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Slow the Progression of Atherosclerotic Plaque

February 2016

By Roger Alvarez

Atherosclerosis is the term used to describe damage and obstruction to the linings of the arteries.1 When blood flow is impeded or blocked, the result can be death or disability from a stroke or heart attack.1

A study on this topic published in The Lancet attracted worldwide attention. It documented that mummified human bodies dating back 4,000 years suffered clogged arteries.2

As Life Extension® has long argued, atherosclerosis is a disease of aging that has always been prevalent.

It took MRI imaging to document clear signs of heart disease in 34% of mummified humans whose estimated mean age at death was 43 years. Those who died at an estimated mean age of 32 years were less likely to show signs of atherosclerosis.2

The prevalence and severity of atherosclerosis worsens with aging. We at Life Extension® receive calls from people who suffer 70% to 95% blockage in their coronary arteries. These individuals often have several stents that prop open the most occluded part of their arteries. These stents or bypass surgery do nothing to slow the deterioration and further narrowing of their atherosclerotic blood vessels.

In a significant advance, two nutrients have been shown to dramatically slow the worsening of atherosclerotic plaque (by 95%), reduce unstable plaque, and improve endothelial function (by 66%).

Those with pre-existing coronary or cerebral atherosclerosis should read this article carefully. It describes the unique ways these two nutrients slash markers of heart attack and stroke risk in controlled human studies.

Urgent Need to Increase Plaque Stability

There is more to preventing atherosclerosis than simply preventing the formation of plaque. Much of the danger posed by plaque occurs when it becomes unstable.

Early on in the process, plaques are soft on the inside but covered with a hard, thick, fibrous cap on the plaque surface that faces the blood flow.

As long as these plaques remain thick, they are stable, meaning they are firm enough to not pose a major risk of rupturing.3,4 Over time, the cap begins to thin and weaken, making the plaque more vulnerable to rupturing. This is a catastrophic event that leads to sudden heart attack and stroke.

An important step in lowering acute cardiovascular risk therefore is to help stabilize plaques. That’s exactly what Centella asiatica does. Stable plaques stay where they are and don’t break loose to cause a tragic outcome.

Centella asiatica, an Asian aquatic plant long used in traditional medicine,1,2 helps stabilize thin-capped fibroatheromas, and in doing so reduces the potential for a rupture. It works by promoting the formation of collagen.5

Urgent Need to Increase Plaque Stability 

While we typically associate collagen with the skin, this structural protein is also a prominent component of thick fibroatheromatous plaques that helps reinforce them, making them less likely to rupture.5,6

The active constituents of Centella asiatica are triterpenoid molecules that improve the synthesis of collagen.1,2,7

By boosting the production of collagen, Centella asiatica extracts promote wound healing.2,8 This is key in stabilizing plaques because a plaque lesion is essentially a wound inside an arterial wall. Ultimately, by promoting collagen synthesis, Centella asiatica promotes remodeling of thin-capped, soft plaques into thicker-capped, harder, and more stable structures that are less likely to rupture and cause a heart attack or stroke.7

In addition to stabilizing plaque lesions by enhancing collagen production, basic lab studies show that Centella asiatica also has the potential to help stop the progression of atherosclerosis. To achieve this, Centella asiatica reduces the adhesion of monocytes, which are immune system-derived cells that infiltrate artery linings to promote progression of atherosclerosis.9

Human Studies on Centella Asiatica

Human studies have now been performed that demonstrate Centella asiatica’s ability to help increase the stability of soft, thin-capped lesions in the arteries of patients with known vulnerable plaques.

