PlaqueTec Liquid Biopsies Give Alternative Data To Systemic Biomarkers

MedicalResearch.com Interview with:
PlaqueTec liquid biopsiesDr. Nick West, MD
PlaqueTec Chief Medical Officer and Consultant Interventional Cardiologist
Royal Papworth Hospital NHS Foundation Trust  

MedicalResearch.com: What is the background for this study?

Response: Recent data have identified residual inflammatory risk as a potential therapeutic target to modulate future risk of coronary and vascular events independent of cholesterol lowering1. This approach has now been validated by the CANTOS study, showing reduction of peripheral blood levels of high-sensitivity CRP (hsCRP) and consequent reduction of the occurrence of major cardiac events in patients who had sustained a myocardial infarction2,3. Although controversy continues to rage regarding the relevance of ‘vulnerable plaque’ versus ‘vulnerable patient’ in the causation of acute coronary events, evolving data suggest a complex interplay between a proinflammatory milieu and ‘vulnerable’ plaque phenotypes 4,5 .

We used a novel dedicated intracoronary sampling catheter, the PlaqueTec Liquid Biopsy SystemTM (LBS), and sought to correlate systemic inflammatory indices with degree of local coronary inflammatory activity. The LBS has previously been validated to safely delineate the presence of gradients of inflammatory biomolecules in human coronary artery disease6. We measured blood levels of a large panel of inflammatory biomolecules using multiplexed assays in peripheral blood and in coronary-derived blood samples after balloon dilatation of coronary stenoses during coronary angioplasty, and assessed systemic levels of hsCRP by ELISA.

MedicalResearch.com: What are the main findings? 

Response: Statistical analysis using K-means indicated our patient population (n=23), predominantly patients with stable angina, segregated into 2 discrete clusters of high and low overall coronary inflammatory states. However, when compared with peripheral (systemic) levels of the same inflammatory biomolecules in each cluster, there was no meaningful relationship. Additionally, there was no difference between median hsCRP measurements between the 2 clusters. Taken together, these data suggest that simply measuring peripheral markers of inflammation may not be able to determine local inflammatory activity within the coronary artery itself. 

MedicalResearch.com: What should readers take away from your report?
What recommendations do you have for future research as a result of this work?

Response: These data provide interesting and hypothesis-generating data that explore the mechanisms of benefit in vascular risk by reducing systemic inflammation; rather than hsCRP acting as a simple ‘barometer’ for likelihood of events, it appears that presence of coronary inflammation may be an independent entity. Further studies are needed to address the complex relationship between systemic and coronary inflammation, and their respective interaction with ‘vulnerable’ plaque phenotypes in modulating patient events.

Disclosures: Dr West acts as a consultant to, and holds equity in, PlaqueTec Ltd.

Citations:

  1. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J 2016; 37: 1720-22.
  2. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377: 1119-31.
  3. Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomissed controlled trial. Lancet 2018; 391: 319-28.
  4. Libby P, Pasterkamp G. Requiem for the vulnerable plaque. Eur Heart J 2015; 36: 2984-7.
  5. Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med 2015; 278: 483-93.
  6. West NEJ, Corrigan JP, Owen RHG et al. Percutaneous sampling of local biomolecule gradients across coronary artery atherosclerotic plaques. J Am Coll Cardiol Basic Trans Science 2017; 2: 646-54.

Citation:

PlaqueTec Data Presented at EAS Show Lack of Correlation 
between Localised Coronary Artery Inflammatory Biomarker Expression and Systemic Elevation of Biomarkers including hsCRP

 

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Epigenetic DNA Variants Predictive of Coronary Artery Disease

MedicalResearch.com Interview with:

Stella Aslibekyan, PhD Associate Professor PhD Program Director Department of Epidemiology University of Alabama at Birmingham

Dr. Aslibekyan

Stella Aslibekyan, PhD
Associate Professor
PhD Program Director
Department of Epidemiology
University of Alabama at Birmingham

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: When the human genome was sequenced in 2003, there were somewhat unrestrained expectations of unraveling all etiologic mysteries and discovering breakthrough treatments. Needless to say, that did not happen, in part because individual genetic variants can only account for a small fraction of trait variability. Since then, epigenetics– the study of mitotically heritable changes in gene expression– has emerged as another promising avenue for understanding disease risk. The best studied epigenetic process in humans is DNA methylation, and earlier studies (including some from our group) have shown interesting associations between changes in methylation in specific genomic regions and cardiovascular disease traits, e.g. plasma cholesterol levels.

