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2017 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults – A REPORT OF THE American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

The new Hypertension Guideline changes the definition of hypertension, which is now considered to be any systolic BP measurement of 130 mm Hg or higher—or any diastolic BP measurement of 80 mm Hg or higher.

 

SOURCE

http://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_497446.pdf

 

 

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SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke

Reporter: Aviva Lev-Ari, PhD, RN

Genes Affirm: High BMI Carries Weighty Heart, Diabetes Risk – Mendelian randomization study adds to ‘burgeoning evidence’

by Crystal Phend, Senior Associate Editor, MedPage Today, July 05, 2017

 

The “genetically instrumented” measure of high BMI exposure — calculated based on 93 single-nucleotide polymorphisms associated with BMI in prior genome-wide association studies — was associated with the following risks (odds ratios given per standard deviation higher BMI):

  • Hypertension (OR 1.64, 95% CI 1.48-1.83)
  • Coronary heart disease (CHD; OR 1.35, 95% CI 1.09-1.69)
  • Type 2 diabetes (OR 2.53, 95% CI 2.04-3.13)
  • Systolic blood pressure (β 1.65 mm Hg, 95% CI 0.78-2.52 mm Hg)
  • Diastolic blood pressure (β 1.37 mm Hg, 95% CI 0.88-1.85 mm Hg)

However, there were no associations with stroke, Donald Lyall, PhD, of the University of Glasgow, and colleagues reported online in JAMA Cardiology.

The associations independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history were found in baseline data from 119,859 participants in the population-based U.K. Biobank who had complete medical, sociodemographic, and genetic data.

“The main advantage of an MR approach is that certain types of study bias can be minimized,” the team noted. “Because DNA is stable and randomly inherited, which helps to mitigate errors from reverse causality and confounding, genetic variation can be used as a proxy for lifetime BMI to overcome limitations such as reverse causality and confounding, a process that hampers observational analyses of obesity and its consequences.”

 

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

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    Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics

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    by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams PhD
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    Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2)

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    Metabolic Genomics & Pharmaceutics (BioMedicine – Metabolomics, Immunology, Infectious Diseases Book 1)

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    Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

    Dec 26, 2015 | Kindle eBook

    by Larry H. Bernstein MD FACP and Aviva Lev-Ari PhD RN
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    Genomics Orientations for Personalized Medicine (Frontiers in Genomics Research Book 1)

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    Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

    Dec 26, 2015 | Kindle eBook

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    Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation: The Art of Scientific & Medical Curation

    Nov 29, 2015 | Kindle eBook

    by Larry H. Bernstein MD FCAP and Aviva Lev-Ari PhD RN
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Pathophysiology in Hypertension: Opposing Roles of Human Adaptive Immunity

Reporter: Aviva Lev-Ari, PhD, RN

T regulatory lymphocytes counteract hypertensive effects by suppressing innate and adaptive immune responses and T effector lymphocytes promote differentiation towards pro-inflammatory T helper cells

 

Dual opposing roles of adaptive immunity in hypertension

, , ,

DOI: http://dx.doi.org/10.1093/eurheartj/ehu119 1238-1244 First published online: 30 March 2014

Abstract

Hypertension involves remodelling and inflammation of the arterial wall. Interactions between vascular and inflammatory cells play a critical role in disease initiation and progression. T effector and regulatory lymphocytes, members of the adaptive immune system, play contrasting roles in hypertension. Signals from the central nervous system and the innate immune system antigen-presenting cells activate T effector lymphocytes and promote their differentiation towards pro-inflammatory T helper (Th) 1 and Th17 phenotypes. Th1 and Th17 effector cells, via production of pro-inflammatory mediators, participate in the low-grade inflammation that leads to blood pressure elevation and end-organ damage. T regulatory lymphocytes, on the other hand, counteract hypertensive effects by suppressing innate and adaptive immune responses. The present review summarizes and discusses the adaptive immune mechanisms that participate in the pathophysiology in hypertension.

  • Blood pressure
  • Adaptive immunity
  • Inflammation
  • T effector lymphocytes
  • T regulatory lymphocytes
  • Cytokines

Conclusion

Experimental and clinical evidence discussed in this review strongly suggests that adaptive immunity, represented by T effector and regulatory lymphocyte subsets, plays a dual role in hypertension (Figure 2). Increased sympathetic outflow as a consequence of stimulation of the CNS by hypertensive stimuli may result in mild blood pressure elevation, causing tissue injury and formation of neoantigens2 and/or damage-associated molecular patterns (DAMPs).80 Activation of innate APCs by DAMPs, or by pathogen-associated molecular patterns (PAMPs) generated in response to low-grade infection,80,81 and direct stimulation by CNS, may be the cause of activation of CD4+, and perhaps CD8+, T effector lymphocytes, and differentiation of CD4+ T cells towards pro-inflammatory Th1/Th17 phenotypes.41 Th1/Th17 effector lymphocytes contribute to the progression of hypertension by producing pro-inflammatory mediators, including ROS, IFN-γ, TNF-α, and IL-17, to promote low-grade inflammation.24,41,42,51,52 T regulatory lymphocytes, on the other hand, counteract hypertensive abnormalities by suppressing innate and adaptive immune responses, perhaps by secreting IL-10.6571 As such, circulating levels of Tregs or their immune-suppressive activity may be affected in hypertension.

 SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

Idris-Khodja et al. (2014) Dual opposing roles of adaptive immunity in hypertension. European Heart Journal (doi: 10.1093/eurheartj/ehu119)

 

Adaptive Immunity

Figure 1

Differentiation of naïve T lymphocytes into various subsets in a normal immune response. Antigen-presenting cells (dendritic cells and monocyte/macrophages) present antigens on major histocompatibility complex (MHC)-II to naïve T cells (Th0) in secondary lymphoid tissues, leading to T-cell clonal expansion and differentiation into effector T cells, such as T helper (Th)1, Th2, and Th17 or T regulatory (Treg) cells according to combined stimulation by different cytokines. Th effector lymphocytes and Tregs migrate into tissues such as the vasculature, particularly at the level of the adventitia and perivascular fat. The effector lymphocytes (Th1 and Th17) cells activate other immune cells and participate in inflammation by producing pro-inflammatory cytokines such as interferon-γ, interleukin (IL)-6, and IL-17. T regulatory lymphocytes suppress innate and adaptive responses via production of anti-inflammatory cytokines IL-10 and transforming growth factor-β. CD, cluster of differentiation; DC, dendritic cell; MΦ, macrophage; NK cell, natural killer cell; Tc, cytotoxic T cell; TCR, T-cell receptor.

IMAGE SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

 

Hypertention

 

IMAGE SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

Figure 2

Proposed role of T effector and regulatory lymphocytes in hypertension. Slight elevation in blood pressure (BP) in response to hypertensive stimuli (angiotensin II, aldosterone, endothelin-1, salt and genetic susceptibility) occurs due to increased central signalling, perhaps causing mild tissue injury and formation of damage-associated molecular patterns (DAMPs) and neoantigens. This may lead to activation of innate antigen-presenting cells (APCs) and, subsequently, activation and polarization of naïve CD4+ T effector lymphocytes (Th0) towards pro-inflammatory T helper (Th)1/Th17 phenotypes. Th1/Th17 may contribute to vascular and kidney damage via production of reactive oxygen species (ROS), interferon (IFN)-γ and interleukin (IL)-17 and lead to maintenance of hypertension and progression of end-organ damage. T regulatory lymphocytes counteract hypertension and associated injury by producing IL-10 or by other mechanisms, and suppression of innate and adaptive immune responses. CD, cluster of differentiation; CNS, central nervous system; MHC-II, major histocompatibility complex-II; PAMPs, pathogen-associated molecular patterns; TCR, T-cell receptor.

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Resveratrol, an antioxidant found in red wine presented since 2003 presented for its potential to lower risk for cardiovascular disease and neurodegeneration by increasing cell survival and slowing aging: 2014 Study – Diet rich in resveratrol offers no health boost

Reporter: Aviva Lev-Ari, PhD, RN

Related to this study are other articles published in this Open Access Online Journal, including:

Novel Cancer Hypothesis Suggests Antioxidants Are Harmful

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/01/27/novel-cancer-hypothesis-suggests-antioxidants-are-harmful/

 

Biology, Physiology and Pathophysiology of Heat Shock Proteins

Curation: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/16/biology-physiology-and-pathophysiology-of-heat-shock-proteins/

 

Nature 425, 191-196 (11 September 2003) | doi:10.1038/nature01960; Received 13 June 2003; Accepted 31 July 2003; Published online 24 August 2003

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

See associated Correspondence: Corder et al. , Nature 426, 119 (November 2003)

Konrad T. Howitz1, Kevin J. Bitterman2, Haim Y. Cohen2, Dudley W. Lamming2, Siva Lavu2, Jason G. Wood2, Robert E. Zipkin1, Phuong Chung1, Anne Kisielewski1, Li-Li Zhang1, Brandy Scherer1 & David A. Sinclair2

  1. BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA
  2. Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Masachusetts 02115, USA
  3. In PubMed:

Correspondence to: David A. Sinclair2Email: david_sinclair@hms.harvard.edu

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeastSaccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases2, 3, 4, 5, 6. Included in this family are SIR-2.1, a Caenorhabditis elegansenzyme that regulates lifespan7, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor8, 9, 10. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

SOURCE

Dr. David Sinclair, now a professor of genetics at Harvard Medical School. He and his colleagues discovered in 2003 that resveratrol could increase cell survival and slow aging in yeast (and later in mice) by activating a “longevity” gene known as SIRT1. Since then, we’ve learned that resveratrol can help

  • prevent skin cancer in mice;
  • protect against high blood pressure, heart failure, and heart disease in mice;
  • improve insulin sensitivity, reduce blood sugar, and blunt obesity induced by a high-fat diet in rodents;
  • protect nerves and the brain in various lab animals.

But the dose of resveratrol administered in experiments is always much higher than you’d normally consume in a daily diet. “You would need to drink a hundred to a thousand glasses of red wine to equal the doses that improve health in mice,” says Dr. Sinclair, who was named one of this year’s Time magazine 100 Most Influential People for his anti-aging research. He wasn’t surprised about the results in the JAMA Archives study.

Still, the disappointing results don’t mean that resveratrol and other molecules like it won’t help extend the lifespan or protect against the development of aging-related diseases. Dr. Sinclair points out that drug companies have now created thousands of new synthetic molecules, “that are up to a thousand times better than resveratrol. They prevent cardiovascular disease and neurodegeneration. They also extend lifespan in mice.”

The molecules don’t have catchy names yet—with current such as SRT1720 and SRT2104—but they’re showing promising results in mice. Dr. Sinclair is again helping to pioneer much of this research.