A two-part study was conducted in order to examine if Centella asiatica extract could help stabilize plaque lesions in the carotid arteries (the main arteries that lead to the brain). The first part was a pilot study in which patients with known high-risk plaque (meaning soft, thin-capped plaque lesions that were more likely to rupture) supplemented with 60 mg of Centella asiatica extract three times a day. After 12 months, the Centella asiatica extract significantly increased the density, or hardness, of plaques in the carotid arteries by an average of 30%.6

The second part of the study was a randomized, placebo-controlled trial using the same dose of Centella asiatica or placebo. Once again, after 12 months, the density (a measure of collagen content and stability of the plaques) was assessed by ultrasound. The results showed that the plaques’ density increased 33% in the supplemented group, with no significant changes in placebo subjects. The Centella asiatica-supplemented subjects also experienced a significant improvement in plaque texture (meaning hardness).6

Just to clarify, the existing plaque density in the Centella asiatica group increased, which improved the stability of the plaque. There was no increase in the occlusion of the carotid arteries, just an improvement in the stability of existing plaque. Perhaps most significantly, subjects taking Centella asiatica experienced half as many cardiovascular events (angina, heart attack, etc.) as the placebo recipients. In addition, while images from magnetic resonance imaging (MRI) revealed evidence of reduced blood flow in brain areas in 17% of the control subjects, this occurred in only 7% of supplemented individuals. This is a significant difference, and one that would sharply reduce the risk of a future stroke.6

Benefits in High-Risk Patients

A similar but more detailed study was carried out in individuals with high-risk (softer, thin-capped) atherosclerotic plaques in their femoral (main leg) arteries.5 The same parameters were followed in this study, with individuals receiving 60 mg of Centella asiatica extract three times daily, or placebo, for 12 months. This group was made up of high-risk individuals with softer, thin-capped atherosclerotic lesions in their femoral arteries.

The results were measured using ultrasound scans. The virtue of ultrasound is that it emits sound waves that can detect whether atherosclerotic plaque is “soft” or “hard.”

Soft tissue reflects back a darker image because this softer plaque absorbs more of the ultrasound wave. Conversely, more desirable “hard” arterial plaque bounces back brighter because it reflects back more sound waves. Prior studies have shown that darker plaques are associated with increased risk of stroke because these soft plaques are more likely to rupture.5

By the end of this study, there was a significant 63% increase in the brightness of the ultrasound echo returned from the lesions in the Centella asiatica-supplemented group. This indicated a lower risk for rupture. Once again, no significant change was seen in placebo recipients.5

In addition, while plaque size increased in control subjects by 23%, Centella asiatica-supplemented patients experienced no change in plaque size.5

Ultimately, treatment with Centella asiatica reduced the risk of plaque thinning, rupture, and subsequent blockage of arteries through stabilization and hardening of plaque lesions.

Now, let’s look at how this natural plaque-stabilizing extract is complemented by Pycnogenol®, which reduces the progression of atherosclerosis.

What You Need to Know
Combat Deadly Atherosclerosis

Combat Deadly Atherosclerosis

  • Atherosclerotic plaques, which are now known to begin in early life, continue to progress even after symptoms develop.
  • While reducing blood lipids, getting exercise, and watching your diet are important parts of a cardiovascular prevention regimen, it is now clear that those are not enough to prevent plaque progression and ultimate rupture, which causes an acute heart attack, stroke, or other cardiovascular event.
  • Two natural botanicals have now been shown to have complementary properties: Pycnogenol® slows plaque progression, while Centella asiatica stabilizes plaque lesions, thickening their caps and reducing their vulnerability to rupture.
  • The combination of the two supplements has undergone clinical trials in more than 2,000 people with atherosclerotic plaque, and has demonstrated a significant reduction, not only in plaque progression and texture, but also in prevention of new cardiovascular symptoms.
  • Each supplement has been tested individually, and both are now available in a single vascular health-promoting formula.

Pycnogenol® Slows Atherosclerosis Progression

Pycnogenol® is a standardized extract derived from the French maritime pine, Pinus pinaster. It consists of a mixture of bioactive compounds calledprocyanidins and phenolic acids,10,11 which have been shown to slow the progression of atherosclerosis.12

Pycnogenol® helps slow this progression by reducing the development of fat cells and cellular signaling molecules that specifically contribute to the formation of plaque.

