Could Lymphedema Cause Arteriosclerosis?

New research is pointing to a possible link between lymphedema and arteriosclerosis – a potentially lethal vascular condition. Is arteriosclerosis a complication of lymphedema that patients should be worried about?

Arteriosclerosis is a hardening and thickening of the arteries. These vascular changes can eventually restrict blood flow to organs and tissues, resulting in severe complications such as myocardial infarction (heart attack) and stroke. Atherosclerosis is a common type of arteriosclerosis, one that includes fatty plaque accumulation within the arteries (Fig. 1).

Fig 1: Progression of atherosclerosis. For the source of this figure and more information on atherosclerosis please see: here

Why would there be a link between lymphedema and arteriosclerosis?

Lymphedema is a disease of the lymphatic system, whereas arteriosclerosis is a disease of the blood vascular system. How could there be a link between these two very different conditions? Here’s how:

1.     Lymphatic vessels are involved in lipoprotein absorption and circulation

Lipids (fats) in the bloodstream are primarily found in complexes called lipoproteins. The accumulation of certain lipoproteins in circulation, such as LDL (low-density lipoprotein), is a key factor involved in the development of atherosclerosis.

Lymphatic vessels play a role in lipoprotein absorption and circulation:

• Lymphatic vessels in the intestine absorb lipids from the food we ingest, and transport them into the blood stream.
• Lymphatic vessels are actively involved in lipid transport throughout the body. Vascular and lymphatic systems work together to maintain fluid balance and transport lipoproteins. A quick explanation: blood vessels deliver nutrient and oxygen-rich fluid to bathe the cells of the body and wash away waste and other products secreted from cells. This includes lipids (fats) released from adipose tissue (fat stores). But not all this fluid returns to the blood, some is instead collected by the lymphatic system for transport back to the blood at the heart. The fluid collected by the lymphatic system (known as ‘lymph’) is lipoprotein rich.

When normal lymphatic transport is disrupted, as in the case of lymphedema, this leads to a build up of lipoprotein rich fluid in the tissues and swelling. Eventually this lymphedema causes the formation of new adipose tissue in the area – an abnormal physiological event triggered by the altered tissue environment.

Lymphedema that impacts lymphatics connected to the small intestine could also disrupt normal absorption and transport of ingested fats.

The consequences of lymphedema on lipid homeostasis (the balance of lipids in the body) are not well understood, and would be expected to vary with the extent and location of lymphedema. However, a potential link to arteriosclerosis seems feasible.

2.     Lymphatic vessels are involved in inflammatory processes

Lymphatic vessels play a significant role in the immune system, carrying immune cells throughout the body, and filtering fluid through lymph nodes. Lymphatic disruption observed in lymphedema is known to alter inflammatory processes. Inflammatory processes are also believed to play a key role in the development of atherosclerosis.

As discussed above, the impact of lymphedema on lipid processing and inflammation provides a possible connection to arteriosclerosis. This sets the stage for what comes next: experimental and clinical evidence of this proposed connection.

The plot thickens

In 2014 two experimental strains of mice were bred together, one with a propensity to develop lymphedema, and the other atherosclerosis (ref 1). The result? The authors of the study concluded that impaired lymphatic function appeared to interfere with proper lipoprotein processing, and caused an increase in blood cholesterol levels and the acceleration of atherosclerosis (fatty plaque build up in the arteries) in the mutant mice.

Additional mouse studies have offered further support for a link between lymphatic function and atherosclerotic processes. But mice, and in particular genetically modified experimental strains of them, are not always a great model for human disease processes.

New data links arteriosclerosis to lymphedema in people

A recent study for the first time has demonstrated a link between lymphedema and arteriosclerosis in humans (ref 2). The authors of this small but interesting study examined arterial stiffness (a symptom of arteriosclerosis) using an indirect measure called the cardio-ankle vascular index (CAVI) in the legs of 24 females with pelvic cancer-related lower extremity lymphedema. Both lymphedematous and non-lymphedematous legs were examined.

