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Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Posted in Atherogenic Processes & Pathology, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Interviews with Scientific Leaders, Medical and Population Genetics, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders on January 21, 2014| Leave a Comment »

Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #107: Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator. Published on 1/21/2014

WordCloud Image Produced by Adam Tubman

This article covers the following related topics:

I. Voices from Cleveland Clinic: Love ‘Em or Leave ‘Em: Experts on Both Sides Debate the New Lipid Guidelines

http://www.medscape.com/viewarticle/819288?nlid=45683_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

II.  JAMA Weighs In on CVD Guidance, Statins in Primary Prevention

http://www.medscape.com/viewarticle/814960

III.  How Good Is the New ACC/AHA Risk Calculator?

http://www.medscape.com/viewarticle/814579

IV.  New Cholesterol Guidelines Abandon LDL Targets

http://www.medscape.com/viewarticle/814152

V. New CV Risk-Assessment Guidance Counts Stroke With CHD Risk

http://www.medscape.com/viewarticle/814206

VI.  NIH Says ATP 4, JNC 8 Guidance Out ‘in a Matter of Months’ (With a Twist)

http://www.medscape.com/viewarticle/806563

VII.  New European Hypertension Guidelines Released: Goal Is Less Than 140 mm Hg for All

http://www.medscape.com/viewarticle/806367

VIII.  New guidelines on primary stroke prevention from AHA/ASA

http://www.medscape.com/viewarticle/790766

IX.  New ACC/AHA/NHLBI Guidance on Lifestyle for CVD Prevention

http://www.medscape.com/viewarticle/814139

X. New Obesity Guidelines: Authoritative ‘Roadmap’ to Treatment

http://www.medscape.com/viewarticle/814202

XI.  USPSTF Updates Adult Obesity-Overweight Screening Guidelines

http://www.medscape.com/viewarticle/766342

Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Love ‘Em or Leave ‘Em: Experts on Both Sides Debate the New Lipid Guidelines

Michael O’Riordan

January 20, 2014

DALLAS, TX and WASHINGTON, DC — It has been two months since the new clinical guidelines for the treatment of cholesterol were published^[1], and feedback is starting to slowly emerge as clinicians begin incorporating the recommendations into clinical practice.

The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, which were developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), were a radical departure from previous iterations, most notably in their abandonment of LDL-cholesterol targets. In the past, clinicians were advised to treat patients with cardiovascular disease to less than 100 mg/dL or the optional goal of less than 70 mg/dL.

As reported by heartwire  at the time, the expert panel stated there was simply no evidence from randomized, controlled clinical trials to support treatment to a specific target. As a result, the new guidelines make no recommendations for specific LDL-cholesterol or non-HDL targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.

Dr Stanley Hazen

For one clinician, Dr Stanley Hazen (Cleveland Clinic, OH), the strict adherence to only clinical-trial data is a limitation and not a strength of the new guidelines.

“First, it ignores a wealth of information on the pathophysiology of the disease process. Second, it presumes that the reason trials are designed is to answer guideline questions,” he told heartwire . “They aren’t. Trials are designed by pharmaceutical companies trying to get claims issued on their drugs. More important, the absence of randomized clinical-trial data does not justify inaction if LDL cholesterol remains elevated.”

Accelerating Vascular Age

In his commentary published January 8, 2014 in the Cleveland Clinic Journal of Medicine, Hazen, along with first author Dr Chad Raymond (Cleveland Clinic, OH), lay out their concerns with the clinical guidelines and highlight some of the shortcoming with the new recommendations^[2].

For Hazen, there are multiple reasons that physicians should continue to treat to specific LDL-cholesterol targets, the first and foremost being that patients are different and no single treatment fits such a large and heterogeneous patient population at risk for cardiovascular disease and stroke. The guidelines simply call for a moderate- or high-dose statin in high-risk patients depending on the clinical scenario and no subsequent assessment of LDL cholesterol.

“In the very highest-risk patients, the ones with extraordinarily high levels of cholesterol, those who get maximally tolerated statins, if there is still a substantial LDL-cholesterol burden, they are going to have substantial residual risk,” he said. “The preponderance of data in aggregate shows that there is higher residual risk proportionate to the LDL level that’s remaining. The new guidelines completely ignore the pathophysiology of the disease process—a disease that takes decades to develop.”

The clinical guidelines are unique among documents past in that the emphasis is strictly on statin therapy rather than LDL-cholesterol-lowering medications more generally. In individuals with atherosclerotic cardiovascular disease, high-intensity statin therapy—such as rosuvastatin (Crestor, AstraZeneca) 20 to 40 mg or atorvastatin 40 to 80 mg—should be used to achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when statin-associated adverse events are present. In that case, doctors should use a moderate-intensity statin. Similarly, for those with LDL-cholesterol levels >190 mg/dL, a high-intensity statin should be used with the goal of achieving at least a 50% reduction in LDL-cholesterol levels.

For Hazen, the new clinical guidelines “turn back the clock on cardiovascular disease prevention” and have the potential to both overtreat older low-risk patients and undertreat those who are young yet are at higher lifetime risk.

For example, he cites a 25-year-old man who presents because his 45-year-old father just died from a heart attack. He has a fasting total cholesterol level of 310 mg/dL, HDL cholesterol of 50 mg/dL, triglyceride level of 400 mg/dL, and LDL cholesterol of 180 mg/dL. Even with the strong family history of premature coronary disease, because of his young age, the current guidelines do not suggest treatment because they do not apply to those less than 40 years old. However, even if his age were 40, his calculated 10-year risk would be <7.5% based on a new and controversial risk calculator published alongside the guidelines.

“I can’t imagine there is a lipidology expert or cardiologist out there who would think that this patient does not deserve aggressive preventive efforts and intervention,” said Hazen. “It is lifetime risk and lifetime exposure to higher LDL cholesterol that contributes to the disease process. Ignoring that scientific fact in a document whose focus is on treating cholesterol to prevent cardiovascular disease is simply illogical.”