In this project, we have combined DNA methylation data on thousands of individuals from multiple international cohorts and interrogated epigenetic contributions to circulating tumor necrosis factor alpha (TNFa), a marker of systemic inflammation. We identified and replicated several epigenomic markers of TNFa, linked them to variation in gene expression, and showed that these methylation changes (which were located in interferon pathway genes) were predictive of coronary heart disease later in life. Interestingly, the variants we discovered were not sequence-dependent (in other words, they were not associated with any genetic mutations), highlighting the role of the environment.

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Personalized Medicine Tool Helps Direct Cardiac Care in Elderly Patients

MedicalResearch.com Interview with:

Joseph A. Ladapo, MD, PhD Principal Substudy Investigator, PRESET Registry Subgroup Analysis, Elderly Patients Associate Professor, Division of General Internal Medicine and Health Services Research David Geffen School of Medicine University of California, Los Angeles

Dr. Ladapo

Joseph A. Ladapo, MD, PhD
Principal Substudy Investigator, PRESET Registry
Subgroup Analysis, Elderly Patients
Associate Professor, Division of General Internal Medicine and Health Services Research
David Geffen School of Medicine
University of California, Los Angeles

MedicalResearch.com: What is the background for this study? 

Response: The mapping of the Human Genome 14 years ago ushered in a new era of precision medicine. Many people are familiar with advances in oncology using precision medicine, but recently, new developments in precision medicine in cardiology have allowed us to develop a tool to differentiate patients likely to have obstructive coronary artery (CAD) from those who have non-cardiac causes of their symptoms.

Diagnosing CAD in the elderly is challenging. Aging individuals often present with atypical symptoms of CAD which can complicate the evaluation process. The typical diagnostic pathway for possible CAD often starts with less invasive testing and progresses to invasive testing, especially in older patients. Invasive procedures pose greater risk in the elderly population than they do in younger patients because of the higher risk of side effects, including bleeding, vascular complications and kidney injury.

Elderly adults evaluated for CAD have a higher pretest probability of CAD and are also at higher risk of experiencing procedure-related complications during their evaluation.[i],[ii] It is also important to note that elderly patients are often underrepresented in clinical trials and other types of comparative effectiveness research.[iii],[iv] For example, the 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Algorithm is only formally approved to be used in individuals up to the age of 75, despite the fact that individuals exceeding this threshold in age experience higher rates of adverse cardiovascular events.[v]

All of this means that the elderly population may have the most to gain from timely and accurate determination of their currently likelihood of obstructive CAD.
This precision medicine tool, the age, sex and gene expression score (ASGES), and its clinical utility in the elderly population is the focus of this study. It was based on patient data from the PRESET Registry, a prospective, multicenter, observational study enrolling stable, symptomatic outpatients from 21 U.S. primary care practices from August 2012 to August 2014.

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Diagnostic Accuracy of FFR-CT Varies Across Spectrum of Coronary Artery Disease

MedicalResearch.com Interview with:
Dr Christopher Michael Cook MBBS Bsc(Hons) MRCP

MRC Clinical Research Fellow
NHLI, Cardiovascular Medicine, Imperial College London 

MedicalResearch.com: What is the background for this study?

Response: FFR-CT is a novel non-invasive technique for estimating the functional significance of a coronary stenosis from CT coronary angiography images. A number of meta-analyses already exist for determining the diagnostic accuracy of FFR-CT (compared to invasive FFR as the reference standard). However, although knowing the overall diagnostic accuracy of FFR-CT is reassuring, in clinical practice a clinician knows not only whether the FFR-CT is positive or negative, but also its actual value. The purpose of this study was to provide clinicians a means of interpreting the diagnostic accuracy of any individual FFR-CT result that may be received in clinical practice.

MedicalResearch.com: What are the main findings?

Response: The main finding of this study is that the diagnostic accuracy of FFR-CT varies markedly across the spectrum of disease. For vessels with FFR-CT above 0.90, 98% met the invasive FFR guideline criterion for deferral. At the other end of the spectrum, for vessels with FFR-CT below 0.60, 86% met the invasive FFR guideline criterion for stenting. However, in between, FFR-CT gives less certainty as to whether the invasive FFR will meet the stenting criterion or not.

MedicalResearch.com: What should readers take away from your report?

Response: Readers can combine the findings of our study with patient specific factors in order to judge when the cost and risk of an invasive angiogram may safely be avoided. Because we now have a more complete picture of what different levels of FFR-CT mean in terms of invasive FFR, it is apparent that a single cut-off value for FFR-CT in deciding on invasive coronary angiography need not always apply. For example, in the asymptomatic patient, further investigations may not be desirable even if an FFR-CT still left a substantial possibility of a positive invasive FFR. Conversely, in the symptomatic patient, the patient and clinician would likely pursue invasive angiography unless the possibility of a positive FFR is very remote.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This study adopted novel methodology to ascertain the probability that both FFR-CT and invasive FFR agreed on the functional classification of a stenosis, for any given individual FFR-CT value. This type of analysis could be used to determine if further iterative versions of the FFR-CT software translate into improved diagnostic performance, particularly in more intermediate disease severities. 

