Beyond HDL

New Insights into HDL Function in Cardiovascular Disease

By: Mark Houston, MD and Sara Gottf ried, MD

The following arti cle is not endorsed and/or supported by The American Academy of Anti -Aging Medicine. The purposes of this publicati on do not imply endorsement and/or support of any author, company or theme related to this arti cle.

INTRODUCTION

High-density lipoprotein (HDL) plays a vital role in lipid biology and coronary heart disease (CHD) pathophysiology. However, a major paradigm shift is happening in the medical community regarding the role of HDL-cholesterol (HDL-C) in dyslipidemia and dyslipidemia-induced cardiovascular disease, especially CHD and myocardial infarction (MI).

HDL are complex nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. HDL is best known for its ability to scavenge for and ferry low-density lipoprotein cholesterol (LDL-C) away from the arteries and back to the liver for redistribution, metabolism, and elimination, as well as for its anti-in ammatory, antithrombotic, anti-immune and antioxidative activity.  e prevailing dogma for the past 30 years was that high total HDL-C (a lab measure re ecting the amount of cholesterol carried by the HDL particles) was cardioprotective, because it re ected better clearance of cholesterol. However, the emerging narrative is that the HDL particle is far more heterogeneous than previously understood. In order for HDL to be cardioprotective, it must be functional. 1 Furthermore, there are genomic, proteomic, and other compositional considerations.  e main takeaway is that because of the heterogeneity of HDL, measurement of HDL-C alone does not provide a complete picture of the protective qualities of HDL vis-à-vis cardiovascular disease.

HDL: THE PARADIGM SHIFT ABOUT THE ROLE OF HDL

LDL is essentially a “garbage” type of particle that deposits cholesterol in cells all over the body, while HDL is like a garbage collector. It literally takes excess cholesterol out of tissue to remove it from the body, usually through the liver.

Epidemiological studies, ranging from the Framingham Study and continuing through to the Atherosclerosis Risk in Communities (ARIC) Study, demonstrated that HDL-C is inversely associated with CHD and MI. 2,3 Speci cally, as the calculation was extended, CHD risk increases by 3% in men and 2% in women for every 1 mg/dL decrement in HDL-C. 4 Put

another way, patients were told that if you have good HDL-C, then you’ll have good “reverse cholesterol transport (RCT),” i.e., the body’s ability to bring cholesterol back to the liver for removal. In the past, it was believed that as long as HDL-C levels were above a certain threshold, a patient was protected from having CHD and/or MI.

New research has updated that perception. Several threads of evidence point to a more nuanced model. Pharmacological interventions in randomized trials that raise HDL-C by twoto three-fold have failed to produce the anticipated reduction in cardiovascular risk. 5-9 Additionally, the level of the apolipoprotein A-I (apoA-I), the primary HDL-associated apolipoprotein, in HDL subtypes is a better predictor of cardiovascular risk than HDL-C concentration. 10 Further studies showed that the antiatherogenic capacity of HDL seems to be mediated by function, in this case, cholesterol e ux capacity (CEC), which is a superior predictor of risk than total HDL-C concentration, 11 though not all data are concordant. Further, data from genomewide association studies (GWAS) have shown that lower HDL-C may not cause CHD, a high HDL-C may not be protective from CHD, and heterogeneity of HDL structure and function may be more to blame. 12,13

In other words, if HDL is the garbage collector, there’s a range of options in the  eet. Some garbage trucks look good but don’t perform. Some have  at tires. But some of the garbage trucks are top of line, some have large carrying capacity and others have small carrying capacity, and others are highly dependable and perform beyond expectations.  at’s the spectrum of HDL function.

We can no longer rely on high HDL-C alone for heart health protection, because experts are now questioning the composition and function of the various types of HDL.

WHAT IS HDL FUNCTION?

Static measurement of HDL-C fails to re ect the dynamics of the HDL particle, its remodeling process, the HDL cargo load, HDL interconversions in the lipid pathway, the hepatic unloading, and resulting function.