A Massive Paradigm Shift

Speaking with heartwire , Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas) suspects there remains some hesitancy on the part of practicing primary-care physicians to adopt the guidelines, mainly because they are a “massive paradigm shift that dramatically changes the approach to disease.” He said while there are always early adopters, there have been some questions as to which major journals and cardiology organizations would line up behind them (and nearly all have, with the exception of the American Association of Clinical Endocrinologists ).

For cardiologists, on the other hand, the shift to focus on four specific types of patients is not so dramatic, because these are patients they routinely see in clinical practice. For de Lemos, it is reasonable to focus on at-risk patients and treat according to that level of risk. He still incorporates measuring LDL-cholesterol levels, however, noting that the measurement can provide some reassurance or concern depending on the threshold achieved with treatment, dietary changes, and exercise.

Dr Mariel Jessup

To heartwire , Dr Mariel Jessup (University of Pennsylvania, Philadelphia), the president of the AHA, said that immediately following their publication many of her colleagues began implementing the guidelines and using the new calculator for risk assessment. In doing so, they identified patients on statins who did not require the lipid-lowering drugs as well as patients who weren’t on them but should be.

“In the first week, we were all coming to terms with what contributes to risk,” said Jessup. She added that she hasn’t heard a great deal of criticism about the guidelines and believes most physicians are getting on board with the new changes.

She noted that a member of the Penn faculty recently delivered medical grand rounds on the new lipid guidelines and while it was mostly positive, one criticism that arose was the emphasis on randomized, controlled clinical-trial data. Jessup said that even though the new guidelines focus on clinical-trial data, this does not negate findings from observational or epidemiological studies.

Dr Roger Blumenthal

Dr Roger Blumenthal (Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, MD), on the other hand, predicts a return to LDL treatment goals in the not-so-distant future.

“I think the guidelines will revert back to the way they were once we get a positive study showing that adding another agent to a statin reduces risk,” Blumenthal said. He predicts positive results with anacetrapib (Merck, Whitehouse Station, NJ), the novel cholesteryl ester transfer protein (CETP) inhibitor, or one of the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, when given on top of statins. “When that happens, the new randomized controlled trial data would support going lower than what would be achieved with giving just 40 mg or 80 mg of atorvastatin.”

In very selected patients, Blumenthal still aggressively targets to low LDL levels, even if this requires adding a second agent. For example, in patients treated with a statin, LDL cholesterol might be reduced to 80 mg or so, but triglyceride levels remain high or HDL cholesterol is low. He notes that the ACCORD study with fenofibrate was borderline nonsignificant in patients with low HDL cholesterol and high triglyceride levels. Beyond fibrates, he notes there have been angiographic studies published in support of the “lower-is-better” hypothesis.

Jessup said that most physicians understand why the LDL targets were eliminated, but many institutions used the thresholds as a performance measure. Penn Health, for example, used the number of patients treated to the old LDL-cholesterol targets as an internal marker of performance for physicians in internal medicine and general practice. “As you struggle to come up with an easily defined target that you can use to talk about quality in a large practice, and not just among cardiologists, that’s one less target you can use,” said Jessup.

Concerns Among Clinicians as Well

Dr Rita Redberg

Dr Rita Redberg (University of California, San Francisco) also has significantconcerns about the new guidelines, albeit for entirely different reasons. An outspoken critic when the guidelines were presented, her views have not changed, telling heartwire that she is already looking forward to the next version of the cholesterol guidelines. When they were first published and presented, Redberg, along with Dr John Abramson (Harvard Medical School, Boston, MA), argued that statins were beneficial for individuals with heart disease but do not reduce the risk of death in individuals with a 10-year risk of cardiovascular disease of less than 20%.

“I have not been implementing these guidelines because I don’t think they’re in the best interests of my patients, and I really do look forward to the revisions,” she said. “I’m all for looking at risk, and I’m all for targeting prevention strategies on the basis of risk, so I think this is a strong point of the new guidelines. However, that is really undermined by the risk calculator, in which anybody over age 65 basically needs to be on a statin. I don’t think the data support this.”

The new cholesterol guidelines weathered a rough roll-out their first week when Drs Paul Ridker and Nancy Cook (Brigham and Women’s Hospital, Boston, MA) calculated the 10-year risk of cardiovascular events in three large-scale primary prevention cohorts—the Women’s Health Study(WHS), the Physicians’ Health Study (PHS), and the Women’s Health Initiative Observational Study (WHI-OS)—and found the new algorithm overestimated the risk by 75% to 150%.

Dr James de Lemos

To de Lemos, the controversial aspect of the new guidelines remains in the primary-prevention population. For those without cardiovascular disease but who have LDL-cholesterol levels ranging from 70 mg/dL to 189 mg/dL and a 10-year risk of cardiovascular disease >7.5%, physicians can initiate treatment with a statin. Given the controversy surrounding the risk calculator, there have been suggestions that people who don’t need statins will receive treatment.

“It doesn’t mean the concept is flawed,” de Lemos told heartwire , “but it just might not be ready to implement widely.” As a result, he suspects that physicians might be keeping the risk calculator at arm’s length until it is studied and debated further. As for his own use, de Lemos said he doesn’t calculate 10-year risk in every patient, even though he is fairly aggressive with initiating statin therapy, and that his decisions are more intuitive and empirical, something which he doesn’t see changing.

Jessup said the risk calculator, as well as the clinical guidelines, will be updated as new information emerges. While she was not able to speak to specifics, Jessup is aware of researchers testing the predictive strength of the risk calculator in different cohorts to see how well it performs. In general, she said the calculator performs reasonably well.

