Risk Factors For Cardiovascular Disease
The main manifestations of cardiovascular disease (CVD) are coronary heart disease (CHD), cerebrovascular disease (stroke) and peripheral vascular disease, and the underlying cause of these is most often atherosclerosis (see Chapter 37). Numerous factors or conditions are known to increase (or decrease) the probability that atherosclerosis will develop, and the presence in an individual of these cardiovascular risk factors can be used to assess the likelihood that overt cardiovascular morbidity and death will occur in the medium term. Table 34.1 presents an abbreviated summary of the impact of major risk factors on CHD as determined by the Framingham Heart Study.
Some risk factors such as age, male sex and family history of CVD are fixed. However, others, including dyslipidaemias, smoking, hypertension, diabetes mellitus, obesity and physical inactivity, are modifiable. These probably account for over 90% of the risk of developing atherosclerotic CVD. The attempt to prevent CVD by targeting modifiable risk factors has become a cornerstone of modern disease management because the occurrence of overt CVD is preceded by the development of subclinical atherosclerosis which takes many years to progress.
Figure 34 illustrates the main mechanisms by which major risk factors are thought to promote the development of atherosclerosis and its most important consequence, CHD. Additional aspects of dyslipidaemias and hypertension are described in Chapters 36–39.
Dyslipidaemias are a heterogeneous group of conditions characterized by abnormal levels of one or more lipoproteins. Lipoproteins are blood-borne particles that contain cholesterol and other lipids. They function to transfer lipids between the intestines, liver and other organs (see Chapter 36).
Dyslipidaemias involving excessive plasma concentrations of low-density lipoprotein (LDL) are associated with rises in plasma cholesterol levels, because LDL contains 70% of total plasma cholesterol. As the level of plasma cholesterol rises, particularly above 240 mg/dL (6.2 mmol/L), there is a progressive increase in the risk of CVD due to the attendant rise in LDL levels. LDL has a pivotal role in causing atherosclerosis because it can be converted to an oxidized form, which damages the vascular wall (see Chapter 37). Drugs that lower plasma LDL (and therefore oxidized LDL) slow the progression of atherosclerosis and reduce the occurrence of CVD. Elevated levels of lipoprotein (a), a form of LDL containing the unique protein apo(a), have been reported to confer additional cardiovascular risk. Apo(a) contains a structural component closely resembling plasminogen, and it may inhibit fibrinolysis (see Chapters 8 and 45) by competing with plasminogen for endogenous activators.
On the other hand, the risk of CVD is inversely related to the plasma concentration of high-density lipoprotein (HDL), possibly because HDL functions to remove cholesterol from body tissues, and may act to inhibit lipoprotein oxidation. The ratio of total to HDL cholesterol is therefore a better predictor of risk than cholesterol levels per se. Low HDL levels often coexist with high levels of plasma triglycerides, which are also correlated with CVD. This is probably due to the atherogenicity of the triglyceride-rich very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL).
Hypertension, defined as a blood pressure above 140/90 mmHg, occurs in ∼25% of the population, and in more than half of people who are middle aged or older. Hypertension promotes atherogenesis, probably by damaging the endothelium and causing other deleterious effects on the walls of large arteries. Hypertension damages blood vessels of the brain and kidneys, increasing the risk of stroke and renal failure. The higher cardiac workload imposed by the increased arterial pressure also causes a thickening of the left ventricular wall. This process, termed left ventricular hypertrophy (LVH), is both a cause and harbinger of more serious cardio- vascular damage. LVH predisposes the myocardium to arrhythmias and ischaemia, and is a major contributor to heart failure, myocardial infarction (MI) and sudden death.
Physical inactivity promotes CVD via multiple mechanisms. Low fitness is associated with reduced plasma HDL, higher levels of blood pressure and insulin resistance, and obesity, itself a CVD risk factor. Studies show that a moderate to high level of fitness is associated with a halving of CVD mortality.
Diabetes mellitus is a metabolic disease present in approximately 5% of the population. Diabetics either lack the hormone insulin entirely, or become resistant to its actions. The latter condition, which usually develops in adulthood, is termed type 2 diabetes mellitus (DM2), and accounts for 95% of diabetics. Diabetes causes progressive damage to both the microvasculature and larger arteries over many years. Approximately 75% of diabetics eventually die from CVD.
