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New Cholesterol Guidelines From A Neurologist’s Perspective

The American Heart Association’s annual premier conference “Scientific Sessions 2018” concluded on Monday. This meeting showcases the latest advancements and discoveries in the field of cardiovascular medicine and is attended by clinicians and researchers from across the world.

Being a vascular neurologist, I have attended the International Stroke Conference organized by the AHA several times, however, this was my first time attending Scientific Sessions. I was able to attend the conference via Live Streaming while sitting in my office in Burlington, Massachusetts.

There are a lot of overlaps between cerebrovascular and cardiovascular disease and I was particularly interested in attending the sessions pertaining to stroke prevention and brain health. One of the most anticipated presentations was the release and discussion of the new AHA/ACC Cholesterol Clinical Practice Guidelines.

Some key takeaways from the updated guidelines:

  • The guidelines continue to underscore the role of lifestyle and dietary habits in addition to lipid lowering medication use to treat cholesterol disorders. There is emphasis on the concept of shared decision making with the patient which should include discussion of their individual risk and the treatment options to reduce that risk.
  • Addition of Ezitimibe and subsequently PCSK-9 inhibitors is now recommended in patients who cannot achieve target LDL levels despite maximum tolerated statin doses. There is some concern about the cost effectiveness of PCSK-9 inhibitors, but these medications are expected to become cheaper in the future.
  • Risk enhancing factors are introduced as part of a personalized approach to risk assessment prior to initiating statin therapy. These include persistent elevation of LDL>160 mg/dL, history of pre-eclampsia, family history of premature atherosclerotic cardiovascular disease, history of chronic kidney disease and chronic inflammatory disease, among others.
  • There is a recommendation for expanding use of calcium score as part of the risk assessment, especially in patients where risk benefit analysis is uncertain.

 

In addition to the guidelines for medications and lifestyle changes to treat cholesterol disorders, I especially enjoyed Dr. Laurence Sperling’s talk about the safety of statins.

Patients should be prescribed statins again at a lower dose or modified drug regimen if the reason for discontinuation was mild side effect symptoms. Although rare, but some patients do develop severe myopathy with statin use. These patients should be prescribed alternate non-statin therapies to achieve the target cholesterol levels. There has not been any proven benefit of Co Q10 to prevent or treat statin associated muscle symptoms. Despite the increased risk of diabetes mellitus with statins, it is recommended to continue the drug in patients who may be at risk or develop new onset DM. These patients should be counseled about the net clinical benefit of these drugs for long term cardiovascular event prevention. It appears reasonable to initiate statin therapy in the presence of an appropriate indication despite a history of stable liver disease. In patients without hepatic disorders, there is no clinical benefit of routine creatine kinase and liver enzyme measurements.

Very often patients have questions and concerns about initiating and continuing their statin medication. I believe that these data and recommendations further reinforce my personal practice to encourage patients to continue their statin medication as the risk benefit ratio remains favorable despite mild side effects.

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Metformin: A diabetes medication with cardiovascular protective effects

What if a diabetes medication can improve cardiovascular events? Since patients with type II diabetes are more prone to cardiac events, the use of diabetes medication to help reduce cardiovascular burden would definitely be beneficial. One of such medications is the drug, Metformin.

Metformin, also know with the trade name of Glucophage, is the first-line of treatment for type II diabetes. It is also often prescribed to patients with metabolic syndrome and patients with polycystic ovarian syndrome to control insulin resistance. Metformin works by increasing insulin sensitivity and decreasing glucose production by the liver. While its molecular mechanism of action is not completely understood, one way metformin exerts its effects is through regulating AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling and detecting cellular energy levels. By regulating AMPK, metformin also lowers inflammation and thus there is an emerging body of evidence suggesting that metformin regulates the immune system and reduces inflammation and can potentially protect against diseases such as inflammatory bowel disease and atherosclerosis. 