Some Docs Finding the Calculator Helpful

Dr Sekar Kathiresan

Dr Sekar Kathiresan (Brigham and Women’s Hospital, Boston, MA), who runs a primary-prevention clinic, does use the new clinical guidelines and the new risk calculator to inform his decisions about whether or not to start patients with a moderate- or high-dose statin. He said Ridker and Cook raise a valid scientific point in terms of how well it is calibrated, but this should be put in perspective, given that physicians for the past 20 years or so have used the Framingham Risk Score, a score derived from a few thousand white individuals from one town in the US. The new risk equation increases the population sampled, includes different ethnicities, and is derived from more than one geographic area.

“Is the pooled-cohort equation perfect?” he asked. “No, it won’t be perfect, because it’s an attempt to estimate risk on a sample of 25 000 people.”

Blumenthal made similar comments, telling heartwire that the risk calculator is a better way to estimate risk in women and African Americans, for example. Given that the risk calculator might overestimate risk, he expands his definition of intermediate risk to include patients with a 5% to 15% 10-year risk of cardiovascular disease. In doing so, even if the risk calculator overestimates by a factor of two, they have some wiggle room in discussing care with the patient.

In addition, Blumenthal said the guidelines emphasize a discussion with the patient about care in those with a 10-year risk exceeding 7.5%, just as would be done with an intermediate-risk patient. The discussion can lead to further refinement of risk by taking family history into account or by performing a computed tomography (CT) scan to assess coronary artery calcium (CAC).

To Kathiresan, moving away from LDL-cholesterol targets will require some time before they become readily accepted, mainly because physicians have gotten used to the targets. For the most part, though, he views the changes to the guidelines as more of a “tweak.”

“I don’t find them as radical as some people do,” Kathiresan told heartwire . “I actually think the major thing that was accomplished was taking the focus away from using medications to change lab tests and to now focus on medication proven to reduce the risk of disease. This is a huge plus for the new guidelines.”

In cardiology, the evidence base is very rich, with many trials and millions of dollars spent to evaluate whether specific medicines work to reduce disease risk in specific clinical situations, he added. This is the evidence that should be used to inform clinical practice. For this reason, he entirely agrees with the new focus on statins and not simply lipid-lowering agents.

“There is an incredible amount of inappropriate use of both niacin and fibrates in the US, all based on the fact that they change lab tests,” said Kathiresan. “The clinical-trial evidence for those two medicines is disappointingly poor.”

Hazen is a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is a paid consultant to the Cleveland Heart Lab, Esperion, Liposciences, Merck, Pfizer, and Procter & Gamble. He has received research funds from Abbott, Astra Zeneca, Cleveland Heart Lab, Esperion, Liposciences, Procter & Gamble, and Takeda. In addition, he is entitled to royalty payments for inventions/discoveries related to cardiovascular diagnostics and therapeutics from Abbott Laboratories, Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposciences . 

de Lemos acknowledges grant support from Roche Diagnostics and Abbott Diagnostics and has consulted for Diadexus. 

Kathiresan reports serving as a consultant to Merck, Pfizer, Celera, and Alnylam.

Jessup, Blumenthal, and Redberg report no conflicts of interest.

REFERENCES

1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association. J Am Coll Cardiol 2013. Article. Circulation 2013. Article.
2. Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: Worth the wait? Cleve Clin J Med 2014; DOI: 10.3949/ccjm.81a.13161. Article

SOURCE

http://www.medscape.com/viewarticle/819288#1

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Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Posted in Atherogenic Processes & Pathology, Best evidence, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cardiovascular Research, Curation, Curation methodology, Diabetes Mellitus, Discovery process, Evidence-based decision-making, Evolutionary cognition, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Indigent Nutrition, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medicare and Medicaid, Metabolomics, Nephrology, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, Uninsured and Underinsured, tagged AMI, Arterial stiffness, comorbidities - type 2 DM, COPD, coronary vascular disease, Diabetes management, Diabetes mellitus type 2, hs-CPR, Nutrition and Metabolism Disorders, Nutritional Supplements, prediabetes, proinflammatory, statins, waist circumference on January 15, 2014| Leave a Comment »

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Curator:  Larry H. Bernstein, MD, FCAP

Article ID #106: Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD). Published 1/15/2014

WordCloud Image Produced by Adam Tubman

This is a multipart article that develops the pathological effects of type-2 diabetes in the progression of a systemic inflammatory disease with a development of neuropathy, and fully developing into cardiovascular disease.  It also identifies a systemic relationship to the development of chronic obstructive pulmonary disease (COPD).

The more we learn about diabetes, we learn about its generalized systemic effects.

This article has the following SIX Parts:

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Part 5.   How to use C-reactive protein in acute coronary care

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

INTRODUCTION

Type 2 diabetes mellitus is a common chronic disease which develops insidiously over time, and is associated with obesity, nutritional imbalance (high fructose beverages, high starch and processed foods, carbohydrate excess intake, and an imbalance of proinflammatory to anti-inflammatory polyunsaturated  fatty acids), which makes it an acquired and manageable disease.  The long term effects of T2DM is played out on cardiovascular disease and stroke-risk, obstructive sleep apnea, progressive renal insufficiency, development of neuropathy, congestive heart failure and chronic obstructive pulmonary disease, all of which are occuring related to an systemic inflammatory condition that proceeds for some time prior to the identification of overt diabetes.
A detailed story of a significant part of these associations continues in the SIX Part series.

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

This article is an abstract only of a related publication of the pathogenesis of autonomic neuropathy in diabetics leading to ischemic heart disease.

Subjects: Medicine (General), Medicine, Medicine (General),
Health Sciences Authors: Popović-Pejičić Snježana, Todorović-Đilas Ljiljana, Pantelinac Pavle
Publisher: Društvo lekara Vojvodine Srpskog lekarskog društva
Publication: Medicinski Pregled 2006; 59(3-4): Pp 118-123 (2006) ISSN(s): 0025-8105  Added to DOAJ: 2010-11-11
http://dx.doi.org/10.2298/MPNS0604118P  http://www.doiserbia.nb.rs/img/doi/0025-8105/2006/0025-81050604118P.pdf

Keywords: diabetes mellitus, autonomic nervous system diseases, heart diseases, myocardial ischemia, comorbidity

Introduction.

