published online December 5, 2012 in the Journal of the American College of Cardiology. “The results of the current study are critical to advance the field and guide more effective use of PET MPI in clinical practice,” Dorbala et al state.

Median follow-up was 2.2 years. During follow-up, there were 169 cardiac arrests and 570 all-cause deaths. Net reclassification improvement and integrated discrimination analyses showed that the risk-adjusted hazard of cardiac death increases as the percentage of abnormal myocardium increases. A mildly abnormal stress test is associated with a 2.3 times greater risk of cardiac death than a normal test. The hazard ratio for a severely abnormal test is 4.9.

The addition of PET MPI measurements of myocardial ischemia and myocardial scarring to traditional clinical information improves the performance of a risk prediction model based on traditional risk factors (C statistic 0.805-0.839) as well as risk reclassification for cardiac death, with small improvements in risk assessments for all-cause death. The assessment of the magnitude of ischemia and scar added to the reclassification of risk for cardiac death in one in every nine patients who underwent clinical PET MPI in the study.

Unlike computed-tomography (CT) coronary angiography, perfusion imaging provides information about myocardial blood flow and accounts for underlying coronary disease, collateral flow, and myocardial adaptation to wall stress and can be used in patients with renal insufficiency, the authors point out. Compared with single-photon-emission computed tomography (SPECT) perfusion imaging, PET MPI offers better image quality, test specificity for the diagnosis of obstructive coronary disease, and identification of scar and ischemia, according to Dorbala et al, and PET MPI uses a lower effective radiation dose. However, while the prognostic value of SPECT MPI has been described in tens of thousands of patients, the prognostic value of PET MPI has been studied in only a few thousand patients.

Does more risk information help?

The value of the prognostic information offered by PET MPI is not yet clear, according to an accompanying editorial by Drs Paul Schoenhagen and Rory Hachamovitch (Cleveland Clinic, OH) [2]. “Rather than assessing whether a test yields improvement in risk assessment, the focus [should be] shifted to whether a test can identify which patients will gain a benefit from a specific therapeutic approach,” they write. “The role of testing [should be] defined in the context of a specific intervention and whether the effectiveness of the intervention is improved by the use of an imaging study to identify optimal candidates for treatment.

“However, this process is neither simple nor inexpensive and will require prospective randomized clinical trials, validating the results and hypotheses generated by observational data,” the editorialists conclude.

Commenting on the study, Dr Kavitha Chinnaiyan (William Beaumont Hospital, Royal Oak, MI) toldheartwire, “While the details of downstream management of these patients are unclear in this paper, the association of ischemia with mortality is clear, as is the reclassification of risk. The next step in terms of management of ischemic patients is really the question here.” She also pointed out that the ongoingISCHEMIA trial, comparing angiography and revascularization plus optimal medical therapy with optimal medical therapy only, may provide more insights on the best option for patients who show more than mild ischemia on stress studies.

Dorbala has received research grants from Astellas Pharma and Bracco Diagnostics; has served on advisory boards for Astellas Pharma; and has received honoraria from MedXcelDisclosures for the coauthors are listed in the paper.Schoenhagen and Hachamovitch report that they have no relationships relevant to the contents of this paper to discloseChinnaiyan has no relevant disclosures.


  1. Dorbala S, Di Carli M, Beanlands RS, et al. Prognostic value of stress myocardial perfusion positron emission tomography. J Am Coll Cardiol 2013; DOI:10.1016/j.jacc.2012.09.044. Available at:
  2. Schoenhagen P and Hachamovitch R. Evaluating the clinical impact of cardiovascular imaging: Is a risk-based stratification paradigm relevant. J Am Coll Cardiol 2013; DOI:10.1016/j.jacc.2012.09.044. Available at:


Other related articles published on this Open Access Online Scientific Journal, include the following:

Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools for Ischemic Assessment

Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN


CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

Aviva Lev-Ari, PhD, RN


Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

Curator: Aviva Lev-Ari, PhD, RN


Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone

Justin D. Pearlman, MD, PhD and Aviva Lev-Ari, PhD, RN


Read Full Post »

Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels

Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The evaluation of coronary artery disease (blocked arterial blood supply to heart muscle) by stress tests is functional: is there enough blockage to starve a region of muscle when demand is high? By starvation we mean ischemia – insufficient supply to meet metabolic demands as expressed by consequent functional impairment, e.g., metabolic, electric, mechanical. In the catheterization laboratory, the evaluation is primarily anatomic – is there a bite missing in the silhouette of a coronary artery consistent with a significant impediment to blood delivery beyond the lesion? Half of all heart attacks are due to such lesions. The other half derive from non-obstructive but unstable lesions that may crack, bleed into the vessel wall, and suddenly clot,  blocking the blood flow. Coronary lesions that restrict blood delivery sufficient to cause demand ischemia (insufficient blood supply to meet high demands) cause angina pectoris.

The focus of flow reserve is to add an assessment of functional significance to anatomic lesions observed at catheterization. The widespread practice of deciding on intervention based on percent diameter reduction imposed by a lesion is obviously flawed. The flow limitation imposed by a lesion depends on its length and shape (entrance and exit effects on flow pattern), not merely the diameter reduction expressed as a percent, that is currently deemed the decision-making “degree of stenosis.” In the midst of a medical emergency heart attack, the target of intervention is the culprit lesion, the one that best explains why a region of muscle is dying. In that case, timely intervention is potentially life saving and does not depend on or wait for measurements. In the non-emergent setting, it is much harder to establish benefit from intervention. If a lesion is flow limiting and explanatory for angina pectoris, then intervention to relieve obstruction offers pain relief and may improve exertion tolerance. In relatively rare circumstances (3-vessel obstruction, left main obstruction) intervention may avoid heart attack and extend life expectancy, but with as good or better outcomes from bypass surgery. Most elective catheter interventions (balloon angioplasty, stent placement) have failed  to establish improved life expectancy or even superiority over medication. Furthermore, stent placement obligates use of strong anti-platelet medications (e.g., aspirin plus clopidogrel) that elevate risk of serious bleeding and stroke. Therefore it is reasonable to require further evidence that a coronary lesion is obstructive and consequential that just percent stenosis (narrowing) as indication for intervention. Fractional flow reserve offers such confirmation of lesion significance.

Fractional flow reserve may prove useful also in the definition of heart attack (myocardial infarction): New Definition of MI Unveiled, Fractional Flow Reserve (FFR) CT for Tagging Ischemia

June 21, 2013

Recorded: May 23, 2013


The use of FFR is relatively widespread in Europe, while its usage is beginning to catch up in the US. But for what reasons? Drs Roxana Mehran,Justin Davies, and Ron Waksman gathered recently to share their thoughts on the role of functional assessment in the cath lab, to evaluate FFR and its alternatives, and discuss what testing the future might hold for the optimal detection of culprit lesions.


Roxana Mehran MD
Professor of Medicine, Divisions of Cardiology and Health Evidence and Policy
Director, Interventional Cardiovascular Research and Clinical Trials
The Zena and Michael A Wiener Cardiovascular Institute
Icahn School of Medicine at Mount Sinai
New York, NY

Dr Mehran has served as an advisor or consultant for AstraZeneca Pharmaceuticals, Regado Biosciences, Abbott Cardiovascular Systems, Janssen (Johnson & Johnson), Merck, and Maya Medical. She has received grants for clinical research from Bristol-Myers Squibb, Sanofi, the Medicines Company, and Lilly/DSI.


Justin Davies MBBS PhD
Consultant Interventional Cardiologist
Hammersmith Hospital
Imperial College
London, United Kingdom

Dr Davies has served as an advisor or consultant for Volcano and Medtronic. He has served as a speaker or a member of a speakers’ bureau for Medtronic and has received grants for clinical research from Volcano, Medtronic, and Abbott.

Ron Waksman MD
Director, Clinical Research and Advanced Education
MedStar Cardiovascular Research Network/Cleveland Clinic Heart and Vascular Institute
Clinical Professor of Medicine (Cardiology)
Georgetown University
Washington, DC

Dr Waksman has served as a speaker or a member of a speakers’ bureau for AstraZeneca Pharmaceuticals, Boston Scientific, and Medtronic.

Roxana Mehran, MD: Hello. My name is Roxana Mehran from Mount Sinai

School of Medicine in New York. It’s my pleasure to welcome you to this editorial

program in which we will look into how FFR usage differs in Europe vs the United


I’m joined by my colleagues Justin Davies from Imperial College London and, of

course, Ron Waksman, an old friend, from the Washington Hospital Center in

DC. Welcome.

Ron Waksman, MD: Thank you.

Dr Mehran: We thought today we’d have a conversation about fractional flow

reserve and the use of functional studies in guiding our interventional

procedures. This has become a very interesting and important modality that has

been incorporated, now, more and more into the cath lab.

Let’s begin, Justin. Maybe you could tell us: what is FFR? How do we use it?

What do you think about it? How important is it to have? Does every cath lab

need to have FFR?

Justin E Davies, MD: I think that it provides cath labs with an objective measure

of stenosis assessment that is quick and relatively easy to use. Often you find

people don’t come to cath labs with preprocedural ischemic assessment, so it

enables a physician in the lab to see if there is ischemia and to effectively

document that. It has clearly got a good, strong evidence base, which has been

developed over a number of years with the founding studies of DEFER and

FAME—and FAME-2, now, which has led to the technique getting into guidelines

and which has propelled its use to widespread practice.

Dr Mehran: There’s no question that functional assessment is quite important,

but what do you think about patients coming into the cath lab, especially in the

United States, without an ischemic assessment? How often are you seeing that

and would you even use [FFR] in a patient who has got a 90% stenosis or 80%

stenosis, Ron?

Dr Waksman: I think we are in a period of transformational culture, now, in terms

of appropriate-use criteria and justifying every lesion that we are doing. I think

that interventional cardiologists are on the defensive—because we have to justify

almost any angioplasty that we are doing, especially with an intermediate lesion.

I think physicians are more flexible in using FFR and looking it as guidance to

support their decision-making.

I would say, still, if it is a 90% lesion even without a functional test I don’t think it

is required, but the 90% is on the eyes of the beholder, so you know that if you

take it to the core lab it is not going to be probably 90%, it is usually going to be

less than that.

And as you know, we have been scrutinized by looking at films and, again, [we

need to] justify. It is true that in the past the algorithm was having a functional

test and going to the cath lab. But this [step] has delayed things, and now people

presenting with some chest discomfort, [who] have risk factors, they sometimes

would be sent to the cath lab as the first method of assessment. I think we have

to take this more carefully and incorporate a functional ischemic assessment in

the cath lab—especially when those lesions are not necessarily unambiguous,

we don’t clearly know that they would derive ischemia.

Dr Mehran: It seems like that is really the way to go. You talked to us about

FAME, FAME-2, [that FFR is] the only modality in the cath lab that actually

improves hard end points like death and MI. I think that was how it got into the

guidelines, obviously. Very important studies. But at what cost? Can we afford to

do this in every single patient who presents with, let’s say, multivessel disease,

as they did in FAME?

Dr Davies: I think, actually, that this is a tremendous opportunity because I think

for us as cardiologists, as Ron said, it is very easy to get yourself into a little bit of

a hole stenting lesions that are not as significant as you may think, and I think

this obviously provides a justification and a safety net for people to deploy stents.

But also I think increasingly going forward when you are taking on potentially

more challenging techniques and you have got three-vessel disease, [FFR]

enables us to assess multivessel disease and perhaps convert a three-vessel

PCI into a two- or [even] a single-vessel PCI, which may move them from getting

a CABG to angioplasty.

Dr Mehran: So actually decreasing the number of stents. Reducing your

devices—hopefully even radiation exposure and contrast media. If you actually

just do an FFR and say, okay, I am done. But you know that we have all

[discussed]: if you want to treat the lesion you use an IVUS; if you don’t want to

treat the lesion you use an FFR. What do you think about that, Ron? Is that

something that is going on in your lab?

Dr Waksman: No. We try to stay away [from that]. I know that is said. But I

would still think that FFR is oversold. For the controversy, I would [argue] that

those studies were investigator-sponsored studies and I don’t think the data are

so relevant today. In DEFER there was a balloon angioplasty. Even in FAME-1, it

was with first-generation stents, and it was not really practice to go after every


I think we have to take these [data] with a grain of salt. To my view, not

everything is definitive. Nevertheless, we do see uptake of the FFR usage in the

lab and for something that used to be under 3% in the US—only a couple of

years ago—it is now reaching up to 20%. More and more people are using [FFR].

There are other modalities that you can use. I think that we try to do a conversion

between the anatomical [minimum lumen area] (MLA) to the IVUS / FFR. It is

controversial, but it is another option. I think we need to learn to use the tool

when we really need it, not to be obsessed with it.

Often, we would have a scenario [where] a patient presents with chest pain. It is

classical angina. It is relieved by nitroglycerin. You have what you think is about

70% lesion in the proximal LAD and then you stick [in] the FFR wire and you get

0.81. Then you have a problem. You can repeat the study. You shoot another

adenosine and now it is 0.79. Then you shoot another one and it is 0.80. It is very

hard for me when you have a binary number to make a decision [based] on that

number. I don’t think we should lose our clinical judgment. It is a nice tool, but

don’t abuse it. Use it when it is really helpful.

Dr Davies: I will share my view. I have to say I agree wholeheartedly with Ron.

To me, if you ask them what are the most important numbers in FFR, people will

say: 0.80 or 0.75. Actually, I think the two most important numbers are 0 when it

is completely occluded and 1. As you get nearer to 0.80 you know that you are

approaching a place where it is going to be likely ischemia and a high probability

of events. Ron is absolutely right. If you have a type A, 90% lesion and you have

an FFR of 0.81—I know [that] in the US you are in difficulties, at the moment,

with these kinds of lesions. I think with the commonsense kind of medical

entirety/holistic approach that would say you should probably stent these people.

Dr Mehran: But isn’t that just so important? Those are really important points

because it is not about the dichotomous number of 0.80 or 0.75. It is about the

clinician and what they feel the scenario is and how it all fits together.

Dr Waksman: I would say even though it is getting very hard to support by

studies but I may not have an 80% or 70% lesion. I would rather have an FFR of

0.92 or 0.96 than 0.81.

Dr Davies: Absolutely.

Dr Mehran: Of course.

Dr Waksman: If I have the choice. You also have to realize that the stents of

today are not the stents of yesterday. I think we see [many fewer] events. I think

that the price of stenting and the likelihood that we would have events is much

lower than in the past. So even if we deviate a little bit, it I don’t think we do an

injustice to the patients [or] put them at high risk. I would challenge that if you

would [do] the same study today as DEFER, with the new second-generation

stents, I am not sure that the results would be the same—as robust—as they

were in the past. As a matter of fact, if you are looking even [at] FAME-2, at the

two groups—[those who] were medically treated and those who were

[interventionally] treated, the curves were actually very similar. I would challenge

that you [would not be replicating these results] with second-generation [stents].

