Posted in Abdominal Aorta, Cardiac and Cardiovascular Surgical Procedures, Cardiovascular Pharmacogenomics, Carotid Artery, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, Pharmacotherapy of Cardiovascular Disease, Spontaneous Coronary Artery Dissection (SCAD), Thoracic Aorta on February 12, 2014| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
VIEW VIDEO
Published on Jun 6, 2013
In this Mayo Clinic Grand Rounds video originally presented on November 30, 2012, cardiologists Rajiv Gulati, MD, PhD, and Sharonne Hayes, MD, discuss “Spontaneous Coronary Artery Dissection: New Insights and New Questions About This-Not-So-Rare Condition.”
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 »
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
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
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.
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Dr Stanley Hazen
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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.
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Dr Mariel Jessup
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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.
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Dr Roger Blumenthal
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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
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Dr Rita Redberg
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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%.
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Dr James de Lemos
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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
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Dr Sekar Kathiresan
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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
SOURCE
Posted in Atherogenic Processes & Pathology, Best evidence, Ca2+ triggered activation, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Curation, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Evidence-based decision-making, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, Immunodiagnostics, Inferential analysis, Medical and Population Genetics, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Nephrology, Nutritional Supplements: Atherogenesis, lipid metabolism, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Quality Assurance, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, tagged 2, Acute coronary syndrome, acute myocardial infarction, American College of Cardiology ACC, Antiplatelet drug, aspartate aminotransferse (AST), Atrial fibrillation, cardiac biomarkers, cardiomyocyte, Cardiomyopathy, CK isoenzyme MB, confounders, coronary artery plaque, Coumadin, Creatine kinase, endothelial cell, hs-troponins, hypercoagulable state, INR, Lactate dehydrogenase, LD isoenzyme(s)-1, miRNAs, myocardial contraction, plaque rupture, platelet activation, practice guidelines, PT, PTT, troponin I, Troponin T, World Health Organization on January 4, 2014| Leave a Comment »
Author and Curator: Larry H Bernstein, MD, FCAP
These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years. The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation. The world health organization (WHO) standard definition then was the presence of two of three:
1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm
2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.
3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.
The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel. Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.
So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century. However, the role of biomarkers broadened. Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury. This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP). The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.
Thus, we have identified the use of traditional cardiac biomarkers for:
1. Diagnosis
2. Therapeutic monitoring
The story is only the beginning. Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic. This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium. The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease. Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.
While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature. There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require
1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement on multitest automated analyzers with high capability in proteomic measurement (MS, time of flight, MS-MS)
Posted in Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Evidence-based decision-making, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Hematopoiesis, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Myelodysplasia, Myelofibrosis, Neurodegenerative Diseases, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Pre-Clinical Animal Model Development, Prescription Drugs Costs, Regenerative Biology and Medicine, Stem Cells for Regenerative Medicine, Translational Effectiveness, Translational Science, tagged biomarkers, biomedical, clinical decision-making, diagnostics, genetic biomarkers, genome modification, genomic technology, genomics, Medical genetics, pharmacogenomics, pharmacotoxicity, structured medical exam, structured medical record on January 3, 2014| Leave a Comment »
Author and Curator: Larry H. Bernstein, MD, FCAP
Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease. This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market. Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured. That is the first issue of concern.
Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked. It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects. In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.
A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon. Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient. Historically, insurance is an actuarial discipline. But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention. Only the timing cannot be predicted. As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.
How does this compute for the physician provider. The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm. Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today. It may provide assessment of risk, or of survival expectation. The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams. Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid. They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.
The relevant questions are:
1. acuity of symptoms and signs.
2. actions to be taken.
3. tests that are needed to clarify the examination findings.
once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.
Where does genetic testing fit into this? At this point, it will only be used
Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cardiovascular Research, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease on January 2, 2014| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction
The GEOSTAT-1 Study
Kristian M. Bailey, MBChB, Simon P.R. Romaine, BSc, Beryl M. Jackson, RGN, Amanda J. Farrin, MSc, Maria Efthymiou, MSc, Julian H. Barth, MD, Joanne Copeland, BSc,Terry McCormack, MBBS, Andrew Whitehead, MSc, Marcus D. Flather, MBBS, Nilesh J. Samani, MD, FMedSci, Jane Nixon, PhD, Alistair S. Hall, MD, PhD, Anthony J. Balmforth, PhD and on behalf of the SPACE ROCKET Trial Group
Author Affiliations
From the Division of Cardiovascular and Diabetes Research (K.M.B., S.P.R.R., B.M.J., A.J.B.), and Division of Cardiovascular and Neuronal Remodelling (A.S.H.), Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; Clinical Trials Research Unit (A.J.F., M.E., J.C., J.N.), University of Leeds, Leeds, United Kingdom; Clinical Biochemistry (J.H.B.), Leeds General Infirmary, Leeds, United Kingdom; Whitby Group Practice (T.M.), Spring Vale Medical Centre, Whitby, North Yorkshire, United Kingdom; Pharmacy Department (A.W.), Leeds General Infirmary, Leeds, United Kingdom; Clinical Trials and Evaluation Unit (M.D.F.), Royal Brompton and Harefield NHS Trust and Imperial College, London, United Kingdom; and Department of Cardiovascular Sciences (N.J.S.), University of Leicester, Leicester, United Kingdom.