Diabetes is strongly associated with macrovascular complications, among which

• ischemic heart disease is the major cause of mortality.

Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine

• both presence and extent of cardiac autonomic neuropathy,

in regard to the type of diabetes mellitus, as well as

• its correlation with coronary disease and
• major cardiovascular risk factors.

Material and methods. We have examined 90 subjects, classified into three groups, with 30 patients each: those with type 1 diabetes, type 2 diabetes and control group of healthy subjects. All patients underwent

• cardiovascular tests (Valsalva maneuver, deep breathing test, response to standing, blood pressure response to standing sustained, handgrip test),
• electrocardiogram,
• treadmill exercise test and
• filled out a questionnaire referring to major cardiovascular risk factors: smoking, obesity, hypertension, and dyslipidemia.

Results. Our results showed that cardiovascular autonomic neuropathy was

• more frequent in type 2 diabetes,
• manifesting as autonomic neuropathy.

In patients with autonomic neuropathy, regardless of the type of diabetes,

• the treadmill test was positive, i.e. strongly correlating with coronary disease.

In regard to coronary disease risk factors,

• the most frequent correlation was found for obesity and hypertension.

Discussion

Cardiovascular autonomic neuropathy is considered to be the principal cause of arteriosclerosis and coronary disease. Our results showed that the occurrence of cardiovascular autonomic neuropathy increases the risk of coronary disease due to dysfunction of autonomic nervous system.

Conclusions

Cardiovascular autonomic neuropathy is a common complication of diabetes that significantly correlates with coronary disease. Early diagnosis of cardiovascular autonomic neuropathy points to increased cardiovascular risk, providing a basis for preventive and therapeutic measures.

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

This second part is a description of a longitudinal cohort study of individuals at high-risk for diabetes.  Unlike the SSA study, the study is not focused on protein-energy malnutrition.

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Johansen NB, Hansen Anne-Louise S, Jensen TM, Philipsen A, Rasmussen SS, Jørgensen ME, Simmons RK, Lauritzen T, Sandbæk A, Witte DR
Publisher: BioMed Central    Date of publication: 2012 Dec Published in: BMC Public Health 2012; 12(1): 1078    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12 http://dx.doi.org/10.1186/1471-2458-12-1078       http://www.biomedcentral.com/1471-2458/12/1078

Keywords: Diabetes, Cardiovascular disease, Primary care, Complications, Microvascular, Impaired fasting glucose, Impaired glucose intolerance, Aortic stiffness, Physical activity, Body composition

Background

Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to

• quantify diabetes progression rates and to examine
• the development of early markers of cardiovascular disease and
• microvascular diabetic complications.

We also require a better understanding of the

• mechanisms that underlie and drive early changes in cardiometabolic physiology.

The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.

Methods/Design

ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006.

• All individuals with impaired glucose regulation at screening,
• those who developed diabetes following screening, and
• a random sub-sample of those at lower levels of diabetes risk

were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included

• detailed measurement of anthropometry,
• body composition,
• biochemistry,
• physical activity and
• cardiovascular risk factors including aortic stiffness and central blood pressure.

All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.

Discussion

The ADDITION-PRO study is designed to increase

• understanding of cardiovascular risk and
• its underlying mechanisms among individuals at high risk of diabetes.

Key features of this study include

• (i) a carefully characterised cohort at different levels of diabetes risk;
• (ii) detailed measurement of cardiovascular and metabolic risk factors;
• (iii) objective measurement of physical activity behaviour; and
• (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease.

Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

This study also addresses the issue of diabetes insulin resistance leading to cardiovascular dysmetabolic syndrome.

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Deedwania Prakash C Publisher: BioMed Central            Date of publication: 2002 Jan
Published in: Trials 2002; 3: 1(2)   ISSN(s): 1468-6708  Added to DOAJ: 2004-06-03
http://dx.doi.org/10.1186/1468-6708-3-2   http://cvm.controlled-trials.com/content/3/1/2

Keywords: cardiovascular dysmetabolic syndrome, coronary heart disease, diabetes mellitus, hyperinsulinemia, insulin resistance

Although diabetes mellitus is predominantly a metabolic disorder,

• recent data suggest that it is as much a vascular disorder.
• Cardiovascular complications are the leading cause
  • of death and disability in patients with diabetes mellitus.

A number of recent reports have emphasized that

• many patients already have atherosclerosis in progression
• at the time they are diagnosed with clinical evidence of diabetes mellitus.

The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to

• the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction.

The evolving knowledge regarding the variety of

• metabolic,
• hormonal, and
• hemodynamic abnormalities in patients with diabetes mellitus

has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that

• insulin resistance, the key abnormality in type II diabetes,
• often precedes clinical features of diabetes by 5–6 years.

Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome

• should help identify those at risk at an early stage.

The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects

• in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus
• by improving insulin sensitivity and related abnormalities.

Early identification and implementation of appropriate therapeutic strategies would be necessary

• to contain the emerging new epidemic of cardiovascular disease related to diabetes.

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Siren Reijo, Eriksson Johan G, Vanhanen Hannu
Publisher: BioMed Central      Date of publication: 2012 Aug
Published in: BMC Public Health 2012; 12: 1(631)    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1471-2458-12-631    http://www.biomedcentral.com/1471-2458/12/631

Keywords: Waist circumference, Type 2 diabetes, Cardiovascular disease, Middle-aged men

Background

Abdominal obesity is a more important risk factor than overall obesity in

• predicting the development of type 2 diabetes and cardiovascular disease.

From a preventive and public health point of view it is crucial that

• risk factors are identified at an early stage,
• in order to change and modify behaviour and lifestyle in high risk individuals.

Methods

Data from a community based study was used to assess

• the risk for type 2 diabetes,
• cardiovascular disease and
• prevalence of metabolic syndrome in middle-aged men.

