MI is a multifactorial disease affected by genetic mutation and various environmental factors like diet, stress, daily routine, etc. A wide range of risk factors, including smoking, hypertension, and hyperlipidemia, lead to MI (Rehman et al., 2020b). Atherosclerosis and thrombogenesis also contribute to the pathogenesis of MI. Apart from the classical risk factors, genetic mutation has been of interest to investigators. Renin-angiotensin-aldosterone system (RAAS) has genes that can be of great interest to studying the genetic susceptibility in MI. Many studies are being conducted to study the genetic risk factors in RAAS to predict the progression of MI. Several studies have shown the influence of RAAS on the development of atherosclerosis and hypertension. Coronary arteriosclerosis and its associated disorders are also seen in individuals having angiotensin II inhibition (Koh et al., 2010). Moreover, inhibition of the angiotensin-converting enzyme (ACE) also influences the development of these diseases. Both of these components of RAAS are potentially active in the initiation and development of MI. Angiotensin II can cause atherosclerotic changes and can rupture the plaque, which is triggered by different mechanisms such as vasoconstriction, thrombogenesis, antifibrinolysis, and vascular smooth muscles. Production of angiotensin II is controlled by AGT, which can be a limiting factor in the production of angiotensin II (Liang et al., 2013b; Wang and Pan, 2014).

AGT is usually found as a liver protein and interacts with renin for the production of angiotensin I, which is a precursor for angiotensin II. The AGT gene is located at 1q42-43 and consists of five exons (Sivitskaia et al., 2008). AGT is a potential factor in determining the level of angiotensin II in tissues and serum, so any mutation or polymorphism in the AGT gene may lead to thrombogenesis and atherogenesis, eventually developing into MI (Brand et al., 2002).

A homozygous variation in the gene at the molecular level can be related to a higher level of AGT in the plasma, and hence, higher risks of hypertension may occur. The polymorphism might occur when methionine at position 235 is replaced by threonine as shown in Fig. 1. Various studies have also demonstrated the role of M235T polymorphism which increases the risk of CHD (Brand et al., 2002; Ji et al., 2010). Several studies have shown the association of AGT polymorphism with the risks of MI (Xu et al., 2007; Zafarmand et al., 2008). However, some studies completely contradict these findings and do not show the association between M235T polymorphism and MI (Brenner et al., 2005; Mehri et al., 2011; Saidi et al., 2009; Um et al., 2005; Um et al., 2003).

Similar to M235T polymorphism, methionine is replaced by threonine at position 174; this polymorphism is more common and is known as T174M (rs699). This genetic polymorphism can alter the functions of AGT, consequently leading to the progression of CVD (Sivitskaia et al., 2008). AGT T174M polymorphism is associated with the risk of developing CAD (Wang, 2013). Various studies conducted among different ethnic groups have shown the association of T174M polymorphism with MI. However, contradicting results are also available regarding this association (Attia et al., 2003).

Apart from AGT, RAAS has another important enzyme that has proved to be significant in regulating blood pressure and plays a vital role in various CVDs. ACE is another popular enzyme responsible for the regulation and maintenance of blood pressure through RAAS. A number of CVDs, such as MI, may arise due to the dysfunction of this enzyme (Liang et al., 2013a). The gene responsible for the encoding of this enzyme in humans is present at chromosome 17q23. The genetic polymorphism involved in this enzyme occurs in the chromosome at intron-16, where the presence or absence of 287 base pair (bp) Alu-type sequence is observed (Cambien et al., 1992). People with a homozygous deletion (DD) genotype are seen to be at higher risk of MI. Interestingly, the individuals who were considered at low risk of MI based on their data of body mass index (BMI) and the plasma concentration of apolipoprotein (Apo) B showed a significant association between MI and genetic polymorphism (Beohar et al., 1995; Schuster et al., 1995).