You have to be taking [FFR] when you really need. I don’t think [that]

systematically you go [to] every lesion and if it meets the criteria of 0.80, you

don’t treat. If it is less, you treat.

Dr Davies: And there are some people who see this as a weakness, but we

don’t do that in any other form of medicine we practice, and I see it as a strength

that you get a continuous range of values. I think the one thing, which we have

also done, is using these techniques purely as an outcome base. But really if you

look back they were designed to describe ischemia and chest pain, so really it is

a very good tool for seeing if chest pain is genuine and if it is likely to benefit from

a stent.

Dr Mehran: That’s right.

Dr. Davies: And that hasn’t been thoroughly explored since the original studies.

Dr Mehran: Those are really excellent points. Now, we have alternatives to FFR.

We talked a little bit about IVUS, but we also know now that, Justin, you have

done a lot of the work on [instantaneous wave-free ratio] iFR. Maybe you can just

tell us: what is iFR? How is it different from FFR and where are we in that? Do

you believe it will replace FFR?

Dr Davies: iFR is a technique which is very similar to perform as FFR. You use

the same pressure wire. It is a software change in the console that essentially

allows us to make a measurement of stenosis severity over a particular phase of

the cardiac cycle without the need for a drug. It typically takes a few seconds to

measure and is very quick.

There have been, to date, about 3000 patients studied, in five clinical trials,

which—with the exception of one study—have all shown, essentially, the same


And we know at the EuroPCR meeting this was, again, replicated this week. At

the moment, we are in a situation where we are advocating the use of a hybrid

approach, similar to the big RESOLVE study, which essentially says that if you

are above an iFR threshold of 0.93 you are safe to defer and below 0.86, to treat.

That gives you about a 90% to 95% agreement with FFR and overall

classification, and the ADVISE-II study shows it saves about 70% of adenosine.

There are potentially quite marked savings in the cath lab.

I think this is out there in clinical practice—in a limited release, in terms of certain

labs around the world on three continents. The general experience has been

very, very good from people in terms of just facilitating the use of physiology.

What I mean by that: I take centers that were relatively small users of FFR and

they found they have done the same number of cases in three months as they

would have done over the whole year. If you ask them why, it’s because it lowers

the burden of doing [the cases]. I think if we then move on to doing triple-vesseldisease

assessment I think it takes five seconds of each.

Dr Mehran: I think there is no question that taking away the adenosine is music

to a lot of people’s ears. We all know that adenosine is not being given perfectly

right in certain laboratories. It really should be an intravenous injection. There is

time needed for nurses to put it together, to put in the IV, the intra-arterial

[injection] has been refuted, etc.

But when I look at iFR I start to think that we are pushing ourselves toward what

Ron was just talking about. I think the validations need to take place. It would be

great to have technology that is well validated, studied, that actually correlates

with events without adenosine. I think that part of it is brilliant. But are we there


Dr Davies: We have had a very good response taking the stuff from the research

lab into the cath lab, so this is what we are using this as a tool, certainly, within

the framework of studies. I think now we are in a position to do large studies. I

will give you an example: we asked all of the investigators who have got these

machines if they are willing to contribute to analysis at the time of PCI. [In the

space of] for four weeks—most of them only had the device that length of time,

they managed to get together 400 cases. [This shows that] doing very large

studies of 1500 or 2000 patients is extremely feasible and very easy to do.

Dr Mehran: I hope you are designing them and actually performing them.

Ron, what do you think about iFR? I love to hear your scrutiny.

Dr Waksman: I think it hasn’t been validated, obviously. I [would] like to get rid of

the adenosine. But I like to see reproducibility of any test. Again, I would say, we

don’t have to lose our brains just because we have numbers. We have a patient

in front of us. He has symptoms and we have lesions that we have to treat.

Obviously if you have a proximal lesion, it’s going to behave differently than a mid

or distal vessel. We know that, for example, if you look at most of the studies, at

just a circumflex of FFR. Most of them will be above 8.0. But you take most

proximal LADs, they probably would fit more into the predictability of ischemia vs

nonischemia. We have to, again, use our brains when we use the numbers and

understand what they mean.

I think that there will be other technologies that [will] try to be alternatives to

FFR—not that FFR is necessarily bad, but there are other ways that you can do

it. There is the heart flow option with a CT. I still think that IVUS is an option.

Not all of them are ideal, but it gives you a variety of options. The message is: we

are trying to treat only the vessels that need to be treated. I think that can also

change the paradigm of treatment. For example, we may turn “three vessel” to

“one vessel” and change the whole syntax score and move patients from CABG

to PCI—which is very attractive for interventional cardiologists.

One other thing that is interesting: recently I heard that SJ Park was presenting a

systematic use on all patients with FFR—which is amazing! It is over 70%. It was

not a randomized study but what he did show by systematically using FFR in his

practice [is that] he reduced, by a lot, the number of PCIs, the number of stents,

and the outcome of those patients was good. You have to compare it in a

randomized fashion. What would be the alternative? And that is the challenge.

You really have to show [efficacy] in a randomized clinical trial. I recognize there

were studies in the past, but they have limitations. I think we [are] moving to

another phase that this has to be tested.

Dr Mehran: Quickly touching on what you just said about noninvasive functional

assessments. More and more we are getting patients who come in with a

multislice CT. Can we use that technology to actually do some of the functional

assessment right then and there? The DEFACTO trial, in my mind, is a negative

study. Where are we with that technology?

Dr Davies: You are absolutely right to say a lot of these patients have CTs and it

is a question of whether we can use information from that CT. As Ron said, there

is HeartFlow technology, which enables you to effectively get a noninvasive

preprocedural virtual FFR measurement. Certainly from a theoretical perspective,

it should be possible to do these calculations. I think the problem that the

HeartFlow team has is translating the computational flow dynamic theory in a

perfect research environment into the clinical practice of getting good-quality

CTs. I think there is probably more work in progress to see that really translate.

Dr Mehran: That’s right.

Dr Waksman: But what we are seeing in the US right now is [that] there is a

decline in the nuclear test and there is increased uptake in FFR. There is a

change in paradigm because of many reasons. Some of them have nothing to do

with medicine. It is more the reimbursement. Because reimbursement went down

on nuclear tests, we see less nuclear tests being performed. Now we are getting

the patients actually to be assessed in the lab and we get [to have] more

confidence with FFR or other technologies. I think we are shifting the traditional

assessment of ischemia, which was in the old days was nuclear or dobutamine

echo, more into those [tests performed] in the lab. And I do believe that the fact

that studies were negative is not the end of the story. We still have to fine-tune.

This is all about software validation and finding the sweet spot. What is the

window that allows you to get good matching? That you can feel comfortable


Dr Mehran: So great technology to look forward to in the future. We are looking

for that kind of noninvasive assessment of functional studies. Let’s now turn to

why we are really here, which is about the regional differences of FFR. In the UK,

in Europe, in the United States, are there regional differences? Let’s better

understand that. And, if so, why? Justin, maybe you could tell us about the UK

and Europe?

Dr Davies: I think [FFR penetration] is somewhere between 15% and 20% of

cases in the UK, which is very high on a worldwide basis. I think some of that has

to do with reimbursement and some of it is to do with the way that doctors are

reimbursed, as well. In terms of the UK, if we put a stent in or not, it has no net

effect on the income to ourselves. So it is very easy for us to follow guidelines

and, in fact, if we don’t, [we] get rapped around the knuckles and told off for not

doing so. I think that is a strong incentive to do it.

I think there are obviously differences from us in other parts of the world with

regard to the reimbursement—the cost of the bits of kit and the availability of the

kit. In some labs around the world, and some territories, getting adenosine is

simply not possible or it is [so] outrageously expensive that people would just say

I am not going to make this measurement and they defer to angiography or, as

Ron said, to IVUS.

Dr Mehran: It seems like the penetration is a little bit the same between the UK

and US? What do you think about the United States?

Dr Waksman: Not yet. I would actually take from what Justin just said. I think

that the main motivation in Europe for the penetration of FFR was monetary. It

was actually to save money to the operator, to the cath lab. This never was the

case in the US. I think the in the US of the uptick is more related to

the appropriateness[-criteria guidelines] and to be on the defensive. The

interventionalist now has to defend himself for every procedure [he is] doing and

to have a backup [as to] why they did this procedure. That was not the case in

the European continent, [where] the main drive was to reduce overall costs on

the capitation system. I always had a problem with that because this is the way

that it was presented and I think that we should give the best to our patients.

We also have to realize that the reason for the uptick could be because of

appropriateness. We actually learned to turn this into a helpful tool for us [and] to

use it not just for those ancillary decisions—that probably should not be related to

the patient (whether it is a cost or whether it is appropriateness), but [also for]

what [it is] really good [for]: to see how we can utilize [it] to do the right procedure

to the right vessel. So it’s another tool.

But as I mentioned before, I think we are seeing an uptick. I don’t think we are

crossing the 20% and we are not as broad as in Europe. When are we going to

get there? It is a question of how much push we are going to see, but one thing

you see [now is] more companies providing FFR systems. That means that there

will be more reps in the labs and more opportunities, and that is usually what will

populate the usage of the device. I have no doubt that we are going to continue

to see an increase.

Dr Davies: It is interesting. I know from the US, and some of the data there,

there is a big difference between diagnostic use of FFR and actually the PCI use.

It is almost used in the US to justify PCI, and I think the angiography use is

somewhere around 3%. If you take that study that SJ Park has just done and you

compare that 70% percent that he was doing with the 3%, there is obviously a

huge potential.

Dr Mehran: Isn’t it interesting that maybe the driving force of doing a functional

assessment in the lab is different in the UK vs the US or Europe vs the United

States? I believe that at the end of the day they both will come to the same

conclusion of doing the right procedure to the right patient, making the correct

diagnosis, treating the right lesion for the right patient, but at the end of the day

actually decreasing costs. While maybe we are seeing in the United States that

appropriate-use criteria is why we are doing this, it has, perhaps, to do with

capitation, as well, for us in the United States, and enhancing the cost in the

system, hopefully, with this kind of functional assessment?

Dr Waksman: I think there is one more important collateral benefit from using

the FFR. That I would say is that we are changing the paradigm. In the old days

we thought we have to treat all the three vessels; we have to have complete

revascularization. I think FFR taught us that actually we may not need to treat all

the three vessels. That is a big advantage of technology. As we are using it we

are starting to see maybe we just have to treat the culprit lesion and move on

and then leave the others either on medical therapy or not treat them at all. That

is a huge change in paradigm.

Dr Mehran: This has been a fantastic conversation among the three of us, and I

just want to close and I want you each to close for me. What do you think is the

future of FFR? What should we be looking forward to as alternatives and what

incorporation of functional assessment in the cath lab as we move to the next

decade of interventional cardiology. Ron?

Dr Waksman: I think that the FFR will continue to grow. I think that there is a

good future for iFR without the adenosine, the wireless, and better wires that you

can use. I think you [could] incorporate an IVUS probe in them—FFR on an IVUS

probe, so you can do both. I think that the combination of anatomical and

physiological [testing] is important. We learned that with IVUS you can optimize

the outcome of the PCI, not only just determine whether you treat or not. So the

future is there. We are coming to do more sophisticated PCIs, and these data will

help us to get better outcomes and also to triage the patients to what should be

the treatment of choice. In the long run—even though the short run shows

reduction of the PCIs—if we use [FFR] carefully it will open us or enable us to do

more complex patients and meet the outcome that is expected.

Dr Mehran: That’s great. Justin?

Dr Davies: I would agree with Ron’s thoughts and also extend them to say I think

we will be doing more of these measurements, but I also think we should be

doing more smartly. As we discussed earlier, if you get these very borderline

lesions in patients who clearly have angina, then this is an indication for treating

your patient and looking at the patient as a whole.

I think we are really going to embrace technology. Medicine is always a little bit

behind the kind of technological leaps compared with smartphones, for instance.

I think techniques such as the HeartFlow technique, techniques such as the ones

we have been working on with iFR, I think will continue to move forward. I think

whereas we only today have discussed things from the purely diagnostic single

ischemic perspective, I think within one or two years you are going to have

techniques freely available in the cath lab that enable us to coregister the

FFR/iFR images onto angiogram in real time, enable you to plan PCI by selecting

which lesions may or may not benefit from therapy, even before you deploy a

stent. I think this, in the SYNTAX era, where we know the potential benefits of

minimizing angioplasty, like Ron said, will really facilitate our practice, and I

suppose the most important thing is lead to the better results for our patients.

Dr Mehran: I think that you both did a beautiful job telling us about the current

and the future technology and even if there are regional differences, at the end of

the day what we are trying to do is use the functional assessment to enhance

outcomes for our patients with cardiovascular disease, to make the right

diagnostic and therapeutic choices in these patients. And the combination of

these technologies that currently exists and hopefully will exist in the future will

absolutely get us there.

Thank you so much for your time this morning and I hope our audience enjoys

this conversation as I did. Thank you.


On this Open Access Online Scientific Journal the following articles published cases and results on Tools for Ischemic Assessment

 Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation

Detection and quantification of myocardial perfusion … – MDLinx

CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

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Revascularization: PCI, Prior History of PCI vs CABG

Accurate Identification and Treatment of Emergent Cardiac Events

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Revascularization: PCI, Prior History of PCI vs CABG

Curator: Aviva Lev-Ari, PhD, RN


UPDATED 9/25/2013

Table. Comparison of Surgical Therapy and Coronary Angioplasty (Open Table in a new window)

Endpoint Pocock et al* Pocock et al BARI Study
CABG(N=358) PTCA(N=374) CABG(N=1303) PTCA(N=1336) CABG(N=914) PTCA(N=915)
Death (%) 0.3 1.9 2.8 3.1 10.7 13.7
Death or MI 4.5 7.2 8.5 8.1 11.7 10.9
Repeat CABG 1.4 16.0§ 0.8 18.3§ 0.7 20.5§
Repeat CABG or PTCA 3.6 30.5§ 3.2 34.5§ 8.0 54.0§
More than mild angina 6.5 14.6§ 12.1 17.8§
*Meta-analysis of results of 3 trials at 1 year. Patients with single-vessel disease were studied.[22] †Meta-analysis of results of 3 trials at 1 year. Patients with multivessel disease were studied.[22] 

‡Reported results are for 5-year follow-up. Patients with multivessel disease were studied.[21] 

§ P < .05.

BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.


Percutaneous coronary intervention (PCI), also known as coronary angioplasty, is a nonsurgical technique for treating multiple conditions, including unstable angina, acute myocardial infarction (MI), and multivessel coronary artery disease (CAD).

Essential update: Cangrelor decreases periprocedural complications of PCI

According to a pooled analysis of 3 CHAMPION trials—CHAMPION-PCI , CHAMPION-PLATFORM , and CHAMPION-PHOENIX—cangrelor can reduce the risk of periprocedural thrombotic complications of PCI.[1, 2, 3] The 3 trials included patients with ST-elevation MI (STEMI), non-STEMI, and stable CAD who were randomly assigned to receive either cangrelor or control therapy consisting of either clopidogrel or placebo.

