The major risk factors contributing to the development of atherosclerotic plaques in blood vessels have been known for many years. However it has now become apparent that this is inadequate since there is a large group of patients who are susceptible to vascular disease despite the fact that they are relatively Iree of these risk factors. The conventional risk factors help to identify only 60-65 per cent of those at risk of Cardio-vascular events. In around 50 per cent of those not identified by conventional risk factors, the initial Cardio-vascular manifestation is myocardial infarction or death. Thus, large numbers of presumed 'low-risk' people die of Cardio-vasculru- disease each year. This inadequacy of the major risk factors to identify thoie at iisk has lead to the search for iiew risk factors and more and more risk factors are being added to the list.
The emerging risk factors can be divided into those that play a role in the pathogenesis and those that can be see11 as surrogate markers for the atherosclerotic process. Table 2.4 shows some of the most important new Cardio-vascular risk factors. While these factors may be importaut in the pathogenesis,their scope in the preventive strategy is at present limited. However further research may put more light on their role and the need for intervention.
Left Ventricular Hypertrophy (T,VH)
LVH develops as the response of the heart to chronic pressure or volu~ne overload and is defined as a left ventricular inass exceeding 13 1 g/m2 ol' body surrace rwea in Inen and 100 g/m2 in women. Its incidei~ce inclcases with age, blood pressure and obesity all of which are risk factors of CAD. LVH is independently associated with increased incidence of Cardio-vascular disease, Cardio-vasculru and all-cause mortality, and stroke, Effective BP control in hy pertensive patients, along with non-pl~arinacological interventions such as weight redu&io~i, sodiuni restriction and aerobic physical exercise, call reduce left ventricular mass. There are no conclusive data that the reduction of left ventricular mass can improve Cardio-vascular outcome indepei~dently or the decrease in BP. Tbcre are also no standard universally accepted criteria for LVH and thilt limits the use of this risk factor in routine clinical practice. Even then LVH is associated with an i~lcreased risk of cardiac events within single studies and has been taken as a variable in risk scoriilg.
Hyperhomocysteinaemia
Homocysteine has been considered as a risk factor for Cirdio-vascular diseases because of many epidemiological and observational studies showing that increased fasting total homocysteine levels (> 15 mmolfl) are independently associated with CAD, peripheral vasculslr disease, cerebro-vascular disease, and CVD death.However, the prospective studies have given controversial results and so the importance of the increased homocysteine levels has not been clearly defined. .
Genetic and nutritional factors, such as deficiencies in folate, vitamin B 12 and vitamin B6, are associated with increased serum levels of homocysteine, while in patients with hyperhornocysteinaernia, supplementation with these vitamins can decrease homocysteine levels. Large randornised clinical trials are being conducted to examine the potential benefits of decreasing homocysteine levels.
Lipoprotein (a) [(Lp(a)] Excess While cholesterol and triglycerides are imporrant lipid risk factors, another lipoprotein factor called Lipoprotein (a) is thought to play a significant role especially in genetic predisposition to coronary artery disease. Lp(a) is a subfraction of LDL but ten times more atherogenic, and its serum level is genetically determined. Being a dual pathogen influencing both atherosclerotic and thrombotic process, it i s considered as a powerful independent risk factor for premature and extensive coronary disease. It is widely believed to be a biological marker for familial CAD, having the same significance as that of a history of premature CAD in the family.
The inherited serum levels of Lp(a) are not influenced by gender, diet, smoking, or other risk factors. The pathological effects of Lp (a) begin at a level of 20-30 mgldl and are magnified in the presence of high LDL, low HDL or a high TCHDLc ratio, again highlighting the significance of lipid fraction interrelationship. There is a ethnic and genetic variability in the level of Lp(a). Indians have a higher level than other groups or races like Chinese or Japanese.