In order to identify those with increased risk for type 2 diabetes and/or cardiovascular disease

• sensitivity and specificity analysis were performed, including
• calculation of positive and negative predictive values, and
• corresponding 95% CI for eleven different cut-off points,
  • with 1 cm intervals (92 to 102 cm), for waist circumference.

Results

A waist circumference ≥94 cm in middle-aged men,

• identified those with increased risk for type 2 diabetes
• and/or for cardiovascular disease

with a sensitivity of 84.4% (95% CI 76.4% to 90.0%), and a specificity of 78.2% (95% CI 68.4% to 85.5%). The positive predictive value was 82.9% (95% CI 74.8% to 88.8%), and negative predictive value 80.0% (95% CI 70.3% to 87.1%), respectively .

Conclusions

Measurement of waist circumference in middle-aged men

• is a reliable test to identify individuals at increased risk for type 2 diabetes and cardiovascular disease.

This measurement should be used more frequently in daily practice in primary care

• in order to identify individuals at risk and when planning health counselling and interventions.

Part 5.  How to use C-reactive protein in acute coronary care

Luigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani, Bertil Lindahl, Nader Rifai,Per Venge,Christian Hamm, and the Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the European Society of Cardiology
Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade2, Aarhus DK-8000,Denmark; Germany, U.K., U.S., Italy
European Heart Journal Advance Access published Nov 7, 2013.  Current Opinion.  http://dx.doi.org/10.1093/eurheartj/eht435

Introduction

 C-reactive protein (CRP) is an acute phase protein and an established marker for detection, risk stratification, and monitoring of infections, and inflammatory and necrotic processes.. Because C-reactive protein is sensitive but not specific, its values must be nterpreted  in the clinical context. Inpatients with acute myocardial infarction (AMI), CRP increases within 4–6h of symptoms, peaks 2–4 days later,and returns to baseline after 7–10 days.

CRP has gained interest recently as a marker for risk stratification in acute coronary syndrome (ACS) when measured by high-sensitivity CRP assays. These assays have greater analytical sensitivity and reliably measure CRP concentrations within the reference range with low imprecision (5–10%). Because of evidence that atherosclerosis is an inflammatory disease, high-sensitivity CRP can be used as a biomarker of risk
in primary prevention and in patients with known cardiovascular disease. The aim of this review is to evaluate the use of CRP in patients with acute coronary disease.

The in-vitro stability of high-sensitivity C-reactive protein is excellent. Specific blood sampling conditions aren’t necessary.  However, retesting may be necessary with some assays if there is marked lipaemia.  Baseline and subsequent measures are in good for agreement for risk stratification despite biological variability of 30–60%.

The upper reference limit is method-dependent but usually 8mg/L for standard assays. The distribution of high-sensitivity CRP concentrations is skewed in both genders with a 50th percentile of_1.5mg/L (excluding women on hormone replacement therapy). Race differences have been reported. Most studies have reported no relationship with age,  but to circadian and seasonal variation. CRP concentrations are increased by smoking, obesity, and hormone replacement therapy and reduced by exercise, moderate alcohol drinking, and statin use. Correction for these factors is essential in reference range studies. CRP assays are not standardized. We recommend  the use of third-generation high-sensitivity CRP assays that combine features of standard and high-sensitivity CRP assays.  Required assay precision should be < 10% in the range of 3 and 10 mg/L.

Biochemical and analytical issues

Critical clinical concepts

(1) CRP concentrations are reported in mg/L
(2) CRP test results are method-dependent

•  classification of patients into risk categories is usually comparable

(3) Third generation CRP assay are recommended
(4) No specific patient preparation before blood sampling is necessary
(5) The in-vitro stability of CRP is high

This is only a portion of the published concensus document. What is relevant to this discussion is that the hs-CRP is an extremely valuable marker for inflammatory disease.  It is not ordered often enough because of the broad range of values that we have become accustomed to for years, and it is elevated in rheumatologic conditions, but even then, it is widely used in pediatrics because children may present with rapidly emergent sepsis with very minimal sympoms.
The hs-CRP has opened a window to subliminal inflammatory disease that is diabetes, with accompanied arteriolar endothelial inflammation.

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Mirrakhimov Aibek E
Publisher: BioMed Central      Date of publication: Oct 2012   ISSN(s): 1475-2840
Published in: Cardiovascular Diabetology 2012; 11(1):132   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1475-2840-11-132      http://www.cardiab.com/content/11/1/132

Keywords: COPD, Dysglycemia, Insulin resistance, Obesity, Metabolic syndrome, Diabetes mellitus endothelial dysfunction, Vasculopathy

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus

• are common and underdiagnosed medical conditions.

It was predicted that chronic obstructive pulmonary disease

• will be the third leading cause of death worldwide by 2020.

The healthcare burden of this disease is even greater

• if we consider the significant impact of chronic obstructive pulmonary disease on
  • the cardiovascular morbidity and mortality.

Chronic obstructive pulmonary disease

• may be considered as a novel risk factor for new onset type 2 diabetes mellitus via

multiple pathophysiological alterations such as:

1. inflammation and oxidative stress,
2. insulin resistance,
3. weight gain and
4. alterations in metabolism of adipokines.

On the other hand, diabetes may act as an independent factor,

• negatively affecting pulmonary structure and function.

Diabetes is associated with an increased risk of

1. pulmonary infections,
2. disease exacerbations and
3. worsened COPD outcomes.

On the top of that, coexistent OSA

• may increase the risk for type 2 DM in some individuals.

The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and

• chronic obstructive pulmonary disease may be viewed as a risk factor for
• the new onset type 2 diabetes mellitus.

Conversely, both types of diabetes mellitus should be viewed as

• strong contributing factors for the development of obstructive lung disease.

Such approach can potentially improve the outcomes and medical control for both conditions,

• and, thus, decrease the healthcare burden of these major medical problems.

CONCLUSIONS

This discussion  presents a spectrum of cardiovascular risk associated with type 2 diabetes mellitus, with high risk for CVD, stroke, endothelial dysfunction, and an association with obesity, measured by waist circumference, and an underlying proinflammatory state that can be measured by CRP.