The primary outcome in this analysis was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours.[2] The frequency of this outcome was significantly lower in cangrelor-treated patients than in control subjects (absolute difference, 1.9%; relative risk reduction [RRR], 19%). Stent thrombosis was also reduced in the cangrelor-treated group (absolute difference, 0.3%; RRR, 41%). Primary safety outcomes were comparable in the 2 groups, but cangrelor-treated patients had a higher rate of mild bleeding.

Indications and contraindications

Clinical indications for PCI include the following:

In an asymptomatic or mildly symptomatic patient, objective evidence of a moderate-sized to large area of viable myocardium or moderate to severe ischemia on noninvasive testing is an indication for PCI. Angiographic indications include hemodynamically significant lesions in vessels serving viable myocardium (vessel diameter >1.5 mm).

Clinical contraindications for PCI include the presence of any significant comorbid conditions (this is a relative contraindication). Angiographic contraindications include the following:

  • Left main stenosis in a patient who is a surgical candidate (except in carefully selected patients[4] )
  • Diffusely diseased small-caliber artery or vein graft
  • Other coronary anatomy not amenable to PCI

In patients with stable angina, medical therapy is recommended as first-line therapy unless one or more of the following indications for cardiac catheterization and PCI or CABG are present:

  • A change in symptom severity
  • Failed medical therapy
  • High-risk coronary anatomy
  • Worsening left ventricular (LV) dysfunction

American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines on the management of unstable angina/non-STEMI recommend that an early invasive approach (angiography and revascularization within 24 hours) should be used to treat patients presenting with the following high-risk features[5] :

  • Recurrent angina at rest or low level of activity
  • Elevated cardiac biomarkers
  • PCI in the past 6 months or prior CABG
  • New ST-segment depression
  • Elevated cardiac biomarkers
  • High-risk findings on noninvasive testing
  • Signs or symptoms of heart failure or new or worsening mitral regurgitation
  • Hemodynamic instability
  • Sustained ventricular tachycardia
  • LV systolic function < 40%
  • High risk score (eg, Thrombolysis in Myocardial Infarction [TIMI] score >2) (see the TIMI Score for Unstable Angina Non ST Elevation Myocardial Infarction calculator)

See Overview for more detail.


Balloon catheters for PCI have the following features:

  • A steerable guide wire precedes the balloon into the artery and permits navigation through the coronary tree
  • Inflation of the balloon compresses and axially redistributes atheromatous plaque and stretches the vessel wall
  • The balloon catheter also serves as an adjunctive device for many other interventional therapies

Atherectomy devices have the following features:

  • These devices are designed to physically remove coronary atheroma, calcium, and excess cellular material
  • Rotational atherectomy, which relies on plaque abrasion and pulverization, is used mostly for fibrotic or heavily calcified lesions that can be wired but not crossed or dilated by a balloon catheter
  • Atherectomy devices may be used to facilitate stent delivery in complex lesions
  • Directional coronary atherectomy (DCA) has been used to debulk coronary plaques
  • Laser atherectomy is not widely used at present
  • Atherectomy is typically followed by balloon dilation and stenting

Intracoronary stents have the following features:

  • Stents differ with respect to composition (eg, stainless steel, cobalt chromium, or nickel chromium), architectural design, and delivery system
  • Drug-eluting stents have demonstrated significant reductions in restenosis and target-lesion revascularization rates
  • In the United States, stents are available that elute the following drugs: sirolimus (Cypher), paclitaxel (Taxus), zotarolimus (Endeavor), and everolimus (Xience V)
  • Stents are conventionally placed after balloon predilation, but in selected coronary lesions, direct stenting may lead to better outcomes

Other devices used for PCI include the following:

  • Thrombus aspiration limits the adverse effects that prolonged time to treatment has on myocardial reperfusion[6]
  • Distal embolic protection during saphenous vein graft intervention has become the standard of care

See Periprocedural Care and Devices for more detail.


Intravascular ultrasonography (IVUS) is used in PCI as follows:

  • Provide information about the plaque, the vessel wall, and the degree of luminal narrowing
  • Assessment of indeterminate lesions
  • Evaluation of adequate stent deployment

Intracoronary Doppler pressure wires are used in PCI as follows:

  • To characterize coronary lesion physiology and estimate lesion severity
  • Comparison of pressure distal to a lesion with aortic pressure enables determination of fractional flow reserve (FFR)
  • An FFR measurement below 0.75-0.80 during maximal hyperemia (induced via administration of adenosine) is consistent with a hemodynamically significant lesion

Antithrombotic therapy

  • Aspirin and heparin have been the traditional adjunctive medical therapies
  • Direct thrombin inhibitors (ie, hirudin, bivalirudin) are slightly better than heparin in preventing ischemic complications during balloon angioplasty but do not affect restenosis rates
  • Low-molecular-weight heparins (LMWHs) are substituted for standard heparin at some centers

Antiplatelet therapy

Patients receiving stents are treated with a combination of aspirin and clopidogrel. Duration of therapy is as follows:

  • Bare-metal stents: A minimum of 4 weeks
  • Drug-eluting stents: A minimum of 12 months

Use of proton pump inhibitors is appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.

Glycoprotein inhibitor therapy

  • Abciximab, tirofiban, and eptifibatide have all been shown to reduce ischemic complications in patients undergoing balloon angioplasty and coronary stenting
  • In primary PCI, GPIIb/IIIa receptor inhibitors have also been shown to improve flow and perfusion and to reduce adverse events
  • Abciximab may improve outcomes in patients when given before arrival in the catheterization lab for primary PCI[7]

See Technique and Medication for more detail.

SOURCE & References for the UPDATE, in

Outcomes comparison between PCI and CABG was explored in the past by authors on this Open Access Online Scientific Journal, in the following articles:

CABG or PCI: Patients with Diabetes – CABG Rein Supreme

To Stent or Not? A Critical Decision

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Age-Dependent Depression in Circulating Endothelial Progenitor Cells in Coronary Artery Bypass Grafting Patients

Now we are reporting  an Original Contribution on this subject which includes also Prior History of PCI, a factor NOT included in the other studies. The major conclusions are the following three:

  1. In a contemporary cohort of STEMI patients undergoing primary PCI, a history of prior CABG was found to be an independent predictor of in-hospital mortality.
  2. In contrast, despite more comorbidities at the time of STEMI, patients with prior PCI had no significant difference in the rates of death, stroke, or periprocedural MI when compared to a STEMI population without prior coronary revascularization.
  3. Thus, only prior surgical — and not percutaneousrevascularization should be considered a significant risk factor in the setting of primary PCI.

Number 1, above is related to patient medical history of cardiovascular disease SEVERITY prior to CABG

Number 2, above indicates that patients can tolerate and benefit several cycles of PCI and stent implantation rather than PCI being a determinant predictor of future prognosis

Number 3, above is as well related to patient medical history of cardiovascular disease SEVERITY prior to CABG

The Original Contribution on this subject is present, below.

The Impact of Previous Revascularization on Clinical Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention

Travis J. Bench, MD1, Puja B. Parikh, MD1, Allen Jeremias, MD1, Sorin J. Brener, MD2, Srihari S. Naidu, MD3,

Richard A. Shlofmitz, MD4, Thomas Pappas, MD4, Kevin P. Marzo, MD3, Luis Gruberg, MD1

Authors Affiliations:

1Division of Cardiovascular Medicine, Stony Brook University Medical Center, Stony Brook, New York,

2Department of Cardiology, Methodist Hospital, Brooklyn, New York,

3Division of Cardiology, Winthrop University Hospital, Mineola,

New York, and

4The Heart Center, St Francis Hospital, Roslyn, New York.

The authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 10, 2012, provisional acceptance given October 20, 2012, final version accepted November 28, 2012.

Address for correspondence: 

Luis Gruberg, MD, FACC, Department of Medicine, Division of Cardiology, Health Sciences Center, T16-080, Stony Brook, NY 11794- 8160. Email:


Abstract : While the impact of prior coronary artery bypass graft surgery (CABG) on in-hospital outcomes in patients with STelevation myocardial infarction (STEMI) has been described, data are limited on patients with prior percutaneous coronary intervention (PCI) undergoing primary PCI in the setting of an STEMI. The aim of the present study was to assess the effect of previous revascularization on in-hospital outcomes in STEMI patients undergoing primary PCI. Between January 2004 and December 2007, a total of 1649 patients underwent primary PCI for STEMI at four New York State hospitals. Baseline clinical and angiographic characteristics and in-hospital outcomes were prospectively collected as part of the New York State PCI Reporting System (PCIRS). Patients with prior surgical or percutaneous coronary revascularization were compared to those without prior coronary revascularization. Of the 1649 patients presenting with STEMI, a total of 93 (5.6%) had prior CABG, 258 (15.7%) had prior PCI, and 1298 (78.7%) had no history of prior coronary revascularization. Patients with prior CABG were significantly older and had higher rates of peripheral vascular disease, diabetes mellitus, congestive heart failure, and prior stroke. Additionally, compared with those patients with a history of prior PCI as well as those without prior coronary revascularization, patients with previous CABG had more left main interventions (24% vs 2% and 2%; P<.001), but were less often treated with drug-eluting stents (47% vs 61% and 72%; P<.001).

Despite a low incidence of adverse in-hospital events, prior CABG was associated with higher all-cause in-hospital mortality (6.5% vs 2.2%; P=.012), and as a result, higher overall MACE (6.5% vs 2.7%; P=.039). By multivariate analysis, prior CABG (odds ratio, 3.40; 95% confidence interval, 1.15-10.00) was independently associated with in-hospital mortality. In contrast, patients with prior PCI had similar rates of MACE (4.3% vs 2.7%; P=.18) and inhospital mortality (3.1% vs 2.2%; P=.4) when compared to the de novo population. Patients with a prior history of CABG, but not prior PCI, undergoing primary PCI in the setting of STEMI have significantly worse in-hospital outcomes when compared with patients who had no prior history of coronary artery revascularization. Thus, only prior surgical — and not percutaneous — revascularization should be considered a significant risk factor in the setting of primary PCI.

J INVASIVE CARDIOL 2013;25(4):166-169

Key words: PCI risk factor, CABG

Demographics and Angiographic Characteristics

Between 2004 and 2007, a total of 25,025 patients underwent PCI at these medical institutions, and their data were prospectively collected and submitted as required by the New York State Department of Health. Of these patients, a total of 1649 underwent primary PCI in the setting of an STEMI and constituted our study population. In this group, a total

No Prior Revascularization (n = 1298)

Prior PCI (n = 258)

Prior CABG (n = 93)


Age (years) 61 ± 13 62 ± 12 67 ± 12 <.001

Male gender 956 (73.6%) 194 (75.2%) 76 (81.7%) .21

White 1165 (89.8%) 231 (89.5%) 87 (93.5%) .51

African-American 78 (6%) 18 (7%) 1 (1.1%) .51

Hispanic 91 (7%) 11 (4.3%) 4 (4.3%) .51

Medical history

Ejection fraction (%) 43 ± 12 44 ± 13 45 ± 11 .079

Diabetes mellitus 196 (15.1%) 69 (26.7%) 27 (29%) <.001

Peripheral vascular disease 53 (4.1%) 25 (9.7%) 12 (12.9%) <.001

Chronic lung disease 47 (3.6%) 17 (6.6%) 4 (4.3%) .09

Congestive heart failure 74 (5.7%) 25 (9.7%) 10 (10.8%) .02

Prior myocardial infarction 3 (0.2%) 1 (0.4%) 1 (1.1%) .35

Prior cerebrovascular event 56 (4.3%) 9 (3.5%) 10 (11%) .01

Chronic dialysis 6 (0.5%) 6 (2.3%) 0 (0%) .004

Creatinine (mg/dL) 1.1 ± 0.8 1.3 ± 1.4 1.3 ± 1.1 .002

Glomerular filtration rate (mL/min/1.73 m2) 79 ± 26 75 ± 28 71 ± 27 .002

Angiographic characteristics

Left main 19 (1.5%) 5 (1.9%) 22 (23.7%) <.001

Left anterior descending 942 (72.6%) 178 (69%) 69 (74.2%) .45

Left circumflex 579 (44.6%) 122 (47.3%) 70 (75.3%) <.001

Right coronary 806 (62.1%) 187 (72.5%) 67 (72%) .002

Graft (arterial or venous) n/a n/a 20 (21.5%)

Stent type

Bare-metal stent 241 (18.6%) 52 (20.2%) 23 (24.7%) .31

Drug-eluting stent 928 (71.5%) 158 (61.2%) 44 (47.3%) <.001

of 1298 patients (78.7%) had no prior history of revascularization,

while 93 patients (5.6%) had a history of previous

CABG and 258 (15.7%) had a history of previous PCI. Considerable

differences in baseline clinical and procedural characteristics were noted among these groups (Table 1).


While STEMI patients with prior CABG are well known to have worse clinical outcomes than those without prior revascularization, a direct comparison between patients who underwent primary PCI in the setting of prior CABG or prior PCI has not yet been reported. The principal findings from the present analysis suggest that in a contemporary, unrestricted patient population presenting with STEMI and undergoing primary PCI, patients with a prior history of CABG are:

(1) usually older and have multiple comorbidities, including peripheral vascular disease, diabetes, and chronic obstructive lung disease;

(2) are more likely to undergo intervention on a native vessel and not a bypass graft;

(3) are more likely to be treated with bare-metal stents; and (4) have higher rates of in-hospital mortality without a significant increase in stroke or MI rates, when compared with patients with a prior history of PCI or patients with no previous history of coronary artery revascularization. Interestingly, these outcomes did not apply to patients with a history of prior PCI in this analysis. Instead, this cohort of patients had no significant difference in the rate of death, stroke, or periprocedural infarction when compared to a STEMI population without prior coronary revascularization, despite a significantly higher burden of comorbidities than those with no prior revascularization.