Various studies have confirmed that individuals with homozygous DD genotype are at the higher risk for MI. This association is even higher in people who were seen to be at low risk. However, some studies have shown contradictory results and do not support this hypothesis. The level of circulating ACE in the blood varies among individuals. This difference is attributed to I/D polymorphism is considered to be responsible for. Individuals with the homozygous DD genotype have higher levels of ACE as compared to those with the homozygous II genotype. However, its functional role is still unclear and is widely under discussion (Liang et al., 2013a).

ACE is considered a dipeptidyl carboxypeptidase. It promotes the activation of angiotensin I to angiotensin II by breaking down the carboxyterminal dipeptide. Angiotensin II is a potent vasoconstrictor. ACE not only activates angiotensin I into angiotensin II, but it also decreases the levels of bradykinin, a vasodilator (Cicoira et al., 2001; Murphey et al., 2000). It also causes the migration and adhesion of macrophages. This reduces the diameter of vessels, which results in atherosclerotic plagues (Larsson et al., 2000). Angiotensin II also has a platelet aggregating effect. It promotes the expression of plasminogen activator-inhibitor 1 and 2, which reduces the fibrinolytic activity in plasma (He et al., 2006). All these mechanisms show the possible role of ACE in MI. The I/D polymorphism in the ACE gene and its association with MI has been under consideration. It has been reported that the difference and variance in the level of ACE are majorly due to the polymorphism in I/D, which can increase the risks of MI (Dai et al., 2016; Keavney et al., 2000).

However, the results are not consistent, and various contradictions have been noted. Thirteen different polymorphisms of the ACE gene were studied among the Nigerian population to investigate the association of these polymorphisms with MI. Among all these polymorphisms, 2350G>A polymorphism showed much significant results. This polymorphism occurred at the 17th exon of chromosome and accounted for about 19% of the total variance in the plasma level of ACE among the population. This polymorphism proved to be of greater significance as compared to I/D polymorphism. The 2350G>A polymorphism was also studied among the Chinese population. Individuals with 2350G>A polymorphism showed a significant association with MI. The individuals with A allele carrier showed a higher risk of MI irrespective of their age, BMI, blood pressure, smoking status, and lipids and apolipoprotein levels in the plasma (Zhu et al., 2001). In another study, the individuals with A allele carrier in the Han Chinese population also had a high risk of MI (Jiang et al., 2013).

The eNOS is an enzyme involved in the synthesis of NO, a relaxing factor. The precursor for this synthesis is L-arginine. About three different isoforms of this enzyme are involved in the production of NO. These three isoforms are inducible nitric oxide synthase (also known as iNOS or NOS2), constitutive neuronal nitric oxide synthase (also known as nNOS or NOS1), and constitutive endothelial nitric oxide synthase (also known as eNOS or NOS3).

The eNOS is involved in the relaxation of vasculature after it moves to vascular smooth muscle cells from the endothelium. It stimulates the guanylate cyclase, which, as a result, increases the concentration of cyclic guanosine monophosphate. ENOS has a vital role in the maintenance and regulation of vascular tone. It acts as a protective agent through several mechanisms, like breaking down the superoxide radicals by reducing leukocyte adhesion and platelet aggregation. It is also involved in the proliferation of smooth muscle cells. All of these mechanisms provide a cumulative atheroprotective and, ultimately, a cardioprotective effect. However, if the synthesis of endothelial-derived NO is disturbed for any reason, it could lead to various abnormalities like thrombosis or even atherosclerosis. Despite different reasons contributing to the disturbance in the synthesis of eNOS, the genetic factor has proven to be of great importance (Dafni et al., 2010; Gluba et al., 2009; Zigra et al., 2013), as shown in Fig. 2.