It does this by suppressing the production of adipose-differentiation-related protein. This protein is crucial for the development of both fat cells and the production of various inflammatory cytokines (signaling molecules) that contribute to plaque formation and progression.13,14 Pycnogenol® achieves this by reducing a major inflammation-signaling molecular complex called nuclear factor kappaB (NF-kappaB). This results in lower levels of inflammation.13,14 As we know, this is critical because chronic inflammation is a major factor in the development of atherosclerosis.

In addition, animal studies show that Pycnogenol® reduces areas of plaque and lipid deposition in mice with atherosclerosis, accompanied by reductions in total cholesterol and triglyceride levels and increases in protective high-density lipoprotein (HDL) cholesterol.13

Atherosclerosis Has Long Plagued Mankind
Atherosclerosis Has Long Plagued Mankind

According to the lead investigator of The Lancet study showing clogged arteries in mummified humans:

“The fact that we found similar levels of atherosclerosis in all of the different cultures we studied, all of whom had very different lifestyles and diets, suggests that atherosclerosis may have been far more common in the ancient world than previously thought.” 5

—Randall Thompson, MD

These findings help confirm that atherosclerosis has always been widespread. The encouraging news is that methods to prevent and even reverse it are being validated in modern clinical studies.

Improving Endothelial Function

Improving endothelial function is also an important step in reducing the development and progression of atherosclerotic plaque.15,16

Lab experiments show that Pycnogenol® stimulates a vital enzyme called endothelial nitric oxide synthase (eNOS). This action is critical to the health of blood vessels because endothelial nitric oxide synthase produces nitric oxide, the signaling molecule that endothelial cells use to communicate with the smooth muscle cells in arterial walls, helping them to relax and open up arteries.17

This ability was demonstrated in lab experiments in which scientists constricted tissue from the aorta, which is the main blood vessel leading from the heart. The aortic constriction was done using norepinephrine and epinephrine that are normally released in response to stress. This technique mimics what happens in human arteries when blood flow is reduced.

What they discovered is that when the aorta was pretreated with Pycnogenol®, it prevented this dangerous constriction of the blood vessels. This beneficial effect occurred as a result of increased nitric oxide synthesis, which signals arterial wall cells to relax, producing a wider artery and increasing blood flow. In addition, scientists found that increasing nitric oxide levels also decreases platelet aggregation and stickiness to vessel walls, reducing the risks of blood clots and enlarging plaques.17

All of these complementary actions have been found to be especially beneficial in humans with coronary artery disease, as we’re about to see.

How Pycnogenol® Benefits Coronary Artery Disease

The coronary arteries are critical because they supply the heart with blood, oxygen, and nutrients. Coronary artery disease develops because of plaque and inflammation that narrow the arteries, decreasing blood flow to the heart.

A human controlled trial demonstrated that Pycnogenol® was able to improve endothelial function in patients with coronary artery disease, an effect that helps to limit the progression of atherosclerosis.18

In this randomized, placebo-controlled crossover study, 23 patients with coronary artery disease received either placebo or Pycnogenol® (200 mg per day) for eight weeks, followed by a two-week “washout” period. After that, the patients received the reverse (crossover) assignment for another eight weeks.18

How Pycnogenol® Benefits Coronary Artery Disease

In order to determine Pycnogenol®’s effect, the scientists assessed the patients’ endothelial function at the start of the study and after each treatment period by measuring flow-mediated dilation (a measure of how much arteries dilate in response to changes in blood flow) in the brachial artery (main artery to the forearm).

What they found was that treatment with Pycnogenol® produced a significant 32% increase in flow-mediated dilation and in endothelial function while placebo treatment produced no significant changes. Furthermore, levels of isoprostanes (an index of how much oxidized fat is present and a measure of overall oxidant stress) fell 7% in treated subjects with no change in placebo recipients.18

This study provides support for Pycnogenol®’s ability to slow the fundamental, early arterial changes leading to plaque formation and progression.