Our findings concur with previous studies that have shown higher mortality rates among patients with prior surgical bypass presenting with acute MI.7,9,14 Despite changes in revascularization strategies over the past 30 years, invasive therapies to treat acute coronary syndromes in patients with prior bypass surgery appear to have yielded less robust results than in other populations. In fact, Stone and colleagues already described in the Primary Angioplasty in Myocardial Infarction (PAMI-2) study that patients with a previous CABG undergoing primary PCI in the setting of an acute MI had significantly greater in-hospital mortality than patients without previous CABG, especially if the infarct-related vessel was a bypass conduit. However, by logistic regression analysis, only advanced age (P=.004), triple-vessel disease (P=.004), and Killip class ≥2 (P=.02) were independent predictors of in-hospital mortality in that study.13 In a more contemporary study of 128 STEMI patients with prior CABG, who were enrolled in the Assessment of PEXelizumab in Acute

Figure 1. In-hospital major adverse cardiac and cerebrovascular events (MACCE), mortality, and stroke rates for patients without prior history of coronary revascularization (light grey bars), prior percutaneous coronary revascularization (PCI) (dark grey bars), and prior coronary artery bypass graft (CABG) (black bars). Vol. 25, No. 4, April 2013 169

STEMI and Prior Revascularization Myocardial Infarction (APEX-AMI) trial, Welsh and colleagues reported that post-CABG patients are less likely to undergo acute reperfusion (only 79% underwent primary PCI), have worse angiographic outcomes following primary PCI, and have higher 90-day mortality rates (19.0% vs 5.7%; P=.05). This difference was even more apparent when the infarct-related artery was a bypass graft that was not successfully reperfused (23.1% vs 8.5%; P=.03).3 These results are similar to our current analysis, where in-hospital mortality rates for patients who underwent primary PCI of a graft were numerically roughly 4 times as high as those undergoing PCI of a native vessel. Likewise, Gurfinkel et al reported a significant reduction in hard endpoints, such as all-cause death and MI at 6 months in patients treated with an invasive approach in the Global Registry of Acute Coronary Events (GRACE).15 In this large, multinational, observational study of 3853 patients with prior bypass surgery presenting with an acute coronary syndrome, only 497 (12.9%) were managed invasively and the rest were treated medically.

Despite significant differences in baseline characteristics, including a higher rate of STEMI in patients treated invasively (14% vs 27%; P<.001), in-hospital mortality was similar in both groups (3.4% vs 3.2%; P=.86). However, at 6-month follow-up, mortality was significantly higher in those patients treated medically (6.5% vs 3.4%; P<.02) as was the combined endpoint of death or MI (11% vs 5.8%; P<.01).

Whether these results apply to patients with a prior history of PCI has not been well defined. By the nature of vascular disease, patients with prior PCI are more likely to have more comorbidities than those without prior revascularization, a finding confirmed in our study. Despite considerable differences in baseline characteristics, however, these differences did not translate into a differential risk after STEMI. In fact, the cohort of patients presenting with STEMI who had a history of prior PCI had no statistically significant difference in in-hospital mortality or overall MACCE when compared to a population of patients presenting with STEMI in the absence of any prior revascularization.

Study limitations. The database utilized was derived from four New York State teaching hospitals and was designed to track quality of care and clinical outcomes. As all studies involving multicenter databases and registries, there is potential error in data entry and availability. Potential confounding comorbidities, including smoking status and family history of coronary artery disease, were not collected in this database, and information regarding long-term follow-up is not available, all of which are important limitations of this analysis. As such, deficiencies such as these limit the conclusions that can be drawn from our multivariate analysis. Additionally, there is no audit of data quality, and the low overall event rates limit effective statistical comparison.


In a contemporary cohort of STEMI patients undergoing primary PCI, a history of prior CABG was found to be an independent predictor of in-hospital mortality. In contrast, despite more comorbidities at the time of STEMI, patients with prior PCI had no significant difference in the rates of death, stroke, or periprocedural MI when compared to a STEMI population without prior coronary revascularization. Thus, only prior surgical — and not percutaneous — revascularization should be considered a significant risk factor in the setting of primary PCI.


1. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Catheter Cardiovasc Interv. 2009;74(7):E25-E68.

2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13-20.

3. Welsh RC, Granger CB, Westerhout CM, et al. Prior coronary artery bypass graft patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. JACC Cardiovasc Interv. 2010;3(3):343-351.

4. Mathew V, Gersh B, Barron H, et al. In-hospital outcome of acute myocardial infarction in patients with prior coronary artery bypass surgery. Am Heart J. 2002;144(3):463-469.

5. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation. 1995;91(6):1659-1668.

6. Dittrich HC, Gilpin E, Nicod P, et al. Outcome after acute myocardial infarction in patients with prior coronary artery bypass surgery. Am J Cardiol. 1993;72(7):507-513.

7. Berry C, Pieper KS, White HD, et al. Patients with prior coronary artery bypass grafting have a poor outcome after myocardial infarction: an analysis of the VALsartan in acute myocardial iNfarcTion trial (VALIANT). Eur Heart J. 2009;30(12):1450-1456.

8. Grines CL, Booth DC, Nissen SE, et al. Mechanism of acute myocardial infarction in patients with prior coronary artery bypass grafting and therapeutic implications. Am J Cardiol. 1990;65(20):1292-1296.

9. Labinaz M, Sketch MH Jr, Ellis SG, et al. Outcome of acute ST-segment elevation myocardial infarction in patients with prior coronary artery bypass surgery receiving thrombolytic therapy. Am Heart J. 2001;141(3):469-477.

10. Peterson LR, Chandra NC, French WJ, Rogers WJ, Weaver WD, Tiefenbrunn AJ. Reperfusion therapy in patients with acute myocardial infarction and prior coronary artery bypass graft surgery (National Registry of Myocardial Infarction-2). Am J Cardiol. 1999;84(11):1287-1291.

11. Nguyen TT, O’Neill WW, Grines CL, et al. One-year survival in patients with acute myocardial infarction and a saphenous vein graft culprit treated with primary angioplasty. Am J Cardiol. 2003;91(10):1250-1254.

12. Al Suwaidi J, Velianou JL, Berger PB, et al. Primary percutaneous coronary interventions in patients with acute myocardial infarction and prior coronary artery bypass grafting, Am Heart J. 2001;142(3):452-459.

13. Stone GW, Brodie BR, Griffin JJ, et al. Clinical and angiographic outcomes in patients with previous coronary artery bypass graft surgery treated with primary balloon angioplasty for acute myocardial infarction. Second Primary Angioplasty in Myocardial Infarction Trial (PAMI-2) Investigators. J Am Coll Cardiol. 2000;35(3):605-611.

14. Labinaz M, Kilaru R, Pieper K, et al. Outcomes of patients with acute coronary syndromes and prior coronary artery bypass grafting: results from the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation. 2002;105(3):322-327.

15. Gurfinkel EP, Perez de la Hoz R, Brito VM, et al. Invasive vs non-invasive treatment in acute coronary syndromes and prior bypass surgery. Int J Cardiol. 2007;119(1):65-72.


Other related studies on this subject published on this Open Access Online Scientific Journal include the following:

Lev-Ari, A. 2/12/2013 Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons


Lev-Ari, A. 12/31/2012 Renal Sympathetic Denervation: Updates on the State of Medicine


Lev-Ari, A. 9/2/2012 Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

Lev-Ari, A. 8/13/2012 Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents


Lev-Ari, A. 7/18/2012 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia


Lev-Ari, A. 6/13/2012 Treatment of Refractory Hypertension via Percutaneous Renal Denervation

Lev-Ari, A. 6/22/2012 Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

Lev-Ari, A. 6/19/2012 Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market


Lev-Ari, A. 6/22/2012 Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites


Lev-Ari, A. 7/23/2012 Heart Remodeling by Design: Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony


Lev-Ari, A. (2006b). First-In-Man Stent Implantation Clinical Trials & Medical Ethical Dilemmas. Bouve College of Health Sciences, Northeastern University, Boston, MA 02115


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Accurate Identification and Treatment of Emergent Cardiac Events

Accurate Identification and Treatment of Emergent Cardiac Events

Author: Larry H Bernstein, MD, FCAP
In the immediately preceding article, I discussed the difficulties in predicting long-term safety for developing drugs, and the cost of failure in early identification.

It is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events, the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on clinical history, physical examination, effective use of the laboratory, and increasingly helpful imaging technology. The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag”
  • signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
    • in the presence of other findings
    • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  1. clinical history
  2. family history
  3. co-morbidities, eg., diabetes, obesity, limited activity?, diet?
    1. stroke and/or peripheral vascular disease
    2. hypertension and/or renal vascular disease
    3. aortic atherosclerosis or valvular heart disease
      • these are evidence, and they make up syndromic classes
  4. Electrocardiogram – 12 lead EKG (as above)
  5. Laboratory tests
    1. isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
    2. isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
    3. cardiac troponin cTnI or cTnT
      • genome testing
      • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.  When you look at the amount of information that has to be presented to the physician, there is serious need for improvement in the electronic medical record to benefit the patient and the caregivers.  Recently, we have a publication on a new test that has been evaluated, closely related to the C-reactive protein (CRP), a test that has generated much discussion over the effect of treatment for patients who have elevated CRP in the absence of increased LDL cholesterol, diabetes, or obvious atherosclerotic comorbidities.  The serum pentraxin 3 test is related to cell mediated immunity, and an evaluation has been published in the Journal of Investigative Medicine.

Journal of Investigative Medicine Feb 2013; 61 (2): 278–285.

Serum Pentraxin 3 Levels Are Associated With the Complexity and Severity of Coronary Artery Disease in Patients With Stable Angina Pectoris
Karakas, Mehmet Fatih MD*; Buyukkaya, Eyup MD*; Kurt, Mustafa MD*; et al.
From the Departments of Cardiology and,Clinical Biochemistry, Mustafa Kemal University, Tayfur Ata Sokmen Medical School, Hatay, Turkey.
Reprints: Mehmet Fatih Karakas, MD, Antakya 31005, Turkey. E-mail:

Background: Atherosclerosis is a complex inflammatory process. Although pentraxin 3 (PTX-3), a newly identified inflammatory marker, was associated with adverse outcomes in stable angina pectoris,

  • an association between PTX-3 and the complexity of coronary artery disease (CAD) has not been reported.

The aim of the present study is to assess

  • the association between the level of PTX-3 and
  • the complexity and severity of CAD assessed with
  • SYNTAX and Gensini scores in patients with stable angina pectoris.

Methods: The study population is 2 groups:

  • 161 patients with anginal symptoms and evidence of ischemia
    • who underwent coronary angiography and
  • 50 age- and sex- matched control subjects without evidence of ischemia .

Patients were grouped into 3 groups according to the complexity and severity of coronary lesions

  • assessed by the SYNTAX score (30 patients with a SYNTAX score of 0 were excluded).

Serum PTX-3 and high-sensitivity C-reactive protein (hs-CRP) levels were measured in both groups.

Results: The PTX-3 levels demonstrated

  • an increase from low to high SYNTAX groups (r = 0.72, P < 0.001).

Whereas the low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001),

  • the hs-CRP levels were not different (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
  • but  the intermediate SYNTAX group had higher hs-CRP levels compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002).

Serum PTX-3 levels and hs-CRP levels were both correlated with the SYNTAX scores and Gensini scores (for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01]; for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002], respectively), and

  • according to the results of univariate and multivariate analyses, for “intermediate and high” SYNTAX scores, age, diabetes mellitus, low-density lipoprotein cholesterol, hs-CRP, and PTX-3
  • were found to be independent predictors, whereas
  • for the presence of “high” SYNTAX score only PTX-3 was found to be an independent predictor.
  • The receiver operating characteristic curve analysis further revealed that the PTX-3 level was
    • a strong indicator of high SYNTAX score with an area under the curve of 0.91 (95% confidence interval, 0.86–0.96).

Conclusions: Pentraxin 3, a novel inflammatory marker, was more tightly associated with the complexity and severity of CAD than hs-CRP and

    • it was found to be an independent predictor for high SYNTAX score.

The association between atherosclerosis and inflammation has been more understood during recent years. Currently, atherosclerosis is considered as a complex inflammatory process in which

    • leukocytes and inflammatory markers are involved.1

Several inflammatory markers

  1.  high-sensitivity C-reactive protein (hs-CRP),
  2. fibrinogen, and
  3. complement C3…. are associated with cardiovascular events.1–5

Pentraxin 3 (PTX-3), that resembles CRP both in structure and function,1 is produced both by

  • hematopoietic cells such as macrophages, dendritic cells, neutrophils, and by
  • nonhematopoietic cells such as fibroblasts and vascular endothelial cells.2

Plasma PTX-3 levels may be elevated in patients with

  1. vasculitis,6
  2. acute myocardial infarction,7,8 and
  3. systemic inflammation or sepsis,9
  4. psoriasis,
  5. unstable angina pectoris, and
  6. heart failure.10–13

Dubin et al14 reported that PTX-3 levels are associated with with adverse outcomes in stable angina pectoris (SAP). Despite reports about the association of PTX-3 and coronary artery disease (CAD),

an association between the level of PTX-3 and the complexity and severity of CAD is not established.15,16 Thus, the aim of this study was

  • to assess the association between the level of PTX-3 and the complexity and severity of CAD assessed with SYNTAX and Gensini scores in SAP patients.


Of 211 patients were prospectively recruited,  161 SAP patients with evidence of ischemia (positive treadmill or myocardial perfusion scan) underwent coronary angiography for suspected CAD, and 50 age- and sex- matched outpatient subjects with a negative treadmill or myocardial perfusion scan test were taken as the control group. Patients were excluded if they had

  •  acute coronary syndrome
  • history of previous myocardial infarction;
  • coronary artery bypass grafting or percutaneous coronary intervention;
  • secondary hypertension (HT);
  • renal failure;
  • hepatic failure;
  • chronic obstructive lung disease and/or
  • manifest heart disease, such as
    • cardiac failure (left ventricular ejection fraction <50%),
    • atrial fibrillation, and
    • moderate to severe cardiac valve disease; and
    • SYNTAX score of zero

Similarly, patients were excluded with

  • infection,
  • acute stress, or chronic systemic inflammatory disease and
  • those who had been receiving medications affecting the number of leukocytes .

Thirty patients were excluded from the study because the coronary angiograms revealed normal coronary arteries (SYNTAX score of 0). All the participants included in the study were informed about the study, and they voluntarily consented to participate. The Serum PTX-3 level was measured on blood samples collected after 12-hour fast just prior to coronary angiography and kept at −80°C until the assays were performed. PTX3 was measured by enzyme immunoassay (EIA) using quantitative kit (human PTX-3/TSG-14 immunoassay, DPTX30; R&D Systems, Inc, Minneapolis, MN). The intra-assay and interassay coefficients of variation ranged from 3.8% to 4.4% and 4.1% to 6.1%, respectively (minimum detectable concentration, 0.025 ng/mL). High-sensitivity CRP was measured in serum by EIA (Immage hs-CRP EIA Kit; Beckman Coulter Inc, Brea, CA). Transthoracic echocardiography was performed, and biplane Simpson’s ejection fraction (%) was calculated before coronary angiography. Hypertension was defined as having at least 2 blood pressure measurements greater than 140/90 mm Hg or using antihypertensive drugs, whereas diabetes mellitus (DM) was defined as having at least 2 fasting blood sugar measurements greater than 126 mg/dL or using antidiabetic drugs. Smoking was categorized into current smokers and nonsmokers. Nonsmokers included ex-smokers who had quit smoking for at least 6 months before the study. Body mass index (BMI) values were calculated based on the height and weight of each patient. Medications used before the coronary angiography were noted. The study was approved by the local ethics committee.
SYNTAX and Gensini Scores
To grade the complexity of CAD, the SYNTAX score was used. Each coronary lesion with a stenosis diameter of 50% or greater in vessels of 1.5 mm or greater was scored. Parameters used in the SYNTAX scoring are shown in Table 1. The latest online updated version (2.11) was used in the calculation of the SYNTAX scores ( The SYNTAX score was classified as follows:

  1. low SYNTAX score (≤22),
  2. intermediate SYNTAX score (23–32)
  3. high SYNTAX score (≥33).