Up until recently, HDL function could not be measured. We only had what were called “indicative markers of HDL function,” such as myeloperoxidase (MPO) and some in ammatory and oxidative stress markers, but these were not the direct assessors of HDL function. However, a new test, currently in beta mode, may soon be available that has the ability to measure RCT and CEC.  is lab test may allow practitioners to determine HDL function simply. Investigators have demonstrated that assessment of CEC is one metric of HDL function and may in fact be a predictor of atherosclerosis and cardiovascular disease risk. 14

New research is painting a broader picture that HDL function may be impaired in other situations of systemic in ammation or oxidative stress (Figure 1) and, such as autoimmunity, suggesting that improvement in HDL function may help beyond cardiovascular risk. 15

Figure 1.  e cardioprotective properties of HDL particles can become dysfunctional under oxidative stress and in ammatory burden.

HDL MAPPING OF VARIOUS SUBSPECIES OF HDL

 ere are  ve di erent forms of HDL particles.  e test used to measure these di erent forms is called “HDL mapping,” which includes α-1, α-2, α-3, α-4, and pre- HDL. All of these forms are important; however, in the past the emphasis had been on the large HDL, which was α-1 in particular with

a little bit of α-2.  e concept has since changed. Some of the small particles, which are necessary to dock on the LDL tissue receptors and remove it, may be just as important in transforming to a larger HDL—which can handle more LDL, take it out, and deposit it in the liver. While the HDL size is important, it may be all types of HDL that play a role in this process.

But even size doesn’t matter without proper function. For example, a patient may have a normal level of all HDL sizes with the HDL mapping, but the HDL function may be abnormal.  ink of it like a garbage truck with four  at tires. Although the garbage truck is large and potentially powerful, it won’t make it to its destination to complete its job (i.e., cleaning up LDL).  at’s why function is the biggest key factor.

THE IMPORTANCE OF HDL PARTICLE NUMBER

 e bene ts of HDL also depend on the number of HDL particles.  is is called HDL particle number, or HDL-P. Based on recent research, the higher the HDL particle number, the more protected you are from CHD and MI. 16  at’s why many researchers agree that HDL function and particle number are the two most important factors when measuring HDL. In fact, in many studies the HDL-P and HDL function measurements are equally predictive of CHD and MI. If we’re able to determine both of these parameters together, we can better predict the role of HDL in providing protection from CHD and MI.

TESTING 1, 2, 3

For any patient with a history of HDL-related problems, the  rst and most important step is to complete an advanced lipid pro le, which will guide treatment options such as nutritional support, exercise, weight loss, and nutraceutical supplementation.  is requires specialized labs—now available all over the United States—that determine all the previously mentioned parameters.

DESIGNING A NUTRITIONAL MEDICINE TREATMENT PROTOCOL

Supplementation can play a key role in HDL management. Keep in mind, there are very few pharmaceutical agents that modify HDL. In fact, most won‘t a ect the lab parameters we’ve covered. However, various nutraceutical supplement and nutritional changes can modify at least one of these key factors. Pomegranate has been shown to change some of the enzymes such as paraoxonase 1 (PON-1) in the HDL particle and allow HDL to better transport cholesterol and to improve HDL’s antioxidant capacity. 17,18

Niacin shows promise for HDL-P and HDL support by improving function, 19 though data are mixed. 20

Lycopene-rich diet or lycopene has been shown to increase apoA-I and other proteins associated with HDL function. 21,22

Green tea extract, or EGCG, can also change the protein or

lipid content of HDL so that the composition is not damaged by things like oxidative stress or in ammation, thereby reducing the risk of HDL dysfunction. 23

Increased intake of virgin olive oil, nuts, legumes, whole grains, and  sh improves HDL function. 24 Speci cally, olive oil and whole-grain consumption raise CEC. More nut and legume intake improves PON-1 activity. Legume intake increases are also related to decreases in cholesteryl ester transfer protein activity. Fish consumption increments are associated with increases in PON-1 activity and declines in cholesteryl ester transfer protein activity, HDL-C concentrations, and functions related to HDL (CEC).