New Study Corroborates Pycnogenol®’s Benefits

Still greater improvements in endothelial function were demonstrated in a 2015 study by leading Pycnogenol® researchers in Italy.19 The study is especially important because it involved people with only borderline high blood pressure, blood lipids, and blood sugar, who as yet had no obvious atherosclerotic changes in their blood vessels and no existing coronary artery disease. In other words, these patients were like most people. They had definitive risk factors, but had not yet developed any clinically relevant disease. They thus were in an ideal situation for early, preventive intervention.

As in the preceding study, the main outcome measure was flow-mediated dilation. In this study, 93 individuals with borderline risk factors were enrolled, including 32 with hypertension, 31 with elevated blood lipids, and 30 with elevated blood sugar.19 All participants continued their use of the best available medical management for their symptoms, while half of the subjects in each group also took 150 mg of Pycnogenol® per day. Measurements of flow-mediated dilation were made at baseline, at eight weeks, and again at 12 weeks.

By the eight-week mark, flow-mediated dilation had increased in the supplemented subjects by 55%, and at 12 weeks by a total of 66%. During the same time period, control patients who had not supplemented with Pycnogenol® showed no significant changes in flow-mediated dilation. Measurements of blood flow by a different method, laser Doppler flux, demonstrated similar increases in blood flow at eight and 12 weeks, with flow at 12 weeks no different from normal values.19

Interpretation of this study suggests, in the authors’ own words, “… an important preventive possibility for borderline hypertensive, hyperglycemic, and hyperlipidemic subjects.”19 Again, it’s essential to point out that the borderline status of these patients reflects the situation in which most people find themselves, that is, with only mild or no symptoms but at growing risk for endothelial dysfunction leading to plaque formation and ultimately, a cardiovascular catastrophe.

Clearly, both Pycnogenol® and Centella asiatica extracts have value individually in reducing plaque progression and promoting plaque stability, with additional early protection by Pycnogenol® from endothelial dysfunction. However, two compelling studies show that when these two supplements are used together, they provide even more powerful benefits.

Combined Benefits of Pycnogenol® and Centella Asiatica

Two studies of the Pycnogenol® plus Centella asiatica extract supplement were performed by the same research group at a prestigious university. Both were designed to explore the impact of this combination of ingredients in subjects with two classifications of atherosclerotic lesions.

The first group had mild atherosclerotic lesions that were producing no symptoms and that were not yet blocking arteries (class IV). The second group had more advanced lesions that extended more than 50% to 60% into arteries (class V). Critically, both studies were carried out in people who, at the time of enrollment, had relatively early cardiovascular disease. This is vital because we know that prevention is always superior to attempts to cure these chronic, age-related disorders and because most readers fall into that category.

Let’s take a look at the first study.

The Dangers of Arterial Plaque
The Dangers of Arterial Plaque

Cardiovascular disease remains the leading cause of death among older adults.20

Atherosclerosis, the thickening and narrowing of arteries, is the cumulative result of elevated cholesterol, chronic inflammation, and other factors. It leads to coronary heart disease (heart attack), stroke, and peripheral vascular disease.20

In recent years, we’ve developed a vastly more sophisticated understanding of the processes leading up to devastating arterial blockage by plaque lesions.

Their foundation begins even before the teen years with the development of so-called fatty streaks, or regions of increased fat in the walls of arteries.20-22 At first, the small damaged fatty streak areas trigger a “healing” response, as if the streak areas were a wound, attracting inflammatory cells that ingest and store excess fats.17

Eventually, arterial plaque begins to take shape as a core of fats develops outside of inflammatory cells.20,22 These plaques become less stable over time, making them more vulnerable to rupture, which leads to heart attacks and strokes.

Anything we can do to slow the progression of early fatty deposits to plaque lesions is beneficial, and anything we can do stabilize these plaques makes the risk of a sudden catastrophic heart attack or stroke much less likely.

Two particular supplements have been found to do just that. Pycnogenol® has been shown to slow the progression of atherosclerotic plaques. A specialized extract of Centella asiatica helps to stabilize those plaques, reducing the risk of a life-threatening rupture.

Together, these two supplements can help prevent plaque progression in those with milder atherosclerosis and reduce the development of symptoms in those with more severe disease.

