To understand the pathophysiology of cardiovascular disease, the physiology of the cardiovascular system must first be discussed. The main function of the circulatory system is to deliver oxygen and necessary nutrients throughout the body and remove the waste products from the surrounding cells. The blood containing these components first goes through the pulmonary circulation (involving the lungs) followed by the systemic circulation (everywhere else other than the lungs). In the pulmonary circulation, the deoxygenated blood enters into the heart via the right atrium and flows into the left ventricle then into the capillaries within the lungs where the deoxygenated blood become oxygenated through the process of simple diffusion. Once the blood has become oxygenated, it exits out of the lungs and enters the heart once more through the left atrium and into the right ventricle before leaving the heart and entering the systemic circulation. Here, within the systemic circulation, the oxygenated blood is transported throughout the rest of the body. Leaving the heart, the blood flows through the arteries into smaller capillaries where the oxygenated blood transfers oxygen into the cells of the body and exchanges the oxygen for carbon dioxide to be excreted. The blood has now become deoxygenated carrying carbon dioxide back from the capillaries into the veins back to the heart to become re-oxygenated where this cycle continues again.
Looking at the vasculature of the human body, it consists of the three main types of blood vessels: the arteries, the veins, and the capillaries (Moore et. al., 2014). The arteries can withstand high pressure that the heart produces when initially pumping blood out into the systemic circulation and this is the result of the thickness of the arterial wall. The arteries become arterioles that deliver the oxygenated blood to the capillaries where the exchange of oxygen and nutrients primarily take place. The blood that passes through the capillary beds flow and into venules before being converging into a vein. At the vein, there is not as high of a blood pressure as in the arteries; therefore, they do not have as thick of a blood vessel wall. However, they do return deoxygenated blood back to the heart via the superior and inferior vena cava. The composition of the blood vessels is made up of three layers: the tunica intima, tunica media, and tunica adventitia (Moore et. al., 2014). The tunic intima is the inner lining of the blood vessels and consists of a single layer of epithelial cells. The capillaries of the body only contain the tunic intima layer. The tunic media is the middle layer of the blood vessels and primarily consist of smooth muscle. In the case of arteries, the tunic media is greater in muscle fibers than the capillaries and veins to withstand the high blood pressure. Lastly, the tunica adventitia is the outer layer of the vessels and is comprised of a connective tissue.
What is cardiovascular disease?
When the process of blood flow becomes compromised, cardiovascular disease can ensue. Cardiovascular disease, also known as heart disease, is not just one disease specifically, but a collection of diseases that disrupts the normal function of the heart and/or blood vessels of the body (also known as the cardiovascular system). With improper function of the heart and blood vessels, oxygen is not able to be transported through the body where it is needed in the cells. Within cardiovascular disease, the most common types include: coronary heart/artery disease, angina, stroke, rheumatic heart disease, congenital heart disease, and peripheral arterial disease (Nason, 2007). In the Native American population, the most prevalent causes of cardiovascular disease are hypertension, coronary artery disease (CAD) and stroke (Eschiti, 2005). However, the causes of cardiovascular diseases that increase the likelihood in Native Americans are influenced by multiple factors. The factors that target the American Indian population more readily can be classified into two groups called cardiometabolic and lifestyle risk factors. The cardiometabolic risk factors are comprised of overweight/obesity, diabetes, hypertension, and high cholesterol (Stoner, Stoner, Young, & Fryer, 2012). In addition, the lifestyle risk factors include: poor nutrition, increase in alcohol consumption, a sedentary lifestyle, physical inactivity, and cigarette smoking (Stoner et al., 2012).
Coronary Artery Disease
Coronary artery disease, a subset of cardiovascular disease, is the leading cause of death in the American Indian population (Sewell et al., 2002). CAD is the inability of the heart to pump blood causing a deprivation of oxygen and necessary nutrients to the heart muscle that can result in ischemia (inadequate blood supply to the cells). Most often, CAD is caused by atherosclerosis which is the thickening and hardening of the blood vessel wall caused by the build-up of plaque. The major contributor to CAD is dyslipidemia which is the abnormal levels of lipoproteins (lipids, phospholipids, cholesterol, and triglycerides) in the body (Brashers, 2012). In order to metabolize these lipoproteins, they must be packaged into chylomicrons and absorbed in the small intestines to be transported to the liver and surrounding cells. These chylomicrons are mainly derived from triglycerides that when extracted are supplied as storage within adipose tissue or delivered to muscles as a source of energy. However, those chylomicrons that are delivered to the liver are broken down and processed into lipoproteins with different densities and functions (Brashers, 2012). These include very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). VLDLs primarily consist of triglycerides and protein, LDLs consist of cholesterol and protein, and HDLs consists of phospholipids and proteins (Brashers, 2012).