Flavonoids such as anthocyanin positively change serum biomarkers related to HDL function in several patient populations, including dyslipidemia, hypertension, and diabetes, resulting in not only increased HDL cholesterol levels, but also HDL antioxidant and CEC. 25

HDL function may be improved by quercetin, 26 glutathione, 27 resveratrol, 28 and phosphatidyl serine, 29 though several of the studies are underpowered, and more functional data are needed. 30

TRACK PATIENT PROGRESS

As HDL-C provides almost no information on HDL function, other measurements will be needed to help tract whether interventions are improving HDL function. Biomarkers of low-grade in ammation (e.g., hs-CRP) and oxidative stress (myeloperoxidase) give information on whether HDL particles are at risk of becoming dysfunctional. Advanced lipid panel (e.g., HDL-P) and HDL mapping help provide additional information on the health of HDL particles. When you complete an HDL map, you’ll  nd that some components may be in the red zone (not good), some in the yellow zone (borderline), or some in the green zone, which is great. Once you receive a patient’s results,

you can institute or alter an existing supplement and lifestyle protocol to positively modify HDL and repeat testing in two to four months to track patient progress. Keeping a close watch and conducting follow-up tests is key and may require you to alter your recommendations as you see  t. Once a patient has achieved optimal levels of all three components, there should be

BIO

a reduction in the event rate for CHD and MI.

CONCLUSION: SUPPORT PATIENTS ON THE PATH TO HEART HEALTH

 e latest discoveries on the key parameters of HDL e ciency have led to promising new treatment methods for better patient outcomes. Recognizing and measuring HDL type and size, function, and particle number are key factors in protecting patients from CHD and MIs.  rough proper nutrition and lifestyle protocols, we can better protect our patient populations from the perils of heart-related health concerns.

Mark Houston, MD, is a highly recognized cardiovascular and hypertension specialist, serving as a physician at St.  omas West Hospital in Nashville, where he holds several leadership positions including Director of the Hypertension Institute and Vascular Biology, Medical Director of Clinical Research, and Section Chief for the Division of Nutrition.

Sara Gottfried, MD, the President of Metagenics Institute, is a board-certi ed gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. SaraGottfried@metagenics.com

REFERENCES

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14 Viaduct Harbour, L2 Auckland, AK, *01010 | NZ Ph: (760) 822-4833 Email: caprice@mitoq.com

www.mitoq.com

MitoQ is a positively-charged antioxidant health brand, created with word-first, multipatented biotechnology in New Zealand. MitoQ supplements are manufactured by MitoQ Limited based in New Zealand. The company is dedicated to advancing the science of mitochondria-targeted antioxidant solutions, promoting mitochondrial health and helping people get the most out of their lives. The company’s world-first ingredient Mitoquinol, holds 39 global patents, has been the subject of over 400 peer-reviewed published papers and $60M in research funding.

Mitochondrial Rescue

11104 Green Bayberry Dr Palm Beach Gardens, FL, 33418 | US Ph: (561) 767-0721 Email: drraja@mitochondrialrescue.com

www.mitochondrialrescue.com

Mitochondrial Rescue is an international organization supporting Practitioners utilizing revolutionary mitochondrial wearable technology and HRV-based complimentary online training coupled with proprietary neuropeptides to quantitatively improve patients’ voltage, mitochondrial oxygen levels, autonomic dysregulation and cellular communication in a telemedicine ecosystem. Mitochondrial Rescue understands that all chronic disease comes from having a lack of mitochondrial power that can be regenerated to improve outcomes with researchdriven peptide therapy. Backed by Research, Built for Resilience!

OxyHealth, LLC

10719 Norwalk Blvd, Santa Fe Springs, CA, 90670 | US Ph: (562) 906-8888 Email: events@oxyhealth.com

www.oxyhealth.com

OxyHealth has forever changed the way the medical industry practices hyperbaric therapy. Since our inception, we are devoted to providing quality and brilliantly safe portable hyperbaric chambers to physicians, professional athletes, wellness centers, and families. All OxyHealth chambers are designed for patients to easily self-treat, which has fostered a cutting-edge trend in hyperbaric technology.

