Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

The endothelium refers to the inner cellular lining of blood vessels and lymphatic tissues. Endothelial dysfunction is characterized by a decreased production of vasodilators, such as nitric oxide, and increased endothelium-derived contracting factors. The resulting effects are considered cardiovascular risk factors and independent predictors of cardiac events. (Desjardins and Balligand 2006)(Hadi et al. 2005) 

Various factors can increase the risk of endothelial dysfunction, including smoking, aging, hypercholesterolemia, hypertension, hyperglycemia, and a family history of premature atherosclerotic disease. These proinflammatory states increase oxidative stress to which the endothelium is especially vulnerable. Unchecked oxidative stress can increase endothelial permeability and promote leukocyte adhesion. (Desjardins and Balligand 2006)(Hadi et al. 2005) 

This protocol highlights five evidence-based dietary ingredients that may help support the vascular endothelium and reduce oxidative stress.

Anthocyanins

320 mg total per day for a minimum of 4 weeks (Li et al. 2015)(Thompson et al. 2017)(Zhu et al. 2013)

Anthocyanins are naturally occurring plant compounds that are responsible for the deep red, purple, and blue colors found in many fruits and vegetables. (Khoo et al. 2017)

Anthocyanins are known for their anti-inflammatory and antioxidant properties. Studies have found that supplementing with anthocyanins may help reduce inflammatory markers, such as TNF-α, C-reactive protein (CRP), IL-6, and IL-1β, and antioxidant markers, such as total radical-trapping antioxidant parameter (TRAP) and ferric reducing antioxidant power (FRAP). (Li et al. 2015)(Xu et al. 2021)(Zhu et al. 2013)

Anthocyanins have also been found to support endothelial function by increasing the responsiveness of blood vessels to changes in blood flow (i.e., ↑ flow-mediated dilatation) and decreasing proatherosclerotic activity at the artery wall (i.e., ↓ sVCAM 1). (Weissgerber 2014)(Zhu et al. 2011)(Zhu et al. 2013) Studies have also shown that supplementation with anthocyanins may help reduce the risk of blood clots. (Thompson et al. 2017)

Anthocyanins in the Fullscript catalog

Coenzyme Q10

Minimum of 100–200 mg once per day for a minimum of 8–12 weeks (Fan et al. 2017)

Coenzyme Q10, otherwise known as CoQ10 or ubiquinone, is a fat-soluble, non-essential nutrient that plays an important role in free radical scavenging. (Díaz-Casado et al. 2019) 

CoQ10 has been shown to decrease inflammatory markers such as CRP, IL-6, and TNF-α. (Fan et al. 2017) Additionally, CoQ10 has also been shown to increase total antioxidant capacity (TAC) and reduce free oxygen radicals like malondialdehyde (MDA). (Sangsefidi et al. 2020)(Yoo and Yum 2018) These therapeutic properties are likely the mechanism by which CoQ10 improves flow-mediated dilatation and endothelial function. (Gao et al. 2012)

Coenzyme Q10 in the Fullscript catalog

Folic acid

Minimum of 5 mg total per day for a minimum of 12 weeks (Alian et al. 2012)(Zamani et al. 2023)

Folic acid, also known as folate and vitamin B9, is a water-soluble B vitamin that has the potential to improve endothelial dysfunction. (Stanhewicz and Kenney 2017) It has been proposed that folic acid may reduce atherogenesis by decreasing oxidative stress (i.e., ↑ TAC and glutathione (GHS), and ↓ MDA levels), (Asbaghi et al. 2021 A) inflammation (i.e., ↓CRP), (Asbaghi et al. 2021 B) blood pressure, cholesterol, and homocysteine levels, and by improving glycemic control. (Zamani et al. 2023)

Supplementation with 5 mg of folic acid per day for a minimum of 12 weeks has been associated with improved endothelial function as measured by improved flow-mediated dilation (FMD)/FMD% and decreased adhesion molecules (i.e., ↓ VCAM) and microalbuminuria (Alian et al. 2012)(Zamani et al. 2023)

Folic acid in the Fullscript catalog

Omega-3 fatty acids 

2–4 g total of EPA/DHA per day for a minimum of 12 weeks (Hu et al. 2019)(Sekikawa et al. 2019)(Wang et al. 2012)

Omega-3 fatty acids, like EPA and DHA, are polyunsaturated fatty acids that are most commonly derived from oily fish. (Calder 2012) Supplementing with omega-3 fatty acids has been shown to decrease atherosclerotic progression and fasting serum triglyceride. (Kastelein et al. 2014)(Sekikawa et al. 2019)

In addition to their antilipidemic and antiatherosclerotic properties, omega-3 fatty acids have also been shown to decrease inflammation (i.e., ↓hs-CRP, IL-6, TNF) (Guo et al. 2022)(Mortazavi et al. 2018) and improve endothelial function (i.e., ↑ FMD). (Wang et al. 2012)

Omega-3 fatty acids in the Fullscript catalog

Vitamin C

Minimum of 500–2000 mg total per day for a minimum of 2 weeks (Ashor et al. 2014)(Ashor et al. 2015)

Vitamin C (ascorbic acid) is an essential, water-soluble vitamin. (Lykkesfeldt et al. 2014) It is well-known for its anti-inflammatory properties (i.e., ↓ CRP,  IL-6) (Ellulu et al. 2015) and ability to reduce free radicals by donating electrons (i.e., ↓ MDA and ↑ sGHS). (Boonthongkaew et al. 2021)(Tessier et al. 2009)

A meta-analysis of 44 randomized controlled trials found that daily supplementation with more than 500 mg of vitamin C reduced endothelial dysfunction as measured by improved FMD, forearm blood flow (FBF), and pulse wave analysis (PWA). (Ashor et al. 2014)

Vitamin C in the Fullscript catalog

Disclaimer

The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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