Until recently, there has been associations that metformin may protect against cardiovascular disease, although exactly how was never been directly studied. A recent study by a group of researchers in Columbia University in New York, published recently in the ATVB journal, looked at the role of metformin and how it may affect cardiovascular disease. The authors show that exposure of liver cells to metformin increased the expression of ABCG5 and ABCG8, two cholesterol transporter molecules responsible for the efflux of cholesterol. The authors also saw the same effect when they gave metformin to mice fed a western diet, also know as high cholesterol, high fat diet. This increase in expression of ABCG5 and ABCG8 was accompanied by an increase in cholesterol clearance from the plasma in these treated mice. This study provides first evidence of how metformin could have a direct cardiovascular disease protective effect.

Since metformin, through regulating AMPK, has an anti-inflammatory effect, this study shows that metformin may have a combined protective impact regarding cardiovascular disease; the first through increasing cholesterol clearance and the second through reducing immune mediated inflammation, overall resulting in lower cholesterol levels and less inflammatory mediators responsible for atherosclerosis progression and thus reducing cardiovascular disease risk. It would be interesting to see if patients who are taking metformin for diabetes treatment have a decrease in cardiovascular events in a controlled manner. Finally, this study highlights the potential of a drug like metformin, not only as a diabetes medication but as a cardiovascular protective drug as well.

Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.

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The Liver’s New Job: Making An Immune Response Towards Cholesterol!

If you think the liver’s only relationship with cholesterol is to control its metabolism and excretion, think again. It turns out the liver is also involved in the immune response towards cholesterol particularly in situations where cholesterol is increased, a recent study published in the Circulation Research journal shows.
 
In a previous post, I wrote about how complex the relationship between heart disease and the immune system is. While most studies that examine the role of the immune system in atherosclerosis focus on immune cells from the blood, lymphoid organs, or look at the immune cells in the aortic walls, there are very few studies that looked at the contribution of the immune system in the liver to atherosclerosis development.
 
As an immunological site, the liver plays an important role in preventing autoimmunity and defending against invaders. Being the largest solid organ in the body, with its rich blood flow and its proximity to the digestive system, the liver is a crucial organ in cholesterol metabolism. The liver is also filled with macrophages, an immune cell that, among its many jobs, specializes in getting rid of extra cholesterol. High cholesterol levels can destroy the liver’s ability to metabolize cholesterol and result in liver failure. However, not much is known about the role of the immune cells in the liver and how do they respond to high cholesterol levels. A research group from the Cardiovascular Medicine Unit in Karolinska Institute, Sweden, examined this exact question. Their study shows that in mouse models, T cells, a type of immune cell that is involved in adaptive immunity, increases in the liver as a result of high cholesterol levels. These liver T cells can travel to the aortic vessels were atherosclerosis occurs, providing first evidence that the liver immune cells may contribute to the immune response during atherosclerosis development.
 
As an immunologist who studies how the immune system affects atherosclerosis development, I am constantly fascinated by new findings in this area. The study made me think of whether the liver’s immune response is responding to the excess cholesterol in the circulation or to that accumulating in the liver. As there are different types of T cells, some that promote atherosclerosis while others reduce disease progression, the study also made me wonder if these different cells generated in the liver tipped the balance in favor or against a protective immune response. Does a similar immune response happen in the liver of people with high cholesterol levels? With these new findings, the door is now open to questions that will help our understanding of the complex relationship between cholesterol, the liver, the immune system and how it all ties together to influence atherosclerosis and heart disease.
 

Dalia Gaddis Headshot
Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development. 

 

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Lipid-lowering Therapy In Young Adults: Do We Need To Re-invent The Wheel Or Just Align It?

Elevated cholesterol levels or hypercholesterolemia can be found for years or even decades, before individuals present with cardiovascular disease and complications such as myocardial infarction, stroke, or sudden cardiac death. The diagnosis of hypercholesterolemia and its treatment along with healthy lifestyle changes including a healthy diet and exercise as well as blood pressure control, are cornerstones of long-term cardiovascular health.1

There has been a substantial decline in cardiovascular disease mortality in the last decade due to improved awareness, therapy for established cardiovascular disease and primary and secondary preventive interventions.1 However, this observation is absent in young adults.2 Over the last decade, unfavorable trends in coronary heart disease and related mortality in younger individuals, i.e. 35-55 year-old, have emerged.2

We have previously shown that there is a phenotype of young adults with premature hypertension and development of resistant hypertension in their 30s.3 This phenotype has been characterized in a cross-sectional study of 2068 patients seen in a university referral clinic for resistant hypertension. In this study 45% of consecutively seen patients were younger than 55 years of age. Amongst them, 23% had high lipids, 25% were obese, 19% had diabetes, and 13% had obstructive sleep apnea. Cardiovascular events such a s history of myocardial infarction, stroke, or heart failure were prevalent were found in >20%. The majority of these predominately obese, resistant hypertensive individuals have excessive aldosterone, cortisol and sodium levels, conditions that are associated with increased cardiovascular morbidity and mortality, independent of blood pressure levels.