NuMedica

9503 E. 55th Place Tulsa, OK, 74145 | US Ph: (800) 869-8100 Email: jose.rivas@numedica.com

www.numedica.com

NuMedica® is a leading brand of clinical nutrition in the professional market. Our mission is to partner with healthcare professionals in helping patients achieve better health. Learn more at www.numedica.com.

Power2Practice

Power2Practice is specifically designed for functional and integrative medicine. With features such as customized note templates, cash-based billing module/superbills, specialty lab integrations, Fullscript interface, Power2Practice gives you all the EMR capabilities you expect, plus the specialized features you need. Our intuitive patient portal facilitates patient communication, online scheduling, appointment reminders and much more. Plus, with the addition of our newly released Televisit module, Power2Practice streamlines the efficiencies of the charting, front office and patient experience.

Ortho Molecular Products

1991 Duncan Place Woodstock, IL, 60098 | US Ph: (815) 206-6586 Email: contactus@ompimail.com

www.orthomolecularproducts.com

For more than 30 years, Ortho Molecular Products has researched and manufactured highquality, efficacious nutraceuticals sold exclusively to thousands of health care professionals nationwide and in Canada. Ortho Molecular Products is headquartered in the Chicagoland area, with FDA-audited, cGMP-certified manufacturing facilities in Stevens Point, WI. Our commitment to efficacy, uncompromising manufacturing and legendary customer service

establishes us as a leader in the nutrition industry.

2907 Butterfield Rd., Suite 100 Oak Brook, IL, 60523 | US Ph: (800) 590-7459 Email: sales@power2practice.com

www.power2practice.com

Precision Analytical Inc.

3138 NE Rivergate, #301c McMinnville, OR, 97128 | US Ph: (503) 687-2050 Email: info@dutchtest.com

www.dutchtest.com

Precision Analytical Inc. is improving global wellness by providing important insight into hormones and their function. Their state-ofthe-art innovation in hormone testing uses the acronym DUTCH (Dried Urine Test for Comprehensive Hormones). Precision is now the world leader in hormone testing as their DUTCH™ test provides the most comprehensive look at hormones through simple collection and helps practitioners answer the most complex clinical questions. Lastly, DUTCH testing is built to optimize HRT monitoring.

Premier Research Labs

3500 Wadley Place, Bldg B Austin, TX, 78728 | US Ph: 800-325-7734 Ext. 2513 Email: cfentanes@prlabs.com

www.prlabs.com/prlabs.com

Comprehensive, clinically tested, professional nutritional product line to meet advanced the practitioner’s needs. Recognized as the world leader in cellular resonant formulations, establishing a high standard in the nutritional industry. PRL’s Quality Control Department includes an advanced, state-of-the-art laboratory staffed with scientists and a sourcing team dedicated to maintaining the high quality and integrity of raw materials that PRL products are known for.

Quest Diagnostics - Cleveland HeartLab

500 Plaza Drive Secaucus, NJ, *07094 | US Ph: (610) 334-3125 Email: swati.x.doshi@questdiagnostics.com

www.questdiagnostics.com

Quest Diagnostics and its Cleveland HeartLab Cardiometabolic Center of Excellence are committed to empowering people to take action to improve health outcomes. Through our menu of advanced cardiovascular tests, our diagnostic insights reveal new avenues to identify cardiovascular risk that go beyond cholesterol testing along. This insight allows more targeted treatment to help improve healthcare management and reduce risk over one’s lifetime. QuestDiagnostics.com.

Professional Health Products Protocol For Life Balance

PO Box 97227 Pittsburgh, PA, 15229 | US Ph: (800) 245-1313 Email: support@phpltd.com

www.phpltd.com

Cutting corners when it comes to quality is a common practice in the supplement industry. PHP is committed to using the highest quality ingredients, backed by science, in our formulations since our beginning in 1978. Integrity and ingenuity goes into every product in our comprehensive line; making the partnership we have with clinicians above industry standard. From homeopathy to pristine ECO glandulars, we proudly offer a variety of products used by clinicians for various conditions.

