The fourth in a series of short articles attempting to explain the science behind fairly common topics and exploring how they relate to ME. This time the topic is the Cardiovascular System – by Andrew Gladman.
The cardiovascular system is not one that is commonly discussed in relation to ME, and yet it is an area that research has shown displays one of the more measurable abnormalities in patients.
Suffice it to say that many of the symptoms that ME patients suffer with, such as muscle fatigue, dysregulation of the nervous system and headaches, could come as a direct consequence of abnormalities in the vascular system.
In this article I aim to explore the general function of the vascular system as well as considering the research, both historic and ongoing, as it relates to ME.
What is the cardiovascular system?
The cardiovascular system is one division of the human circulatory system, the other being the lymphatic system, and is comprised of the heart and the blood vessels i.e. the veins and the capillaries. Its primary role is to transport nutrients, oxygen and hormones to cells throughout the body and take the cellular waste products to organs such as the kidneys and liver for detoxification and eventual excretion.
These chemicals and molecules are all transported within the blood which is comprised of the following unit parts:
- Red blood cells: These contain a protein known as haemoglobin to which oxygen and carbon dioxide can bind, in order that they can be transported to and from respiring cells.
- White blood cells: These are integral cells in the immune system, the topic of immunity and the immune system was discussed at much greater length in a previous article of this series.
- Platelets: These coagulate the blood in the event of, for example, a cut.
- Plasma: All the nutrients, hormones and waste products are dissolved within the blood plasma – recognisable as a transparent yellow liquid.
The heart is the organ central to the cardiovascular system – both literally and figuratively. It is a hollow muscle and its sole purpose is to pump blood around the body transporting the nutrients to respiring tissue as previously discussed.
To achieve this purpose the heart is subdivided into 4 sections as shown on the adjacent diagram these are the right atrium, the right ventricle, the left atrium and the left valve (right and left are switched as heart diagrams are always portrayed as you would see the heart on another individual.)
Fundamentally de-oxygenated blood from the body returns from the body tissues via the veins and enters the right atrium by large veins known as the superior and inferior vena cava. This blood is then moved into the right ventricle through the bicuspid valve (this valve ensures blood in the ventricle cannot move back into the atrium – the left side of the heart has a valve with a similar function).
The heart then beats and this blood is pumped up through the pulmonary arteries towards the lung where oxygen is picked up by the red blood cells haemoglobin molecules. This blood then returns to the heart though the pulmonary veins and enters the left atrium.
It moves through into the left ventricle and another beat of the heart pumps it to the aorta which branches out into many smaller arteries that travel throughout the body and are connected to every tissue and organ. Once the blood becomes de-oxygenated again, the entire process repeats. This process is described and illustrated well in the video attached to the diagram above.
As a little aside, the heartbeat is controlled and regulated in two separate processes. Firstly, there is a small region of muscle tissue in the heart that creates a small electric impulse which is often described as the hearts own pacemaker and keeps the heartbeat regular and constant – this region is known as the sinoatrial node.
There are also two veins of the autonomic nervous system which can directly increase or decrease the heart rate through the release of chemicals in the heart. These two veins work antagonistically, that is against one another.
This is because the autonomic nervous system is sub-divided into two, the sympathetic and parasympathetic nervous systems and these two nerves are often described as the sympathetic accelerator and parasympathetic decelerator. This division of the nervous system is one topic that will be discussed in the next article of this series.
Viewed simply, the cardiovascular system functions through a figure of eight loop with the heart lying at the centre. The upper loop is to the lung and the lower loop is to the rest of the bodily organs and tissues, after each loop the blood returns to the heart to be pumped into the other loop of the figure of eight.
The blood vessels…
As referenced earlier in this article, there are three different types of blood vessels. Arteries and veins and their role in the vascular system are quite common knowledge for the majority of people; fundamentally the arteries carry blood away from the heart to the tissues of the body while the veins return this blood from the tissues back to the heart. Arteries and veins are comprised of the following layers going from the inside of the blood vessel out:
- Tunica intima: a single thin layer of endothelial cells surrounded by connective tissue, the function of these cells is discussed at much greater length later in this article, however, to use a vast oversimplification, this is a semi permeable membrane that allows certain molecules and cells in and out of the blood vessel – it also prevents the adhesion of red blood cells to the inside of the blood vessels hence preventing blood clots.