There is evidence that patients with DM2 have both endothelial damage and increased levels of oxidized LDL. Both effects may be a result of mechanisms associated with the hyperglycaemia characteristic of this condition. Also, blood coagulability is increased in DM2 because of elevated plasminogen activator inhibitor 1 (PAI-1) and increased platelet aggregability.
A set of cardiovascular risk factors including high plasma triglycerides, low plasma HDL, hypertension, elevated plasma glucose and obesity (particularly abdominal) are often associated with each other. This combination of risk factors is closely linked to, and could arise as a result of, insulin resistance. Individuals with three or more of these risk factors are said to have metabolic syndrome.
Atherosclerosis can be viewed as a chronic low-grade inflammation which is localized to certain sites of the vascular wall. This causes the release into the plasma of numerous inflammatory mediators and related substances. Many studies have shown that an elevated serum level of one of these, the acute phase reactant C-reactive protein (CRP), is predictive of future CVD, although recent epidemiological studies, which have taken advantage of the fact that differences in the basal levels of serum CRP occur naturally in the population due to genetic variation, show that CRP does not cause CVD. Although proposed to be a potentially valuable risk marker that could be used to predict future CVD (and therefore indicate the need for preventative treatment) even in apparently healthy people with low LDL, many question whether
CRP levels are truly independent of other established risk factors (e.g. metabolic syndrome).
Tobacco smoking causes CVD by lowering HDL, increasing blood coagulability and damaging the endothelium, thereby promoting atherosclerosis. In addition, nicotine-induced cardiac stimulation and a carbon monoxide-mediated reduction of the oxygen-carrying capacity of the blood also occur. These effects, coupled with an increased occurrence of coronary spasm, set the stage for cardiac ischaemia and MI. Epidemiological evidence suggests that CVD risk is not reduced with low tar cigarettes.
High plasma levels of homocysteine, a metabolite of the amino acid methionine, are proposed to be a CVD risk factor, although the evidence for this association is controversial. Hyperhomo cysteinaemia may increase cardiovascular risk by causing overproduction of the endogenous endothelial nitric oxide synthase (eNOS) inhibitor asymmetrical dimethyl arginine (ADMA; see Chapter 24), because homocysteine can serve as a donor of methyl groups that are enzymatically transferred to arginine to form ADMA.
Epidemiological studies show that psychosocial stress (e.g. depression, anxiety, anger) can substantially increase the risk of the development and recurrence of CVD. For example, the INTERHEART study reported in 2004 that people who had had an MI were more than 2.5 times as likely to report pre-existing psychosocial stress than age-matched controls. Although the reasons for this have not been definitively established, it is known that negative emotions can result in activation of the sympathetic nervous system (which can cause various deleterious effects on the cardiovascular system including a raised blood pressure and more frequent cardiac arrhythmias), and also that anxiety and depression engender unhealthy lifestyles. This may be of great importance for CVD management; one meta-analysis of 23 clinical trials reported that patients who had an MI were more than 40% less likely to die or have another MI over the next 2 years when given interventions designed to reduce psychosocial stress.
Fixed risk factors
Family history of CVD
Numerous epidemiological surveys have shown the existence of a familial predisposition to CVD. This arises in part because many CVD risk factors (e.g. hypertension) have a multifactorial genetic basis (are due to multiple abnormal genes interacting with environmental influences). Additional deleterious genetic influences are also probably involved, because the familial predisposition remains if epidemiological data are corrected for known risk factors. For example, the angiotensin-converting enzyme (ACE) gene can exist in two forms, characterized by the insertion or deletion of a 287-base-pair DNA segment within intron 16. Those homozygous for the deletion polymorphism have higher plasma ACE concentrations, which may modestly increase the risk of MI.
Middle-aged women are much less likely than men to develop CVD. This difference progressively narrows after the menopause, and is mainly oestrogen mediated. The potentially beneficial actions of oestrogen include acting as an antioxidant, lowering LDL and raising HDL, stimulating the expression and activity of nitric oxide synthase, causing vasodilatation and increasing the production of plasminogen.