Quicksilver Scientific

1960 Cherry St Louisville, CO, 80027 | US Ph: (303) 531-0861 Ext. 146 Email: bree.rankin@quicksilverscientific.com

www.quicksilverscientific.com

Quicksilver Scientific® is a leading manufacturer of advanced nutritional systems with a focus on detoxification. We specialize in superior liposomal delivery systems and heavy metal testing to support optimal health. We are passionate about health and well-being and are committed to improving the lives of everyone we touch. 244 Knollwood Drive Bloomingdale, IL, 60108 | US Ph: (877) 776-8610 Email: sales@protocolforlife.com

www.protocolforlife.com

Protocol For Life Balance is a well-researched, potent, and efficacious brand of high-quality dietary supplements and natural products sold exclusively through licensed healthcare practitioners. Protocol For Life Balance offers many unique formulas and products, that come with a money -back guarantee if any patient is less than 100% satisfied. Our mission is simply to provide quality products that lead to healthy patients and satisfied physicians. Family

Owned and Operated.

Regenative Labs

1700 West Main St., Ste. 3 Pensacola, FL, 32502 | US Ph: (800) 891-3452 Email: info@regenativelabs.com

www.regenativelabs.com

Regenative Labs™ believes products from Umbilical Cord tissue present a more effective alternative to NSAID and steroid injections in reducing or eliminating pain associated with musculoskeletal injuries. All Regenative Labs™ Umbilical Cord tissue products are obtained from full-term, C-section live deliveries donated by consenting donors. These non-embryonic tissues undergo extensive testing prior to procurement. We have a state-of-the-art lab and spare no expense when it comes to technology necessary to produce top quality regenerative products.

Riordan Technologies T.A. Sciences

11496 Luna Rd., Suite 800 Dallas, TX, 75234 | US Ph: (972) 807-5916 Email: info@signaturebiologics.com

www.neilriordan.com/about

Riordan Technologies represents a group of companies pioneered by Neil Riordan, PA, Ph.D.: Dallas-based Aidan Products, Signature Biologics, and Riordan Medical Institute, and Panama-based Stem Cell Institute and Medistem. Riordan Technologies’ network of companies have long been involved in innovative technological advances across multiple scientific fields. Riordan Technologies strives to improve the human condition through innovation in scientific research, regenerative medicine, and stem cell therapy.

Toolbox Genomics

2950 Buskirk Ave., Ste.300 Walnut Creek, CA, 94597 | US Ph: (415) 722-4393 Email: info@toolboxgenomics.com

www.toolboxgenomics.com

Toolbox Genomics is revolutionizing precision medicine through actionable genetic insights. We offer a comprehensive, end-to-end DNA testing and reporting solution for practitioners. Using a simple buccal swab, practitioners are able to see Health Action Plans which focus on clinically relevant interpretation and application. Driven by Toolbox’s genetic risk score algorithm, recommendations for intervention cover 5 domains: Supplements, Diet, Exercise, Lifestyle and Further Testing. We focus on being the genomic experts so you don’t have to. 420 Lexington Ave., Suite 2900 New York, NY, 10170 | US Ph: (212) 588-8805 Email: eric@tasciences.com

www.tasciences.com

T.A. Sciences® is dedicated exclusively to creating research-based, clinically tested wellness products that help address cellular aging through the science of Telomerase Activation. Built upon a foundation strongly grounded in scientific evidence, T.A. Sciences® is widely recognized as the leader in the field of Telomere Biology. T.A. Sciences® spends over $1 million each year on leading edge scientific research, including double-blind, placebocontrolled studies proving the safety and effectiveness of its premiere product, TA-65.

University Compounding Pharmacy

UNIVERSITY COMPOUNDING PHARMACY (UCP) a nationally recognized leader in drug and device therapies. For 28 years our expert Pharmacists and experienced Physician Liaison team have been dedicated to support an unbiased product line, devising the management of BHRT conditions for your patients. We meet FDA & BOP prescription requirements and dispense in nearly 50 states.