The genetic polymorphism in the gene encoding for endothelial-derived NO can seriously affect these cardioprotective effects. The gene for eNOS can be found on the chromosome 7q35-36. It has 26 exons and extends to 21 kb (21000 bp). The most common or probably the only known polymorphism of eNOS is G894T at exon 7 which results in a change in the activity of eNOS and ultimately leading to endothelial dysfunction and various CVDs. This polymorphism is also known as E298D because the amino acid glutamic acid (E) is replaced by aspartic acid (D) and is associated with various CVDs, including MI. However, the results are still contradictory. Positive association has been seen between MI and E298D polymorphism in English, German, and Japanese populations. Nonetheless, a number of studies do not support this association; no such association was found among the Austrian, Korean, Dutch, and French populations (Gardemann et al., 2002; Jo et al., 2006; Morray et al., 2007; Park et al., 2004; Schmoelzer et al., 2003).

Genetic polymorphism of MTHFR leads to the transformation of the amino acid; alanine to valine at position 226 in proteins which results in MI (Xuan et al., 2011). The gene consists of 11 exons, with the size ranging from 102 to 432 bp, which are found on chromosome 1 (1p36.3). According to the analysis of the entire genomic structure, both alternative initiation and alternative splicing may occur (Dikmen et al., 2006). MTHFR is involved in the reduction of 5, 10 methylenetetrahydrofolates to 5, methyltetrahydrofolate, which delivers a methyl group to homocysteine to produce methionine. Mutation of MTHFR results in an increase in homocysteine due to altered folic acid metabolism, resulting in MI (Shaker and Ismail, 2014). The SNPs in MTHFR are at positions 677 (MTHFR 677C>T), 1298 (MTHFR 1298A>C), 1317 (MTHFR 1317T>C), and 1793 (MTHFR 1793G>A) (Böttiger et al., 2007). The 5,10 MTHFR is an enzyme encoded by the region 1p36.3 of the chromosome. MTHFR reduces 5,10 methylenetetrahydrofolates into 5-methylenetetrahydrofolate which is involved in re-methylation (by acting as a methyl donor) of homocysteine into methionine (Biselli et al., 2010). Increased level of homocysteine has been seen to be associated with various CVDs, including MI. This factor is highly independent of other traditional risk factors for CVDs. Recent studies have provided evidence on how homocysteine leads to various CVDs. It promotes the formation of thrombus and causes platelet aggregation due to endothelial dysfunction or injury (Biselli et al., 2010; Brattström et al., 1998; Xuan et al., 2011).

How a low level of MTHFR can lead to an increase in the level of homocysteine that ultimately leads to various CVDs, can be clearly elucidated. The level of MTHFR can be altered due to various physiological reasons. However, recent developments are being made to analyze the genetic causes for the decreased level of MTHFR. Genetic polymorphism has been widely studied to investigate the alteration in the plasma level of this enzyme. A very common MTHFR polymorphism is the C677T mutation, with cysteine being replaced by thymine at the 677th position in the nucleotide sequence, consequently changing amino acid alanine to valine at the 226th position in the protein formed. This mutation changes the thermostability of the enzyme, which further affects its activity as shown in Fig. 3. This polymorphism reduces the activity of this enzyme by up to 50%, which causes an increase in the level of homocysteine and a decrease in the concentration of folic acid in the plasma. Decreased folic acid also leads to various CVDs, as folic acid improves the function of the endothelium. The polymorphism-producing homozygous genotype showed a higher level of homocysteine in the plasma than in the heterozygous condition. However, the homocysteine level in a heterozygous mutated individual is seen to be still greater than that in the control or non-mutated individuals (Doshi et al., 2001; Kerkeni et al., 2006).

The MTHFR C677T polymorphism varies widely across the globe. The ethnic and demographic factors come into play that are not yet clearly understood. The homozygous genotype was seen to be highest among Italians and Hispanics. The lowest homozygous genotype among Europeans is found among Germans. About 13% homozygous genotype was found among the British population. About 10%–14% of homozygous polymorphism is seen in populations from America, Canada, Australia, and Brazil (Liew and Gupta, 2015).