Table 1

The severity of CAD was determined by the Gensini score, which

  • measures the extent of coronary stenosis according to degree and location.18

In the Gensini scoring system,

  • larger segments are more heavily weighted ranging from 0.5 to 5.0
    • left main coronary artery × 5;
    • proximal segment of the left anterior descending coronary artery [LAD] × 2.5;
    • proximal segment of the circumflex artery × 2.5;
    • midsegment of the LAD × 1.5;
    • right coronary artery distal segment of the LAD,
    • posterolateral artery, and obtuse marginal artery × 1;
    • and others × 0.5.

The narrowing of the coronary artery lumen is rated

  1. 2 for 0% to 25% stenosis,
  2. 4 for 26% to 50%,
  3. 8 for 51% to 75%,
  4. 16 for 76% to 90%,
  5. 32 for 91% to 99%,
  6. 64 for 100%.

The Gensini index is the sum of the total weights for each segment. All angiographic variables of the SYNTAX and Gensini score were computed by

  • 2 experienced cardiologists who were blinded to the procedural data and clinical outcomes.

The final decision was reached by consensus when a conflict occurred.The number of diseased vessels with

  • greater than 50% luminal stenosis was scored from 1 to 3 (namely, 1-, 2-, or 3-vessel disease), and
  • a lesion greater than 50% in the left main coronary artery was regarded as a 2-vessel disease.

Statistical Analyses

Statistical analyses were conducted with SPSS 17 (SPSS Inc, Chicago, IL) software package program.
Continuous variables were expressed as mean ± SD or median ± interquartile range values, whereas categorical variables were presented as percentages.
The differences between normally distributed numeric variables were evaluated by Student t test or 1-way analysis of variance, whereas

  • non–normally distributed variables were analyzed by Mann-Whitney U test or Kruskal-Wallis variance analysis as appropriate.

χ2 Test was used for the comparison of categorical variables. Pearson test was used for correlation analysis.
To determine the independent predictors of “intermediate and high” SYNTAX scores and only “high” SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed
    • (in the first model SYNTAX cutoff was 22, whereas
    • in the second model SYNTAX cutoff was 33).

The standardized parameters that were found to have a significance (P < 0.10) in the univariate analysis were evaluated by stepwise logistic regression analysis.
Ninety-five percent confidence interval (CI) and odds ratio (OR) per SD increase were presented together. Interobserver and intraobserver variability for SYNTAX scores

  • was done by Bland-Altman analysis.

An exploratory evaluation of additional cut points was performed using the receiver operating characteristic (ROC) curve analysis.
All the P values were 2-sided, and a P < 0.05 was considered as statistically significant.
Baseline Characteristics
In total, 181 patients (50.2 ± 6.5 years, 52.5% were composed of males) were included in the study. Baseline clinical, angiographic, and laboratory characteristics of the patients
relative to SYNTAX score groups are shown in Table 2. Age, sex, HT, DM, BMI, and medication were not different between the groups. Baseline clinical and laboratory characteristics
of patients according to PTX-3 quartiles are shown in Table 3. The Bland-Altman analysis revealed that the degrees of intraobserver and interobserver variability for SYNTAX score
and Gensini score readings were 5% and 6% for SYNTAX and 8% and 9% for Gensini,
Table 2
Table 3

The PTX-3 levels demonstrated an increase from the low SYNTAX group to the high SYNTAX group (r = 0.87, P < 0.001).
The low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001); similarly,
the PTX-3 levels were higher in the high SYNTAX group than in both

  • the intermediate SYNTAX group (0.84 ± 0.08 vs 0.55 ± 0.01 ng/mL, P < 0.001) and
  • the low SYNTAX group (0.84 ± 0.08 vs 0.50 ± 0.01 ng/mL, P < 0.001).
  • there was no difference in levels of PTX-3 between the low and the intermediate SYNTAX group (0.50 ± 0.01 vs 0.55 ± 0.01 ng/mL, P = 0.09).

On the other hand, there was no difference in levels of hs-CRP between the control and the low SYNTAX group (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
The intermediate SYNTAX group had statistically significantly higher hs-CRP levels

  • compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002);
  • the hs-CRP levels were not different between the high SYNTAX group
    • and the intermediate SYNTAX group. (1.3 ± 0.66 vs 1.3 ± 0.43 mg/dL, P = 0.99).

Univariate correlation analysis revealed a positive correlation between serum PTX-3 levels and hs-CRP levels with

  • the SYNTAX and Gensini scores
    • for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01];
    • for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002],  (Fig. 1).

In addition to that, the Gensini and SYNTAX scores are found to be well correlated with each other (r = 0.80, P < 0.001).
When the SYNTAX score was taken as continuous variable, multivariate linear regression analysis revealed that

  • the SYNTAX score was correlated with PTX-3 and hs-CRP (for PTX-3: β = 0.84 [P < 0.001]; hs-CRP: β =0.08 [P = 0.032]).

Figure 1

For determining the predictors of intermediate and high SYNTAX scores and only-high SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed among the patients who underwent coronary angiography.

For predicting the intermediate and high SYNTAX scores, the SYNTAX score was dichotomized into

  • high (score ≥22) and
  • low (<22) groups,

whereas for predicting the only-high SYNTAX scores, the SYNTAX score was dichotomized into

  • 2 groups with a score of 33 or greater and a score of less than 33.

In the first multivariate analysis (where SYNTAX cutoff was 22), the parameters showing significance in the univariate analysis

  • age,
  • sex,
  • HT,
  • DM,
  • low-density lipoprotein cholesterol [LDL-C],
  • hs-CRP,
  • PTX-3

were evaluated by multivariate analysis to determine the

  • independent predictors of intermediate and high SYNTAX scores.

In the univariate analysis, higher values of

  • age (OR, 1.5 [95% CI, 1.1–2.0]; P = 0.01),
  • LDL-C (OR, 1.3 [95% CI, 0.98–1.8]; P = 0.068),
  • hs-CRP (OR, 2.6 [95% CI, 1.8–3.8]; P < 0.001), and
  • PTX-3 (OR, 13.6 [95% CI, 6.4–28.9]; P < 0.001)
    • were associated with higher SYNTAX scores,
  • HT (OR, 0.44 [95% CI, 0.24–0.80]; P = 0.008) and
  • DM (OR, 0.48 [95% CI, 0.25–0.91]; P = 0.02)
    • were associated with lower SYNTAX scores.

In the multivariate analysis – age, DM, LDL-C, hs-CRP, and PTX-3 – were found to be

  • independent predictors of “intermediate to high” SYNTAX score (Table 4).


  • age (OR, 2.5 [95% CI, 1.3–4.8]; P = 0.007),
  • LDL-C (OR, 2.8 [95% CI, 1.5–5.2]; P = 0.001),
  • hs-CRP (OR, 3.3 [95% CI, 1.8–6.1]; P < 0.001), and
  • PTX-3 (OR, 35.4 [95% CI, 10.1–123.6]; P < 0.001)
    • were associated with increased SYNTAX scores,

whereas DM (OR, 0.08 [95% CI, 0.02–0.33]; P < 0.001) was associated with lower SYNTAX score (Table 4).

In the second univariate and multivariate analyses (where SYNTAX cutoff was 33),

  • the parameters that showed significance in the univariate analysis were age, LDL-C, glucose, hs-CRP, and PTX-3.
  • In the univariate analysis, increased
    • age (OR, 1.5 [95% CI, 1.0–2.3]; P = 0.05),
    • LDL-C (OR, 1.5 [95% CI, 0.97–2.2]; P = 0.07),
    • hs-CRP (OR, 1.4 [95% CI, 0.97–2.1]; P = 0.072), and
    • PTX-3 (OR, 18.5 [95% CI, 6.6–51.8]; P < 0.001)
      • were found to be associated with increased SYNTAX scores.

When these parameters were evaluated with multivariate analysis, only PTX-3 (OR, 18.4 [95% CI, 6.2–54.2]; P < 0.001)

    • was found to be an independent predictor for high SYNTAX score (Table 4).

Table 4

The ROC curve analysis further revealed that the PTX-3 level was a strong indicator of high SYNTAX score with

  • an area under the curve (AUC) of 0.91 (95% CI, 0.86–0.96) (Fig. 2).

The optimal cutoff of PTX-3 for the high SYNTAX score was 0.75 ng/mL.
Sensitivity, specificity, positive predictive value, and negative predictive value to identify high SYNTAX score for the PTX-3 level

  • were 90%, 84%, 97%, and 60%, respectively.
  • the ROC curve analysis of PTX-3 for intermediate-high SYNTAX score revealed that the AUC value was 0.82 (95% CI, 0.75–0.89).

The optimal threshold of PTX-3 level that

  • maximized the combined specificity and sensitivity to predict
    • intermediate to high SYNTAX score was 0.73 ng/mL.

For the cutoff value of 0.73 ng/mL, sensitivity, specificity, positive predictive value, and negative predictive value

  • to identify intermediate-high SYNTAX score were 56%, 98%, 97%, and 56%, respectively.

Figure 2

In the ROC analysis of hs-CRP for high SYNTAX scores, the AUC value was found to be 0.68 (95% CI, 0.59–0.77; P < 0.001).
The optimal threshold of hs-CRP that maximized the combined specificity and sensitivity to predict for high SYNTAX scores was 0.89 mg/dL.
Similarly, the ROC analysis of hs-CRP for the intermediate-high SYNTAX scores revealed an AUC of 0.74 (95% CI, 0.65–0.83; P = 0.001).
The cutoff value of hs-CRP to predict the intermediate-high SYNTAX scores with a maximized sensitivity and specificity was 0.66 mg/dL.
In this particular study, we investigated the relationship between the serum PTX-3 level and the severity of CAD

  • assessed by SYNTAX and Gensini scores in patients with SAP.

The PTX-3, was significantly higher than control group in the patients with CAD, and the serum PTX-3 levels

  • were associated with the SYNTAX and Gensini scores.

When compared with the hs-CRP, the PTX-3 was found to be more tightly associated with the complexity and severity of CAD in the patients with SAP.
Pentraxin 3, an acute-phase reactant that is functionally and structurally similar to CRP,1 is produced both by different kinds of cells such as

  • macrophages, dendritic cells, neutrophils, fibroblasts, and vascular endothelial cells.2
  • Pentraxin 3 is released following the inflammatory stimuli19; therefore, it may reflect the local inflammatory status in tissues.20

Serum PTX-3 levels were shown to be elevated in patients with

  • vasculitis,6 acute myocardial infarction,7,8 and systemic inflammation or sepsis,9 psoriasis, unstable angina pectoris, and heart failure.10–13

Higher PTX3 levels were reported to be associated with worse cardiovascular outcomes

  1. after acute coronary syndromes,8,21
  2. in the elderly people without known cardiovascular disease22 and
  3. associated with overall mortality in patients with stable coronary disease,
  4. independent of systemic inflammation.14

There are 2 reports investigating the association of PTX-3 level and the atherosclerotic burden.15,16 In one of these reports,

  • Knoflach et al.15 took B-mode ultrasonography as the atherosclerosis index.

They did not provide any information about coronary anatomy, and in the other report, Soeki et al.16 evaluated 40 patients who

  • underwent coronary angiography and measured their Gensini scores.

However, in none of the studies were the SYNTAX score and Gensini score used together to assess the degree of coronary atherosclerotic burden.
To our knowledge, this is the first report that showed the association of PTX-3 levels with the complexity and severity of CAD assessed by

  • SYNTAX and Gensini scores in patients with stable coronary disease.

Chronic low-grade inflammation has been thought to play a major role in the pathogenesis of atherosclerosis.23,24 Previous studies have reported that

  • levels of inflammatory markers such as hs-CRP, interleukin 6, and so on were increased in atherosclerosis.25

In the present study, both the SYNTAX and the Gensini scores were found to be correlated with serum PTX-3 and hs-CRP levels,

  • which in turn might reflect the degree of inflammation.

The SYNTAX score is an important tool in the classification of complex CAD26 and can give predictive information about short- and long-term outcomes

  • in patients with stable CAD who undergo percutaneous coronary intervention.27–30

Although the SYNTAX score is currently used for assessing the angiographic complexity of CAD rather than the severity of coronary atherosclerotic burden,

  • because more complex lesions tend to have more atherosclerotic burden,
  • the SYNTAX scores may also reflect the severity of coronary atherosclerotic burden.

The Gensini score, a well-known and widely used scoring system to evaluate the severity of CAD,18 was measured and

  • found to be well correlated with the SYNTAX score,
    • which supports the idea that angiographically more complex lesions tend to have more atherosclerotic burden.

When compared with the hs-CRP,

  • the PTX-3 seems to be more tightly associated with coronary disease burden (r = 0.36 vs r = 0.87).

We found out that the serum PTX-3 levels were higher than those in the control group, even in the low SYNTAX group.
On the other side, the serum hs-CRP levels were not different in the control and the low SYNTAX groups.
It was reported that the leukocytes mainly found in the coronary artery lumen are the neutrophils.31
It is also known that PTX-3 is stored in specific granules of neutrophils and released in response to inflammatory signals.32
The reason why serum PTX-3 levels seem more tightly associated with the coronary disease burden

  • when compared with serum hs-CRP levels may be the association of the
  • on-site presence of neutrophils and local inflammatory signal–triggered release of  PTX-3.

On the other hand, some human studies revealed that PTX-3 was produced more in areas of atherosclerosis and may contribute to its pathogenesis.31
Some other studies suggested that PTX-3 may be part of a protective mechanism in

  • vascular repair via inhibiting fibroblast growth factor 2 or some other growth factors responsible for smooth muscle proliferation.33,34

But still, the exact role of PTX-3 in the pathophysiology of atherosclerosis seems to be obscure for the time being. It is well established that atherosclerosis
has an inflammatory background in most of the cases. In addition to that, high blood CRP level is known as an indicator of future cardiovascular disease risk
even in healthy individuals.35 According to the results of univariate and multivariate analyses, for intermediate and high SYNTAX scores,

  1. age, DM, LDL-C, hs-CRP, and PTX-3 were found to be independent predictors, whereas for the presence of
  2. high SYNTAX score, only PTX-3 was found to be an independent predictor.

Because of the tighter association with atherosclerotic burden and the on-site vascular presence,

    • PTX-3 may be a promising candidate marker for vascular inflammation and future cardiovascular events.