SOURCE

http://www.health.harvard.edu/blog/diet-rich-resveratrol-offers-health-boost-201405157153

 

 

Original Investigation |

Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults

Richard D. Semba, MD, MPH1; Luigi Ferrucci, MD, PhD2; Benedetta Bartali, PhD3; Mireia Urpí-Sarda, PhD4,5; Raul Zamora-Ros, PhD4,5; Kai Sun, MS1; Antonio Cherubini, MD, PhD6; Stefania Bandinelli, MD7; Cristina Andres-Lacueva, PhD4,5
ABSTRACT

Importance  Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms.

Objective  To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.

Design  Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study (“Aging in the Chianti Region”), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older.

Exposures  Twenty-four–hour urinary resveratrol metabolites.

Main Outcomes and Measures  Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease.

Results  Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer.

Conclusions and Relevance  In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

SOURCE

http://archinte.jamanetwork.com/article.aspx?articleid=1868537

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Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes

Curator: Aviva Lev-Ari, PhD, RN

CABG improves survival for individuals with coronary artery disease and compromised left ventricular function,” said NHLBI Director Gary H. Gibbons, MD

Monday, April 4, 2016

Original article

http://www.nejm.org/doi/full/10.1056/NEJMoa1602001

Study results show bypass surgery extends lives of patients with heart failure

Research may lead to improved outcomes for large number of patients who previously had limited therapeutic options.

Scientists funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health have found that a greater number of patients with coronary artery disease may benefit from coronary artery bypass graft (CABG) surgery than previously thought.

CABG — a surgical procedure to help improve blood flow to the heart by bypassing arteries clogged with cholesterol plaques — was thought to be too risky for patients with the long-term effects of coronary artery disease: left ventricular dysfunction (when the left side of the heart is unable to pump normally) and heart failure. Studies of the safety and effectiveness of CABG in the 1970s excluded most patients with these two conditions. The procedure was typically used to relieve angina, or chest pain.

“With limited data showing any benefit for patients with left ventricular dysfunction and heart failure, physicians and patients were less likely to engage in such an invasive, and thus risky, procedure as CABG for diagnosis and treatment,” said lead author Eric J. Velazquez, MD, FACP, FACC, FASE, FAHA, of Duke University Medical Center. “Patients with these conditions largely received medical therapy alone and had poor outcomes.”

Dr. Velazquez and his team conducted a five-year global, randomized controlled clinical trial, called the Surgical Treatment for Ischemic Heart Failure (STICH) study, and a five-year extension study (STICHES(link is external)), to evaluate whether CABG plus guideline-directed medical therapy had a durable benefit over medical therapy alone for patients with coronary artery disease and left ventricular dysfunction. The researchers found that CABG added to medical therapy led to significantly lower rates of death and hospitalization among patients with coronary artery disease, left ventricular dysfunction, and heart failure.

“Our results usher in a new era in the treatment of coronary artery disease because we now have evidence that with CABG and medical therapy, there is a 16 percent reduction in the risk of death from any cause over 10 years,” Dr. Velazquez said.

He added that there is also a median survival benefit of nearly a year and a half, and that he and his team saw that the addition of CABG to medical therapy prevented a death from any cause for every 14 patients they treated. Their data further suggest that the reduction in the risk of death could be even greater in real-world practice.

“Conducting this trial was critically important to determine in a scientifically rigorous study that CABG improves survival for individuals with coronary artery disease and compromised left ventricular function,” said NHLBI Director Gary H. Gibbons, MD. “The current 10-year follow-up provides new important insights about patient subgroups that are more likely to benefit from CABG as compared to medical therapy alone. As such, we now have a solid evidence base to inform patient care and the future development of clinical practice recommendations.”

Dr. Velazquez noted that the results are particularly important because the prevalence of left ventricular dysfunction and heart failure is expected to increase to approximately 8 million individuals by 2030 in the U.S. alone. The increase in the projected prevalence is a result of advances in the management of cardiovascular disease and its risk factors, increasingly transforming coronary artery disease into a chronic disease with long-term effects such as left ventricular dysfunction and heart failure.

George Sopko, MD, MPH, the program director in NHLBI’s Division of Cardiovascular Sciences who administered the study grant, added that this investigation, published in The New England Journal of Medicine (April 2016), is one of only a few cardiovascular trials with 10 years of follow-up and with approximately 98 percent of the patients followed throughout the study period.

“It is unusual to have this quality of follow-up for so long,” said Dr. Sopko. “It speaks to the rigor of the results.” He added that the results are very generalizable, as the study included a diverse patient population spread across 22 countries and various health systems.