- Tunica media: comprised of elastic fibers, connective tissue and smooth muscle. This layer controls the blood pressure through muscle contraction or relaxation, by narrowing or widening the central space (lumen) of the blood vessel. This layer is the thickest in arteries whereas it is very thin in veins, hence veins do not have much effect upon blood pressure.
- Tunica externa: made entirely of connective tissue, this layer is very strong and prevents the blood vessel from rupturing which could occur due to the high pressures inside the vessel relative to the outside. This layer is thickest in the veins.
Capillaries on the other hand consist simply of a thin layer of endothelial cells surrounded by connective tissue for strength. The function of the capillaries is to bridge the gap between the artery and the vein. Once the oxygenated and nutrient rich blood is transported from the heart to the respiring tissue, the artery then branches off numerous times until the branches become very small and interconnected inside the tissue. These highly branched and simple blood vessels are known as capillaries – they are very simple to allow for maximum diffusion of the oxygen and nutrients from the blood into the tissue. The capillaries then come together once again, exiting the tissue, and attach to a vein to allow for the return of the now de-oxygenated blood back to the heart.
One of the key cells within blood vessels are the endothelial cells which form the major layer within the tunica intima (above). The reason such emphasis is being placed upon this layer is the numerous research findings relating to endothelial dysfunction within ME, although this will be discussed in more depth, below.
Endothelial cells are incredibly important within the human body. They are primarily found lining the interiors of blood and lymphatic vessels, being present throughout the entire circulatory system; from the heart down to a single thin layer which line the capillaries.
There are many functions provided by these cells including control of blood pressure, through vasoconstriction and vasodilation, formation of new blood vessels (angiogenesis), providing a semi-permeable barrier between the blood vessels and the surrounding tissue while also aiding in the process of blood clotting.
The large number of unique and important functions has led some researchers and scientists to regard the endothelium as an independent organ within the body. Interestingly there are also highly specialised and differentiated endothelial cells elsewhere in the body performing important filtering tasks; examples being the blood brain barrier and the renal glomerulus.
One of the major functions of the endothelium is the control of vascular tone, meaning the degree to which a blood vessel is dilated. This is achieved through processes known as vasoconstriction and vasodilation.
The endothelium plays a dynamic role in both processes through the production and release of many different vasoactive chemicals. To control vasodilation the endothelium releases endothelium-derived relaxing factors (EDRFs) such as nitric oxide (NO). While to control vasocontriction the endothelium releases endothelium derived contracting factors such as thromboxane and endothelin.
These chemicals are produced and released directly by the endothelial cells, with the end result being stimulation of the surrounding smooth muscle to either relax or contract – hence dilating or contracting the blood vessel. Through this process of homeostasis, blood pressure can be tightly controlled while this mechanism is also used as an important mechanism in internal heat and temperature regulation.
Why is the cardiovascular system important in ME?
In previous decades, the cardiovascular system and its involvement in the disease pathology of ME was quite an exciting area. Dr. David Bell published several papers on the possibility of lowered circulating blood volume in patients suffering from ME – blood volume being the total volume of blood, including both plasma and red blood cells, in the circulatory system of an individual. This can be tied together quite nicely with the common impaired blood pressure variability ME patients also experience. Continuing with this line of thought, the issue of low blood volume could then combine or possibly be party causative for the orthostatic intolerance many ME patients experience.
One of the most recent, and in my opinion most exciting pieces of research relating to ME in the last few years, is the work of Newton et al at the Univerity of Dundee. Their study from February 2012 outlined the discovery that ME patients have measurable large and small artery endothelial dysfunction relative to age and gender matched healthy controls. This could have quite far reaching consequences, not least when attempting to find biological mechanisms to explain the symptom presentation of ME.
