Cardiac Lymphatics: An Example of Systems Biology in Medicine

Abstract

When evaluated from the 2017 perspective, the 1981 Lemole cardiac lymphatic drainage model for the origin of atherosclerosis appears very prescient. The concept proposed by Dr Lemole is rooted in a systems biology understanding of the origin of disease (itself a very novel concept in 1981). The Lemole hypothesis for the origin of atherosclerosis pioneered the application of systems thinking in cardiology and brought the importance of lifestyle factors and physical medicine approaches for the prevention and treatment of cardiac disease to the threshold of a mechanistic understanding. It is this type of systems biology approach to clinical problem solving that forms the heuristic of the functional medicine model.

In November 1998, I had the opportunity to interview the esteemed cardiovascular surgeon Dr Gerald M. Lemole for Functional Medicine Update, a monthly audio journal I had been publishing for many years.¹ Thirty years earlier—in 1968—Dr Lemole was a member of the surgical team that performed the first successful heart transplant in the United States. At age 32, he was named chief of cardiothoracic surgery at Temple University; in 1975, he was promoted to full professor at Temple, which made him the youngest full professor of surgery in the United States at that time. Later in his career, Dr Lemole went on to serve as the chief of cardiovascular surgery at Christiana Care Health Services and in this role he performed thousands of cardiovascular surgical procedures between 1986 and 2006. I cannot overstate the profound ways my 1998 conversation with Dr Lemole influenced my thinking about key areas of health and disease, because it was this discussion that introduced me to a new and much more robust understanding of the complex etiology of heart disease.

In 1981, Dr Lemole authored a paper titled “The Role of Lymphstasis in Atherogenesis.”² In this paper, he described the role of the cardiac lymphatic system in transporting lipoproteins and cholesterol from the extravascular myocardial tissue into the bloodstream, where they could then be metabolized. At that time, little was known about this second fluid transport system and the specifics of how lymphatic filtration was involved in the clearance of lipids from the coronary wall. Based on his careful observations as a surgeon, Dr Lemole postulated that impairment in lymphatic clearance of lipids was a critical factor in the genesis of arteriosclerosis seen clinically in patients with lymphostasis. He believed that the functional defect in this important process was alteration in lymphatic transport in the cardiac lymphatic system, and that this defect correlated with the then-known Framingham cardiovascular disease risk factors. He suggested that the inverse association between high-density lipoprotein (HDL) levels and cardiovascular risk could be due to the fact that HDL particles transport cholesterol through the arterial wall to the lymphatics (reverse cholesterol transport). Just recently, Dr Lemole sent me a 2016 article he published in the Annals of Thoracic Surgery that revisited the lymphostasis connection to atherosclerosis and reviewed the considerable progress that had been made in the understanding of the cardiac lymphatic system since 1981.³ Intrigued, I suggested a phone call, and during our conversation in January Dr Lemole said this: “I feel that my 1981 hypothesis describing the role of lymphostasis in the etiology of heart disease has started to emerge as an important concept that can lead to actionable approaches to its prevention and treatment.” Following our call, I set out to review the literature that has been published on this subject during the past few years. After spending a considerable amount of time immersed in this research, I agree with him completely.

To fully understand the cardiac lymphatic system, we need to go back to the 1620s. This is the era when 2 important functions in the body—blood and lymphatic circulation—were first described in manuscripts titled De Moto Cordis and De Lactibus Sive Lacteis Venis. During those very early days of medical research, visible anatomy, which in this case would be the heart and its pump-like function, made exploration of the blood circulation system easier than study of the lymphatic circulatory system. As a consequence, much more was learned about the cardiovascular system than the lymphatic system during the next 3-plus centuries.⁴

The Lymphatic System and Its Role in Systemic Chronic Disease

Today—in our modern world of the 21st century—new methods for studying the lymphatic system have been developed, especially during the last 15 years. The lymphatic circulatory system is now recognized to work closely with the cardiovascular system. It is a network that is also an essential component of the immune system, playing major roles in both host defense and adaptive immunity. In addition, it is recognized as the principal system involved in transport of antigens from tissues. Lymphatic system anatomy demonstrates that lymphatic vessels regulate fluid flux in the body and contain junctions between endothelial cells that transport fluids and macromolecules across the tissue space. The flow of lymphatic fluid depends on mechanical forces exerted by muscle contraction and gravity. In the intestines, the lymphatic system absorbs lipids, thereby transporting fats and fat soluble substances such as vitamins A, D, and E into the blood.⁵