SOURCE

http://www.nih.gov/news-events/news-releases/study-results-show-bypass-surgery-extends-lives-patients-heart-failure

http://www.nejm.org/doi/full/10.1056/NEJMoa1602001

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

Articles on Heart Failure N=6

https://pharmaceuticalintelligence.com/?s=Heart+Failure

Articles on coronary artery bypass graft CABG N=36

https://pharmaceuticalintelligence.com/?s=CABG

Articles on Pharmacotherapy of Cardiovascular Diseases N=296

https://pharmaceuticalintelligence.com/?s=Pharmacotherapy+of+Cardiovascular+Disease

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Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Medical Interpretation of Study Results and the Pharmacological Treatment Context of PCSK9 Inhibitors

Author: Larry H. Bernstein, MD, FCAP 

 

The Rausse-3 Clinical Trial accompanied by editorial has been published in the Apr 3, 2016 issue of JAMA comparing toleration to and efficacy of Evolocumab vs Ezetimibe in patients with Statin-related muscle intolerance.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance – The GAUSS-3 Randomized Clinical Trial. SE Nissen, E Stroes, RE Dent-Acosta, et al. JAMA Apr 3, 2016 http://dx.doi.org:10.1001/jama.2016.3608

PCSK9 Inhibitors for Statin Intolerance? DD Waters, PY Hsue, S Bangalore. JAMA Apr 03, 2016. http://dx.doi.org:/10.1001/jama.2016.3670

The main conclusion is as follows:

The very long-term outcomes reported for early statin primary prevention trials17,18are impressive. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized patients with hypertension and multiple risk factors to receive atorvastatin (10 mg daily) or to placebo and was stopped after a median follow-up of 3.3 years because of benefit.17  Approximately 8 years later, 11 years after randomization, total mortality, cardiovascular mortality, and noncardiovascular mortality were all significantly reduced in patients who had been in the statin group. Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Whether PCSK9 inhibitors will have the same impressive long-term outcomes will not be known for many years.

Importance  Muscle-related statin intolerance is reported by 5% to 20% of patients.

Objective  To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab.

Design, Setting, and Participants  Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.

Interventions  Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily).

Main Outcome and Measures  Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels.

Results  Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).

Conclusions and Relevance  Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

Trial Registration  clinicaltrials.gov Identifier: NCT01984424

Background:

Administration of HMG-CoA reductase inhibitors (statins) to reduce levels of low-density lipoprotein cholesterol (LDL-C) represents an essential component of contemporary strategies to reduce morbidity and mortality from atherosclerotic vascular disease.1 However, a significant proportion of patients with clinical indications for statin treatment report inability to tolerate evidence-based doses, most commonly because of muscle-related adverse effects.2 These patients typically report muscle pain or weakness when treatment is initiated or dosage increased and relief when the drug is discontinued or the dosage reduced. Although some patients with statin-associated muscle symptoms experience marked elevation in serum creatine kinase (CK) levels, most do not. Accordingly, diagnosis of this disorder remains largely subjective, based on the presence of patient-reported symptoms.3 The incidence of similar symptoms in placebo-treated patients has resulted in skepticism about the true incidence of statin intolerance.

Patients with muscle-related intolerance often refuse to take statins despite elevated LDL-C levels and a high risk of major cardiovascular events. Current management may include very low or intermittent administration of statins or use of ezetimibe, but these strategies seldom achieve the greater than 50% reduction recommended by current guidelines.1,4,5 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors markedly lower LDL-C levels and have shown potential as an alternative therapy for patients who experience intolerable adverse effects during statin therapy.6– 8 Currently available data suggest that muscle-related adverse effects are uncommon with PCSK9 inhibitors, even in patients with a history of such symptoms, but prior trials relied exclusively on medical history to document statin intolerance.

The GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3) trial was designed as a 2-stage randomized clinical trial to first identify patients with statin-induced muscle symptoms during a placebo-controlled statin rechallenge procedure and subsequently to compare the effectiveness and tolerability of 2 nonstatin therapies—ezetimibe or evolocumab, a recently approved PCSK9 inhibitor.

Figure 2.

Time to First Occurrence of a Muscle-Related Adverse Effect Resulting in Discontinuation of Study Drug During Period 1 and Period 2 of Phase A, GAUSS-3 Trial

Atorvastatin dose, 20 mg daily; placebo indicates matching placebo. GAUSS-3 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3

http://amaprod.silverchaircdn.com/data/Journals/JAMA/0/joi160031f2.png

The two curves compare phase 1 versus phase 2 with the first showing a separation at about day 60 and the second at about day 18. The hazard ratios are 1.34 vs 1.96 for cumulative event probability with p < 0.02 vs 0.001.

Lipid values at week 22 and week 24 during phase B are reported in the eTable in Supplement 3; the effect of ezetimibe and evolocumab on LDL-C levels during phase B is displayed graphically in Figure 3.
For the first coprimary end point, LDL-C level for the mean of weeks 22 and 24 was 183.0 mg/dL (95% CI, 167.4 to 198.6; least-squares mean percent change from baseline, −16.7% [95% CI, −20.5% to −12.9%]) for ezetimibe and 103.6 mg/dL (95% CI, 92.5 to 114.8; mean percent change, −54.5% [95% CI, −57.2% to −51.8%]) for evolocumab)—a mean difference of −37.8% (95% CI, −42.3% to −33.3%) (P < .001). For the other coprimary end point, LDL-C level at week 24 was 181.5 mg/dL (95% CI, 164.9 to 198.0; least-squares mean percent change from baseline, −16.7% [95% CI, −20.8% to −12.5%]) for ezetimibe and 104.1 mg/dL (95% CI, 92.4 to 115.7; mean percent change, −52.8% [95% CI, −55.8% to −49.8%]) for evolocumab—a mean difference of −36.1% (95% CI, –41.1% to –31.1%) (P < .001).

Figure 3.