The major limitation of the current study is the number of patients included. It would be better to include more patients to increase the statistical power.

Besides, the SYNTAX and Gensini scores give us an idea about the complexity and severity of coronary atherosclerosis; however,
with coronary angiography alone, it is not possible to understand the extent of coronary plaque. In addition to that, the coronary anatomy of the
control group was not known, which was another limitation. Our selected population was free of other confounders of systemic inflammation, and
we did not have data about inflammatory markers other than hs-CRP, such as interleukin 6, tumor necrosis factor α, and so on, which may be accepted
as a limitation. Another limitation of the current study is that because there was no long-term follow-up of the patients, it did not provide any prognostic
data in terms of future cardiovascular events.
Pentraxin 3, a novel inflammatory marker, is associated with the complexity and severity of the CAD assessed by the SYNTAX and the Gensini scores in patients with SAP and seems to be more tightly associated with coronary atherosclerotic burden than hs-CRP.


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Keywords:  pentraxin 3; coronary artery disease; SYNTAX score; hs-CRP; inflammation

This is not the only recent finding that adds to the ability to evaluate these patients.  An as yet unpublished paper, expected to be published soon reports on

QRS fragmentation as a Prognostic test in Acute Coronary Syndrome,  and this reviewer expects the work to have a high impact.  The authors state that
QRS complex fragmentation is a promising bed-side test for assessment of prognosis in those patients.  Presence of fragmented QRS in surface ECG during ACS

  • represents myocardial scar or fibrosis and reflect severity of coronary lesions and a correlation between fQRS and depression of Lv function is established.

There are still other indicators that need to be considered, such as the mean arterial blood pressure.

There has been review and revisions of the guidelines for treatment of UA/NSTEMI within the last year, with differences being resolved among the Europeans and US.

Guidelines Updated for Unstable Angina/Non-ST Elevation Myocardial Infarction
According to the current study by Jneid and colleagues, new evidence is available on the management of unstable angina. This report replaces the 2007 American College of Cardiology Foundation/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (UA/NSTEMI) that were updated by the 2011 guidelines.

This guideline was reviewed by

  • 2 official reviewers each nominated by the ACCF and the AHA, as well as
  • 1 or 2 reviewers each from the American College of Emergency Physicians; the Society for Cardiovascular Angiography and Interventions; and the Society of Thoracic Surgeons; and
  • 29 individual content reviewers, including members of the ACCF Interventional Scientific Council.

The recommendations in this focused update are considered current

  • until they are superseded in another focused update or the full-text guideline is revised, and are official policy of both the ACCF and the AHA.

American cardiology societies have caught up with the European Society of Cardiology by

  • issuing their second update to the UA/NSTEMI guidelines in 18 months,
  • with the 2012 focused update replacing the 2011 guidelines [1].

The new recommendations include ticagrelor (Brilinta) as one of the options for antiplatelet therapy alongside prasugrel (Effient) and clopidogrel, bringing them in line with European.
The European guidance, however, gave precedence to the new antiplatelets over clopidogrel, whereas the American update “places ticagrelor on an equal footing with the other two antiplatelets available
this is the main reason for the update,” lead author Dr Hani Jneid (Baylor College of Medicine, Houston, TX), told heartwire . “Doctors now have a choice for second-line therapy after aspirin, depending on

  • the patient’s clinical scenario,
  • physician preference, and cost,”
    • now that clopidogrel is available generically.

The US decision to recommend

  • first prasugrel–in its 2011 update to the UA/NSTEMI guidelines–and
  • now ticagrelor as equivalent antiplatelet therapy choices to clopidogrel after aspirin
    • puts it somewhat at odds with the Europeans,
    • who reserve clopidogrel use for those who cannot take the newer agents.

The reason for the Americans differing stance is that because while they are faster acting and more potent–

  • the cost-effectiveness of the new agents is not known.
  • it isn’t clear how the efficacy observed in pivotal clinical trials of these agents is going to translate into real-world benefit,
  • and issues such as bleeding with prasugrel and compliance with a twice-daily drug such as ticagrelor remain concerns.

Bulk of 2012 Update on How to Use Ticagrelor
The 2012 ACCF/AHA focused update for the management of UA/NSTEMI stresses that

  • all patients at medium/high risk should receive dual antiplatelet therapy on admission,
  • with aspirin being first-line, indefinite therapy.

The bulk of the update centers on how to use ticagrelor which–

  • like prasugrel or clopidogrel–
  • can be added to aspirin for up to 12 months (or longer, at the discretion of the treating clinician).

Jneid notes it’s important to remember that prasugrel can only be used in the cath lab

  • in patients undergoing percutaneous coronary intervention (PCI),
  • whereas ticagrelor, like clopidogrel, can be used in medically managed or PCI patients.

And he emphasizes that, in line with the FDA’s black-box warning on ticagrelor,

The 81-mg aspirin dose is also considered a reasonable option in preference to a higher maintenance dose of 325 mg in

  • any acute coronary syndrome (ACS) patient following PCI, he adds, as
  • this strategy is believed to result in equal efficacy and lower bleeding risk.

With regard to how long antiplatelet therapy should be stopped before planned cardiac surgery, the recommendation is

  • five days for ticagrelor–the same as that advised for clopidogrel.
  • and seven days prior to surgery for prasugrel.

Jneid also highlights other important recommendations from the 2011 focused update carried over to 2012:

It is “reasonable” to proceed with cardiac catheterization and revascularization within

  • 12–24 hours of admission in initially stable, very high-risk patients with ACS.

An invasive strategy is “reasonable” in patients with

  • mild and moderate chronic kidney disease.

In those with diabetes hospitalized with ACS, insulin use should target glucose levels <180 mg/dL,

  • a less-intensive reduction than previously recommended.

Platelet function or genotype testing for clopidogrel resistance are both considered “reasonable”

  • if clinicians think the results will alter management,
  • but Jneid acknowledged that “there is not much evidence to support these assays” .

Committee Encourages Participation in Registries
Jneid observes that unstable angina and NSTEMI are “very common” conditions that carry a high risk of death and recurrent heart attacks,

  • which is why “the AHA and ACCF constantly update their guidelines so that physicians can provide patients with
  • the most appropriate, aggressive therapy with the goal of improving health and survival.”

To this end, he notes that the writing panel encourages

  • clinicians and hospitals to participate in quality-of-care registries designed
  • to track and measure outcomes, complications, and
  • adherence to evidence-based medicines.

Conflicts of interest for the writing committee are listed in the paper.


Jneid H, Anderson JL, Wright SR, et al. 2012 ACCF/AHA focused update on the guideline for the management of patients with unstable angina/non-ST elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the ACCF/AHA.
Circulation 2012;      Available at:

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What is the Role of Plasma Viscosity in Hemostasis and Vascular Disease Risk?

Author: Larry H Bernstein, MD


Curator: Aviva Lev-Ari, PhD, RN

This is the first of a two part discussion of viscosity, hemostasis, and vascular risk

Part II:  Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Thesis Statement: The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans.  (Seminal study)

G. D. Sloop, MD.
Department of Pathology, Louisiana State University School of Medicine,
New Orleans, LA 70112, U.S.A.

  •  Increased blood or plasma viscosity has been associated with increased atherogenesis, and that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with atherosclerosis risk.
  • Low-density lipoprotein-cholesterol was more strongly correlated with blood viscosity than was total cholesterol (r = 0.4149, P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density lipoprotein-cholesterol levels were inversely associated with blood viscosity (r = – 0.4018, P = 0.0341).
  • To confirm these effects, viscometry was performed on erythrocytes, suspended in saline, which had been incubated in plasma of various low-density lipoprotein/high-density lipoprotein ratios. Viscosity correlated directly with low-density lipoprotein/high-density lipoprotein ratio (n = 23, r = 0.8561, P < 0.01).
  • Low-density lipoprotein receptor occupancy data suggests that these effects on viscosity are mediated by erythrocyte aggregation.
  • These results demonstrate that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity in healthy subjects may play a role in atherogenesis by modulating the dwell or residence time of atherogenic particles in the vicinity of the endothelium.

This discussion is an additional perspective on the series on coagulation, and earlier posts that were on flow dynamics.

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

Atrial Fibrillation: The Latest Management Strategies

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Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Nitric Oxide Signalling Pathways            AviralvatsaEndothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells

Septic Shock: Drotrecogin Alfa (Activated) in Septic Shock

Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation   LHB

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?  SJWilliamspa

Vascular Wall Shear Stress

Shear Stress

  1. The basic principles concerning mechanical stress applies to pathophysiological mechanisms in the vascular bed. In physics, stress is the internal distribution of forces within a body that balance and react to the external loads applied to it. Blood flow in the circulation leads to the development of superficial stresses near the vessel walls in either of two categories:

a) circumferential stress due to pulse pressure variation inside the vessel;
b) shear stress due to blood flow.

  1. The direction of the shear stress vector is determined the blood flow velocity vector adjacent to applied against the vessel wall.
  2. Friction is the opposing force applied by the wall.
  3. Shear stresses are disturbed by turbulent flow, regions of flow recirculation or flow separation.
  4. The notions of shear rate and fluid viscosity are crucial for the assessment of shear stress.

Fluid Flow and Shear Stress

  1. Shear rate is defined as the rate at which adjacent layers of fluid move with respect to each other, usually expressed as reciprocal seconds.
  2. The size of the shear rate gives an indication of the shape of the velocity profile for a given situation.
  3. The determination of shear stresses on a surface is based on the fundamental assumption of fluid mechanics, according to which the velocity of fluid upon the surface is zero (no-slip condition).
  4. Assuming that the blood is an ideal Newtonian fluid with constant viscosity, the flow is steady and laminar and the vessel is straight, cylindrical and inelastic, which is not the case. Under ideal conditions a parabolic velocity profile could be assumed.

The following assumptions have been made:

  1. The blood is considered as a Newtonian fluid.
  2. The vessel cross sectional area is cylindrical.
  3. The vessel is straight with inelastic walls.
  4. The blood flow is steady and laminar.

The Haagen-Poisseuille equation indicates that shear stress is directly proportional to blood flow rate and inversely proportional to vessel diameter.

  1. Viscosity is a property of a fluid that offers resistance to flow, and it is a measure of the combined effects of adhesion and cohesion.
  2. Viscosity increases as temperature decreases.
  3. Blood viscosity (non-Newtonian fluid) depends on shear rate, which is determined by blood platelets, red cells, etc.
  4. Blood viscosity is slightly affected by shear rate changes at low levels of hematocrit, but as hematocrit increases, the effect of shear rate changes becomes greater.
  5. the dependence of blood viscosity on hematocrit is more pronounced in the microcirculation than in larger vessels, due to hematocrit variations observed in small vessels (lumen diameter <100 Ìm).

The significant change of hematocrit in relation to vessel diameter is associated with the tendency of red blood cells to travel closer to the centre of the vessels. Thus, the greater the decrease in vessel lumen, the smaller the number of red blood cells that pass through, resulting in a decrease in blood viscosity.

Shear stress and vascular endothelium

  1. Endothelium responds to shear stress depending on the kind and the magnitude of shear stresses.
  2. the exposure of vascular endothelium to shear forces in the normal value range stimulates endothelial cells to release agents with direct or indirect antithrombotic properties, such as
  • prostacyclin,
  • nitric oxide (NO),
  • calcium,
  • thrombomodulin, etc.

Changes in shear stress magnitude activate cellular proliferation mechanisms as well as vascular remodeling processes.

  1. a high grade of shear stress increases wall thickness and expands the vessel’s diameter
  2. low shear stress induces a reduction in vessel diameter.
  3. Shear stresses are maintained at a mean of about 15 dynes/cm2.
  4. The presence of low shear stresses is frequently accompanied by unstable flow conditions
  • turbulence flow,
  • regions of blood recirculation,
  • “stagnant” blood areas.

(Papaioannou TG, Stefanadis C. Vascular Wall Shear Stress: Basic Principles and Methods. Hellenic J Cardiol 2005; 46: 9-15.)

Hemorheology and Microvascular Disorders

Blood flow in large arteries is dominated by inertial forces exhibited at high flow velocities, while viscosity is negligible. When the flow velocity is compromised by deceleration at a bifurcation, endothelial cell dysfunction can occur along the outer wall at the bifurcation.

In sharp contrast, the flow of blood in micro-vessels is dominated by viscous shear forces since the inertial forces are negligible due to low flow velocities. Shear stress is a critical parameter in micro-vascular flow, and a force-balance approach is proposed for determining micro-vascular shear stress. When the attractive forces between erythrocytes are greater than the shear force produced by micro-vascular flow, tissue perfusion itself cannot be sustained.

The yield stress parameter is presented as a diagnostic candidate for future clinical research, specifically, as a fluid dynamic biomarker for micro-vascular disorders. The relation between the yield stress and diastolic blood viscosity (DBV) is described using the Casson model for viscosity, from which one may be able determine thresholds of DBV where the risk of microvascular disorders is high.

Cho Y-Il, and Cho DJ. Hemorheology and Microvascular Disorders. Korean Circ J 2011; 41:287-295.
Print ISSN 1738-5520 / On-line ISSN 1738-5555

Blood Rheology in Genesis of Atherothrombosis

Elevated blood viscosity is an integral component of vascular shear stress that contributes to the

  • site specificity of atherogenesis,
  • rapid growth of atherosclerotic lesions, and
  • increases their propensity to rupture.

Ex vivo measurements of whole blood viscosity (WBV) is a predictor of cardiovascular events in apparently both healthy individuals and cardiovascular disease patients. The association of an elevated WBV and incident cardiovascular events remains significant in multivariate models that adjust for major cardiovascular risk factors.

These prospective data suggest that measurement of WBV may be valuable as part of routine cardiovascular profiling, thereby potentially useful data for risk stratification and therapeutic interventions.

The recent development of a high throughput blood viscometer, which is capable of rapidly performing blood viscosity measurements across 10,000 shear rates using a single blood sample, enables the assessment of blood flow characteristics in different regions of the circulatory system and opens new opportunities for detecting and monitoring cardiovascular diseases.

Cowan AQ, Cho DJ, & Rosenson RS. Importance of Blood Rheology in the Pathophysiology of Athero-thrombosis. Cardiovasc Drugs Ther 2012; 26:339–348. DOI 10.1007/s10557-012-6402-4


English: shear stress

English: shear stress (Photo credit: Wikipedia)

English: Shear rate dependency on fluid type a...

English: Shear rate dependency on fluid type and applied shear stress. (Photo credit: Wikipedia)

Inflammatory, haemostatic, and rheological markers

Markers of inflammation, hemostasis, and blood rheology have been ascertained to be risk factors for coronary heart disease and stroke. Their role in peripheral arterial disease (PAD) is not well established and some of them, including the pro-inflammatory cytokine interleukin-6 (IL-6), have not been examined before in prospective epidemiological studies.