Correspondence to Alistair S. Hall, Clinical Cardiology, Multidisciplinary Cardiovascular Research Centre (MCRC), G Floor, Jubilee Building, Leeds General Infirmary, Leeds, LS1 3EX, United Kingdom. E-mail A.S.Hall@leeds.ac.uk
* Dr Bailey, Mr Romaine, Dr Hall, and Dr Balmforth contributed equally to this study.
Abstract
Background— Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy.
Methods and Results— The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415).
Conclusion— The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg.
Clinical Trial Registration— URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.
SOURCE:
Circulation: Cardiovascular Genetics.2010; 3: 276-285
Published online before print March 5, 2010,
doi: 10.1161/ CIRCGENETICS.109.898502
Posted in Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical on January 2, 2014| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES)
Yuxin Niu, PhD*, Yan Gong, PhD*, Taimour Y. Langaee, PhD, Heather M. Davis, PharmD, Hazem Elewa, PhD, Amber L. Beitelshees, PharmD, MPH, James I. Moss, PhD, Rhonda M. Cooper-DeHoff, PharmD, Carl J. Pepine, MD and Julie A. Johnson, PharmD
Author Affiliations
From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.N., Y.G., T.Y.L., H.M.D., H.E., J.I.M., R.M.C.-D., J.A.J.), College of Pharmacy, University of Florida, Gainesville, Fla; Division of Endocrinology, Diabetes and Nutrition (A.L.B.), University of Maryland School of Medicine, Baltimore, Md; and Division of Cardiovascular Medicine (R.M.C.-D., C.J.P., J.A.J.), University of Florida College of Medicine, Gainesville, Fla.
Correspondence to Julie A. Johnson, PharmD, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610. E-mail Johnson@cop.ufl.edu
↵* Drs Niu and Gong contributed equally to this work.
Abstract
Background— Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.
Methods and Results— SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.
Conclusions— These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.
Our association study suggests significant pharmacogenetic effects for the promoter SNP rs2357928 in CACNB2 such that for minor allele homozygotes, a verapamil SR-based CCB treatment strategy is associated with substantially higher risk for adverse cardiovascular outcome compared with an atenolol-based BB treatment strategy. These findings were validated in a second ethnic group and further supported by in vitro studies suggesting differential transcriptional activity with this promoter SNP. Additional studies in other cohorts are required, but these data suggest that this CACNB2 SNP may have future potential for guiding selection of antihypertensive drug therapy among patients with CAD.
Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier:NCT00133692.
SOURCE:
Circulation: Cardiovascular Genetics.2010; 3: 548-555
http://circgenetics.ahajournals.org/content/3/6/548.full?related-urls=yes&legid=circcvg;3/6/548
doi: 10.1161/ CIRCGENETICS.110.957654
Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, tagged Blood pressure, Genome-wide association study, Hypertension, Single-nucleotide polymorphism, University of Florida on January 2, 2014| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives
Results From the Pharmacogenomic Evaluation of Antihypertensive Responses Study
Yan Gong, PhD, Caitrin W. McDonough, PhD, Zhiying Wang, MS, Wei Hou, PhD,Rhonda M. Cooper-DeHoff, PharmD, MS, Taimour Y. Langaee, PhD, Amber L. Beitelshees, PharmD, MPH, Arlene B. Chapman, MD, John G. Gums, PharmD, Kent R. Bailey, PhD, Eric Boerwinkle, PhD, Stephen T. Turner, MD and Julie A. Johnson, PharmD
Author Affiliations
From the Department of Pharmacotherapy and Translational Research (Y.G., C.W.M., R.M.C.-D., T.Y.L., J.G.G., J.A.J.), Department of Biostatistics, College of Medicine (W.H.), Division of Cardiovascular Medicine, College of Medicine (R.M.C.-D., J.A.J.), and Department of Community Health and Family Medicine (J.G.G.), University of Florida, Gainesville, FL; Division of Epidemiology, University of Texas at Houston, Houston, TX (Z.W., E.B.); Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD (A.L.B.); Renal Division, Emory University, Atlanta, GA (A.B.C.); and Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (S.T.T.).
Correspondence to Yan Gong, PhD, Department of Pharmacotherapy and Translational Research, University of Florida, PO Box 100486, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail gong@cop.ufl.edu.
Abstract
Background—To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs.
Methods and Results—We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical Pvalues were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected α of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3×10–6 for systolic BP; P=1.6×10–6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test.
Conclusions—These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.
SOURCE:
Circulation: Cardiovascular Genetics.2012; 5: 686-691
Published online before print October 19, 2012,
doi: 10.1161/ CIRCGENETICS.112.964080
2012pharmaceutical
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