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.
Male sex
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.