In the Edinburgh Artery Study, we studied the development of PAD in the general population and evaluated 17 potential blood markers as predictors of incident PAD. At baseline (1987), 1519 men and women free of PAD aged 55–74 were recruited. After 17 years, 208 subjects had developed symptomatic PAD. In analysis adjusted for cardiovascular risk factors and baseline cardiovascular disease (CVD), only

  1. C-reactive protein 1.30 (1.08, 1.56)
  2. fibrinogen               1.16 (1.05, 1.17)
  3. lipoprotein (a)        1.22 (1.04, 1.44),
  4. hematocrit 1.22 (1.08, 1.38) [hazard ratio (95% CI) ]

-corresponding to an increase equal to the inter-tertile range-

were significantly (P , 0.01) associated with PAD.

These markers provided very little prognostic information for incident PAD to that obtained by cardiovascular risk factors and the ankle brachial index. Other markers included:

  • IL-6
  • intracellular adhesion molecule 1 (ICAM-1)
  • D-dimer
  • tissue plasminogen activator antigen
  • plasma and blood viscosities

having weak associations, were considerably attenuated when accounting for CVD risk factors.

Tzoulaki I, Murray GD, Lee AJ, Rumley A, et al. Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. European Heart Journal (2007) 28, 354–362. doi:10.1093/eurheartj/ehl441


Leukocyte and platelet adhesion under flow

Leukocyte adhesion under flow in the microvasculature is mediated by

  • binding between cell surface receptors and
  • complementary ligands expressed on the surface of the endothelium.

Leukocytes adhere to endothelium in a two-step mechanism:

  1. rolling (primarily mediated by selectins) followed by
  2. firm adhesion (primarily mediated by integrins).

These investigators simulated the adhesion of a cell to a surface in flow, and elucidated the relationship between receptor–ligand functional properties and the dynamics of adhesion using a computational method called ‘‘Adhesive Dynamics.’’

Behaviors that are observed in simulations include

  • firm adhesion,
  • transient adhesion (rolling), and
  • no adhesion.

They varied the

  • dissociative properties,
  • association rate,
  • bond elasticity, and
  • shear rate

and found that the

  1. unstressed dissociation rate, kro,
  2. and the bond interaction length, γ,

are the most important molecular properties controlling the dynamics of adhesion.

(Chang KC, Tees DFJ andHammer DA. The state diagram for cell adhesion under flow: Leukocyte rolling and firm adhesion. PNAS 2000; 97(21):11262-11267.)

  • The effect of leukocyte adhesion on blood flow in small vessels is treated as a homogeneous Newtonian fluid is sufficient to explain resistance changes in venular microcirculation.
  • The Casson model represents the effect of red blood cell aggregation and requires the non-Newtonian fluid flow model of resistance changes in small venules.

In this model the blood vessel is considered as a circular cylinder and the leukocyte is considered as a truncated spherical protrusion in the inner side of the blood vessel.

Numerical simulations demonstrated that for a Casson fluid with hematocrit of 0.4 and flow rate Q = 0:072 nl/s, a single leukocyte increases flow resistance by 5% in a 32 m diameter and 100 m long vessel. For a smaller vessel of 18 m, the flow resistance increases by 15%.

(Das B, Johnson PC, and Popel AS. Computational fluid dynamic studies of leukocyte adhesion effects on non-Newtonian blood flow through microvessels. Biorheology  2000; 37:239–258.)

Adhesive interactions between leukocytes

The mechanics of how blood cells interact with one another and with biological or synthetic surfaces is quite complex: owing to

  • the deformability of cells,
  • the variation in vessel geometry, and
  • the large number of competing chemistries present

(Lipowski et al., 1991, 1996).

Adhesive interactions between white blood cells and the interior surface of the blood vessels they contact are important in

  • inflammation and in
  • the progression of heart disease.

Parallel-plate micro-channels have been used to characterize the strength of these interactions. Recent computational and experimental work by several laboratories are directed at bridging the gap between

  • behavior observed in flow chamber experiments, and
  • cell surface interactions observed in the micro-vessels

What follows is a computational simulation of specific adhesive interactions between cells and surfaces under flow. In the adhesive dynamics formulation, adhesion molecules are modeled as compliant springs. The Bell model is used to describe the kinetics of single biomolecular bond failure, which relates

  1. the rate of dissociation kr to
  2. the magnitude of the force on the bond F.

The rate of formation directly follows from the Boltzmann distribution for affinity. The expression for the binding rate must also incorporate the effect of the relative motion of the two surfaces. Unless firmly adhered to a surface, white blood cells can be effectively modeled as rigid spherical particles. This is consistent with good agreement between bead versus cell in vitro experiments (Chang and Hammer, 2000).

Various methods have been used to bring clarity to the complex range of transient interactions between

  • cells,
  • neighboring cells, and
  • bounding surfaces under flow.

Knowledge gained from these investigations of flow systems may prove useful in microfluidic applications where the transport of

  • blood cells and
  • solubilized, bioactive molecules is needed, or
  • in miniaturized diagnostic devices

where cell mechanics or binding affinities can be correlated with clinical pathologies.

(King MR. Cell-Surface Adhesive Interactions in Microchannels and Microvessels.   First International Conference on Microchannels and Minichannels. 2003, Rochester, NY. Pp 1-6. ICMM2003-1012.

Monitoring Blood Viscosity to Improve Cognitive Function

Blood viscosity, the metric for the thickness and stickiness of blood, is associated with all major risk factors for cardiovascular disease, complications of diabetes, and it is highly predictive of stroke and MI, as well as cognitive decline. While elevated blood viscosity has a role in the etiology of atherosclerosis,  there is strong evidence for a causal role in the development of dementia.  It follows that improving blood viscosity should lead to improvements in cognitive as well as cardiovascular function.

Factors Affecting Blood Viscosity

Five cardinal factors are:

  1. Hematocrit,
  2. erythrocyte deformability,
  3. plasma viscosity,
  4. erythrocyte aggregation, and
  5. temperature

First to consider is hematocrit. Erythrocyte deformability is the ability of red blood cells to elongate and fold themselves for better hemodynamic flow in large vessels as well as for more efficient passage through capillaries.  The more deformable the red blood cells, the less viscous the blood.  Young red blood cells are flexible and tend to stiffen over their 120 day life-span.  Erythrocyte deformability is, after hematocrit, the second most important determinant of blood viscosity.

The third factor is plasma viscosity.  An important determinant of plasma viscosity is hydration status, but it is also determined by the presence of high molecular-weight proteins, especially immune globulins and fibrinogen.

Erythrocyte aggregation, the tendency of red blood cells to be attracted to each other and stick together is not well understood, but erythrocyte deformability and plasma proteins play important roles.

Blood, like most other fluids, is less viscous at higher temperatures. It is estimated that a 1°C increase in temperature results in a 2% decrease in blood viscosity.

Viscous Blood is Abrasive Blood

Maintaining efficient blood flow through the vessels forms layers, or lamina, that slide easily over each other.

  • Faster flowing blood can be found in the central layers and
  • Slower moving blood in the outer layers near the vessel walls.
  • Hyper-viscous blood doesn’t slide as smoothly as less viscous blood.
  • The turbulence damages the delicate intima of the blood vessel.

One of the most common locations for the development of atherosclerotic plaques is at the bifurcation of the carotid arteries, and the positioning of these plaques can be mapped to the turbulent blood flow patterns of this region.

Blood viscosity is highly correlated with thickening of the carotid intima-media, a prelude to plaque formation.  As the carotid arteries become progressively more occluded, there is decreased blood supply to the brain.

Hyper-viscosity also impacts the brain at the level of micro-perfusion.  Stiffened red blood cells have a decreased ability to bend and fold as they pass through capillaries. This leads to endothelial abrasion.  The capillary walls thicken and diffusion of oxygen and nutrients into the tissues decreases. The effect is most pronounced in those tissues where perfusion is essential for unimpaired function, such as the brain.

Diabetes, Blood Viscosity, and Dementia

While diabetics have elevated blood viscosity, blood viscosity is a risk factor that predicts progression from metabolic syndrome to diabetes. Red blood cell flexibility is greatly reduced by fluctuations in the osmolality of the blood which is affected by blood glucose concentration.  Uncontrolled, this leads to  small vessel disease.

  • Blindness,
  • kidney insufficiency, and
  • leg ischemia

develop as these organs are the dependent on micro-perfusion.

The Rotterdam Study and other research point to decreased cognitive function and increased dementia among diabetics as being further manifestations of the decreased perfusion that accompanies elevated blood viscosity.


Blood Viscosity, Cognitive Decline, and Alzheimer’s

Multiple forms of cognitive decline, including dementia and Alzheimers’ are impacted by increased blood viscosity. The Edinburgh Artery Study (2010) showed that blood viscosity predicted cognitive decline over a four year period in 452 elderly subjects (p<0.05).  Blood viscosity, an important determinant of the circulatory flow, was significantly linked with cognitive function.  The associations between cardiovascular risk factors, vascular dementia, and Alzheimer’s disease were presented by de la Torre (2002) (nine points of evidence) in a compelling argument that Alzheimer’s is a vascular disorder characterized by impaired micro-perfusion to the brain.

Testing for Blood Viscosity

The most recent technology uses an automated scanning capillary tube viscometer capable of measuring viscosity over the complete range of physiologic values experienced in a cardiac cycle (10,000 shear rates) with a single continuous measurement. This test provides clinicians with measurements of blood viscosity at both systolic and diastolic pressures.

Blood viscosity testing is indicated for a wide range of patients, as good tissue perfusion is central to good health regardless of what system is being addressed.  Patients with signs of cognitive decline should be high on the list of those appropriate to test, and those patients with a history or family history of heart disease, stroke, hypertension, diabetes, metabolic syndrome, migraines, smoking, alcoholism or other risk factors associated with the development of Alzheimer’s disease.

Source: Larsen P, Monitoring Blood Viscosity to Improve Cognitive Function

  1. World Health Organization. Dementia: A Public Health Priority. April, 2012.
  2. Sloop GD. A unifying theory of atherogenesis. Med Hypotheses. 1996; 47:321-5.
  3. Kensey KR and Cho, Y. Physical Principles and Circulation: Hemodynamics. In: The Origin of Atherosclerosis: What Really Initiates the Inflammatory Process. 2nd Ed. Summersville, WV: SegMedica; 2007:33-50.
  4. Hofman A., Ott A, et. al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet, 1997, 349 (9046): 151-154


 Sleep Apnea and Blood Viscosity.

Obstructive sleep apnea (OSA) is an important public health concern, which affects around 2–4% of the population. Left untreated, it causes a decrease not only in quality of life, but also of life expectancy. Despite the fact that knowledge about the mechanisms of development of cardiovascular disease in patients with OSA is still incomplete, observations confirm a relationship between sleep disordered breathing and the rheological properties of blood.

Tażbirek M, Słowińska L, Kawalski M, Pierzchała W.   The rheological properties of blood and the risk of cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS) Folia Histochemica et Cytobiologica 2011; 49(2):206–210.

Hemostatic and Rheological Risk Factors and the Risk Stratification

Backgound: Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD). We hypothesize, that hemostatic
and rheological risk factors may be of major relevance for the incidence and the risk stratification of these patients.

  • Methods: In 243 patients with coronary artery disease and stable angina pectoris parameters of metabolism, hemostasis, blood rheology and endogenous fibrinolysis were assessed.

Patients were prospectively followed for 2 years in respect to elective revascularizations and acute coronary syndromes.

Results: During follow-up 88 patients presented with cardiac events, 22 of those were admitted to the hospital because of acute events, 5 Patients were excluded due to non- cardiac death.

Patients with clinical events were found to be more frequently diabetic and presented with a more progressed coronary atherosclerosis. Even though patients with diabetes mellitus demonstrated a comparable level of multivessel disease (71% vs. 70%) the rate of elective revascularization was higher (41% vs. 28%, p < 0.05). The results were also unfavorable for
the incidence of acute cardiovascular events (18% vs. 8%, p < 0.01).

In comparison to non-diabetic patients diabetics demonstrated significantly elevated levels of

  • fibrinogen (352 ± 76 vs. 312 ± 64 mg/dl, p < 0.01),
  • plasma viscosity (1.38 ± 0.23 vs. 1.31 ± 0.16 mPas, p < 0.01),
  • red blood cell aggregation (13.2 ± 2.5 vs. 12.1 ± 3.1 E, p < 0.05) and

plasmin-activator-inhibitor (6.11 ± 3.4 vs. 4.7 ± 2.7 U/l, p < 0.05).

Conclusion: Pathological alterations of fibrinogen, blood rheology and plasminogen-activatorinhibtor as indicators of a procoagulant state are of major relevance for the
short-term incidence of cardiac events, especially in patients with diabetes mellitus type 2, and may be used to stratify patients to specific therapies.

parameters of metabolism, hemostasis, endogenous fibrinolysis and blood rheology for patients with and without diabetes mellitus.

diabetes mellitus non-diabetic patients p-value
glucose (mg/dl) 157 ± 67 88 ± 12 <0,0001
fibrinogen (mg/dl) 351 ± 76 312 ± 64 <0,01
plasma viscosity (mPa × s-1) 1,38 ± 0,23 1,31 ± 0,16 <0,01

Jax TW, Peters AJ, Plehn G, and  Schoebel FC. Hemostatic risk factors in patients with coronary artery disease and type 2 diabetes – a two year follow-up of 243 patients. Cardiovascular Diabetology 2009; 8:48-57.  doi:10.1186/1475-2840-8-48


Abnormal Viscosity in Pregnancy

Abnormal hemorheology has been shown to be in almost all conditions associated with accelerated atherosclerotic cardiovascular disorders. The aim of this study is to test the hypothesis that high concentration of plasma Triglyceride (TG) predicts altered hemorheological variables in normal pregnancy.

Sixty pregnant women attending antenatal clinic of the University of Ilorin Teaching Hospital at 14-36 weeks of gestation (aged 21-36 years) were recruited after giving informed consent to participate in the study. They consisted of 28 primigravidae and 32 multigravidae. Twenty-four healthy non-pregnant women of similar age and socioeconomical status were also recruited. The study showed that fasting plasma Triglyceride (TG) increased significantly in primigravidae and multigravidae.

There was a positive correlation between plasma TG level and blood viscosity (r = 0.36, p<0.01). TG also correlated positively with hematocrit (r = 0.48, p<0.001), hemoglobin concentration (r = 0.43, p<0.001) and white blood cell count (r = 0.38, p<0.01) in the pregnant group as a whole. In primigravidae, there was a strong correlation between TG and

o          blood viscosity (r = 0.63, p<0.001),

o          hematocrit (r = 0.88, p<0.001),

o          hemoglobin concentration (r = 0.85, p<0.001).

However, there was an insignificant correlation between TG and the hemorheological variables in multigravidae.

Plasma TG concentration in primigravidae is strongly associated with blood viscosity also with hematocrit and hemoglobin concentration, but the association is lost in multigravidae. Therefore, TG could be considered as an important potential indicator of altered blood rheology in primigravidae, but not in multigravidae.

