A total of 57 million deaths were reported worldwide in 2008, and the majority of those deaths were caused by either non-cardiovascular diseases (36 million; 63%) or cardiovascular diseases (17.3 million; 30%) according to the World Health Organization (WHO, 2011). The highest mortality rates are associated with ischemic heart diseases and cerebrovascular diseases, which account for 45% and 29% of the cardiovascular-related deaths in men and 37% and 33% of cardiovascular-related deaths in women, respectively (see Figure 1). Ischemic heart disease is considered the most common cardiovascular cause of death as it accounts for 7.6 million deaths worldwide (Institute of Medicine [IOM], 2010). Therefore, the purpose of this review is to describe the risk factors, pathophysiology, available treatments, and future research directions for improving available ischemic heart disease prophylaxis and management.
Figure 1. Proportion of deaths associated with different categories of cardiovascular diseases in men (left) and women (right) worldwide.
Note. Retrieved from “Global atlas on cardiovascular disease prevention and control: Policies, strategies and interventions,” by the World Health Organization, 2011, p. 9. Copyright 2011 by the World Health Organization.
Epidemiology and Causes of Cardiovascular Diseases
The prevalence and outcomes of cardiovascular diseases are determined by a country’s level of development, as well as various other demographic variables, including race, age, and gender. Most cardiovascular diseases that can be treated with medication are successfully managed in developed regions, but in low and middle income countries, the prevalence of cardiovascular conditions remains unchanged because of poor health care accessibility. For example 80% of rheumatic heart disease cases occur in less developed countries (IOM, 2011). A summary of the pathogenesis and pathophysiology, as well as the most commonly affected populations, by type of cardiovascular condition are reported in Table 1.
As a general rule, the incidence of heart disease is more common among people from backgrounds with a low socioeconomic status, but other demographic factors were also found to increase risk of cardiovascular disease development and prognosis. For example, males tend to develop cardiovascular diseases approximately 4.3 years earlier than women, but poor treatment prognosis is more common among women than among men (IOM, 2011). Differences in heart disease prevalence by race are sometimes attributed to socioeconomic inequalities in developed countries, but physiological differences among different racial and ethnic groups also account for those differences. It was found that Asian Indians and African Americans have significantly higher levels of lipoprotein(a) (Lp(a)), which was associated with increased risk for ischemic heart disease and stroke, compared to Caucasians and the Chinese (IOM, 2011).
Notes. Data retrieved from the “Global atlas on cardiovascular disease prevention and control: Policies, strategies and interventions,” by the World Health Organization, 2011. Copyright 2011 by the World Health Organization.
Ischemic Heart Disease
Ischemic heart disease is the most prevalent cardiovascular disease worldwide, but it is the most common in Asia and Africa (Figure 2). It is expected that the disparities in mortality rates associated with ischemic heart disease among regions are caused by inequality in heat care accessibility (WHO, 2011). Preventive care in developed countries implements therapeutic lifestyle changes as the first-line therapy for addressing cardiovascular risk factors, so a lower ischemic heart disease incidence and mortality rate is expected in those countries. An alternative explanation can be found in different Lp(a) levels by race, which tend to be elevated among Asian Indians and African Americans, but not among ethnic Chinese or Caucasian groups.
Figure 2. Worldwide mortality rate associated with ischemic heart disease, age standardized, per 100,000.
Note. Retrieved from “Global atlas on cardiovascular disease prevention and control: Policies, strategies and interventions,” by the World Health Organization, 2011, p. 17. Copyright 2011 by the World Health Organization.
Lipid alteration has been associated with the development of plaque in artery walls, which causes atherosclerosis and leads to the onset of ischemic heart disease. Specifically, increased low-density lipoprotein cholesterol (LDL-C) levels have been observed in cases of atherosclerosis, which precedes ischemic heart disease, and their role in the pathogenesis of ischemic heart disease is attributed to lifestyle factors or genetic mutations of the Niemann–Pick C1-like 1 (NPC1L1) gene. The combination of sedentary behaviors and energy-dense diets rich in fat, sodium, and simple carbohydrates are lifestyle factors that can increase LDL-C levels (IOM, 2010). The NPC1L1 gene is responsible for encoding the NPC1L1 protein, which transports dietary cholesterol between from the lumen to the enterocytes, so over-expression of the NPC1L1 gene can elevate LDL-C levels (Myocardial Infarction Genetics Consortium Investigators, 2014).
Artery walls need to be flexible to withstand the internal pressure caused by circulation, but they harden and become narrow as modified LDL-C becomes trapped in the artery walls. Once they are trapped inside the walls, LDL-C molecules facilitate atherosclerosis as a result of progressive oxidation and interactions with microinflammation mediators (Chilton, 2004). Progressive oxidation of the molecules facilitates growth by increasing the deposition of cholesterol esthers, whereas the microinflammation mediated by proinflammatory cytokines increases LDL-C binding to endothelial and vascular muscle cells. Monocytes and T lymphocytes are elevated in all stages of increased cardiovascular risk, whereas elevated C-reactive protein levels were associated with acute stages of ischemic heart disease (Chilton, 2004). As the blood vessels attempt to increase their diameter to maintain the necessary blood and oxygen supply by remodeling, the connectivity tissue binding the walls and the plaque weakens, making the structure susceptible to ruptures.
Pharmacological Treatments for Cardiovascular Diseases
The type of pharmacological treatment used to treat cardiovascular conditions depends on their pathogenesis. The first line of therapy usually includes therapeutic lifestyle changes to address the risk factors of cardiovascular events, but medication or surgical procedures are necessary in chronic and acute cases of cardiovascular events. Evidence-based treatments that were found to improve survival rates and quality of life in patients with cardiovascular diseases are listed in Table 2. The mechanisms of action of the drugs used to treat cardiovascular conditions are described in Table 3.
Ischemic heart disease guidelines created by the American Heart Association in 2013 recommend using “statin therapy in primary prevention patients with a predicted 10-year risk of greater than or equal to 7.5%, and consideration of statin therapy in patients with 10-year risks of between 5% and 7.5%” (Ridker and Cook, 2013, p. 1762). For acute cases, the addition of ezetimbe to statin therapy is used because it was associated with an additional decrease in LDL-C levels by 24% on average (Cannon et al., 2015).
Notes. ACE = Angiotensin-converting enzyme, HMG-CoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A, MRA = Mineralocorticoid/aldosterone receptor antagonists
Unmet Medical/Therapeutic Needs
Three unmet therapeutic needs have been observed in the current literature. First, low pharmacotherapy adherence rates were reported in patients who were treated for acute cardiovascular events, so those finding indicate that it will be necessary to develop patient education and support strategies for improving treatment adherence (Rosenson et al., 2015). Second, even though statins are recommended for primary prevention of ischemic heart disease in diabetes patients as well, individuals with type 2 diabetes or with non-diabetic dysglycaemia are also at risk for cardiovascular complications associated with glucose levels. The addition of metformin, a glucose-lowering drug, to statin therapy did not have a significant effect on reducing risk factors associated with ischemic heart disease, so future research needs to explore alternative pharmacological approaches (Preiss et al., 2014). Third, genetic factors can account for up to 60% variability in ischemic heart disease risk, so it will be important to focus future research on developing new generations of drugs for inactivating or activating genes associated with cardiovascular diseases (Mega et al., 2015). The development of those types of drugs will improve treatment efficacy and enable individualized care delivery by targeting specific causes of cardiovascular disease.
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