However there are no data showing that the decrease in Lp(a) levels is associated with a decrease in the incidence of Cardio-vascular or cerebro-vascular disease. The value of the routine screening for, andlor treating Lp(a) excess, is therefore still debatable. Even then Lp(a) levels should probably be taken into account inpatients with CAD without established risk factors. The other factors should be rigorously modified or eliminated because, as has been seen, in hypercholesterolaemic patients with increased Lp(a) levels, the decrease in LDL cholesterol levels is followed by neutralisation of the atherogenic potential of Lp(a).
Increased Fibrinogen Levels and Other Thrombogenic Factors Thsombogenesis is an important component in the pathological process of atherosclerosis and so it is not surprising that a number of studies have clearly shown the association of increased plasma fibrinogen levels with Cardio-vascular disease and that the reduction of the increased fibrinogen levels in CAD patiellts could decrease the incidence of cardiac death and ischaemic stroke. The substantial variability of plasma fibrinogen levels because of a number of factors including the assay used, socio-economic and metabolic factors, etc., limit the wide application of this coagulation factor as a risk marker in everyday clinical practice.
However it is important to note that smoking cessation, weight loss, regular exercise, moderate alcohol consumption and drugs like fibrates can significantly reduce plasma fibrinogen levels.Several other factors participating in blood coagulation have been associated with CVD risk, including factor VII levels, plasrninogen activator inhibitor - 1 (PAI-1) and increased platelet aggregation. Many randomised controlled trials have shown the beneficial effect of antiplatelet agents in the prevention of Cardio-vascular events in patients with established vascular disease.
Oxidative Stress
In the risk conferred by LDL cholesterol, the oxidative modification of LDL plays a central role, because it is mostly the oxidised LDL molecule that causes endothelid dysfunction and damage to the vessel wall. However, the role of antioxidant therapy for the prevention of vascular disease is not well established.In fact, while epide&ological and observational studies have shown that highintakes of vitamins E, C and A may provide protection against Gal-dio-vascular disease, the results of placebo-controlled primary prcve~ition studies failed to show any benefit from the use of antioxidant vitamins. However, some secondary prevention studies have suggested potential beneficial effects of antioxidants.
Infectious Agents
Recently there has been increasing interest in the relation between chro~iic low- grade systemic inflammation and mortality of coronary artery disease. Evidences Prom laboratory, sero-epidemiological, pathological studies and lately li.on1 prospective clinical trials in unstable coronary syndromes, point to tlie strong association of chronic infections with aetiology and psogrcssion of atherosclerosis and coronary artery diseasc. Chronic subcli~ijcal inkctions with il number uf organisins (both bacterial and viral) including Chlamydia pneumoniac,Cytomegalovirus, Helicobactcr pylori, 1-Ierpes simplex vilus ctc., hove been implicated as risk i'acturs 1i)r initiating and modu1;lting the atlieroscleroric procchs.Of these infectious agents, Clilan~ydia ~~neumoniac,a colnmon respisntosy pathogen, appears to be the most plausible cantlidate acting with or independcnrly of other Cardio-vascular risk factors. However, these arc n rlumbcr of qucstio~ls concerning tlie extent to which these micro-orgtnis~ns play a role in the pathoge~iesis of atherosclerosis and the matter still remains unsettled.
Inflaml~~atio~i and Atherosclerosis is clearly iln inl'l:~mmalory tiiscaseIt has recently becn stated that athe~*osclerosis and does not ~~esult simply fro111 the nccumulation of lipids. I?,vidcnce li~lhing inflammation to athemsclerosis stems I'rom st~~tlics
i)cusiug on acute a t ~ d c-hro~lic
phases of CAD. Elevatcd levcls of acute-phnsc reactants and cyroki~ic prorluction with a focal predominance of inflammatory cells in thc vulnerable placlues liave been fou~id in patients witli u~istablc coronary syndronies. Thus, ~narkcrs of' inflamniation, such as C-rcactivc protein, I~ave heen desc~.ihcd 21s a potcntinl predictor for futurc Ciudio-vascular cveiits. The circulating lcvcls of these inflammatory markers are altered by 11.catmenl witli lipid lowering drugs likc slatins.However, there is ns yet no consensus on the use of antibiotics a~id thc allti-inflammatory agents in prevention of CAD or management of acutc cor.ot1;u.y syndrome.