Mean Percent Change in Low-Density Lipoprotein Cholesterol Level During Randomized Treatment With Ezetimibe or Evolocumab, GAUSS-3 Trial

Ezetimibe dose, 10 mg daily; evolocumab dose, 140 mg 3 times monthly (420 mg total dosage). GAUSS-3 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3. Error bars indicate 95% CIs.

http://amaprod.silverchaircdn.com/data/Journals/JAMA/0/joi160031f3.png

The first cosecondary end point, absolute change in LDL-C level for the mean of weeks 22 and 24, showed a least-squares mean change of −31.0 mg/dL (95% CI, −38.4 to −23.5) for ezetimibe and −106.8 mg/dL (95% CI, −112.2 to −101.4) for evolocumab—a mean difference of −75.8 mg/dL (95% CI, −84.7 to −67.0) (P < .001). The other cosecondary end point, absolute change in LDL-C level at week 24, showed a least-squares mean change of −31.2 mg/dL (95% CI, −39.2 to −23.3) for ezetimibe and −102.9 mg/dL (95% CI, −108.7 to −97.2) for evolocumab—a mean difference of −71.7 mg/dL (95% CI, −81.3 to −62.2) (P < .001).

Statin intolerance related to muscle symptoms represents a major unresolved challenge to the delivery of optimal cardiovascular care. The reported incidence of statin-associated muscle symptoms in observational studies ranges from 5% to 29% of treated patients, varying by statin and dose.2 Often, despite multiple attempts to find a statin regimen acceptable to the patient, practitioners resort to less effective therapies. Alternative approaches typically include use of ezetimibe or administration of statins intermittently or at dosages below the approved starting dose.4,5,12 These alternative therapeutic strategies provide less LDL-C reduction than recommended by current practice guidelines and result in higher LDL-C levels than most practitioners consider acceptable for optimal reduction of cardiovascular risk.

Both coprimary end points showed a 16.7% reduction with ezetimibe and a more than 50% reduction with evolocumab. These reductions in LDL-C levels are consistent with current labeling for both products. Despite very high baseline values, the LDL-C goal of less than 70 mg/dL was achieved in nearly 30% of evolocumab-treated patients and 1.4% of ezetimibe-treated patients (Table 3). The LDL-C reduction for both drugs was stable by 4 weeks and sustained during the course of the 24 weeks of treatment (Figure 3).

Because some patients cannot tolerate statins, the need for alternative LDL-C–lowering strategies in such patients is self-evident. Previous trials have suggested that PCSK9 inhibitors are effective at lowering LDL-C levels and well tolerated by patients with a history of statin-associated muscle symptoms.6– 8  The studies did not use a placebo-controlled statin rechallenge procedure to identify the presence of statin intolerance.

To our knowledge, the GAUSS-3 trial represents the largest and most comprehensive study using a blinded rechallenge procedure to assess the ability of patients with a history of muscle-related adverse effects to tolerate statins. The trial provides insights into the time course of statin-associated muscle-related adverse effects. As shown in Figure 2A, initial randomization to either atorvastatin or placebo in phase A resulted in similar rates of muscle symptoms during the first 50 days, with a modest increase in occurrence with atorvastatin near the end of the 10-week exposure (HR, 1.34 [95% CI, 1.05 to 1.71]; P = .02). After crossover to period 2, larger numbers of patients experienced symptoms in the atorvastatin treatment group, with differences in event rates occurring relatively early (HR, 1.96 [95% CI, 1.44 to 2.66]; P < .001) (Figure 2B).

 

1

Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  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 Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25, pt B):2889-2934.
PubMed   |  Link to Article

2

Stroes  ES, Thompson  PD, Corsini  A,  et al; European Atherosclerosis Society Consensus Panel.  Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022.
PubMed   |  Link to Article

3

Zhang  H, Plutzky  J, Skentzos  S,  et al.  Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534.
PubMed   |  Link to Article

4

Baigent  C, Blackwell  L, Emberson  J,  et al; Cholesterol Treatment Trialists’ (CTT) Collaboration.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
PubMed   |  Link to Article

 

Original Investigation |

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin IntoleranceThe GAUSS-3 Randomized Clinical Trial FREE ONLINE FIRST

Steven E. Nissen, MD1; Erik Stroes, MD, PhD2; Ricardo E. Dent-Acosta, MD3; Robert S. Rosenson, MD4; Sam J. Lehman, MBBS, PhD5; Naveed Sattar, MD, PhD6; David Preiss, MD7,8; Eric Bruckert, MD9; Richard Češka, MD10,11; Norman Lepor, MD12; Christie M. Ballantyne, MD13; Ioanna Gouni-Berthold, MD14; Mary Elliott, MS3; Danielle M. Brennan, MS1; Scott M. Wasserman, MD3; Ransi Somaratne, MD, MBA3; Rob Scott, MD3; Evan A. Stein, MD, PhD15 ; for the GAUSS-3 Investigators

[] Author Affiliations

1Cleveland Clinic, Cleveland, Ohio
2University of Amsterdam Faculty of Medicine, Amsterdam, the Netherlands
3Amgen Inc, Thousand Oaks, California
4School of Medicine at Mount Sinai, New York, New York
5Flinders University, Bedford Park, SA, Australia
6University of Glasgow, Glasgow, United Kingdom
7Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
8Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom
9University Hospital of Paris 6, Paris, France
10Charles University in Prague, Prague, Czech Republic
11General University Hospital in Prague, Prague, Czech Republic
12David Geffen School of Medicine at the University of California, Los Angeles
13Baylor College of Medicine, Houston, Texas
14Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
15Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio
JAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608
Text Size: A A A

Importance  Muscle-related statin intolerance is reported by 5% to 20% of patients.

