Alcohols Effect on Cardiovascular Disease and the Genetic Modifier of the Alcohol Metabolism - Research Paper Example

?Alcohol's effect on cardiovascular disease and the genetic modifier of the alcohol metabolism  Introduction Alcohol is one of the more interesting factors affecting CVD, as low concentrations are said to induce protective mechanisms, while higher concentrations increase the risk for these ailments. In a review of nine, nationally representative, large-scale studies in the US, it was found that compared with those that do not drink alcohol, relative risks were 0.95 (95% confidence interval [CI]: 0.88 to 1.02) among lifetime infrequent drinkers, 1.02 (95% CI: 0.94 to 1.11) among former drinkers, 0.69 (95% CI: 0.59 to 0.82) among light drinkers, 0.62 (95% CI: 0.50 to 0.77) among moderate drinkers, and 0.95 (95% CI: 0.82 to 1.10) among heavy drinkers (Mukamal, et al., 2010). Thus, although the effects were inconclusive among lifetime infrequent drinkers, among former drinkers and among heavy drinkers, alcohol consumption seemed to decrease the risk of CVD among those who drink light to moderate amounts of alcohol. Despite the promise of alcohol consumption in the protection against CVD, future studies are derailed by the difficulty in conducting studies on the effects of alcohol and CVD, since dietary patterns, physical activity and smoking all affect volume and type of alcohol consumed and drinking patterns, aside from causing CVD directly. It must be noted that healthy behaviors decreasing the risk for CVD are associated with low to moderate alcohol consumption. These factors affecting alcohol intake and CVD should also be taken into consideration when studying the connection between alcohol and heart disease (Ruidavets, et al., 2004). Moreover, it must be noted that the association of alcohol consumption and Chronic Heart Disease (CHD) mortality tend to be stronger than that for cerebrovascular (CV) mortality (Mukamal, et al., 2010; Drogan, et al., 2012). Because of this, other factors, such as genetics, should also be kept in mind when considering ways to better prevent CVD in a patient. Review of Related Literature Factors affecting relationship between alcohol and CVD With CVD being a multifactorial illness, the magnitude of protective or aggravating effects of alcohol to CVD can possibly be different across subgroups. It must be noted that steady intake, and not binge drinking, is the one that have cardio-protective benefits. Prospective studies also show that wines seem to be better in decreasing mortality than beer and spirits (Gronbaek, 2006). 1. Comorbidities According to Gronbaek (2006), the J-shaped curve describing the effects of alcohol consumption and CVD is only valid in middle-aged and the elderly, as well as those already at risk of developing coronary heart problem. Meanwhile, a study reported inverse association between alcohol and intima media thickness in non-diabetics, but a J-shaped relation in those with glucose tolerance (Cooper, et al., 2002). 2. Ethnicity Non-hispanic whites seem to be more protected from CVD by light to moderate alcohol consumption. Also, the U- or J-shaped curve representing alcohol-CVD mortality is said to be not true among the African Americans (Sempos, et al., 2003). In fact, alcohol intake was also found to increase the risk of myocardial infarction among black Africans, but lowers it for white and mixed-race Africans (Steyn, et al., 2005). However, the participants in these surveys are very limited, and they do not describe the general population of the US. Despite this, it may be a reflection of ancestral variations in alcohol dehydrogenase 1B isoforms, or other alcohol-metabolizing enzymes (Edenberg, et al., 2006). 3. Genetic factors The J-shaped curve describing alcohol and CVD relation is observed also in diabetics with the CC genotype of the interleukin-6 promoter polymorphism, which affect inflammatory pathways (Jerrard-Dunne, et al., 2003). 4. Sex Compared to non- and occasional drinkers (0 to 6 g alcohol/day), there is a reduced risk of MI among females consuming >12g alcohol/day (HR = 0.31; 95% CI: 0.10–0.97). On the other hand, the level needed to reduce risk of MI among males is twice to five times more than that needed by females, amounting to 24 to 60 g/d (HR = 0.57; 95% CI: 0.33–0.98) (Drogan, et al., 2012). Relationships of alcohol drinking to different CVD A table in the paper of Klatsky (2010) summarized the relationship of light and heavy alcohol drinking to different CVD, as found in studies. Evidences suggest that light drinking protects from coronary disease and ischemic stroke, although its effects on hypertension and arrhythmia are still uncertain. In contrast, dilated cardiomyopathy, beriberi, Arsenic or cobalt Beer drinker’s disease and hemorrhagic stroke have no relation with light alcohol drinking. On the other hand, heavy alcohol consumption is a probable causative factor for dilated cardiomyopathy, hypertension and arrhythmia. It also plays a role in the development of Arsenic or cobalt Beer drinker’s disease. Despite this, it is postulated that heavy alcohol drinking can still protect from