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CVD is the major worldwide cause of mortality and a plethora of interventions have been tried with minimal reduction in risk. (2017. J Royal Soc Med Cardiovasc Dis 6: 1–9)


The Cardiovascular System


The cardiovascular system consists of the heart, with its intricate conduits of branching elastic pipes, the arteries and arterioles; the tissue beds supplied by the capillaries; and finally a system of converging pipes, the venules and veins. The system traverses the whole human body carrying blood; arteries are blood vessels that transport blood away from the heart, and veins transport the blood back to the heart. Capillaries carry blood to tissue cells and are the exchange sites of nutrients, gases, wastes, etc.  The blood contains oxygen, nutrients, wastes, and immune and other functional cells that help provide for homeostasis and basic functions of human cells and organs.


The pumping action of the heart usually maintains a balance between cardiac output and venous return. Cardiac output is the amount of blood pumped out by each ventricle in one minute. The normal adult blood volume is 5 liters and passes through the heart once a minute, but cardiac output varies with the demands of the body.


The pulsations generated by the pumping action of the heart radiate out along the arteries and at discontinuities such as vessel bifurcations, the pulsations are partially reflected, back toward the heart, and partially transmitted along the vessel, becoming damped as they approach the distal arterioles. The arterioles regulate the distribution of blood flow to the various capillary beds before the blood is returned in a relatively steady stream to the heart. The changing velocity profiles across the various vessels are reflections of the hemodynamic characteristics of the cardiovascular system. 



Our cardiovascular system circulate and transport nutrients (amino acids and electrolytes), oxygen, carbon dioxide, hormones, and blood cells to and from the cells in the body.


As blood flows through peripheral tissues, blood pressure forces water and solutes out of the plasma, across capillary walls, which involve. diffusion, filtration, and re-absorption . Ions and small organic molecules enter or leave the bloodstream by diffusion between adjacent endothelial cells. On the other hand, large water–soluble compounds including plasma proteins are normally unable to cross the endothelial lining except at fenestrated capillaries, such as those of the hypothalamus, the kidneys, many endocrine organs, and the intestinal tract. Lipids, such as fatty acids and steroids, and lipid–soluble materials, including soluble gases such as oxygen and carbon dioxide, can cross capillary walls by diffusion through the endothelial cell membranes.



The Nature of CVD


Cardiovascular disease consists of a family of diseases affecting both arteries and veins: diseases in the arteries include coronary heart disease (CHD), myocardial infarction (MI), stroke, hypertension, atrial fibrillation, congestive heart failure (CHF), congenital heart condition, and peripheral arterial disease (PAD); and in the veins are deep venous thrombosis (DVT) and pulmonary embolism (PE). Microorganisms are the first life forms on Earth, but it was only in the 1930s that they were discovered as root cause of infectious disease, which led to the development of the antibiotics. Before antibiotics, the available drugs against infectious disease were an array of symptom-targeted drugs including wine, soybean, myrrh, opium, iodide, mercury, arsenic, sulfa (2006. Infectious disease epidemiology: theory and practice. Publisher: Jones & Bartlett).


Much like microorganisms, the existence of glycocalyx was discovered more than 50 years ago (1966. Fed Proc 25:1773–1783), but the significance of this structure was not recognized, partly because it is destroyed upon conventional tissue fixation and not seen in most light microscopic examinations. Glycocalyx is a protective lining at the surface of the endothelium found in every healthy blood vessel, which is made of proteoglycan (a complex network of protein (glycoprotein) and disaccharide sugar (glycosaminoglycan). This complex network forms a dynamic layer between the flowing blood and the endothelium, continuously changing in thickness depending on shear or blood flow pressure. Thus, the shear generated by blood flow regulates the balance between biosynthesis and shedding of the various glycocalyx components. The core protein groups of this layer are syndecans and glypicans promiscuously bound with different glycosaminoglycan including heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan or hyaluronic acid (2007.Pflugers Arch; 454: 345–359).