Lipid-lowering drugs, so-called statins, have been shown to reduce cardiovascular disease and mortality. Lipid lowering with statins in patients with hypercholesterolemia has a proven survival benefit for both primary prevention (ie, in patients without clinical evidence of coronary disease) and secondary prevention (ie, in patients with established coronary disease), even when serum cholesterol concentrations are “normal” for the population or borderline high. The mechanisms by which lipid-lowering therapy is beneficial are incompletely understood since absolute levels of cholesterol before or during treatment only explain parts while cholesterol-independent effects have been also described.1 Among the non-lipid mechanisms that may be involved are plaque stabilization, reduced inflammation, improvement of endothelial and arterial function, and decreased blood clotting.
 
In 2013 the American College of Cardiology and American Heart Association developed a new guideline for the management of hyperlipidemia. While previous guidelines recommended to initiate or adjust predominantly in response to lipid values these 2013 ACC/AHA guidelines target patients to fixed dose of statin therapy corresponding to atherosclerotic cardiovascular disease (ASCVD) or other risk factors. The four at-risk populations of individuals that are thought to benefit from statin therapy based on this guideline include:

  1. Adult patients with clinical ASCV
  2. Adult patients with primary elevations of LDL–C ≥190 mg/dL
  3. Patients 40-75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD
  4. Patients 40-75 years of age without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher

In our cohort half of obese young patients under the age of 40 would per se not qualify to be treated with a statin. Patients between the ages of 40-55 are in the majority of cases not considered “eligible” since age is one of the most powerful nominators in the risk calculator and, anecdotally, when we evaluate these patients for statin eligibility for primary prevention, we usually calculate an estimated 10-year CVD risk score of <5%.

At their first visits we always discuss life style changes, since younger patients may be more motivated to eat healthier, exercise, and lose weight, but consistent, successful lifestyle changes are often difficult to accomplish.

When we consider statin treatment for primary prevention even if the ASCVD risk score is <7.5%, there are a lot of unknowns. Aside from statins being contraindicated in young women who are or want to become pregnant or are breastfeeding, it is not known if there are short-term benefits of therapy. There are few data on the safety of statins over decades of therapy and possible side effects of statin therapy could outweigh potential benefits.

Furthermore, we don’t know whether long-term treatment leads to better outcomes and who are the individuals who are going to benefit. With evolving advances in precision medicine, we may be able to “customize” primary prevention especially for this group and identify young individuals in whom premature cardiovascular events can be prevented.

However, the question remains: how can we prevent cardiovascular events in young adults?

Data of young adults who suffered a cardiovascular event will help to elucidate underlying mechanisms and optimal therapy regimens. 
 

Premature CHD in young adults versus CHD 02012018

This problem has been recognized and resulted in the YOUNG-MI Registry, a retrospective study examining a cohort of young adults age ≤50 years with a first-time MI.  The study uses electronic health records of 2 large academic centers, as well as detailed chart review of all patients, to generate high-quality longitudinal data regarding the clinical characteristics, management, and outcomes of patients who experience a myocardial infarction at a young age. Findings are thought to provide important insights regarding prevention, risk stratification, treatment, and outcomes of cardiovascular disease in this understudied population, as well as identify disparities which, if addressed, can lead to further improvement in patient outcomes.  