The emerging risk factors can be divided into those that play a role in the pathogenesis and those that can be see11 as surrogate markers for the atherosclerotic process. Table 2.4 shows some of the most important new Cardio-vascular risk factors. While these factors may be importaut in the pathogenesis,their scope in the preventive strategy is at present limited. However further research may put more light on their role and the need for intervention.
Left Ventricular Hypertrophy (T,VH)
LVH develops as the response of the heart to chronic pressure or volu~ne overload and is defined as a left ventricular inass exceeding 13 1 g/m2 ol' body surrace rwea in Inen and 100 g/m2 in women. Its incidei~ce inclcases with age, blood pressure and obesity all of which are risk factors of CAD. LVH is independently associated with increased incidence of Cardio-vascular disease, Cardio-vasculru and all-cause mortality, and stroke, Effective BP control in hy pertensive patients, along with non-pl~arinacological interventions such as weight redu&io~i, sodiuni restriction and aerobic physical exercise, call reduce left ventricular mass. There are no conclusive data that the reduction of left ventricular mass can improve Cardio-vascular outcome indepei~dently or the decrease in BP. Tbcre are also no standard universally accepted criteria for LVH and thilt limits the use of this risk factor in routine clinical practice. Even then LVH is associated with an i~lcreased risk of cardiac events within single studies and has been taken as a variable in risk scoriilg.
Hyperhomocysteinaemia
Homocysteine has been considered as a risk factor for Cirdio-vascular diseases because of many epidemiological and observational studies showing that increased fasting total homocysteine levels (> 15 mmolfl) are independently associated with CAD, peripheral vasculslr disease, cerebro-vascular disease, and CVD death.However, the prospective studies have given controversial results and so the importance of the increased homocysteine levels has not been clearly defined. .
Genetic and nutritional factors, such as deficiencies in folate, vitamin B 12 and vitamin B6, are associated with increased serum levels of homocysteine, while in patients with hyperhornocysteinaernia, supplementation with these vitamins can decrease homocysteine levels. Large randornised clinical trials are being conducted to examine the potential benefits of decreasing homocysteine levels.
Lipoprotein (a) [(Lp(a)] Excess While cholesterol and triglycerides are imporrant lipid risk factors, another lipoprotein factor called Lipoprotein (a) is thought to play a significant role especially in genetic predisposition to coronary artery disease. Lp(a) is a subfraction of LDL but ten times more atherogenic, and its serum level is genetically determined. Being a dual pathogen influencing both atherosclerotic and thrombotic process, it i s considered as a powerful independent risk factor for premature and extensive coronary disease. It is widely believed to be a biological marker for familial CAD, having the same significance as that of a history of premature CAD in the family.
The inherited serum levels of Lp(a) are not influenced by gender, diet, smoking, or other risk factors. The pathological effects of Lp (a) begin at a level of 20-30 mgldl and are magnified in the presence of high LDL, low HDL or a high TCHDLc ratio, again highlighting the significance of lipid fraction interrelationship. There is a ethnic and genetic variability in the level of Lp(a). Indians have a higher level than other groups or races like Chinese or Japanese.
However there are no data showing that the decrease in Lp(a) levels is associated with a decrease in the incidence of Cardio-vascular or cerebro-vascular disease. The value of the routine screening for, andlor treating Lp(a) excess, is therefore still debatable. Even then Lp(a) levels should probably be taken into account inpatients with CAD without established risk factors. The other factors should be rigorously modified or eliminated because, as has been seen, in hypercholesterolaemic patients with increased Lp(a) levels, the decrease in LDL cholesterol levels is followed by neutralisation of the atherogenic potential of Lp(a).