Reduced Risk of Progression of Plaques

The first study was performed among 1,363 subjects aged 45 to 60, who appeared healthy and had no conventional cardiovascular risk factors.12 All subjects had plaques that did not yet narrow the diameter of the carotid or femoral arteries by more than 50%, as seen on ultrasound, and no subjects were experiencing signs or symptoms of cardiovascular disease.

After enrollment, subjects were divided into six different groups:

  • Controls, who received only education, exercise, diet, and lifestyle recommendations (which were also given to the subjects in all of the treatment groups)
  • Pycnogenol® 50 mg daily (low-dose)
  • Pycnogenol® 100 mg daily (higher-dose)
  • Aspirin, 100 mg daily or ticlopidine (a prescription antiplatelet drug) for aspirin-intolerant subjects
  • Aspirin, 100 mg daily plus Pycnogenol® 100 mg daily
  • Pycnogenol® 100 mg plus Centella asiatica extract 100 mg daily.

All subjects underwent an ultrasound measurement every six months for 30 months in order to determine arterial wall structure and number of plaques that progressed from not blocking blood flow (class IV) to blocking blood flow (class V).

Reduced Risk of Progression of Plaques 

By the end of the study, plaque progression was increased in all groups not receiving 100 mg per day of Pycnogenol®, indicating the ability of this dose of Pycnogenol® to prevent plaque progression. 12 The following is a breakdown of the percentage of plaques that worsened from class IV to a class V:

  • 21.3% in control patients (worst responding group)
  • 16.6% of the aspirin/ticlopidine group
  • 8.4% in low-dose Pycnogenol®
  • 5.3% in higher-dose Pycnogenol®
  • 4.0% in Pycnogenol® plus aspirin
  • 1.1% in the Pycnogenol® and Centella asiatica group (best responding group by far)

Indeed, the risk of plaque progression in the group taking Pycnogenol® and Centella asiatica was 95% lower than in the control group. This was far superior to the standard antiplatelet therapy group (aspirin/ticlopidine), which was only modestly better than the control (worst responding) group.

Powerful Combination Combats Plaque Progression

Confirming the findings of earlier studies, Italian researchers followed a group of middle-aged individuals with atherosclerotic plaques for four years. Study participants were assigned to receive Pycnogenol® or a combination of Pycnogenol® and Centella asiatica. Plaque progression was assessed through arterial ultrasound every six months. Although both supplemented groups showed reductions in the progression of arterial plaque, the reduction was more pronounced in the group receiving the combination. This led researchers to conclude, “Pycnogenol® and the combination Pycnogenol® plus Centella asiatica reduce the progression of arterial plaques and the progression to clinical stages.” 23

Impact on Advanced Atherosclerosis

Impact on Advanced Atherosclerosis 

The researchers’ next study was carried out on 824 subjects with more advanced atherosclerosis, namely, with at least one carotid or femoral arterial lesion that extended more than 50% into the arterial wall (class V) but who were, again, without symptoms at the start of the study.24

The same doses and group assignments were used as in the prior study, and patients were followed up for 42 months.

Once again, in all groups not receiving 100 mg of Pycnogenol®, the plaque lesions increased significantly, but they did not meaningfully increase in any of the groups receiving 100 mg of Pycnogenol®.24 The following is a breakdown of each group’s percentage of plaques that worsened from class V (meaning symptom-free) to class VI (those with symptoms):

  • 48% of control subjects (worst responding group)
  • 21% of the aspirin/ticlopidine group
  • 10% of Pycnogenol® 100 mg alone
  • 11% in Pycnogenol® plus aspirin
  • 6.5% of the Pycnogenol® and Centella asiatica group (best responding group)

Remember that in this study, progression was defined as going from a symptom-free state to one in which symptoms occurred. These were not minor symptoms, but rather those of significant loss of blood flow to the brain, such as numbness, tingling, or loss of function on the same side of the brain (for those with carotid artery plaque), or to the leg, such as pain, pallor, or numbness in the leg (for those with femoral artery plaque).