In the case of dyslipidemia, there is an abnormal amount of these lipoprotein concentrations within the blood. To determine risk of coronary artery disease, high levels of LDLs (greater than 200 mg/dL) and low levels of HDLs (less than 40 mg/dL) are seen. Such levels associated with high dietary intake of fat and cholesterol in combination with genetic predisposition increase the likelihood of developing CAD. In the study by Tsai et al. (2015), they discussed there is an autosomal dominant trait in the PCSK9 gene that when mutated resulted in hypercholesterolemia. The function of this gene is to regulate cholesterol metabolism through the degradation of the LDL receptor preventing LDL lipoproteins from binding. Due to the gain of function mutation of PCSK9, the inability of the LDL to bind to their receptor decreases LDL uptake causing an increase in LDL concentration in the blood. Tsai et. al. (2015) were able to identify within the PCSK9 gene, the location of single nucleotide polymorphisms (SNPs) that were associated with the increase in LDL levels in Native Americans. The SNPs discovered in the PCSK9 gene were classified into either common or rare variants. The common variants discovered were rs12067569 and rs505151 (E670G) (Tsai et al., 2015). Both of these variants contribute to increased LDL levels. As for the rare variant, rs11591147 (R46L), it is a missense mutation that induced lower LDL levels. Knowing the exact allele location that influences the effect of LDL levels in the body could aid in the prevention of cardiovascular disease. In such case, PCSK9, specifically E670G, can be targeted through PCSK9 inhibitors as a treatment for hypercholesterolemia (Figure 1).
Figure 1. Mechanism of PCSK9 inhibitors ("PCSK9 Inhibitor Mechanism of Action", 2018)
Atherosclerosis
With atherosclerosis being one of the main components in coronary artery disease, it is strongly caused by the high LDL cholesterol levels. To remove LDL from the plasma it is based on receptor-mediated endocytosis (Choy, Siow, Mymin, & Karmin, 2004). The LDL receptors that initiate the endocytosis of LDL is made up of negatively charged glycoproteins and any mutation to the LDL receptors can disrupt the catabolism of LDL resulting in increased levels of it in the plasma. An alternative way LDL concentration can be increased is through excess secretion of LDL from the liver. For LDL to cause atherosclerosis, it causes endothelial damage in the arteries through atherosclerotic lesions. These lesions are caused by the uptake of LDL by monocytes and macrophages that have been attracted to the arterial wall (Choy et al., 2004). The attraction of macrophages into the arterial wall is stimulated by the chemokine MCP-1. To initiate its effects, MCP-1 binds to CCR2 chemokine receptors that are located on the macrophages (Choy et al., 2004). Therefore, when the expression of the chemoattractant and its receptor are upregulated, it leads to the chemotaxis of more monocytes and macrophages to the atherosclerotic lesion area. Once these monocytes and macrophages have taken up LDL within them, they become hardened into foam cells that reside within the tunica intima wall of the arteries resulting in plaque build-up. In order for LDL to be taken up by monocytes and macrophages, they must first be modified through acetylation (Choy et al., 2004). This modification process allows for the oxidation of LDL (oxidized LDL, ox-LDL) and is the first step in atherosclerotic lesion development (Figure 2).
Figure 2. Serum LDL levels transformed into a foam cell (plaque) (Choy et al., 2004, p. 215)
After some time, the foam cells (plaque) build up to cause an obstruction in the artery that may either be partial or completely blocked. With a partial obstruction, it runs the risk that a small piece of the plaque may break off from the high pressure of the blood flow and be transported to another area of the body to be blocked. Regardless, in either case, once an artery has become obstructed, that area of the body is not able to receive the appropriate oxygen and nutrients for normal function and will lead to ischemia.
Low-Density Lipoproteins and Obesity
Obesity, a strong cardiovascular disease risk factor in Native Americans, is often associated with high LDL levels. Proof can be seen in the study by Welty et al. (2002), where they conducted a longitudinal study assessing the changes of cardiovascular risk over four years. In their study, looking at lipoprotein profiles, they seen an increase in LDL levels that could lead to the chance of developing a cardiovascular disease. Based on the study by Weinbrenner et al. (2006), oxidative stress caused by obesity leads to atherosclerosis when there is high levels of circulating oxidized LDL (ox-LDL) present. In relation to their study, they measured the waist circumference (WC), an indirect measure of abdominal fat/obesity, of each individual who participated in their study to see if there was a correlation between WC and ox-LDL levels. As a result of their study, they were able to conclude that there was indeed a correlation between WC and ox-LDL levels. The greater the waist circumference of an individual, the greater concentration of ox-LDL levels circulating.
Risk Factors of Cardiovascular Disease
In most cases, Native Americans develop cardiovascular disease from both cardiometabolic and lifestyle risk. As stated previously, the cardiometabolic risk factors are comprised of overweight/obesity, diabetes, hypertension, and high cholesterol (Stoner et al., 2012). Looking at the effects of cardiometabolic risk factors, CVD was seen to have a higher prevalence among American Indians than non-Indians. In the Harwell et. al. (2001) study, they were able to conclude high cholesterol affected 14% of CVD Native American patients as compared to 23% of non-Native Americans. Diabetes was 12% versus 6%, overweight 80% versus 54%, obesity 38% versus 16% and smoking 38% versus 18%, respectively (Harwell et al., 2001). Therefore, we can determine that the main cardiometabolic contributor to CVD is overweight/obesity and should be the core target of preventative measures.