The epidemiology and prevalence of MTHFR C677T polymorphism vary in various ethnic groups across the globe. The location and environmental factors also contribute to the polymorphism of this gene. The homozygous 677C>T was seen to be the highest among the Italians. This allele frequency was higher in Hispanics but was lower in American Blacks and those from some areas of Africa. This homozygous allele frequency ranges from less than 1% in Africans to about 20% among Americans (Botto and Yang, 2000).

In a study conducted among Europeans, Italians had the highest frequency of the C677T homozygous allele, whereas Germans were at the bottom of this list with the lowest frequency of the homozygous allele (Adams et al., 1996; Bowen et al., 1998; Markus et al., 1997). Among the British, the prevalence of the homozygous allele was about 13%. In different countries with a white population, like Canada, Australia, Brazil, and America, the C677T homozygous population ranged from 10%–14%. The Hispanic white population in California showed about 21% of homozygous allele and the rate was approximately 21% among Colombians. However, limited data is available about the Asian population. Eleven percent of the Japanese population had the homozygous allele, and the sub-Saharan Africans had zero percent (Liew and Gupta, 2015).

In Japan, an interesting study was conducted to relate age with the prevalence of the homozygous C677T allele. About 7% of people above the age of 80 years showed homozygous allele, whereas the percentage increased to 14% among the age group of 55-79 years. The homozygosity increased to 19% among individuals from the 14 to 55 years age group (Matsushita et al., 1997). However, not many elaborate studies have been conducted on the association of different age groups with the homozygous allele frequency among various populations.

Nowadays, in modern scientific research, detection and analyses of several gene SNPs are carried out to determine the molecular basics of different diseases. Genetic SNPs act as biological markers, which help to determine the possible risk factors and mechanisms for disease prevalence (Garrigós et al., 2017). With respect to the MI disease progression with genetic variants, the expression of some specific biochemical parameters is altered. Therefore, some strategies would lead to a clinical paradigm shift, moving treatment focus away from blockage and infarction treatment and toward treatment of the underlying illness process. These included drug therapy, thrombolytic therapy, percutaneous coronary interventions, and coronary artery bypass grafting.

Drug therapies include angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEI), β-receptor blockers, and aldosterone receptor antagonists (Er et al., 2016; Eyuboglu, 2015; González-Cambeiro et al., 2016).

The main method for treating MI at the moment is thrombolytic therapy. According to numerous clinical investigations, the best curative outcome was reached by thrombolytic therapy administered within 6 h after the onset of MI, and the earlier treatment is initiated, the better the curative outcome (Jariwala and Chandra, 2010). Currently, the most commonly used thrombolytic drugs are urokinase, streptokinase, and tissue-type plasminogen activators. Although these thrombolytic medications are effective at breaking up blood clots, they can also cause unwanted bleeding, such as mucosal bleeding, subcutaneous bleeding, or potentially fatal intracerebral hemorrhage. However, only one-third of patients with MI satisfied the criteria for thrombolytic therapy (Burlen et al., 2017; Kunamneni and Durvasula, 2014; Omraninava et al., 2016).

In comparison to thrombolytic therapy, PCI eliminates the thrombus, and the post-intervention reperfusion rate ranges from 95% to 99%. However, there are some potential risks associated with PCI as well, including the possibility of bleeding or infection at the catheter insertion site, an allergic reaction to the contrast dye used, a blood clot in the blood vessel being treated, a ruptured coronary artery, and total closure of the coronary artery (Peng et al., 2017).

Coronary artery bypass grafting (CABG) is a surgical procedure that efficiently treats CHD and myocardial ischemia. Additionally, it is a successful approach for treating patients with acute problems like restenosis. Emergency CABG will decrease myocardial damage and lower hospital mortality and unpleasant effects once the immediate problems follow surgery (Chang et al., 2016).

However, for the treatment and prevention of CVDs, more awareness and practice are required. Disparities and the understanding of cardiac illnesses would provide facilitations to the health care specialists to determine the novel disease biomarkers and precision medication for the treatment and prevention of CVD risks (Graham, 2015).