Tailor Made Compounding, LLC

200 Moore Drive Nicholasville, KY, 40356 | US Ph: (859) 887-0013 Email: ataylor@tailormadehealth.com

www.tailormadecompounding.com

Tailor Made Compounding medications are designed to complement existing therapies but, more often, provide a more suitable alternative to standard prescription and over-the-counter medicines. We don’t believe in a ‘one size fits all’ approach to health. Our patients and physicians have unique needs and can rely on us for the highest quality, custom, compounding solutions. Specializing in peptides, hormone replacement therapy and IV formulations. Tailor Made Compounding, positively disrupting medicine

1875 3rd Ave. San Diego, CA, 92101 | US Ph: (800) 985-8065 Ext. 5700 Email: customersupport@ucprx.com

www.ucprx.com

using innovative technology.

Vital Nutrients

45 Kenneth Dooley Drive Middletown, CT, *06457 | US Ph: (860) 740-5543 Email: ssedlock@vitalnutrients.net

Vital Nutrients is dedicated to manufacturing high quality supplements that promote health, wellness and vitality. Our stringent standards and extensive laboratory analyses has led to our supplements being used and trusted by hospitals, healthcare practitioners and consumers worldwide. Nothing is more important than the quality of our supplements.

Vitelle Labs Wells Pharmacy Network

Your CBD Store

8365 Ontario Street, Ste 120 Vancouver, BC, V5X 3E8 | CA Ph: (604) 279-5552 Email: info@vitellelab.com

www.vitellelab.com

For over 20 years Vitelle Labs has been on the frontline of evidence-based, result-oriented skincare manufacturing sold through proprietary turn-key private label programs direct to professionals. Find out what many Medical Spas and Physicians already know, that privately branded skincare from Vitelle can enhance your patient’s treatment homecare experience. As a leader in natural skincare science, Vitelle prefers botanical-origin ingredients synergistically paired with peptides, plant stem cells, growth factors and cutting edge actives.

ZRT Laboratory

8605 SW Creekside Pl Beaverton, OR, 97008 | US Ph: (866) 600-1636 Email: info@zrtlab.com

www.zrtlab.com

ZRT laboratory, a CLIA-certified commercial and research laboratory, is the recognized leader in innovative and meaningful hormone and wellness testing. ZRT provides comprehensive test results that allow providers to create personalized treatments for optimal outcomes, with the help of our knowledgeable clinical consultants. 3420 Fairlane Farms Rd., Ste.300 Wellington, FL, 33414 | US Ph: (800) 622-4510 Email: info@wellsrx.com

www.wellsrx.com

Wells Pharmacy Network is a privately held, nationwide, compounding pharmacy specializing in solutions for wellness and anti-aging medicine including: Bio-Identical Hormone Replacement Therapy, Peptide & Regenerative Therapies, Weight Management, Sexual Wellness, Aesthetic Dermatology and Thyroid & Adrenal Health. This includes operating a 20,000SF 503A pharmacy and a 21,000SF FDA Registered 503B Outsourcing Facility that produces bulk medication. Our mission is to elevate compounding industry standards through a unique combination of superior science and service. 411 19th Street South St. Petersburg, FL, 33712 | US Ph: (813) 426-1708 Email: dseaman@cbdrx4u.com

www.cbdrx4u.com

Your CBD Store began with one woman, one story, and one store. Today, we have countless success stories and over 600 stores nationwide. We believe in providing the most transparent and dependable CBD products that utilize natural plant synergies. That’s why we have rigorous standards for quality and consistency and harvest only the highest-quality hemp products, grown in the U.S. We are dedicated to our community; earnestly providing contributions to our local and

national partnerships.

SEPTEMBER 9

OCTOBER 10

SEPTEMBER 11-13

Bio-Identi cal Replacement Therapy Symposium

Module III: Neurology

Module VII: Infl ammaging and AutoImmunity

OCTOBER 3

Business Power Summits

OCTOBER 17-18

IV Therapy Symposium

Pellet Therapy

Module IV: Gastroenterology

DECEMBER 12

DECEMBER 11-13 | LAS VEGAS

28 th Annual World Congress

Module I - Endocrinology

Module V: Clinical Intensives