Olatunji LA, Soladoye AO, Fawole AA, Jimoh RO and Olatunji VA. Association between Plasma Triglyceride and Hemorheological Variables in Nigerian Primigravidae and Multigravidae.

Research Journal of Medical Sciences 2008; 2(3):116-120. ISSN: 1815-9346.


Retinal Vein Occlusion

Retinal vein occlusion (RVO) is an important cause of permanent visual loss. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of RVO. Aim of this case-control study was to evaluate the possible association between hemorheology and RVO. In 180 RVO patients and in 180 healthy subjects comparable for age and gender we analysed the whole hemorheological profile: [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV), and fibrinogen]. WBV and PLV were measured using a rotational viscosimeter, whereas DI was measured by a microcomputer-assisted filtrometer. WBV at 0.512 sec-1 and 94.5 sec-1 shear rates as well as DI, but not PLV, were significantly different in patients as compared to healthy subjects.

At the logistic univariate analysis, a significant association between the

  • highest tertiles of WBV at 94.5 sec-1 shear rate (OR:4.91,95%CI 2.95–8.17;p<0.0001),
  • WBV at 0.512 sec-1 shear rate (OR: 2.31, 95%CI 1.42–3.77; p<0.0001), and
  • the lowest tertile of DI (OR: 0.18, 95%CI 0.10–0.32; p<0.0001) and RVO was found.

After adjustment for potential confounders,

  • the highest tertiles of WBV at 0.512 sec-1 shear rate (OR: 3.23, 95%CI 1.39–7.48; p=0.006),
  • WBV at 94.5 sec-1 shear rate (OR: 6.74, 95%CI 3.06–14.86; p<0.0001) and
  • the lowest tertile of DI (OR:0.20,95%CI 0.09–0.44,p<0.0001)

remained significantly associated with the disease. In conclusion, the data indicate that an alteration of hemorheological parameters may modulate the susceptibility to the RVO.

Sofi F, Mannini L, Marcucci R, Bolli P, Sodi A, et al.  Role of hemorheological factors in patients with retinal vein occlusion. In Blood Coagulation, Fibrinolysis and Cellular Haemostasis.  Thromb Haemost 2007; 98:1215–1219.

Summary:  This discussion is a two part sequence that first establishes the known strong relationship between blood flow viscosity, shear stress, and plasma triglycerides (VLDL) as risk factors for hemostatic disorders leading to thromboembolic disease, and the association with atherosclerotic disease affecting the heart, the brain (via carotid blood flow), peripheral circulation, the kidneys, and retinopathy as well.

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Reporter: Aviva Lev-Ari, PhD, RN

Updated 3/10/2013

Since August 25, 2012, when the ESC: New Definition of MI Unveiled was reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco as was reported  By Chris Kaiser, Cardiology Editor, MedPage Today,  a new discussion emerged by ACC asking if FFR CT is Ready for prime time or not?

By Lisa Fratt
Mar 09, 2013

SAN FRANCISCO—Is there a better way to measure fractional flow reserve (FFR), Bon-Kwon Koo, MD, of Seoul National University queried a crowded room March 9 during an educational session at the American College of Cardiology (ACC) scientific session.

The current model is good for patients, safe and effective, Koo said. However, it requires an invasive procedure and is expensive. FFR CT may provide a method to measure FFR without an invasive procedure.

FFRCT extracts geometry from a CT scan to determine boundary conditions and fluid properties. In addition, velocity and pressure can be calculated. The hitch is that a supercomputer is required to solve the blood flow equation, said Koo. The results provide anatomical and functional data, thus giving a possible answer to the question at hand.

FFRCT may change daily practice in several ways. Most importantly, it may be a novel, fast, risk-free, noninvasive cost-saving way to measure FFR and identify patients who may not need to be sent to the cath lab for stenting or PCI. It can provide information to help surgeons plan strategies before invasive procedures, bypass procedures or interventional procedures. Noninvasive CT-derived FFR also can predict the functional significance of coronary lesions.

Despite its promise, however, FFR CT is not ready for prime time, Koo said. FFR CT depends on the diagnostic accuracy of coronary CT angiography stenosis, which is less than true stenosis. With current technologies, true stenosis provides the required diagnostic accuracy.

FFRCT is promising, but further development of the technology is required, Koo concluded.—ready-prime-time-or-not

ESC: New Definition of MI Unveiled

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: August 25, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — An international, multispecialty task force has published a new definition of myocardial infarction that was prompted by the new generation of highly sensitive cardiac troponin (cTn) assays.

The highly sensitive assays are capable of detecting cTn in conditions other than MI, such as pulmonary embolism, cardiomyopathy, and left bundle branch block, and so result in false positives, according to the task force writing group.

The expert consensus document dips into a controversial area by setting levels of cTn for MI associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).

“This is one of the most controversial areas in the definition of myocardial infarction,” Anthony DeMaria, MD, from the University of California in San Diego and editor-in-chief of the Journal of the American College of Cardiology, told MedPage Today.

“There are a large number of people undergoing PCI in the setting of an acute MI. It’s almost impossible to know whether a subsequent increase in troponin was part and parcel of the acute MI or related to the procedure itself,” DeMaria said.

The consensus document, titled “Third Universal Definition of Myocardial Infarction,” set the cTn levels for MI associated with PCI as elevation of troponin greater than 5 times the 99th percentile upper reference limit (URL) in patients with normal baseline levels or a rise in troponin values greater than 20% if the baseline values are elevated and are stable or falling.

“Some people speculate that troponin may be too sensitive in this situation and what is needed is evidence that an elevation of some degree of troponin following a procedure actually results in some alteration of the natural history of the patient,” DeMaria said. “In other words, the definition of acute MI after a procedure really is of significance if it increases the risk of subsequent events such as death.”

In CABG, the task force set the troponin values as greater than 10 x 99th percentile URL during the first 48 hours when baseline values are normal.

DeMaria said there are several ongoing studies examining the correlation of elevated cTn with subsequent events. As this is the third definition of MI since 2000, there most likely will be more refinements as new data emerge, he said.

The document is being copublished online in several journals including the Journal of the American College of CardiologyCirculation, the European Heart Journal, and Global Heart.

The task force was in touch with the FDA during the development of this new definition, which means it could be used as the basis for clinical trial protocols designed according to FDA regulations.

“A universal definition for MI is of great benefit for clinical studies, since it will allow a standardized approach for interpretation and comparison across different trials,” the task force writing group explained.

When different definitions have been used in trials, it hampers “comparison and generalization between these trials,” they said.

Also of significance in this document is the inclusion of imaging as a means to identify or confirm an MI. The document spells out the strengths of echocardiography, nuclear imaging, MRI, and CT in the setting of acute MI.

“Imaging is playing an increasingly important role,” DeMaria said. “In the absence of focal symptoms or with an inconclusive ECG, it’s important to recognize the concomitant potential of ancillary measures, primarily imaging, to help with the diagnosis of a myocardial infarction.”

Thygesen reported relationships with Edwards Lifesciences, Servier, St. Jude Medical, Roche Pharma, and Roche Diagnostics. Her co-authors and reviewers reported relationships with Bayer Healthcare, Daiichi Sankyo, Johnson & Johnson, sanofi aventis, Servier, Novartis, Boehringer-Ingelheim, Genzyme, Eli Lilly, OrthoClinical Diagnostics, Abbott Laboratories, Alere, Brahms, Siemens Healthcare, Roche Pharma, Radiometer, BioRad, Diagenics, Response Medical, Takeda Pharmaceuticals, Regado Biosciences, Bristol-Myers Squibb, Merck Sharp and Dohme, GlaxoSmithKline, Merck, Portola Pharmaceuticals, AstraZeneca, Regado Biosciences, Scios, Ortho-Biotech, Pfizer, Kai Pharmaceuticals, Iroko Cardio, Philips, GE Healthcare, Boston Scientific, Lantheus, Medtronic, St. Jude Medical, Biotronik, Impulse Dynamics, Edwards Lifesciences, Health System Networks, Health Station Networks, Insight Telehealth Systems, Elsevier Sciences, Gilead, Evolva, Medicines Company, F. Hoffman La Roche, Torrent, Vifor International, Corthera, Nanosphere, Bayer Schering Pharma, Cardiorentis, Molecular Insight Pharmaceuticals, Berlin Chemie, Menarini, Cordis, Beckman Coulter, Amgen, Critical Diagnostics, Tethys Bioscience, Roche Diagnostics, bioMérieux, Genentech, Ikaria, Singulex, BG Medicine, Shionogi, Amylin, DiaDexus, Orion, WebMD,, Pozen, Maquet, BHFZ, Covidien, Rapidscan, Actelion, Athera, Symetis, Schering-Plough, OrbusNeich, Terumo, Cardio3 Biosciences, Micell, Ablynx, Therabel, Kowa, Zentiva, Chugai Pharma, Automedics Medical Systems, Essentialis, Biosensors, Vascular Solutions, Zoll Medical, JaBA Recordati, Actavis, PharmaSwiss, Eisai, Medscape, Accumetrics, Bial Portela, AGA, Novo-Nordisk, Janssen-Cilag, Valtech, Otsuka Pharmaceuticals, Meda Pharma, CEPHALON, Intracellular Therapies USA, Santhera, TROPHOS, Pierre-Fabre, and Lundbeck.

DeMaria reported relationships with Gilead, ResMed Foundation, Lantheus, Cardiovascular Biotherapeutics, Angioblast Systems, General Electric Medical Systems, and Cardionet.

Primary source: European Heart Journal

Source reference:
Thygesen K, et al “Third universal definition of myocardial infarction” Eur Heart J 2012; DOI: 10.1093/eurheartj/ehs184.

ESC: FFR CT Has Potential for Tagging Ischemia

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: August 26, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

MUNICH — Using CT imaging to assess the hemodynamic significance of coronary lesions is “promising” but needs more research before it displaces conventional invasive fractional flow reserve (FFR), researchers said.

Using FFR as the reference standard, FFRCTplus CT angiography (CTA) had good sensitivity (90%) and negative predictive value (84%) on a per patient basis for detecting ischemia, which indicates a low rate of false-negative studies, according to James K. Min, MD, of Cedars-Sinai Heart Institute in Los Angeles, and colleagues.

Although FFRCT plus CTA were superior to CTA alone, the specificity (54%) and negative predictive value (67%) of the combination remained low compared with conventional FFR, indicating that a considerable number of false-positive studies would endure, Min reported here during a Hot-Line session at the European Society of Cardiology meeting.

The results of this proof of concept study show that FFRCT can “impart considerable discriminatory power” to detect and exclude ischemia in patients with suspected CAD, Min said.

However, future studies should be conducted to determine the cost-effectiveness of FFRCT in guiding decisions to stent, particularly given the potentially high false-positive rate, he added.

“Non-invasive FFR is a dream for all interventional cardiologists,” said study discussant Jean-Pierre Bassand, MD, of the University Hospital Jean-Minjoz in Besançon, France. Although Bassand praised the DeFACTO study, he expressed concern about the discrepancy between the accuracy of FFR versus FFRCT.

For example, compared with FFR, the sensitivity and specificity of FFRCT in cases of greater than 90% or less than 30% stenosis were 83% and 76%, respectively. The per-vessel correlation of FFRCT to FFR was 0.63.

“What matters is the correlation with FFR,” he concluded.

A single non-invasive imaging test that can identify obstructive coronary artery disease (CAD) and determine the physiological significance of those lesions would be ideal. At present, nuclear stress imaging fulfills the first part, but it cannot label stenoses as hemodynamically significant or not. Also, nuclear stress testing suffers from high rates of both false-negative and false-positive studies, Min said.

The results of this study are in line with stress imaging: per patient diagnostic accuracy of 73% (95% CI 67% to 78%). Min said that studies are being designed to compare FFRCT plus CTA with stress imaging.

“For patients considered for invasive therapy, this type of test could help exclude those who don’t need to be stented,” Spencer King III, MD, of St. Joseph’s Hospital in Atlanta told MedPage Today.

“The excitement about this CT approach is that it moves things closer to being able to assess physiology and anatomy in a single non-invasive test,” added King, who is also a past president of the American College of Cardiology.

However, the process of calculating the FFR values from CT data currently takes about 6 hours, Min told MedPage Today. The CT data are sent offsite to HeartFlow, the company that makes the software. Whether such processing would be done onsite in the future is not yet determined, Min said. He also expects the processing time to drop to about 2 hours by the year’s end.

HeartFlow has already received EU mark to use the software in Europe and is in the process of applying for FDA approval, Min said.

Conventional FFR uses a pressure wire inserted through the groin to the coronary arteries to determine the hemodynamic significance of lesions. The same data can be gleaned during a typical CTA exam with software that calculates computational fluid dynamics,without additional radiation exposure. The median radiation exposure among the study centers was 6.4 mSv (range 4.4 to 15 mSv).

The original FAME study found the use of FFR to guide stenting was better than relying on angiography alone in patients with multivessel disease. A second study, FAME II, was stopped early because of the overwhelming benefit seen in patients with stable CAD when FFR guided stenting versus patients randomized to optimal medical therapy.

Because FFRCT is a novel technique, it has not been adequately evaluated in its ability to identify patients with ischemia, Min said.

The researchers therefore designed the DeFACTO (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) study, which sought to evaluate the accuracy of FFRCT while using invasive FFR as the reference standard.

The study was also simultaneously published online in the Journal of the American Medical Association.

The 252 patients with suspected or known CAD were recruited from 17 centers in five countries between October 2010 and October 2011. They were scheduled to undergo diagnostic catheter angiography.

The mean age of patients was 63, 70% were men, and a majority were white. Nearly half of the patients had obstructive CAD (>50% stenosis).

Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. Invasive coronary angiography and FFR identified 46.5% of 408 vessels with obstructive CAD, while CT and FFRCT identified 52.3% of 406 vessels.

A total of 172 patients had an FFR value <0.80, which indicates an ischemic lesion.

The diagnostic accuracy of FFRCT plus CT was 73% (95% CI 67% to 78%), but this did not meet the prespecified primary endpoint of greater than 70% of the lower bound of the 95% confidence interval, Min said.

However, Min emphasized that FFRCT was superior to CTA alone in all categories.

The researchers concluded that the results show the potential of FFRCT as a “promising” non-invasive tool to identify ischemia.

King added that despite not meeting the prespecified primary endpoint, “it’s an encouraging early study.”

This study was funded by HeartFlow

Min reported relationships with GE Healthcare and Philips Medical. Some of his co-authors reported relationships with GE Healthcare, Siemens Medical Systems, Lantheus Medical Imaging, Boston Scientific, Merck, Abbott Vascular, Medtronic, Cordis, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, and sanofi-aventis.

King reporeted relationships with Merck & Company, Wyeth Pharmaceuticals, Celonova Biosciences, and Northpoint Domain.


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