Objective  To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab.

Design, Setting, and Participants  Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.

Interventions  Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily).

Main Outcome and Measures  Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels.

Results  Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).

Conclusions and Relevance  Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

Trial Registration  clinicaltrials.gov Identifier: NCT01984424

SOURCE

http://jama.jamanetwork.com/article.aspx?articleID=2511043

 

Online First

April 03, 2016

Original Investigation

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial  

Steven E. Nissen, MD; Erik Stroes, MD, PhD; Ricardo E. Dent-Acosta, MD; et al

Editorial: PCSK9 Inhibitors for Statin Intolerance; David D. Waters, MD; Priscilla Y. Hsue, MD; Sripal Bangalore, MD, MHA

SOURCE

From: “JAMA” <updates@jamanetwork.org>

Date: April 3, 2016 at 9:24:38 AM EDT

To: NULL NULL <AVIVALEV-ARI@ALUM.BERKELEY.EDU>

Subject: JAMA Online First: American College of Cardiology presentation

Reply-To: “JAMA” <reply_ceqbnh_pyfoqdl@ecasend.com>

 

Study shows no clinical benefit from Lilly’s failed cholesterol drug

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PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

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SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR

Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease? – The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

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Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

 

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Introduction

The role for triglycerides as a risk factor for cardiovascular disease is not new, going back to Donald Frederickson’s classification of hyperlipidemias, at least with respect to Type I and Type IIb. Whether there was a mechanism beyond the observations was yet an open question.  The paper that follows addresses such a question.

 

Large Genetic Studies Support Role For Triglycerides In Cardiovascular Disease

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

 

Two  papers published in the New England Journal of Medicine offer new genetic evidence to support the increasingly accepted though still controversial view that triglycerides play an important causal role in cardiovascular disease. If fully validated the new findings could lead to new drugs to prevent and treat cardiovascular disease, though others caution that there is still a long way to go before this could happen.

Both studies describe the impact of genetic mutations on a gene (ANGPTL4) which encodes for a protein (angiopoietin-like 4) that inhibits lipoprotein lipase, an enzyme that plays a key role in breaking down and removing triglycerides from the blood. The large studies found that people with  mutations that inactivate ANGPTL4 have lower levels of triglycerides, higher levels of HDL cholesterol, and decreased risk for cardiovascular disease.

The findings, writes Sander Kersten (Wageningen University, the Netherlands) in an accompanying editorial, “suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.”

The Genetics of Dyslipidemia — When Less Is More

Sander Kersten, Ph.D.   Mar 2, 2016;   http://dx.doi.org:/10.1056/NEJMe1601117

Two groups of investigators now describe in the Journal important genetic evidence showing a causal role of plasma triglycerides in coronary heart disease. Stitziel and colleagues2 tested 54,003 coding-sequence variants covering 13,715 human genes in more than 72,000 patients with coronary artery disease and 120,000 controls. Dewey and colleagues3 sequenced the exons of the gene encoding angiopoietin-like 4 (ANGPTL4) in samples obtained from nearly 43,000 participants in the DiscovEHR human genetics study. The two groups found a significant association between an inactivating mutation (E40K) in ANGPTL4 and both low plasma triglyceride levels and high levels of HDL cholesterol. ANGPTL4 is an inhibitor of lipoprotein lipase, the enzyme that breaks down plasma triglycerides along the capillaries in heart, muscle, and fat.4 Extensive research has shown that ANGPTL4 orchestrates the processing of triglyceride-rich lipoproteins during physiologic conditions such as fasting, exercise, and cold exposure.4 The E40K mutation in ANGPTL4 was previously shown to nearly eliminate the ability of ANGPTL4 to inhibit lipoprotein lipase, a mechanism that may result in part from the destabilization of ANGPTL4.5

The key finding in each study was that carriers of the E40K mutation and other rare mutations in ANGPTL4 had a lower risk of coronary artery disease than did noncarriers, a result that is consistent with the lower triglyceride levels and higher HDL cholesterol levels among mutation carriers. These findings confirm previous data6 and provide convincing genetic evidence that an elevated plasma triglyceride level increases the risk of coronary heart disease. In combination with extensive recent data on other genetic variants that modulate plasma triglyceride levels, the studies suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.

However, as a cautionary note, Talmud and colleagues7 previously found that the presence of the E40K variant was associated with an increased risk of coronary heart disease after adjustment for the altered plasma lipids. Consistent with this hypothesis, the overexpression of Angptl4 in mice was found to protect against atherosclerosis independent of plasma lipids.8

The studies also “implicate targeted inactivation of ANGPTL4 as a potential weapon in the war on heart disease,” though he also points to a previous study that did not support this hypothesis. Sekar Kathiresan (Broad Institute), senior author of one of the NEJM studies, told me that the previous study was small and “basically got the result wrong. Between, the two papers in this NEJM issue, we are looking at 10X more data.”

Recent large genetic studies have resulted in an important change in the field. Many researchers now believe that HDL, which was once thought to play an important protective role in atherosclerosis, is only a marker of disease. In contrast, triglycerides are now thought by many to play an important functional role.

One of the NEJM papers showed that a human monoclonal antibody to ANGPTL4 lowered triglyceride levels in animals. The study was funded by Regeneron and was performed by researchers at Regeneron and Geisinger, as part of an ongoing collaboration using deidentified genetic data from Geisinger patients. In their NEJM paper the researchers reported inflammation and other side effects in the animals treated with the antibody, but they said that no such problem has been observed in humans who have mutations that have the same functional effect as the antibody.