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Circulating Endothelial Progenitors Cells (cEPCs) as Biomarkers

Posted in Atherogenic Processes & Pathology, Best evidence, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone marrow derived cells, Cardiovascular Research, Chemical Genetics, Circulating Progenitor Cells, Curation, Cytoskeleton, Diagnostic Immunology, Discovery process, Endothelial cells, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Immunodiagnostics, Interviews with Scientific Leaders, Metabolomics, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Proteomics, Technology Advance Assessment of, Translational Effectiveness, Translational Research, Translational Science, Umbilical cord cells, tagged CEC subtypes, cell function correlation, cell identification by labelling, Circulating Progenitor Endothelial Cells, endothelial cell, Endothelial progenitor cell, increased number of CECs, ischemic dardiac disease, myocardial infarction, target cell blockers on January 14, 2014| Leave a Comment »

Circulating Endothelial Progenitors Cells (cEPCs) as Biomarkers

Article Curator: Larry H. Bernstein, MD, FCAP

and

Topic Curator: Aviva Lev-Ari, PhD, RN

Article ID #105: Circulating Endothelial Progenitors Cells (cEPCs) as Biomarkers. Published on 1/14/2014

WordCloud Image Produced by Adam Tubman

Circulating progenitor cells have gained much interest rapidly in the past year primarily in identification of damaged tissue that has turnover of cells that are identifiable in the circulation.  This has to require a sensitivity for identification at one or two logs lower than circulating hematopoietic cells.  I mention this untested view only because cells of the circulation are detected routinely by automated hematology instruments like those of Beckman-Coulter and Siemens, with graphical presentation of results.  The Sysmex also reports immature granulocytes that are a small percent of the neutrophil count.  In the evaluation of leukemias, flow cytometry has been used for years, but require a preparative step.  Cell types have been identified by acidic and basic dye stains to identify basophilic, acidophilic and neutrophilic granulocyte series, and by size of the cell population, and nuclear features, differentiating mature and nucleated red cells, the granulocyte series, monocytes and lymphocytes, as well as platelets (aggregation gives an underestimate of platelet count).  But to detect cancer cells or damaged endothelial cells, the number of cells in the circulation requires and antibody to the surface with a visualizable ligand attached to an antibody for identification.  Visualization could be by a fluorophor, or perhaps a luciferase reaction.  Here are two articles that identify circulating endothelial cells, making them suitable for biomarkers of cardiovascular injury.  Whether they can detect early predictive ischemia, or frank AMI needs investigation.  The concept of piecemeal necrosis in the heart may be applicable to cardiomyocyte injury that is found unexpectedly at autopsy as “silent infarct”.

Circulating endothelial progenitors–cells as biomarkers

Rosenzweig, Anthony
N Engl J Med. 2005 Sep 8;353(10):1055-7

Comment on

Circulating endothelial progenitor cells and cardiovascular outcomes

[N Engl J Med. 2005]  PMID: 16148292 [PubMed – indexed for MEDLINE]

Endothelial injury and dysfunction are thought to be critical events in the  pathogenesis of atherosclerosis. Thus,

• understanding the mechanisms that  maintain and restore endothelial function
  • may have important clinical  implications.

A series of clinical and basic studies prompted by the discovery 

• of bone marrow derived endothelial progenitor cells1 have
• provided insights into these processes and
  • opened a door to the development of new therapeutic approaches.

Growing evidence suggests that bone marrow derived endothelial progenitor cells circulate in the blood and

• play an important role in the formation of new blood vessels as well as
• contribute to vascular homeostasis in the adult.

Circulating endothelial progenitor cells were initially identified

• through their expression of CD34
  (a surface marker common to hematopoietic stem cells and mature endothelial cells)
• and vascular endothelial cell growth-factor receptor 2
  (VEGFR2 or kinase-domain related [KDR] receptor),

but not of other markers seen on fully differentiated endothelial cells.1

Subsequent studies have also used other identifiers, such as

• the stem-cell marker CD133, and
• functional assays, including
  • the ability to form endothelial colonies.

Endothelial progenitor cells defined in these ways probably represent

• a heterogeneous population, which,
• in combination with the lack of a consensual definition,

complicates the interpretation of work in this field.

Nevertheless, numerous studies in animals have shown that endothelial  progenitor cells can integrate into new and existing blood vessels.2,3,4
Intravenous injection of cytokine-mobilized human endothelial progenitor cells

• improved myocardial neoangiogenesis and
• the recovery of functioning in a rat model of infarction.3

Repeated injection of bone marrow derived cells in a mouse model of atherosclerosis

• reduced the rate of plaque formation without altering serum lipids levels, and
• donor endothelial progenitor cells could subsequently be identified in the recipient’s blood vessels.4

Previous clinical studies have shown that

• traditional risk factors for coronary atherosclerosis
• are associated with low levels of circulating endothelial progenitor cells,5 whereas
• protective interventions, including statin therapy6 and exercise,7
  • appear to increase the supply of these cells.

Hill et al. found that even in healthy volunteers,

• levels of endothelial progenitor cells were inversely correlated with the Framingham risk score and
• actually appeared to predict vascular function better than the Framingham risk score.5

Together, these data suggest that circulating endothelial progenitor cells may participate

• not only in forming new blood vessels
• but also in maintaining the integrity and function of vascular  endothelium,

thereby mitigating disease processes such as atherosclerosis.

In this issue of the Journal, Werner and colleagues have further advanced our understanding of the clinical implications of endothelial progenitor cells.8 Endothelial progenitor cells were quantitated in 519 patients with coronary artery disease who

• were followed for one year after undergoing catheterization.

Patients with higher levels of endothelial progenitor cells had

• a reduced risk of death from cardiovascular causes and of
• the composite end point of major cardiovascular events.

These relationships were preserved even

• after adjustment for traditional risk factors and prognostic variables.