By studying lymphedema in patients who have undergone cancer treatment, we have gained a greater understanding of the role of lymphatics in acute and chronic inflammatory disorders. Atherosclerosis is now recognized to be associated with chronic inflammation of the vascular system as a result of an increase in vascular endothelial permeability and immune cell extravasation into the artery wall.⁶ This results in transport of macrophages and cholesterol into the aortic intima, which then engulf lipid to become foam cells. This process initiates the release of many proinflammatory mediators, which are associated with the production of proatherogenic oxidized low-density lipoprotein (LDL). According to my research, Dr Lemole was the first—in 1981—to recognize the role of the cardiac lymphatic system in facilitating the flux of these atherogenic agents out of the artery wall and their “detoxification” through metabolism and excretion. In his original paper, Dr Lemole suggested the need for further studies in immunology, lipid metabolism, and vessel pathology to better understand the role of the cardiac lymphatic system in the cardiovascular disease process.

Interest in the lymphatic biology associated with cardiovascular disease is now growing exponentially. Using animal models, it has now been demonstrated that there is a strong association between defects in cardiac lymphatic function and the initiation and progression of cardiovascular disease.⁶ Lymph fluid is rich in lipoproteins such as HDL, as well as immune cells, electrolytes, nutrients, and antibodies. The flow rate of lymphatic fluid is believed to control lymphatic function. It is also known that a broad panel of inflammatory cytokines, proteins, and growth factors are found in lymph fluid, and this plays an important role in modulating immune system function. These observations have resulted in an understanding that specific therapies targeting improvement in the function of lymphatic flow should have beneficial effects in both the prevention and treatment of cardiovascular disease. In a recent review titled “Lymph Vessels: The Forgotten Second Circulation in Health and Disease,” the authors summarize the significant progress that has been made in understanding the role of altered function of the cardiac lymphatic system in atherogenesis related to the accumulation of inflammatory mediators and immune active cells in the vascular wall.⁷ They point out that the rapid increase in understanding is a result of progress in the technology of in vivo imaging of lymphatic vessels using lymphoscintigraphy, magnetic resonance lymphangiography, and near infrared imaging. Advancements in these technologies, coupled with the ability to measure immune biomarkers discovered during the past 20 years, have resulted in greater insight into the role that lymphatic flow has on blood vessel inflammation, lipid metabolism, and vessel biology.

Recently, a unique signaling system, angiopoietin-Tie, has been discovered in the endothelial cells that form the inner layer of blood and lymphatic vessels and are important regulators involved in the pathogenesis of vascular diseases.⁸ Alterations in the function of this signaling system have been found to be associated with dysfunctions in lymphatic function. This finding further demonstrates connections of the cardiovascular and lymphatic systems to cardiovascular disease.

Relationship Between PCSK9 and the Cardiac Lymphatic System

Another important discovery that relates to the etiology of cardiovascular disease is the existence of a relationship between alterations in PCSK9 activity, LDL receptor modulation, and lymphatic function.⁹ It is well known that atherosclerosis is associated with cholesterol-laden plaque formation due to LDL cholesterol accumulation in the artery wall. The formation of arterial plaque is related to expression and activity of the LDL receptor that is present on the outer membrane of many cell types, including the macrophage and the hepatocyte. Its functional activity is critical for regulating proper clearance of LDL cholesterol. Apolipoprotein B100 (apoB) is the apolipoprotein and ligand of the LDL receptor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a down-regulator of the LDL receptor and its activity prevents the degradation of apoB. New PCSK9 inhibitor drugs are designed to block activity of PCSK9, thereby increasing the activity of the LDL receptor and reducing LDL levels and infiltration of lipid into the artery wall. Recent studies have indicated that cardiac lymphatic vessels play an important role in macrophage uptake of LDL cholesterol and reduction of atherosclerosis risk. It has been reported that PCSK9 is involved in modulating the function of cardiac lymphatics by inhibiting lymphatic uptake of LDL. In animal studies it has been demonstrated that inhibition of PCSK9 resulted in improved collecting lymphatic vessel function and a reduction of atherosclerosis. Furthermore, it was found that lymphatic dysfunction occurred prior to the atherosclerotic plaque formation, suggesting that lymphatic dysfunction was a primary contributor to atherosclerosis.¹⁰ This work suggests that LDL receptor modulation is associated with lymphatic dysfunction, setting the stage for lipid infiltration into the artery wall and resultant atherosclerosis. The conclusion derived from this work is that there is a biological system that connects arterial function with LDL receptor activity, arterial lipid and immune cell infiltration, PCSK9 activity, and cardiac lymphatic function. Both statins and PCSK9 inhibiting drugs influence this system at different points in the process and have influence on the function of the cardiac lymphatic system.