Increased Fibrinogen Levels and Other Thrombogenic Factors Thsombogenesis is an important component in the pathological process of atherosclerosis and so it is not surprising that a number of studies have clearly shown the association of increased plasma fibrinogen levels with Cardio-vascular disease and that the reduction of the increased fibrinogen levels in CAD patiellts could decrease the incidence of cardiac death and ischaemic stroke. The substantial variability of plasma fibrinogen levels because of a number of factors including the assay used, socio-economic and metabolic factors, etc., limit the wide application of this coagulation factor as a risk marker in everyday clinical practice.
However it is important to note that smoking cessation, weight loss, regular exercise, moderate alcohol consumption and drugs like fibrates can significantly reduce plasma fibrinogen levels.Several other factors participating in blood coagulation have been associated with CVD risk, including factor VII levels, plasrninogen activator inhibitor - 1 (PAI-1) and increased platelet aggregation. Many randomised controlled trials have shown the beneficial effect of antiplatelet agents in the prevention of Cardio-vascular events in patients with established vascular disease.
Oxidative Stress
In the risk conferred by LDL cholesterol, the oxidative modification of LDL plays a central role, because it is mostly the oxidised LDL molecule that causes endothelid dysfunction and damage to the vessel wall. However, the role of antioxidant therapy for the prevention of vascular disease is not well established.In fact, while epide&ological and observational studies have shown that highintakes of vitamins E, C and A may provide protection against Gal-dio-vascular disease, the results of placebo-controlled primary prcve~ition studies failed to show any benefit from the use of antioxidant vitamins. However, some secondary prevention studies have suggested potential beneficial effects of antioxidants.
Infectious Agents
Recently there has been increasing interest in the relation between chro~iic low- grade systemic inflammation and mortality of coronary artery disease. Evidences Prom laboratory, sero-epidemiological, pathological studies and lately li.on1 prospective clinical trials in unstable coronary syndromes, point to tlie strong association of chronic infections with aetiology and psogrcssion of atherosclerosis and coronary artery diseasc. Chronic subcli~ijcal inkctions with il number uf organisins (both bacterial and viral) including Chlamydia pneumoniac,Cytomegalovirus, Helicobactcr pylori, 1-Ierpes simplex vilus ctc., hove been implicated as risk i'acturs 1i)r initiating and modu1;lting the atlieroscleroric procchs.Of these infectious agents, Clilan~ydia ~~neumoniac,a colnmon respisntosy pathogen, appears to be the most plausible cantlidate acting with or independcnrly of other Cardio-vascular risk factors. However, these arc n rlumbcr of qucstio~ls concerning tlie extent to which these micro-orgtnis~ns play a role in the pathoge~iesis of atherosclerosis and the matter still remains unsettled.
Inflaml~~atio~i and Atherosclerosis is clearly iln inl'l:~mmalory tiiscaseIt has recently becn stated that athe~*osclerosis and does not ~~esult simply fro111 the nccumulation of lipids. I?,vidcnce li~lhing inflammation to athemsclerosis stems I'rom st~~tlics
i)cusiug on acute a t ~ d c-hro~lic
phases of CAD. Elevatcd levcls of acute-phnsc reactants and cyroki~ic prorluction with a focal predominance of inflammatory cells in thc vulnerable placlues liave been fou~id in patients witli u~istablc coronary syndronies. Thus, ~narkcrs of' inflamniation, such as C-rcactivc protein, I~ave heen desc~.ihcd 21s a potcntinl predictor for futurc Ciudio-vascular cveiits. The circulating lcvcls of these inflammatory markers are altered by 11.catmenl witli lipid lowering drugs likc slatins.However, there is ns yet no consensus on the use of antibiotics a~id thc allti-inflammatory agents in prevention of CAD or management of acutc cor.ot1;u.y syndrome.
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