A similar relationship was seen

• whether endothelial progenitor cells were  identified by virtue of expression
  either of CD34 and KDR or of CD133 or
• because of their ability to form endothelial colonies,

further strengthening the authors’ conclusions. Repeated catheterization was not performed in this  cohort, so

• we do not know whether the reduction in clinical events reflected a slowed progression of atherosclerosis or some other clinical effect.

A  dissociation between anatomical measures of atherosclerosis and clinical events has been well documented in other settings.

Although this study is consistent with prior work suggesting that circulating endothelial progenitor cells may play a protective role in vascular homeostasis, other explanations

• for the association between endothelial progenitor number and outcome remain possible.

Changes in the number of endothelial progenitor cells and

• in clinical events might reflect a common underlying etiology,
  • • rather than a causal relation.

For example, a defect in the production of nitric oxide, which plays an important role

• in both the mobilization of endothelial progenitor cells9 and blood-vessel function, might account for both observations.

Similarly, the number of endothelial progenitor cells

• may mirror a person’s regenerative capacity more broadly and
• predict clinical events on that basis.

Even if endothelial progenitor cells are mechanistically linked to clinical cardiovascular events,

• such clinical studies do not distinguish between the possibility
• that the protection is mediated through the integration of endothelial  progenitor cells into blood vessels and

its possible mediation by other  mechanisms, such as the

• paracrine benefits of endothelial progenitor  cell secreted products.

Although such questions will undoubtedly continue to provide fertile ground  for fundamental investigation,

• the report by Werner and colleagues has more  immediate clinical implications.

First, it suggests that circulating cell  populations may represent a new class of biomarkers

• that naturally integrate  diverse genetic and environmental effects,
• thereby providing robust  physiological and prognostic insights.

Second, in the context of coronary  disease, the study shows that

• the number of endothelial progenitor cells is an independent predictor of hard clinical outcomes.

As with other biomarkers, a demonstration of clinical usefulness will ultimately require

• the examination of other patient populations, as well as
• a demonstration that clinical therapy can be guided and enhanced by this information.

Finally, the increased risk associated with reduced levels of endothelial progenitor cells

• supports the growing interest in the therapeutic potential of enhancing the level of these cells.

The most dramatic extension of this line of reasoning involves

transferring  bone marrow or peripheral blood cells that are likely to include endothelial  progenitor cells to patients with coronary artery disease. Although it would be premature to judge the clinical success of these strategies, early trials, including one randomized (though incompletely blinded) trial, have suggested

• at least short-term functional benefits of intracoronary infusion of bone marrow cells after acute infarction.10

Trials are planned to address more definitively the potential benefits of such cells

• in the settings of acute infarction and chronic ischemic cardiomyopathy.

Such efforts would be aided substantially by the identification of specific markers as well as

• an improved understanding of the role of subtypes of endothelial progenitor cells and
• of the mechanisms by which they work.

Ironically, the data presented by Werner and colleagues in combination with work showing

• the impaired functioning of endothelial progenitor cells in high-risk patients5 suggest
• that the patients most in need of endothelial progenitor cells may be
  • • those who are least able to donate them for autologous transplantation.

Whether these limitations can be overcome through

• ex vivo expansion or  genetic modification of endothelial progenitor cells is unclear.

In addition to possible cell-based therapies, work on endothelial progenitor cells provides yet another rationale

• for redoubling efforts to comply with established therapeutic guidelines,
• including lifestyle modifications and the use of statin therapy,
  • • both of which appear to enhance the number of circulating endothelial progenitor cells.

Whether there will be a downside to enhancing the number and function of  endothelial progenitor cells remains unclear,

• although obvious concerns  include exacerbating conditions that are characterized by adverse vessel  formation,
  • such as diabetic retinopathy and tumor angiogenesis.

Small studies have suggested an association between high levels of circulating endothelial progenitor cells and the risk of certain cancers, such as multiple myeloma.11 Moreover, studies in animals show that

• bone marrow derived endothelial progenitors participate in tumor angiogenesis, thereby
  • • enhancing tumor growth.12

In the study by Werner and colleagues,

• the number of deaths from cardiovascular causes among patients with high levels of endothelial progenitor cells
• was substantially lower than that among patients with lower levels of these cells,
• without a reduction in the risk of death overall.8

Although this finding could raise the specter of a counterbalancing adverse effect of endothelial progenitor cells,

• there was no apparent pattern in the deaths due to other causes,
• and no deaths from cancer were noted in this population.

It is possible that as we learn more about the biology of endothelial progenitor cells, there may be opportunities

• to target vessel formation more specifically.

In addition, therapeutic strategies

• tailored to individualized risk will undoubtedly help in practice.

For example, in the study by Werner et al.,

• patients in the group with the lowest baseline levels of endothelial progenitor cells
• had a risk of death from cardiovascular causes of 8.3 percent during one year of follow-up,
• suggesting that the benefits of enhancing the function and number of endothelial progenitor cells
  • • may well outweigh the risks in such high-risk populations.

Additional studies will be necessary to address these questions definitively. Larger studies

• of longer duration performed in different cohorts will be required to determine fully
  • the clinical usefulness of endothelial progenitor cells as a biomarker.

Rigorous interventional studies will indicate

• whether levels of endothelial progenitor cells can be used to guide therapy and
• whether cell transfer has a role in augmenting the levels of these cells.

Basic-science studies should help guide these clinical efforts by

• further defining the desirable subpopulations of endothelial progenitor cells and
• the mechanisms by which they mediate their effects.

By establishing a connection between circulating endothelial progenitor cells and hard clinical end points, Werner and colleagues

• provide a potent stimulus for clinical and basic studies to address these important issues.

Source Information

From the Program in Cardiovascular Gene Therapy, Massachusetts General  Hospital, and Harvard Medical School ― both in Boston.

References

Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor  endothelial cells for angiogenesis. Science 1997;275:964-967.

Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced  mobilization of bone marrow-derived endothelial progenitor cells for  neovascularization. Nat Med 1999;5:434-438.

Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001; 7: 430-436.

Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003; 108: 457-463.

Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.

Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial  progenitor cells by statin therapy in patients with stable coronary artery  disease. Circulation 2001; 103: 2885-2890.

Laufs U, Werner N, Link A, et al. Physical training increases endothelial  progenitor cells, inhibits neointima formation, and enhances angiogenesis.  Circulation 2004; 109: 220-226.

Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999-1007.

Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med  2003; 9: 1370-1376.

Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow  cell transfer after myocardial infarction: the BOOST randomised controlled  clinical trial. Lancet 2004; 364: 141-148.

Zhang H, Vakil V, Braunstein M, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005; 105: 3286-3294.

Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194-1201.

Fluid phase biopsy for detection and characterization of circulating endothelial cells in myocardial infarction.

Kelly Bethel, Madelyn S Luttgen, Samir Damani, Anand Kolatkar, Rachelle Lamy, Mohsen Sabouri-Ghomi, Sarah Topol, Eric J Topol, Peter Kuhn

Physical Biology (Impact Factor: 2.62). 01/2014; 11(1):016002. http://dx.doi.org/10.1088/1478-3975/11/1/016002
Source: PubMed

Elevated levels of circulating endothelial cells (CECs) occur in response to various pathological conditions including myocardial infarction (MI). Here, we adapted

• a fluid phase biopsy technology platform that successfully detects circulating tumor cells in the blood of cancer patients (HD-CTC assay),
• to create a high-definition circulating endothelial cell (HD-CEC) assay for the detection and characterization of CECs.

Peripheral blood samples were collected from 79 MI patients, 25 healthy controls and six patients undergoing vascular surgery (VS). CECs were defined

• by positive staining for DAPI, CD146 and von Willebrand Factor
• and negative staining for CD45.

In addition, CECs exhibited distinct morphological features that

• enable differentiation from surrounding white blood cells.

1. CECs were found both as individual cells and as aggregates.
2. CEC numbers were higher in MI patients compared with healthy controls.
3. VS patients had lower CEC counts when compared with MI patients

but were not different from healthy controls.

Both HD-CEC and CellSearch® assays could discriminate

• MI patients from healthy controls with comparable accuracy

but the HD-CEC assay exhibited

• higher specificity while maintaining high sensitivity.

Our HD-CEC assay may be used as a robust diagnostic biomarker in MI patients.

MicroRNA function in endothelial cells

Solving the mystery of an unknown target gene using microRNA Target Site Blockers

Dr. Virginie Mattot

Dr. Virgine Mattot works in the team “Angiogenesis, endothelium activation and Cancer” directed by Dr. Fabrice Soncin at the Institut de Biologie de Lille in France where she studies the roles played by microRNAs in endothelial cells during physiological and pathological processes such as angiogenesis or endothelium activation. She has been using Target Site Blockers to investigate the role of microRNAs on putative targets which functions are yet unknown.

What is the main focus of the research conducted in your lab?

We are studying endothelial cell functions with a particular interest

• in angiogenesis and endothelium activation during physiological and tumoral vascular development.

How did your research lead to the study of microRNAs?

A few years ago, we identified in my team

• a new endothelial cell-specific gene which harbors a microRNA in its intronic sequence.

We have since been working on understanding

• the functions of both this new gene and
• its intronic microRNA in endothelial cells

What is the aim of your current project?

While we were searching for the functions of the intronic microRNA,

• we identified an unknown gene as a putative target.

The aim of my project was to investigate if this unknown gene was actually a genuine target and

• if regulation of this gene by the microRNA was involved in endothelial cell function.

We had already characterized the endothelial cell phenotype associated with the inhibition of our intronic microRNA.

We then used miRCURY LNA™ Target Site Blockers to demonstrate

• that the expression of this unknown gene is actually controlled by this microRNA.

Further, we also demonstrated that the microRNA regulates

• specific endothelial cell properties through regulation of this unknown gene.

How did you perform the experiments and analyze the results?

LNA™ enhanced target site blockers (TSB) for our microRNA were designed by Exiqon.
We transfected the TSBs into endothelial cells using our standard procedure and

• analysed the induced phenotype.

As a control for these experiments, a mutated version of the TSB was designed by Exiqon and

• transfected into endothelial cells.

We first verified that this TSB was functional by

• analyzing the expression of the miRNA target
  • • against which the TSB was directed in transfected cells.

Finally, we showed that the TSB induced similar phenotypes as those found when we inhibited the microRNA in the same cells. 

What were some specific challenges in your experiments and how did you overcome them?

The fact that the target gene for our microRNA was unknown was a major challenge. Without specific available tools, like antibodies,

• it becomes difficult to demonstrate the effect of the microRNA on the gene in question and
• to show that the unknown gene is indeed responsible for the functions of the microRNA.

However through the use of specific target site blockers, we were able to demonstrate

• that this unknown gene was associated with the phenotype observed
  • when the microRNA was inhibited in endothelial cells.

How do you feel about your results so far?

We are very pleased with the results of the TSB experiments and

• altogether these results demonstrate that our miRNA of interest
• is functional in endothelial cells
  • through the regulation of a target gene with a previously unknown role.

What do you find to be the main benefits/advantage of the LNA™ microRNA target site blockers from Exiqon?

Target Site Blockers are efficient tools to demonstrate the

• specific involvement of putative microRNA targets
• in the function played by this microRNA.

The use of LNA™ allows the design of short oligonucleotides that are very specific and easy to work with. 

What would be your advice to colleagues about getting started with microRNA functional analysis?

In order to address the role played by a microRNA,

• it is essential to perform both gain and loss of functions experiments.

What are the next steps in the current project and how do you plan to perform them?

We plan to use microRNA inhibitor libraries to identify

• more microRNAs specifically involved in the processes that we currently study.

When and where will be hear /read more about your studies?

We are currently in the process of submitting a manuscript regarding the function of my microRNA of interest.

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