MedicalResearch.com: Is there anything else you would like to add?

Response:

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Cook CM, Petraco R, Shun-Shin MJ, Ahmad Y, Nijjer S, Al-Lamee R, Kikuta Y, Shiono Y, Mayet J, Francis DP, Sen S, Davies JE. Diagnostic Accuracy of Computed Tomography–Derived Fractional Flow Reserve A Systematic Review . JAMA Cardiol. Published online May 24, 2017. doi:10.1001/jamacardio.2017.1314

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Study Evaluates Effects of Calcification of Occluded Coronary Arteries During PCI

MedicalResearch.com Interview with:

Emmanouil S. Brilakis, MD, PhD Director, Center for Advanced Coronary Interventions Minneapolis Heart Institute Minneapolis, Minnesota 55407 Adjunct Professor of Medicine University of Texas Southwestern Medical School at Dallas

Dr, Brilakis

Emmanouil S. Brilakis, MD, PhD
Director, Center for Advanced Coronary Interventions
Minneapolis Heart Institute
Minneapolis, Minnesota 55407
Adjunct Professor of Medicine
University of Texas Southwestern Medical School at Dallas

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Calcification in the coronary arteries might hinder lesion crossing, equipment delivery and stent expansion and contribute to higher rates of in-stent restenosis, as well as stent thrombosis. In this project we sought to examine the impact of calcific deposits on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a contemporary, multicenter registry.

We analyzed the outcomes of 1,476 consecutive CTO PCIs performed in 1,453 patients between 2012 and 2016 at 11 US centers. Data collection was performed in a dedicated online database (PROGRESS CTO: Prospective Global Registry for the Study of Chronic Total Occlusion Intervention, Clinicaltrials.gov Identifier: NCT02061436).

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Cardiac Magnetic Resonance Can Exclude Clinically Relevant Coronary Artery Disease

MedicalResearch.com Interview with:

Pr. Juerg Schwitter MD Médecin Chef Cardiologie Directeur du Centre de la RM Cardiaque du CHUV Centre Hospitalier Universitaire Vaudois - CHUV Suisse

Pr. Schwitter

Pr. Juerg Schwitter MD
Médecin Chef Cardiologie
Directeur du Centre de la RM Cardiaque du CHUV
Centre Hospitalier Universitaire Vaudois – CHUV
Suisse 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Coronary artery disease (CAD) is still one of the leading causes of death in the industrialized world and as such, it is also an important cost driver in the health care systems of most countries. For the European Union, the estimated costs for CAD management were 60 billion Euros in 2009, of which approximately 20 billion Euros were attributed to direct health care costs (1). In 2015, the total costs of CAD management in the United States were estimated to be 47 billion dollars (2).

Substantial progress has been achieved regarding the treatment of CAD including drug treatment but also revascularizations procedures. There exists a large body of evidence demonstrating myocardial ischemia as one of the most important factors determining the patient’s prognosis and reduction of ischemia has been shown to improve outcome.

On the other hand, techniques to detect CAD, i.e. relevant myocardial ischemia, were insufficient in the past. Evaluation of myocardial perfusion by first-pass perfusion cardiac magnetic resonance (CMR) is now closing this gap (3) and CMR is recommended by most international guidelines for the work-up of known or suspected CAD (4,5).

Still, a major issue was not clarified until now, i.e. “how much ischemia is required to trigger revascularization procedures”. Thus, this large study was undertaken to assess at which level of ischemia burden, patients can be safely deferred from revascularization and can be managed by risk factor treatment only. Of note, this crucial question was addressed in both, patients with suspected CAD but also in patients with known (and sometimes already advanced) CAD, thereby answering this question in the setting of daily clinical practice.

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Study Raised Concerns About Ability of Appropriate Use Criteria To Guide Decision Making

MedicalResearch.com Interview with:
Harindra C. Wijeysundera MD PhD FRCPC
Interventional Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre
Scientist, Sunnybrook Research Institute (SRI)
Assistant Professor, Dept. of Medicine & Institute of Health Policy, Management and Evaluation
University of Toronto Adjunct Scientist, Institute for Clinical Evaluative Sciences (ICES)
Toronto, ON, Canada

Medical Research: What is the background for this study? What are the main findings?