The authors concluded that lymphedema duration and the extent of lymphedema were independent risk factors for arterial stiffening. In other words, the authors suggested that the longer you have lymphedema, or the greater the lymphatic deficiency you have, the more likely you are to exhibit arterial hardening, one of the hallmarks of arteriosclerosis.

However, this study is by no means definitive. Putting aside the obvious issues with this type of strictly observational study (such as the inability to draw conclusions about any cause-effect relationship), if lymphedema does in fact promote arterial hardening as this paper suggests, it remains to be seen if this hardening is clinically significant. In other words, could vascular changes caused by lymphedema actually increase the risk of heart attack or stroke?

There is one more thing to consider here: is this apparent link between lymphedema and arteriosclerotic processes limited to forms of lymphedema that significantly impede the function of deep lymphatic vessels of the lower extremities – such as in the case of pelvic cancer-related lower extremity lymphedema examined in this study? Unlike lymphedema present in other areas of the body, lymphedema in the pelvis could influence the ability of the lymphatic system to process fats from the gastrointestinal tract.

And vice versa: high cholesterol may exacerbate lymphedema

Interestingly, this possible connection between lymphedema and arteriosclerosis may be a two-way street.

High levels of cholesterol (hypercholesterolemia) in adult mice (more specifically, an experimental mouse strain with a genetic deficiency in the ability to efficiently process lipoproteins) appears to cause lymphatic leakage, reduced lymphatic function, and tissue swelling (ref 3). In fact, this relationship appears to be ‘dose-dependent’: as levels of cholesterol increased, lymph vessel integrity and function was found to further decrease.

The authors of this study concluded that the degeneration of lymphatic function appeared to be a direct response to hypercholesterolemia. But this conclusion once again needs to be tempered. First, we are talking about an experimental mouse strain. Second, this mutant mouse line also exhibits abnormal inflammatory responses, and could also foreseeably suffer from some unidentified lymphatic malformation during development. The authors can’t really rule out either of these alternative possibilities.

So, we can conclude that if you have lymphedema, hypercholesterolemia MAY exacerbate lymphatic vessel dysfunction and worsen your symptoms.

Take home messages

There is certainly sufficient medical evidence to suggest that you should eat well, exercise and otherwise stay as healthy as you can, to avoid arteriosclerosis.  You don’t need to believe in a potential link between lymphedema and arteriosclerosis to convince you of this.

Nevertheless, if you do have lymphedema you should consider three important takeaways from this new area of research:

1. Your lymphedema MAY predispose you to arteriosclerotic changes which MAY further push you down the path towards arteriosclerosis. Therefore, you MAY wish to be more cautious about your blood vessel health compared to the average Joe/Josephine.
2. Prolonged levels of high circulating cholesterol MAY worsen your lymphedema symptoms, and further progress your condition.
3. Lymphatic function and cholesterol metabolism MAY operate in a beneficial cycle – improving one may help improve the other, which may in turn help improve the first, and on and on. But unfortunately there is a flip side to this coin: a potentially vicious cycle of ever-worsening lymphatic function and cholesterol metabolism.

References

1. Vuorio T., Nurmi H., Moulton K. Lymphatic vessel insufficiency in hypercholesterolemic mice alters lipoprotein levels and promotes artherogenesis. Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1162-70.
2. Yamamoto T., Yamamoto N., Yamashita M., et al. Relationship Between Lyphedema and Arteriosclerosis: Higher Cardio-Ankle Vascular Index (CAVI) in Lymphedematous Limbs. Ann Plast Surg. 2016 Mar;76(3):336-9.
3. Ying Lim H., Rutkoweski J.M., Helft J., et al. Hypercholesterolemic Mice Exhibit Lymphatic Vessel Dysfunction and Degeneration. Am J Pathol. 2009 Sep;175(3):1328-37.