A NEW PARADIGM FOR CVD
Our proposal involves the development of diagnostics and therapies against cardiovascular disease (CVD) focusing on the prevention of clot formation or thromboembolism, the fatal component of CVD.
DEFINING THE PROBLEM
Problem #1: Cardiovascular disease (CVD), particularly coronary heart disease (CHD) remains the No. 1 disease killer and keeps rising in the US and the world. By 2030, 23.6 million people are predicted to die from CVD (World Heart Federation report). In the U.S., 42% of all deaths annually are a direct result of CVD; one person dies every 33 seconds from heart disease. and it is the leading cause of death for all Americans, age 35 and older. (CDC, NCHS. Underlying Cause of Death -Vital Statistics Cooperative Program).
Problem #2: Current drugs target symptoms. For example, hypertension is treated with diuretics, ACE inhibitors, ARBs, Ca antagonists, β-blockers; lipidemia is treated with statins, bile-sequestrants, fibrates, niacin; and, blood pooling is treated with anti-platelets, anti-coagulants and fibrinolytics. Symptom-targeted drugs are at best palliative.
Problem #3: The “war on cholesterol” to treat CVD has permeated the core of everyday life including policy makers, insurers, health care providers, clinicians, diagnostics, Wall Street, etc.
Problem # 4: Lack of alternative drugs perpetuates the lore of ‘cholesterol drugs’ including PCSK9 inhibitors
Multi-factorial Root Causes of CVD
Blood flow at arterial forks and bends naturally slows down (e.g., aortic arch, carotid, coronaries)
(a) fat diet packaged by very low density lipoprotein (VLDL) increases arterial blood viscosity
(b) high fat diet and high VLDL stagnate blood flow causing low endothelial shear stress (ESS)
(c) very low ESS creates ‘whirpool flow’ trapping blood debris (dead cells, microbes, pollutants)
(d) debris plus ‘oxidative effects of ‘reactive oxygen species (ROS) attracts immune cells creating inflammation
(e) Inflammation disrupts the glycocalyx lining, exposing the endothelium and subsequently endothelial tiny gaps
(f) tiny gaps create osmotic imbalance, infiltration of macrophages and form ‘foam cells’, which matures into plaques
Moreover, osmotic imbalance trigger electrolyte leakage and a number of CVD diseases including hypertension
(a) glycocalyx serves as a natural nests for blood flow regulators e.g., the blood thinner lipoprotein lipase (LPL), antothrombin III (AT-III) and superoxide dismutase (SOD), which prevents breakdown of nitric oxide (NO)
(b) loss of ‘glycocalyx nest’ further contributes to blood flow disruption
Disruption of the glycocalyx sheds component parts (detritus)
(a) detritus includes pieces of glycosaminoglycans (GAG), glycoproteins and proteoglycans
(b) published studies confirm the correlation between glycocalyx shedding and many vascular pathophysiologies.
(c) detritus shed into the blood stream are the foundation of Arterez companion diagnostic panels and therapies
Dynamics of healthy blood flow
Body cells are organized in 4 tissues including epithelium nervous, muscle and connective tissue. Epithelium covers body surfaces, lines internal closed cavities including glands, body tubes and the vascular system. Epithelial tissues: protect underlying tissues from radiation, desiccation, toxins, pathogens, and physical trauma; regulate exchange of chemicals between tissues and a body cavity; secrete hormones into the blood vascular system, provide sensation. Endothelial cells line the internal surface of the circulatory system including the lumen of the arteries, veins, lymphatic vessels, blood capillaries and cavities of the heart. Yet another layer on top of the endothelium is glycocalyx, which provides the first line of protection from physical, chemical, and biological wear and tear.
Glycocalyx protects the endothelium
Glycocalyx is a fuzz-like carbohydrate-rich coat that covers the membrane of endothelial cells, which filters off cell debris and prevents adhesion of coagulatory and inflammatory cells to the vascular endothelial lining. Other critical function of the glycocalyx include: 1) transmits fluid shearing forces to the cytoskeleton of endothelial cells and stimulates the production of nitric oxide, which is vital in controlling blood flow and blood pressure; 2) regulate the supply of nutrients and oxygen, and the removal of waste and carbon dioxide; and, 3) maintains capillary integrity, and prevents loss of fluid through leakage.
Disruption to the glycocalyx triggers diseases
The GCX is an extracellular matrix that covers the luminal surface of the vascular system. This structure is not just a barrier for vascular permeability but contributes to various functions including signal sensing and transmission to the endothelium. Thus, pathological changes to this structure are involved in the development of various diseases.
Gaps allow debris infiltration, creates plaques
Destruction of the glycoclyx exposes the endothelium to injury creating ‘tiny gaps’ in the endothelial wall, subsequently blood debris and macrophage infiltration to form plaques. Plaques rupture and heal naturally, but certain plaques generate clots that become amplified and degenerate into thromboembolism causing heart attack or stroke. Biological pollutants (dead cells, microorganisms) and chemical pollutants (xenobiotics) are key risk factors in the pathophysiology of CVD.
Electrolyte leakage triggers hypertention, etc
A natural sequence to the ‘tiny gaps’ is edema (fluid buildup) and osmotic imbalance (concentration of solution). Thus, electrolytes that normally reside outside the cell (extracellular) like sodium (Na), potassium (K), calcium (Ca), chloride (Cl), and bicarbonate (HCO3), diffuse inside through the ‘gap’. On the other hand, electrolytes normally found inside the cell, such as potassium (K), magnesium (Mg), and phosphate (PO4) diffuse out. These electrolyte imbalance create various circulatory abnormalities most notably hypertension, heart failure, and venous blood clots.
Formation of clot starts with a disrupted glycocalyx (primary clot) and progresses into a secondary clot (embolus), this is the fatal component of CVD. Thromboembolism is the breakage of amplified (large) clot to become an embolus and clog downstream vessel that is too small to let it pass causing stroke (clogged artery to the brain), heart attack (clogged artery to the heart), or PAD (clogged artery to the arms or legs).