Dr. Wijeysundera: Given the rapid increase in health care costs, there has been growing emphasis on the more rational use of resources.  One such effort is the development of appropriate use  criteria.  Such criteria have been developed in many areas of medicine, including in cardiology for diagnostic angiography.  The underlying rationale for a test to be appropriate is that its anticipated benefit outweighs its anticipated harms.  However, there is a paucity of empirical evidence validating this conceptual framework. Our goal was to validate the 2012 appropriate use criteria for diagnostic coronary angiography, by examining the relationship between the appropriateness of a coronary angiography in patients with suspected stable ischemic heart disease and the proportion of patients who were found to have obstructive coronary artery disease.  We used data obtained from the Cardiac Care Network registry of Ontario, Canada.  This is a population based registry of all cardiac procedures in the province of Ontario.  We examined 48,336 patients and found that 58.2% of angiographic studies were classified as appropriate, 10.8% were classified as inappropriate, and 31.0% were classified as uncertain. Overall, 45.5% of patients had obstructive CAD. In patients with appropriate indications for angiography, 52.9% had obstructive CAD, with 40.0% undergoing revascularization. In those with inappropriate indications, 30.9% had obstructive CAD and 18.9% underwent revascularization; in those with uncertain indications, 36.7% had obstructive CAD and 25.9% had revascularization. Although more patients with appropriate indications had obstructive CAD and underwent revascularization (P < 0.001), a substantial proportion of those with inappropriate or uncertain indications had important coronary disease.  Our conclusion was that despite the association between appropriateness category and obstructive CAD, this study raises concerns about the ability of the appropriate use  criteria to guide clinical decision making.

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Using Coronary Fractional Flow Reserve To Predict Clinical Outcomes

Nils P. Johnson, M.D., M.S. Assistant Professor - Cardiovascular Medicine Department of Internal Medicine University of Texas Health Science Center Houston TexasMedicalResearch.com Interview with
Nils P. Johnson, M.D., M.S.
Assistant Professor – Cardiovascular Medicine
Department of Internal Medicine
University of Texas Health Science Center
Houston Texas

Medical Research: What are the main findings of the study?

Dr. Johnson: Our study had 3 main findings.

  • First, the numeric fractional flow reserve (FFR) value related continuously to risk, such that clinical events increased as FFR decreased and revascularization showed larger net benefit  for lower baseline FFR values.
  • Second, fractional flow reserve measured immediately after  stenting also showed an inverse relationship with prognosis, likely due to its relationship with diffuse disease.
  • Third, an fractional flow reserve-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief.
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Which BNP Better Predicts CV Events in Stable Coronary Heart Disease?

MedicalResearch.com Interview with:
Rakesh K. Mishra, MD
San Francisco Veterans Affairs Medical Center
San Francisco, CA 94121.

Medical Research: What are the main findings of the study?

Dr. Mishra: Increased levels of both BNP and NT-proBNP are associated with elevated risk of adverse cardiovascular events in patients with stable coronary artery disease. However, when added to existing clinical models of risk, NT-proBNP is superior to BNP for risk reclassification.
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Coronary Artery Disease: Vitamin D Did Not Affect Disease Progression

Eirik Magnus Meek Degerud Department of Clincal Medicine University of BergenMedicalResearch.com Interview with: 
Eirik Magnus Meek Degerud
Department of Clincal Medicine University of Bergen


MedicalResearch.com: What are the main findings of the study?

Answer: That among patients with established coronary artery disease there was no observable relationship between the amount of vitamin D circulating in their blood and the extent of disease progression during the following year.

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Diabetes with CAD: Genetic Link Related to Glutamic Acid Metabolism

Lu Qi, MD, PhD, FAHA Assistant Professor of Medicine Harvard Medical School Assistant Professor of Nutrition Harvard School of Public HealthMedicalResearch.com Interview with:
Lu Qi, MD, PhD, FAHA
Assistant Professor of Medicine
Harvard Medical School
Assistant Professor of Nutrition
Harvard School of Public Health

MedicalResearch.com: What are the main findings of the study?

Answer: The main findings include, we for the first time identified a genetic variant predisposing to high risk of coronary heart disease in patients with type 2 diabetes, using genome-wide association (GWA) approach. More interesting, we demonstrated that the variant may affect expression of a gene involved in metabolism of amino acid glutamic acid, which has been related to insulin secretion and heart health in previous studies.
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Coronary Artery Disease: Hypertension and Prognostic Score

Dr. Anthony Bavry, MD MPH Interventional Cardiology Assistant Professor of Medicine University of Florida 1600 SW Archer Road Gainesville, FL 32610MedicalResearch.com Interview with
Dr. Anthony Bavry, MD MPH
Interventional Cardiology
Assistant Professor of Medicine
University of Florida
1600 SW Archer Road
Gainesville, FL 32610

MedicalResearch.com: What are the main findings of the study?

Dr. Bavry: Among individuals with chronic stable coronary artery disease, it is possible to define a group who are at relatively low risk for adverse cardiovascular events.

MedicalResearch.com:Were any of the findings unexpected?

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