coronary disease and ischemic stroke. Findings Alcohol dehydrogenase ADH is an enzyme that catalyzes the oxidation of alcohols to aldehydes. The five ADH classes, differing based on their maximal activities and affinities for ethanol, result from functional polymorphisms in ADH1B and ADH1C genes. The ADH g1g1 isoenzyme from ADH1C*1/1 has a 2.5-fold higher Vmax of ethanol oxidation, compared to the homodimeric g2 isoenzyme resulting from homozygous ADH1C*2/2. For ADH1B, the protein coded by homozygous ADH1B*2/2 has a 40 times greater Vmax than that of ADH1B*1/1-coded isoenzyme (Drogan, et al., 2012). Interestingly, it was found that having the slow-coding ADH1B* 1/1 genotype is associated with higher median alcohol consumption (Drogan, et al., 2012). Moreover, ADH1B*2, together with ADH1B*3, was found to be significantly lower in individuals diagnosed with alcohol dependence (Ramchandani, 2012). According to a few studies, the slower metabolizing ADH isoenzymes are associated with greater cardioprotective effect (Heidrich, et al., 2007). As an example, Hines, et al. (2001) showed that individuals with ADH1C*2/2 have a lower risk of myocardial infarction than the participants with ADH1C*1/1. To say that this is true for all classes of ADH, however, is too generalized, as many studies show no benefits or even adverse effects upon alcohol consumption among slow metabolizers. A study among Japanese men showed that ASH1B*1 is associated with a higher prevalence of cerebral infarction (Suzuki, et al., 2012). In addition, the benefits of alcohol intake among ADH1C*2/2 are inconclusive, because of the conflicting findings of numerous studies. In fact, the most recent meta-analysis to date, conducted by Drogan, et al. (2012), slow-metabolizers bearing the ADH1B*1/1 genotype have an increased risk for both coronary and cerebral events. In the end, there is not enough evidence to show that polymorphisms in ADH1B or ADH1C affect CVD risk. CYP2E1 Cytochrome P450 IIE1 (CYP2E1) is a polymorphic xenobiotic-metabolizing enzyme responsible for the metabolism of exogenous chemicals being introduced in the body. It is particularly important in the cholesterol and steroid metabolism. It induces the production of reactive oxygen species (ROS) that can activate pro-inflammatory pathways (Onyimba, et al., 2011). Unlike that in ADH, studies regarding the influence of CYP2E1 polymorphism on alcohol and CVD relation are much fewer. CYP2E1 gene upregulation has been associated with heart disease, including dilated cardiomyopathy in mice, which is characterized by dilated left ventricle, thin wall and dysfunctional contraction. Despite these findings, CYP2E1 overexpression is thought to be an initially protective mechanism through which endogenous ketones are metabolized to meet the energy demands of the heart. However, this process increases ROS production, leading ultimately to CVD (Lu, et al., 2012). In mice (Bailey, et al., 2009) and rat animal models (Bailey, et al., 2006), it has been shown that the induction of hepatic CYP2E1 is increased among those given alcohol chronically. This has been found to be further increased with the addition of cigarette exposure. This might explain why some studies have found a J-shaped curve describing alcohol-CVD relation: the low alcohol induces enough CYP2E1 to provide energy to the heart, while high levels are already detrimental. This may also explain why the benefits of alcohol are only seen among those who have sustained cardiac pathologies already. Looking at whether CYP2E1 polymorphisms affect the influence of the protein to alcohol-CVD relation, a prospective study conducted by Salama, et al. (2002) revealed the possibility that having CYP2E1*5B gene increases the risk of developing atherosclerosis by 2.5x. However, a more recent study did not associate this particular genotype to coronary artery disease (Bazo, et al., 2011). Discussion Induction of cardiovascular disease by alcohol The product of ADH degradation of alcohol, aldehyde, reacts non-enzymatically with sulfhydrul and amino groups of amino acids to deform protein structure, to denature proteins, or to alter function (Vasdev, Gill & Singal, 2006). Protein denaturation also causes oxidative stress, and increased ROS concentration result to cellular and DNA damage. The death in cells forming the vascular lining leads to inflammatory reactions that thicken the vessels’ walls. As a result, the peripheral resistance increases, and hypertension ensues, making it more and more difficult for the heart to pump blood to the tissues (Martinet, et al., 2002). Thus, if an individual has a ADH1B*1/1 or ADH1C1*1, and is thus a slow alcohol metabolizer, then he or she will not produce too much aldehydes that destroy proteins. Protective mechanisms of alcohol Vasdev, Gill & Singal (2006) have suggested possible biochemical mechanisms that connect alcohol to cardiovascular protection. Aside from producing aldehyde, the metabolism of alcohol by low Km ADH produces reduced nicotinamide adenine dinucleotide (NADH), which counteracts aldehyde by producing antioxidants cysteine, glutathione and paraoxinase, thereby decreasing