In other words, these figures for the Pycnogenol® and Centella asiatica combination reflect a 7.4-fold reduction in risk of developing profoundly disturbing symptoms of cardiovascular disease compared with controls, and a 3.22-fold reduction compared with the antiplatelet (aspirin/ticlopidine) group.

Even more exciting is that when compared to the control group, those in the Pycnogenol® and Centella asiatica group had a nearly 4-fold reduction in the risk of being hospitalized for a full-blown cardiovascular event.

Atherosclerosis Begins Early in Life

Long before a heart attack or stroke occurs, dangerous fatty plaques begin to form in the arteries, starting as early as the teen years.21 Progression to vascular disease can occur slowly over decades.

The hidden danger is that the symptoms of cardiovascular problems are not always apparent until it’s too late.

Despite the billions of dollars spent on statin drugs and surgical interventions such as stents and bypass, heart disease remains the number one cause of death for Americans.26 More needs to be done to reduce this epidemic.

Researchers have identified two specialized botanicals compounds, Centella asiatica and Pycnogenol® that have been shown in university studies to slow the progression of dangerous arterial plaques, while also stabilizing existing plaques.

In one human study, the risk of plaque progression in the group taking Pycnogenol® and Centella asiatica was 95% lower than in the control group.12 In addition, Pycnogenol® has been shown to improve endothelial function by 66% in just 12 weeks.19

When used together, both of these extracts help reduce two of the major causes of heart disease in those with milder atherosclerosis, while reducing the development of symptoms in those with more severe disease.12,24

Summary

Cardiovascular disease, including heart attacks, strokes, and peripheral vascular disease, remains the leading cause of disability and death in Americans and others around the world. We’ve focused for years on lowering blood cholesterol and other lipids, but that turns out to be only part of the story.

New findings show that a person’s risk for having a cardiovascular “event” is highest for those with the most advanced arterial plaques, particularly those with thin caps and soft cores that are vulnerable to rupture, and then catastrophically block the artery.

Two supplements in particular have been found to help prevent dangerous atherosclerosis.

Pycnogenol® has been demonstrated to slow the progression of atherosclerotic plaques. Centella asiatica preserves the hard, thick cap on atherosclerotic plaques. Such thick-capped plaques are less likely to rupture and produce a potentially fatal cardiovascular event.

When used together, these two supplements help to prevent plaque progression in those with milder atherosclerosis, and to reduce the development of symptoms in those with more severe disease.

In addition to efforts to lower lipid/glucose levels, a combination of Pycnogenol® and Centella asiatica provides the backup that most adults need for more comprehensive cardiovascular protection.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Ultrasonic Classes of Atherosclerotic Lesions12

Ultrasonic

Class

Ultrasonic

Characteristics

CLASS I

Normal artery

Intimal surface is a straight line; intima, media, and adventitia are clearly separated

CLASS II

Intimal irregularities ± medial granulation

Intimal surface is irregular and/or adventitia appears granular; separation of

intima media and adventitia is not clear; intima-media thickness (IMT) <1 mm

CLASS III

Intima media thickening (>1 mm)

Appearances as in Class II, but intima-media thickness >1 mm

CLASS IV

Non-stenotic atherosclerotic plaque

Localized thickening >1.5 mm producing less than 50% diameter stenosis

CLASS V

Stenotic atherosclerotic plaque

Localized thickening producing more than 50% diameter stenosis

CLASS VI

Symptomatic stenotic atherosclerotic plaque

As in Class V but associated with ipsilateral cerebral hemispheric symptoms or lower limb ischemic symptoms

Intima refers to the innermost layer of the artery, composed of endothelial cells, while media refers to the smooth muscle layer that comprises the artery wall, and adventitia is the loose connective tissue surrounding the artery. IMT: intima-media thickness, a long-term measure of atherosclerosis that is predictiveof future cardiovascular events (thicker is more severe disease).25 Stenotic means measurable narrowing of the blood flow channel inside the artery. All classes lower than VI occur without symptoms.