Coding Variation in ANGPTL4, LPL, and SVEP1and the Risk of Coronary Disease Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

March 2, 2016     http://dx.doi.org:/10.1056/NEJMoa1507652

Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease,1-3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example of such advances is the development of a new class of therapeutic agents that is based on the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) as a regulator of low-density lipoprotein (LDL) cholesterol4 and the discovery that low-frequency and loss-of-function variants in this gene protect against coronary artery disease.5,6

Recently, low-frequency coding variation across the genome was systematically tabulated with the use of next-generation exome and whole-genome sequencing data from more than 12,000 persons of various ancestries (including a major contribution from the National Heart, Lung, and Blood Institute Exome Sequencing Project). Protein-altering variants (i.e., nonsynonymous, splice-site, and nonsense single-nucleotide substitutions) that were observed at least twice among these 12,000 persons were included in a genotyping array (hereafter referred to as the exome array). In addition, the exome array contains previously described variants from genomewide association studies, a sparse genomewide grid of common markers, markers that are informative with regard to ancestry (i.e., African American, Native American, and European), and some additional content. Additional information on the design of the exome array is provided at http://genome.sph.umich.edu/wiki/Exome_Chip_Design. In this study, we focused on the 220,231 autosomal variants that were present on the array and were expected to alter protein sequence (i.e., missense, nonsense, splice-site, and frameshift variants) and used these to test the contribution of low-frequency coding variation to the risk of coronary artery disease.

Low-Frequency Coding Variants Associated with Coronary Artery Disease

The discovery cohort comprised 120,575 persons (42,335 patients and 78,240 controls) (Table S1 in the Supplementary Appendix). In the discovery cohort, we found significant associations between low-frequency coding variants in theLPA and PCSK9 genes and coronary artery disease (Table 1

TABLE 1

Low-Frequency Coding Variations Previously Associated with Coronary Artery Disease.). Both gene loci also harbor common noncoding variants associated with coronary artery disease that had previously been discovered through genomewide association studies. These variants were also present on the exome array and had significant associations with coronary artery disease in our study (Table 1). In a conditional analysis, the associations between coronary artery disease and the low-frequency coding variants in both LPA and PCSK9 were found to be independent of the associations between coronary artery disease and the more common variants (Table 1). ….

We found a significant association between SVEP1 p.D2702G and blood pressure (Table 3TABLE 3   Association between Low-Frequency Variants and Traditional Risk Factors., and Table S7 in the Supplementary Appendix). The allele associated with an increased risk of coronary artery disease was also associated with higher systolic blood pressure (0.94 mm Hg higher for each copy of the allele among allele carriers, P=3.0×10−7) and higher diastolic blood pressure (0.57 mm Hg higher for each copy of the allele among allele carriers, P=4.4×10−7). We did not find an association between SVEP1 p.D2702G and any plasma lipid trait. In contrast, ANGPTL4 p.E40K was not associated with blood pressure but instead was found to be associated with significantly lower levels of triglycerides (approximately 0.3 standard deviation units lower for each copy of the allele among allele carriers, P=1.6×10−13) (Table 3) and with higher levels of high-density lipoprotein (HDL) cholesterol (approximately 0.3 standard deviation units higher for each copy of the allele among allele carriers, P=8.2×10−11) (Table 3). In a conditional analysis, these effects appeared to be at least partially independent of each other (Table S8 in the Supplementary Appendix). We did not observe any significant association between ANGPTL4 p.E40K and LDL cholesterol level (Table 3). Both SVEP1 p.D2702G and ANGPTL4 p.E40K were nominally associated with type 2 diabetes in a direction concordant with the associated risk of coronary artery disease.

ANGPTL4 Loss-of-Function Mutations, Plasma Lipid Levels, and Coronary Artery Disease

The finding that a missense allele in ANGPTL4 reduced the risk of coronary artery disease, potentially by reducing triglyceride levels, raised the possibility that complete loss-of-function variants in ANGPTL4 may have an even more dramatic effect on triglyceride concentrations and the risk of coronary artery disease. We therefore examined sequence data for the seven protein-coding exons of ANGPTL4 in 6924 patients with early-onset myocardial infarction and 6834 controls free from coronary artery disease (details of the patients and controls are provided in Table S3 in the Supplementary Appendix). We discovered a total of 10 variants that were predicted to lead to loss of gene function (Figure 1A FIGURE 1    

Loss-of-Function Alleles in ANGPTL4 and Plasma Lipid Levels., and Table S9 in the Supplementary Appendix), carried by 28 heterozygous persons; no homozygous or compound heterozygous persons were discovered. Carriers of loss-of-function alleles had significantly lower levels of triglycerides than did noncarriers (a mean of 35% lower among carriers, P=0.003) (Figure 1B, and Table S10 in the Supplementary Appendix), with no significant difference in LDL or HDL cholesterol levels. Moreover, we found a lower risk of coronary artery disease among carriers of loss-of-function alleles (9 carriers among 6924 patients vs. 19 carriers among 6834 controls; odds ratio for disease, 0.47; P=0.04) (Table S11 in the Supplementary Appendix). A similar investigation was performed for the 48 protein-coding exons of SVEP1; however, only 3 loss-of-function allele carriers were discovered (2 carriers among 6924 patients vs. 1 carrier among 6834 controls).