oxidative stress and secondary production of aldehydes through lipid peroxidation. NADH also binds and degrades aldehydes. There are many mechanisms postulated to connect alcohol consumption and cardiovascular diseases. One of the earlier developed mechanisms behind the protective role of alcohol is the increase in the levels of high-density lipoprotein (HDL)-cholesterol complex and associated apoproteins (Brien, et al., 2011). It has also been shown to lower serum fibrinogen and lipoprotein A levels, as well as increase components of the fibrinolytic pathways, which decreases the likelihood of developing atherosclerosis and thrombi that lead to ischemic heart diseases and stroke, respectively (Catena, et al., 2003). Moreover, it induces decreased C-reactive protein levels and other inflammatory mediators (Albert, Glynn and Ridker, 2003). Ethanol preconditioning, in which alcohol directly affects ischemic myocardium in order to improve acute myocardial infarction, has also been suggested (de Lorgeril, et al., 2002). Current issues on research The relationship of CVD and alcohol is one of the most interesting things to study about because of its dynamic feature. In addition, the continuously increasing prevalence of CVD makes studies on its prevention and cure much needed. Thus, to unequivocally demonstrate and explain this relationship’s validity is a necessary step in creating public healthcare programs that will make significant impact in general. However, looking at the findings, it is quite glaring that although there is sound theoretical basis as to the cardio-protective mechanism of alcohol, as mediated by enzymes such as ADH and CYP2E1, studies have disagreeing results whether the benefits of alcohol on CVD is significant or not. These contradicting findings might result from the fact that it is difficult to conduct high validity studies that tries to establish, more so to explain, the true correlation of alcohol and CVD, and the factors that affect this relation. Currently, it is feasible only to establish correlations, because causality needs the conduct of randomized trials. However, it may be unethical to do a randomized trial, because alcohol is a potentially toxic substance (de Lorgeril & Salen, 2004). In addition, the role of certain polymorphisms in modulating the effects of alcohol on CVD is hard to describe because certain genotypes occur at a much lower frequency in European or American populations, which are the subject of most studies currently conducted. - In fact, the effects of ADH1B*2 on CVD is hard to validate because of the low frequency of this allele in Western populations (Drogan, et al., 2012). It must also be noted that there are confounding factors that may decrease or augment the effects of alcohol on CVD. Smoking has been discussed earlier. Because there are too many factors affecting the relation of alcohol and CVD, it is understandable that the effect of alcohol on preventing chronic heart disease may not be the same for other CVD, such as stroke, which is a totally different condition compared with other heart and vascular ailments. Finally, it must be taken into account that alcohol not only affects the heart, but other organs as well. Various epidemiologic studies have already shown evidences that alcohol, together with exposure to cigarette smoke and alcohol, increases the risk and severity of liver diseases (Bailey, et al., 2009). Thus, even if various population studies have validated the benefits of alcohol on CVD, or even if alcohol is indeed cardioprotective in individuals with a particular set of ADH and CYP2E1 polymorphisms, alcohol consumption, especially if chronic or through binge drinking, can lead to non-cardiovascular ailments such as liver cirrhosis. Conclusion CVD is a general term encompassing heart and vascular ailments. Aside from its variety, a lot of factors, such as age, ethnicity, sex, and comorbidities, have also been associated with its development. The effects of these factors are believed to be modulated by enzymes, such as ADH and CYP2E1. ADH metabolizes alcohol to produce aldehyde and NADH. The former causes protein denaturation, cell death and eventual atherosclerosis, while the latter is an antioxidant preventing cell death. Its protective or harmful effects thus depend on what metabolite is produced more, aldehyde or NADH? On the other hand, CYP2E1, when induced by alcohol, provides energy for the heart, while promoting pro-inflammatory signaling. Because ADH and CYP2E1 seem to be two-edged swords, their polymorphisms were looked at to provide answers as to whether alcohol is a protective or harmful agent. However, meta- analyses, as well as prospective and observational studies have not found any significant findings with regards to determining the extent of alcohol’s effect to CVD using ADH or CYP2E1 enzymes. Since it is not yet established which individuals can truly benefit from alcohol intake, it is better to suggest abstinence, or at least light alcohol drinking, since other diseases, such as liver cirrhosis, can also develop with heavy alcohol consumption. 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