More Feathers in the Cap of Icosapent Ethyl

I am reminded of my late mentor, Dr. Peter O. Kwiterovich, Jr. who used to say when we published new research findings that “this is another feather in your cap”! Well, this expression could not be truer than what we have been witnessing with icosapent ethyl (IPE), the highly purified omega-3 fatty acid, EPA. First there was the landmark study, REDUCE-IT where IPE reduced the risk of cardiovascular death, heart attack, stroke, bypass/stent placement and rehospitalization for unstable by an astounding 25% in statin treated men and women with high triglycerides and cardiovascular risk. To date, IPE remains the best treatment for patients at similar underlying risk.

Last week, 2 new feathers were added to the IPE cap during presentations at the European Society of Cardiology (ESC), one of medicine’s premier international meetings. The first paper presented by my colleague, Dr. Deepak Bhatt found IPE to reduce the risk of the 2 types of heart attacks (ST and non-ST elevation) by 40% and 27%, respectively. The second feather was the result of another analysis showing that IPE eradicated the excess risk of cardiovascular events attributable to cigarette smoking; the manuscript is published in the European Heart Journal Cardiovascular Pharmacotherapy. For a comprehensive review of other IPE “feathers”, check out the excellent new review by Dr. Prakriti Gaba published in JCL.

During an ESC presentation, the prominent Danish Professor and Lipid Expert, Dr. Borge Nordestgaard, commented to me that every analysis performed for IPE has shown strikingly positive results. Could the reason for IPEs success be that the compound has unique characteristics that other fatty acids don’t? In fact, my colleague Dr. Preston Mason has performed a number of elegant studies demonstrating that to be the case. Specifically, IPE reduces inflammation and oxidative stress while improving endothelial function.

You certainly don’t have to convince me that IPE acts different fatty acids. Decades ago, we examined the role of purified EPA in human cells and found favorable effects that were not observed with other fatty acids- perhaps a presage of good things to come for IPE.

Michael Miller, MD is a cardiologist and Chief of Medicine at the Corporal Michael J Crescenz VA Medical Center and Vice Chair of Medicine at the Hospital of the University of Pennsylvania. Prior to his arrival in Philadelphia, he was Professor of Cardiovascular Medicine, Epidemiology and Public Health at the University of Maryland School of Medicine. He is the author of numerous scientific publications and several books, including Heal Your Heart published by Penguin Random House. Check him out on twitter: @mmillermd1

Let’s Shake on It: Surprising Clues to Heart Disease & Overall Health

Observant physicians can identify important clues about the heart (and overall) health of their patients simply by being attentive to physical appearance and interactions.   While telemedicine has provided an invaluable service during the COVID19 pandemic, many, if not most of us have missed the informative “personal touch”  we have with our patients.

Perhaps the first clue we receive when patients walk through the door is through a simple handshake.  While some of my patients continue to feel more comfortable with a fist/elbow bump greeting since COVID-19, a sizeable proportion have returned to handshakes following vaccination.

As it turns out, grip strength is a strong predictor of cardiovascular and all-cause mortality.

Grip strength can be measured using a hand dynamometer that is relatively inexpensive and readily commercially available. One study found that for each 11% decrease in grip strength, there was a 17% increased risk of death from heart disease. Another study showed that in men and women aged 60 and over, reduced grip strength was also associated with reduced mobility, functional status and cognitive function.

A third study of 500,000 men and women conducted in the United Kingdom also found reduced grip strength to be associated with a 15-30% higher risk of lung and heart disease as well as certain cancers (breast, colon, lung) over the 7 year follow-up period.  Finally, a more recent UK study in 68,000 middle aged men and women (average age, 63.8 years) found greater grip strength to be associated with a diet enriched in omega-3 fats (oily fish such as salmon and sardines) and magnesium (greens, nuts, seeds, whole grains, dark chocolate).

Listed below are several other physical signs that provide important clues when it comes to increased risk of cardiovascular disease.