Coding Variation in LPL and the Risk of Coronary Artery Disease

On the basis of the fact that a loss of ANGPTL4 function was associated with reduced risk of coronary artery disease and that ANGPTL4 inhibits lipoprotein lipase (LPL), one would expect a gain of LPL function to also be associated with a lower risk of coronary artery disease, whereas a loss of LPL function would be expected to be associated with a higher risk. In observations consistent with these expectations, we found a low-frequency missense variant in LPL on the exome array that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio for disease, 1.13; P=2.0×10−4) (Table S12 in the Supplementary Appendix); previous studies have shown that this allele (also known as p.D9N) is associated with LPL activity that is 20% lower in allele carriers than in noncarriers.8 We also identified a nonsense mutation in LPL on the exome array that was significantly associated with a reduced risk of coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10−7) (Table S12 in the Supplementary Appendix). Contrary to most instances in which the premature introduction of a stop codon leads to loss of gene function, this nonsense mutation, which occurs in the penultimate codon of the gene, paradoxically induces a gain of LPL function.9 …..

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing.10 Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL.11 The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol.12 We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization.13 Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease14,15; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

An important caveat  to this research is that it is still very early. Most promising therapeutic targets do not work out. James Stein (University of Wisconsin) praised the papers but also offered a word of caution. “This is great science and important research that sheds light on the genetic regulation of TG-rich lipoproteins, serum TG levels, and CVD risk,” he said. “Since it is hard, if not impossible, to disconnect TG-rich lipoproteins from LDL, we should be humble in extrapolating these findings to clinical medicine in an era of low LDL due to statins and PCSK9 inhibitors. I hope this research identifies new targets for drug therapy and better understanding of CVD risk prediction– only time will tell.”

Previous studies with fibrates and other drugs have failed to convincingly show that lowering triglycerides is beneficial. Kathiresan said that what really seems to matter is “how you alter the plasma triglyceride-rich lipoproteins (TRLs).” Some genes that alter TRLs have other metabolic effects. As an example he cited a gene that lowers TRLs but increases the risk for type 2 diabetes. The NEJM papers, by observing the effect of specific mutations, therefore point the way to targets that may be clinically significant.

Conclusions:  The work that has been presented puts a new light on the possible role of triglycerides in the development of congenitally predetermined cardiovascular disease. It does not necessarily establish a general link to mechanism of cardiovascular disease, but it opens up new pathways to our understanding.

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

John Contois commented on your update
“Are triglycerides a CHD risk factor? The answer is still maybe. Triglyceride-rich lipoproteins are inextricably linked to LDL metabolism and LDL particle number (and apo B). Still these are important new data and targets for novel therapeutics.”

 

Risk of Dis-lipids Syndromes in Modern Society

 

Risk of Dis-lipids Syndrome in Modern Society

Aurelian Udristioiuᶪ, Manole Cojocaru²
¹Department of Biochemistry, Clinical Laboratory, Emergency County Hospital Targu Jiu & Titu Maiorescu University, Bucharest, Romania,
Department of Physiology, Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

Abstract
Aim of this work was to emphasis the preclinical evaluation of dis-lipids syndromes types at the patients which were presented to a routine control for checking health status, in the hospital ambulatory.
Material and Method:
Were analyzed 60 patients, registered in Clinical Laboratory, assessing by running on the Hitachi 912 Analyzer, the principal biochemical parameters of lipid metabolism: Cholesterol, Triglycerides and fractions of Cholesterol, HDL and LDL. From the total of 60 patients 35 were females and 25 males.
Results
The persons with an alarm signal of atherosclerotic process were in 28 % and persons with low HDL was in 17%. The cases with atherosclerotic index, report-LDL/HDL>3.5 for men and 2.5 for women were in 14 % , the cases with predictive value with coronary risk, report-CO/HDL>5 were presented in 5 % and the cases with dis-lipid syndrome type 2- 4, with high Cholesterol and Triglycerides, were presented in 30% percent.
Conclusions
Lipids controls, and its fractions, are necessary to be prevented atherosclerotic process in the incipient status of ill.

 

http://video.epccs.eu/video_1466.html

 

 

REFERENCES

http://www.nejm.org/doi/full/10.1056/NEJMe1601117

http://www.nejm.org/doi/full/10.1056/NEJMoa1507652

March 2, 2016 Regeneron Genetics Center Publication in New England Journal of Medicine Links ANGPTL4 Inhibition and Risk of Coronary Artery Disease Demonstrates power of large-scale Precision Medicine initiatives

http://files.shareholder.com/downloads/REGN/1634352863x0x879015/042D3D02-04CB-4DD1-89FE-53927F422025/REGN_News_2016_3_2_General_Releases.pdf

e-Books by Leaders in Pharmaceutical Business Intelligence (LPBI) Group

  • Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

http://www.amazon.com/dp/B012BB0ZF0

  • Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

  • Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics, on Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

  • Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

  • Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

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

Editorial & Publication of Articles in e-Books by  Leaders in Pharmaceutical Business Intelligence:  Contributions of Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

TRIGLYCERIDES

https://pharmaceuticalintelligence.com/?s=Triglycerides

HDL

https://pharmaceuticalintelligence.com/?s=HDL

PCSK9

https://pharmaceuticalintelligence.com/?s=PCSK9

STATINS

https://pharmaceuticalintelligence.com/?s=Statins

STATIN

https://pharmaceuticalintelligence.com/?s=STATIN

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