Today, the glycocalyx is recognized as a key structure for maintaining vascular wall integrity. Any disruption or decrease in thickness results in chronic vascular disease (2010. Cardiovascular Research. 87: 300 – 310); for example chronic stagnant blood flow, common in bifurcated section of the arteries, triggers glycocalyx shedding and plaque formation. In the heart, disrupted glycocalyx in the coronaries result in poor blood flow (coronary perfusion); at the arteriolar level, a damaged glycocalyx slows down blood flow and decrease nitric oxide (NO) production creating constrictive vessel; and, at the capillary level, disrupted glycocalyx reduces blood flow to tissues or muscles. In addition, the glycocalyx harbors a wide array of enzymes that regulate proper blood flow including. superoxide dismutase (SOD), an enzyme which neutralizes reactive oxygen species; antithrombin (AT-III), a natural anticoagulant (blood thinner); and, lipoprotein lipase (LPL), an enzyme that releases triglycerides from chylomicrons and very low-density lipoproteins (VLDL) for energy. 


In stagnant blood, contaminants (bacterial infections, pollutants, etc) or debris congregate, which attract immune cells like monocytes and white blood cells (WBC). These immune cells release inflammatory cytokines and oxidative free radicals or reactive oxygen species (ROS). Over time, chronic inflammation and oxidative damage disrupt the protective glycocalyx lining of the blood vessel and create ‘tiny gaps’ on the endothelial wall. The “tiny gaps” in the arterial lining creates an osmotic imbalance, allowing infiltration of blood debris; accumulation of debris produce sticky or adhesive material (e-selectin) and along with macrophages (activated white blood cells) they form a “sticky foam cell” complex, which altogether attempt to plug a leaky wall. Such sticky cells recruit other blood debris (e.g., dead cells, calcium, fibers), which matures into plaque (atheroma). The processes leading to atheroma (atherosclerosis) generally begin in the early years of life, as young as 5 years old, but the symptoms generally do not become apparent until after the age of 40 years. Although members of the CVD family are totally different in clinical presentations, they are basically atherosclerosis-related and share a common feature, which is the plaque.


A natural sequence osmotic imbalance is edema (fluid buildup) and (concentration of solution). Thus, electrolytes that normally reside outside the cell (extracellular)  like sodium (Na), potassium (K), calcium (Ca), chloride (Cl), and bicarbonate (HCO3), leak through the ‘gap’ from the outside to inside of the cell, while electrolytes normally found inside the cell, such as potassium (K), magnesium (Mg), and phosphate (PO4) leak through outside towards the interstices. These electrolyte imbalance create various circulatory abnormalities most notably hypertension, heart failure, and venous blood clots.


The majority of plaques are stable and harmless; some ruptured plaques results in intra plaque hemorrhages (bleeding into the lipid core) but heals naturally (1994 BrMed Bull. 1994; 50:789-802). Plaque ruptures when the endothelial glycocalyx is denuded exposing the highly thrombogenic constituents (lipids, tissue factor, collagens) to the blood stream and activate the coagulation or thromboembolic cascade (1988. Br Heart J 60:459–465). Thromboembolism is a process leading to the formation of thrombus (blood clot), which dislodges from its origin to form an embolus that flows downstream in the blood vessel tree and clogs up blood flow. Thrombus is a solid mass consisting of platelets, fibrin and blood components; embolus is a piece of thrombus broken free and carried into the bloodstream, which is the fatal component in CVD: loose thrombus wedges on a rigid arterial vessel narrowed by hypertension, causing stroke (clogged artery to the brain), heart attack (clogged artery to the heart), or pulmonary embolism (PE) (clogged pulmonary artery).  


Plaque disruption has been studied most extensively (particularly in coronary arteries) to establish correlations between the morphology of the culprit plaques, degree of thrombus formation and types of ensuing ischemic coronary syndromes (1996. Circulation 94:2013–2020).  In coronary arteries of patients with severe pre-existing stenosis, occlusive embolus is fatal (1989. Br Heart J 50:127–134). The concept is that plaques with an unstable morphology are the main risk factor for coronary heart disease (CHD). On the other hand, most plaques that develop during a lifetime remain unnoticed and have no clinical implications at least on the short term. However, plaques may grow in the long term through the stimulant effect of blood components like thrombin and platelet-derived growth factor (PDGF). These large plaques may rupture but remain clinically silent (1989. Eur Heart J 10:203–208). Conversely, not all acute cardiovascular events are the result of plaque rupture (1996. Heart 76:112–117), but even smaller non-occluding thrombi may lead to clinical symptoms (1992. N Engl J Med;26:242–250). Because of its complexity and the clinical sequelae, atherosclerosis continues to be the main subject in pathology research.

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