1. Progressive skin tanning: In the absence of sun exposure, progressive skin tanning may be indicative of acquired hemochromatosis, a condition of iron overload due to excessive intake of iron or multiple blood transfusions.  In this condition tanning may be seen throughout the body, including the face and upper eyelids. Affected individuals should avoid Vitamin C supplementation because of increased iron availability that in turn, may promote disease progression.
2. Bilateral carpel tunnel syndrome:  While carpel tunnel syndrome can occur with repetitive motion/ overuse of a wrist such as from continuous typing/surfing the internet, the development of carpel tunnel syndrome in both hands especially in the absence of repetitive motion/overuse may be due to transthyretin cardiac (hATTR) amyloidosis. This disorder results from the accumulation of abnormal (amyloid) proteins that deposit in various organs and tissues.  Fortunately, treatment is now available for this condition.
3. Blueish Tint of Eye Whites (sclera): In adults, the appearance of blue sclera may be indicative of Ehlers Danlos Syndrome, a connective tissue disorder characterized by joint hypermobility (“double jointed”), skin that is easily stretchable (and susceptible to bruising) and heart involvement (e.g., aortic dilation).
4. Brown discoloration on Neck and Armpits: Also known as Acanthosis Nigricans, dark velvety patches occur in the back of the neck, below the breasts, armpits and groin regions that occur in association with insulin resistance, metabolic syndrome and diabetes.
5. Premature Graying and Baldness: A study of nearly 1400 young men (under age 40) from South Asia found that premature thinning or graying of hair was also associated with a 5-6 fold increased likelihood of premature heart disease.
6. Poor Dentition: A recent study found that spending less than 2 minutes tooth brushing twice daily was associated with a greater than 2-fold increased risk of poor vascular health (as measured by endothelial function).
7. Painful Mouth Sores: Consider Behcet’s disease in someone with a history of recurrent (painful) mouth sores and new onset heart failure.
8. Large Tongue: In addition to amyloid, a large tongue (macroglossia) may be observed with an underactive thyroid (hypothyroidism) especially when accompanied by high levels of (LDL) cholesterol.
9. Split Uvula: A split or bifid uvula is seen in the Loeys-Dietz Syndrome, a disorder affecting connective tissue and associated with aortic enlargement/dissection. The disorder is named after Dr. Bart Loeys and my colleague, Dr. Hal Dietz.
10. Yellowish-Orange Tonsils: Yellowish-orange tonsils is a classic feature of Tangier Disease, a disorder characterized by extremely low levels (e.g., less than 10 mg/dL) of HDL (the good cholesterol).
11. Nodules on the legs: Clues to the diagnosis of sarcoidosis are tender raised reddish bumps (nodules) on the front of the lower legs (Erythema nodosum) combined with heart-related symptoms such as palpitations, dizziness or progressive shortness of breath.
12. Itchy Rash on Chest, Back & Arms:  Very high levels of triglycerides (e.g., greater than 1000 mg/dL) may be associated with a yellowish-red (papular) rash on the chest, back and arms and is often due to poorly controlled diabetes.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland.  Check him out on twitter: @mmillermd1

 

EPA versus EPA/DHA: What Have Clinical Trials Taught Us?

Our new review paper out this week entitled “A Fishy Topic: VITAL, REDUCE-IT, STRENGTH and Beyond; Putting Omega-3 Fatty Acids into Practice in 2021” was designed to reduce the confusion surrounding the use of the marine derived omega 3 fatty acids, EPA (eiscosapentanoic acid) and DHA (docosahexanoic acid).  Coincidentally, this paper compliments last week’s publication in the Lancet journal, EClinical Medicine entitled, “Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis” led by my colleagues,  Drs. Safi Khan and Deepak Bhatt and showing that EPA but not the combination of EPA+DHA was associated with reduced risk of cardiovascular events such as heart attacks, strokes and heart related death (see Figure).

As both EPA and DHA are extracted from oily fish including salmon, sardines, anchovies and herring and both lower triglycerides to a similar degree, why have clinical trials using EPA compared to EPA+DHA shown contrasting results?   Elegant work from Dr. Preston Mason and his co-workers have provided important insights at the cellular level demonstrating that EPA possesses cardioprotective anti-inflammatory, anti-oxidant, endothelial normalizing and membrane stabilizing properties that become suppressed in the presence of DHA.  Thus while DHA plays a pivotal role in brain growth and development, clinical trials to date have not borne out similar benefits with respect to cardioprotection.

I’ve been intrigued with EPA for more that a quarter century after we first observed dramatic differences in the way EPA was processed into cellular lipids when compared to prototypic saturated and monounsaturated fatty acids.   As differences between EPA, DHA and other fatty acids continue to emerge, listed below are a series of highlights related to the intake of these fats whether as a supplement or in medicinal form.

1. Dietary supplements such as “fish oil” capsules are NOT regulated by the FDA and should not be viewed in the same context as OTC products (such as Advil) that are regulated.
2. Fish oil capsules, a dietary supplement not regulated by the FDA, has been shown to contain a number of impurities such as saturated fat and oxidized lipids that impair its effectiveness.
3. EPA but not DHA exhibits heart protective antioxidant, anti-inflammatory and membrane/plaque stabilizing properties that help to reduce the risk of cardiovascular disease.
4. In the MESA study, higher blood levels of OM3 (inclusive of EPA) were associated with reduced risk of hospitalization for bleeding events.
5. In the REDUCE-IT USA study, 4 grams of Icosapent ethyl, the prescription form of highly purified EPA, was associated with a 30% reduction of death from all causes.
6. In the REDUCE-IT trial, total primary events (cardiovascular death, heart attack stroke, stent placement, bypass surgery or hospitalization for unstable angina) were reduced by 30%.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore,MD.  He is a Scientific Advisor for Amarin, Corp. and Steering Committee Member of the REDUCE-IT trial.  Dr. Miller is also the author of several books; including his most recent,  “Heal Your Heart…“