References

  1. James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules. 2009;14(10):3922-41.
  2. Thompson, Randall C et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. The Lancet, Volume 381, Issue 9873, 1211 - 1222
  3. Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol. 2007;50(10):940-9.
  4. Leskinen MJ, Kovanen PT, Lindstedt KA. Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells—a potential mechanism for the weakening and rupture of atherosclerotic plaques. Biochem Pharmacol. 2003;66(8):1493-8.
  5. Incandela L, Belcaro G, Nicolaides AN, et al. Modification of the echogenicity of femoral plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, randomized, placebo-controlled trial. Angiology. 2001;52 Suppl 2:S69-73.
  6. Cesarone MR, Belcaro G, Nicolaides AN, et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial. Angiology. 2001;52 Suppl 2:S19-25.
  7. Incandela L, Cesarone MR, Cacchio M, et al. Total triterpenic fraction of Centella asiatica in chronic venous insufficiency and in high-perfusion microangiopathy. Angiology. 2001;52 Suppl 2:S9-13.
  8. Belcaro G, Maquart FX, Scoccianti M, et al. TECA (Titrated Extract of Centella Asiatica): new microcirculatory, biomolecular, and vascular application in preventive and clinical medicine. A status paper. Panminerva Med. 2011;53(3 Suppl 1):105-18.
  9. Ivanov V, Ivanova S, Kalinovsky T, et al. Plant-derived micronutrients suppress monocyte adhesion to cultured human aortic endothelial cell layer by modulating its extracellular matrix composition. J Cardiovasc Pharmacol. 2008;52(1):55-65.
  10. D’Andrea G. Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia. 2010;81(7):724-36.
  11. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. 2002;40(4):158-68.
  12. Belcaro G, Dugall M, Hosoi M, et al. Pycnogenol® and Centella Asiatica for asymptomatic atherosclerosis progression. Int Angiol. 2014;33(1):20-6.
  13. Luo H, Wang J, Qiao C, et al. Pycnogenol attenuates atherosclerosis by regulating lipid maetabolism through the TLR4-NF-kappaB pathway. Exp Mol Med. 2015;47:e191.
  14. Gu JQ, Ikuyama S, Wei P, et al. Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages. Am J Physiol Endocrinol Metab. 2008;295(6):E1390-400.
  15. Badimon L, Hernandez Vera R, Vilahur G. Atherothrombotic risk in obesity. Hamostaseologie. 2013;33(4):259-68.
  16. Chistiakov DA, Revin VV, Sobenin IA, et al. Vascular endothelium: functioning in norm, changes in atherosclerosis and current dietary approaches to improve endothelial function. Mini Rev Med Chem. 2015;15(4):338-50.
  17. Fitzpatrick DF, Bing B, Rohdewald P. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol. 1998;32(4):509-15.
  18. Enseleit F, Sudano I, Periat D, et al. Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study. Eur Heart J. 2012;33(13):1589-97.
  19. Hu S, Belcaro G, Cornelli U, et al. Effects of Pycnogenol® on endothelial dysfunction in borderline hypertensive, hyperlipidemic, and hyperglycemic individuals: the borderline study. Int Angiol. 2015;34(1):43-52.
  20. Bentzon JF, Otsuka F, Virmani R, et al. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-66.
  21. Available at: http://my.clevelandclinic.org/services/heart/disorders/coronary-artery-disease/understandingcad. Accessed November 16, 2015.
  22. Sakakura K, Nakano M, Otsuka F, et al. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ. 2013;22(6):399-411.
  23. Belcaro G, Dugall M, Ippolito E, et al. Pycnogenol® and Centella Asiatica for preventing asymptomatic atherosclerosis progression into clinical events. Minerva Cardioangiol. 2015 Oct 27.
  24. Belcaro G, Ippolito E, Dugall M, et al. Pycnogenol® and Centella asiatica in the management of asymptomatic atherosclerosis progression. Int Angiol. 2015;34(2):150-7.
  25. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115(4):459-67.
  26. Available at: http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Accessed November 16, 2015.