Work of this nature indicates that cardiac lymphatic function may represent a new therapeutic target for the prevention and treatment of atherosclerosis.¹¹ Progress that has been made in the understanding of lymphatic biology due to the development of novel imaging techniques, combined with the increased understanding of the role of lymphatics in immune function and lipid metabolism, provides strong support for the hypothesis Dr Lemole formed and articulated more than 30 years ago. The implication of these discoveries is that lymphangiogenic therapy could be beneficial in the prevention and treatment of cardiovascular diseases.

Dr Lemole’s Suggested Therapeutic Approach to Cardiac Lymphatic Dysfunction

What is “lymphangiogenic therapy?” We can begin to answer that question by referring back to Dr Lemole’s original hypothesis. He suggested that improvement in cardiac lymphatic function could be achieved without the use of medications by introducing a natural systems biology approach to care that included increased movement, physical manipulation and massage, and structured exercise; recent research has demonstrated these techniques to be effective.^12,13,14,15 Dr Lemole also suggested that dietary modification—decreasing saturated fat intake and increasing omega-3 fats along with specific plant foods that are high in antioxidants, B vitamins, and anti-inflammatory phytochemicals—would be helpful in improving lymphatic function. Although there is a need for more research in this area, some preliminary studies indicate that specific nutrients help to support lymphatic function. In 1993, Garaev et al¹⁶ reported that the combination of vitamin E and mannitol (a lymphatic drainage stimulant) had a positive effect on lymphatic drainage after acute myocardial infarction. Earlier work—in 1974—by Foldi et al¹⁷ suggested that lymphatic drainage was impaired by B-complex vitamin deficiency. In 2011, Zhou et al¹⁸ reported on an animal model that indicated that omega-3 fatty acids support proper lymphatic drainage by reducing inflammation. In addition, it has been reported that intervening with anti-inflammatories assists in improving lymphatic drainage that has been compromised due to inflammation, suggesting that a diet that is higher in anti-inflammatory phytochemicals could be of value to certain individuals.^19,20

Phytochemicals as Lymphogogues

Calcium dobesilate has been used as a lymphagogue to stimulate lymphatic drainage in chronic venous diseases, including thoracic duct occlusion and retinopathy.²¹ In 2008, researchers reported on a placebo-controlled clinical trial in patients with various venous diseases who received 1 capsule of 500 mg of calcium dobesilate every 8 hours for 49 days, which resulted in significant improvement in normalization of lympho-gammagraphy (capture index and speed of lymph flow) versus placebo. Statistically significant improvement in the measurements of fluid retention associated with improved lymphatic function was noted only in the patients treated with calcium dobesilate.²²

Calcium dobesilate is the calcium salt of dobesilic acid, which is 2,5-dihydroxybenzenesulfonic acid (a member of the phenolic family of molecules). It is related to more complex polyphenolic plant flavonoids such as quercetin (isolated from many fruits), as well as vegetables such as apples, grapes, berries, onions, garlic, escine (isolated from the seeds of the horse chestnut), and hesperidin (isolated from citrus). It is known that these phytochemicals have influence on reducing edema in conditions such as diabetic retinopathy. Daflon and Detralex are drugs that are composed of extracts of flavonoids that are used in the treatment of neovascularization and fluid retention. When these flavonoids are metabolized by the liver they are converted into sulfated derivatives that resemble dobesilic acid.²³ This suggests that various phytochemicals found in plant-rich diets can have favorable influence on lymphatic function.

When evaluated from the 2017 perspective, the 1981 Lemole cardiac lymphatic drainage model for the origin of atherosclerosis appears very prescient. The concept proposed by Dr Lemole is rooted in a systems biology understanding of the origin of disease (itself a very novel concept in 1981).²⁴ The Lemole hypothesis for the origin of atherosclerosis pioneered the application of systems thinking in cardiology and brought the importance of lifestyle factors and physical medicine approaches for the prevention and treatment of cardiac disease to the threshold of a mechanistic understanding. It is this type of systems biology approach to clinical problem solving that forms the heuristic of the functional medicine model.²⁵

Biography

Jeffrey Bland, PhD, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.