Interestingly, such endothelial dysfunction would likely have a detrimental effect upon the secretion of vasoactive peptides such as nitric oxide and endothelin which have primary roles as vaso-constricting and vaso-dilating molecules. Many of these chemicals and peptides also have other roles. For example, nitric oxide is also a neurotransmitter and performs functions within the immune system – activating and deactivating certain cells of both the innate and adaptive immune responses. Certainly many readers will be aware of nitric oxide as a frequently discussed chemical in ME and it’s certainly interesting that it has roles to play in both the cardiovascular and nervous systems – two systems that appear integral to the pathology of this disease.
There is a huge array of evidence and reports of orthostatic intolerance (OI) within ME. OI is thought to occur directly through dysregulation of blood pressure, therefore the links are clear to draw with the observed endothelial dysfunction. This area has several researchers looking into it including Professor Julia Newton whose work approaches the abnormalities from the perspective of an autonomic nervous system (the role of which will be explored at greater depth in the next article of this series). One of her studies concluded:
“The heart MRI scans showed that a third of people with ME/CFS have impaired bioenergetic function in their hearts which has a knock on effect upon the function of their hearts.”
This is clearly relatable to the observed endothelial dysfunction and likely has some relation to a dysfunctional autonomic nervous system, wherein the impaired function could come as a direct result of inability to correctly dilate or constrict blood vessels. Furthermore, Professor Newton’s recent findings of increased lactic acid buildup in muscle tissue could potentially relate to decreased peripheral blood flow through endothelial dysfunction in the blood vessels.
If you are interested in the work of Professor Newton, be sure to read this recent interview, where she discusses her recent and continuing research.
…and to Fibromyalgia?
Very recently a new hypothesis has been proposed relating to the cardiovascular system that could explain the pathological mechanisms of Fibromyalgia – a condition that is often regarded as being similar and perhaps linked to ME.
This hypothesis proposes that the pathology of Fibromyalgia is related to a cardiovascular defect which causes temperature regulation, among other functions carried out by the capillaries, to become dysfunctional.
As previously discussed the cardiovascular system is the crucial component in temperature homeostasis within the body, and as part of this mechanism there exist small connections between arterioles and veins known as AV shunts which act not dis-similarly to valves within a steam engine, allowing blood to flow directly from the arteriole into the vein, bypassing the capillary bed and hence preventing heat loss.
In Fibromyalgia it appears that there is an underlying defect within these AV shunts which is causing dysfunction within standard capillary function. Muscle tissue and neurones are therefore not receiving the required oxygen and nutrients while simultaneously waste products are not being transported away at a sufficient rate.
The combination of starved muscles, buildup of waste products, such as lactic acid, and the dysregulation in temperature control are all hypothesised to combine, forming the symptoms associated with fibromyalgia – in spite of no observable anatomical defects.
Much of the pain associated with the condition is hypothesised to stem from hypersensitive neurones within these tissues. These neurones are transmitting nerve impulses which are perceived as pain, in spite of no trigger. This oversensitivity is caused by the waste build-up and lack of oxygen disrupting standard neurone function. Research attempting to prove this hypothesis is ongoing but looks promising and given the history ME and fibromyalgia share, this is certainly an interesting story to follow.
I hope it is clear, from the research outlined above, that the cardiovascular system looks to play a central role in the diseases pathology of ME and indeed Fibromyalgia. In the past it has appeared that hypotheses relating to vascular function in ME have been overshadowed by hypotheses relating to infectious agents, however the cardiovascular system has very recently become quite exciting and looks set to continue this way.
As discussed in a previous article within the series, the current talking point for many affected by ME is that relating to the autoimmune hypothesis and possible treatment with Rituximab, but it will be interesting to follow both autoimmune and cardiovascular research advances, as I feel they offer the best hope for more understanding of the disease.
I am in no doubt that eventually both lines of research will hold interesting answers that the ME community deserves after so many years treading water.[appeal]?