In a recent study from this registry, Singh et al. analyzed retrospectively the statin eligibility of young adults after a myocardial infarction. In this study the statin eligibility, based on the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, for primary prevention in adults <50 years who experienced a first-time type 1 myocardial infarction were evaluated. The median age of analyzed patients was 45 years, 20% were women, the majority had at least 1 traditional cardiovascular risk factor and 57% had experienced a ST-segment elevation myocardial infarction. Surprisingly, the median estimated 10-year atherosclerotic cardiovascular disease risk score was only 4.8% (interquartile range 2.8-8.0%). Only 49% and 29% would have met criteria for statin eligibility as per the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, respectively. These findings were even more noticeable in women where 63% were not eligible for statins according to either one of the guidelines as opposed to 46% of men only. To summarize these findings, the majority of young adults who present with a heart attack would not have met current guideline-based treatment thresholds for statin therapy prior to their myocardial infarction.

It highlights the need for better risk assessment tools for young adults.  Further, much more needs to be known about risk profiles, optimal prevention, and treatment to improve outcomes in these young understudied adults.

References

  1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Jr., Tomaselli GF and American College of Cardiology/American Heart Association Task Force on Practice G. 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. Circulation. 2014;129:S1-45.
  2. Ghazi L, Oparil S, Calhoun DA, Lin CP and Dudenbostel T. Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant. Hypertension. 2017;69:827-835.
  3. Ghazi L, Dudenbostel T, Xing D, Ejem D, Turner-Henson A, Joiner CI, Affuso O, Azuero A, Oparil S, Calhoun DA, Rice M and Hage FG. Assessment of vascular function in low socioeconomic status preschool children: a pilot study. J Am Soc Hypertens. 2016.
     

Tanja Dudenbostel Headshot

Tanja Dudenbostel is an Internist, Hypertension Specialist within Cardiology at the University of Alabama at Birmingham where I divide my time as an Assistant Professor between clinical research and seeing patients in cardiology.

 

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Can Increasing HDL Reduce Heart Disease? An Issue Of Constant Debate!

A couple of years ago I was fortunate to attend the HDL workshop that followed the ATVB council conference, which was held in San Francisco. The workshop’s main focus was to discuss and debate high-density lipoproteins (HDL), or what is commonly known as “the good cholesterol,” and how it influences heart disease.
 
You may ask, “HDL-cholesterol is good for your heart, so why dedicate two days to discuss what is already know?!” Here is where it gets interesting. While we look forward to lab results showing high HDL-cholesterol levels and low levels of LDL-cholesterol (bad cholesterol) as an indication of reduced risk for cardiovascular disease, the actual answer to the benefits of HDL for cardiovascular disease is far from a simple yes or no. Yes, having high HDL-cholesterol indeed reduces the risk of heart disease, but this does not hold true for patients with metabolic conditions like diabetes, or chronic inflammation like chronic kidney disease.  In fact, multiple clinical studies that aimed at increasing levels of HDL-cholesterol have failed to reduce cardiovascular events. It is now becoming evident that just increasing the quantity of HDL-cholesterol alone is not sufficient to ensure cardiovascular free events.
 
Scientists are discovering that there is more to HDL-cholesterol than its concentration. The size of these HDL molecules, their composition, and their ability to remove lipids from the blood stream for excretion are more indicative of HDL protective function.  In addition, scientists are also finding that HDL has other compelling properties that can lower cardiovascular risk indirectly. HDL can reduce inflammation, protects from cell death and promotes wound healing. HDL also had antithrombotic effects (prevents blood clots formation), all of which would decrease the possibility of a cardiovascular incident.
 
So why not measure for the functionality of HDL rather than its mere concentration to determine one’s risk for cardiovascular disease? This was a topic for discussion at the HDL workshop. The methods used to measure HDL functionality are far from being standardized for use in clinical settings. More work is needed to find techniques that can be used routinely and reliably across clinical laboratories.
 
It is worth to note that the increase in HDL-cholesterol levels that are triggered by life style changes: healthy diets and physical exercise, does in fact correlate with reduced risk of cardiovascular disease. Researchers think life style change does not only increase HDL-cholesterol but also has an effect on its function and on other metabolic parameters. So until science figures a more clinically feasible way to measure HDL functionality, it would still be a good practice to continue whatever healthy diet and exercise regimen you are on and to aim to keep those HDL-cholesterol numbers high and those LDL-cholesterol numbers low.

Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.