Aside from the cardiometabolic risks, lifestyle factors only add to the severity of developing CVD. The lifestyle risk factors include: poor nutrition, increase in alcohol consumption, a sedentary lifestyle, high stress, physical inactivity, and cigarette smoking (Stoner et al., 2012). Looking at poor nutrition, Native Americans often live on or near American Indian reservations that lack the opportunity to purchase healthier options of food. Therefore, they rely on processed foods that are cheap to buy within their location convenience contributing to their increase in high LDL levels. As for alcohol consumption, Native Americans are at a high risk of developing an alcohol use disorder (AUD) (Criado, Gilder, Kalafut, & Ehlers, 2016). The main AUD most prevalent among the Native population is binge drinking and is characterized at 5 drinks per day for males and 4 drinks per day for females (Stoner et al., 2012). Smoking, on the other hand, is still very prevalent among the Native population. Welty et. al. (2002) seen that even though Native Americans in their study decreased their smoking habit within their four-year study, their habit still exceeded the national rates. Lastly, with most American Indians either overweight or obese, it reduces their motivation to be physically active resulting in most to live a sedentary lifestyle.
Prevention of Cardiovascular Disease
In order to manage cardiovascular disease risk factors, a healthy lifestyle would aid in prevention immensely. This can be accomplished by a healthy diet, regular exercise, no smoking, reduced/managed stress, routine medical check-ups, preventative individualized or community-based programs, and closer/affordable access to healthcare facilities that the state, city, or Native tribe can better aid with. However, with these preventative measures, most literature focuses on describing the problems affecting the Native American population and understanding those problems (Stoner et al., 2012). There is a lack of research focusing on strategies that have been deemed effective at lowering cardiovascular disease rates in this ethnic group. Yet, most strategies that have been implemented target the population as a whole (community-based preventative measures) with very little positive results. This conclusion can be derived based on cardiovascular disease rates not improving in the Native American population.
Most of these population-based preventative measures are used to prevent risk factors as a population with little effect at the individualized level. It is a “good for all†strategy and more cost efficient (Bovet, Chiolero, Paccaud, & Banatvala, 2015). However, a more personalized approach should be enacted to treat Native American cardiovascular diseases by targeting high risk individuals. Having a “high-risk strategy†involves more interaction between the health care provider and his/her patient. It is a “good for some†approach and can be used to detect underlying causes leading to cardiovascular diseases (Bovet et al., 2015). The combination of both an individualized and population-based preventative strategy could reinforce each other to provide better outcomes for the patient but require patients to be actively engaged to see results.
An example of an individualized approach that could be helpful in preventing CVDs is prevention of obesity through the gut microbiome. The microbiome in the human body incorporates bacterial, fungal, and protozoal microorganisms that constitute each person’s microbiota (Davis, 2016). With each person’s microbiota different from the next persons and its flexibility in composition through dietary implementation, targeting the microbiome is a possibility to facilitate obesity prevention and regulate weight loss. The limitation with microbiome obesity regulation is most microorganisms within the gut are anaerobic organisms. Therefore, to isolate the bacteria from the gut, it is difficult due to most being viable only under anaerobic conditions. This leaves about 30% of the gut microorganisms to be tested and analyzed on its obesity effect in aerobic conditions (Davis, 2016).
Some research has been done in looking at the gut microbe diversity in humans that are overweight/obese and those who are of normal weight. It has been confirmed that there is a low diversity of microorganisms in the gut of overweight/obese individuals leading to an increase in adipose storage, dyslipidemia, impaired glucose homeostasis, and an increase in inflammation (Davis, 2016). Looking more closely within obese individual’s microbiota, the organism Firmicutes (related to the development of obesity) are highly prevalent than Bacteroidetes (that may regulate proper weight) seen more in normal weight individuals (Davis, 2016). To determine whether the microbiota can change based on diet, obese individuals were given a diet of low-fats and low-carbohydrates. Results showed their Firmicutes microorganism population decreased and the Bacteroidetes increased. In addition to altering dietary substance, altering caloric intake also seemed to have an effect on bacteria in the gut microbiome. Davis (2016) reported that a high caloric intake was proportional to growth of Firmicutes by 20% and a decline in Bacteroidetes by 20%. With an escalation of Firmicutes, it comes with the chance of an individual to gain weight.
Knowing which microorganisms are involved in developing obesity, there is the possibility to alter the composition of the gut microbiome in individuals who are susceptible in developing CVDs. Through this approach, it is personalized to the individual seeking preventative measures because each individual’s microbiome is unique to him/herself. Possible treatments involving the gut microbiome include increasing dietary intake of prebiotics, probiotics, or synbiotics that will increase the microorganisms in the microbiota responsible for weight regulation (Davis, 2016). Ultimately, this preventative technique will reduce the obesity risk factor that plays a key role in developing cardiovascular disease and may be the stepping stone in decreasing CVD rates in the Native American population.