Cardiovascular risk and risk reduction: a review of recent literature.

An account is given of recent literature regarding the major cardiovascular risk factors. It considers high blood pressure, high blood cholesterol, smoking, as well as insulin resistance and its metabolic consequences. The focus is on the current available evidence in terms of causal associations of these risk factors with the occurrence of cardiovascular disease, and the evidence of the benefits of risk factor lowering. The multiplicative effect of risk factors and their multifactorial role in the genesis of cardiovascular disease is now firmly established and will affect the mode of approach to preventive measures. The main preventive options currently available are twofold, a population-wide approach and a high risk approach. The suitability of primary health care as one of the main providers of preventive care is today widely acknowledged. The need for cardiovascular risk assessment to be multifactorial and made in terms of overall actual risk is of paramount importance. The implications of this overall issue for countries like those of the Middle East, where the prevalence of cardiovascular disease is on the rise, are of great concern.

INTRODUCTION

Atherosclerosis is a very old disease, which has been found in the mummies of Egyptian pharaohs. It is a pathological entity and its clinical counterpart is cardiovascular disease (CVD). Only in recent times have its consequences reached epidemic proportions, mainly in Western affluent societies, although that epidemic is breaking through to other non-Western populations today. The clinical manifestations of atherosclerosis are manifold, but still constitute only the tip of the iceberg. To some extent atherosclerosis is universal, the pathogenesis is complex, but it is likely that more than 90% of the facts about the processes involved are now known, although how these facts fit into an overall comprehensible framework is less understood1.

In the developed world cardiovascular disease (CVD) accounts for almost half of all deaths. In some of the countries there has occured a decline in mortality in recent times, whereas in other countries it has increased2. When crude death rates drop below 15 per 1000 persons and life expectancy at birth increases to 55-60 years, the proportion of mortality due to CVD approaches 20-25%, and non-communicable diseases become a major public health problem3. This has become the case in the Eastern Mediterranean Region4. In light of the proportionately large part of the total disease burden, fatal and non-fatal, played by cardiovascular diseases it has become increasingly important to try to forestall that trend.

THE RELATION OF EXPOSURE TO RISK

Blood pressure - diastolic:

One of the first studies to implicate blood pressure was the Framingham heart study in the US, wherein a cohort of 5070 men and women aged 30-62 years have been followed up since the late 1940s5. In a landmark review of the evidence MacMahon et a16 pooled the results of nine major prospective observational studies, including a total of 420,000 individuals with 843 strokes and 4856 coronary heart diseases (CHD) events as end-points. They had a mean follow-up period of 10 years. By correcting for within-patients fluctuations of diastolic blood pressure (DBP) over time (regression dilution bias) MacMahon et al were able to show that these previous studies had underestimated the true association between DBP and risk of stroke and CHD events by about 60%. Their analysis also showed that within the range of DBP studied (70-110 mmHg) the risk of raised DBP was continuous and graded, without any evidence of any threshold below which lower levels of DBP were not associated with lower risk of stroke and CHD. Thirdly and not the least, prolonged differences over time in DBP of only 5 mmHg was shown to be associated with at least 34% less stroke and at least 20% less risk of CHD. These pooled results of epidemiologic data have come to be an important milestone in the search for evidence, linking blood pressure with risk of CHD and stroke.

Blood pressure - systolic:

The risk marker of blood pressure had for long been thought to be only the level of DBP. The Multiple Risk Factor. Intervention Trial group (MRFIT) study7 in the US is the largest single cohort study which has ever been done. It was designed as a randomised, multicentre primary prevention trial to study the effect of a risk factor intervention, relating to blood cholesterol, blood pressure and cigarette smoking. An analysis of its data set8 regarding the association between blood pressure and CHD showed a strong, continuous, and graded relationship of not only DBP but of systolic blood pressure (SBP) as well. In terms of relative risk for CHD, the data show that the lowest risk is seen at levels of less than 120 mmHg for SBP, and less than 80 mmHg for DBP. Furthermore SBP came out as being the stronger predictor for CHD. This finding is also supported by similar results from the Framingham cohorts5.

The diet-heart hypothesis and total blood cholesterol:

From the late 1940s onwards an extensive body of scientific knowledge implicates diet rich in animal fat (high-saturated-fat) in the atherosclerotic process, mediated through raised blood cholesterol. It constitutes a wealth of prospective epidemiological studies throughout the world as well as clinical angiographic correlations, postmortem investigations, and animal experiments. Many clinical trials of cholesterol lowering in persons with elevated cholesterol levels, also provide supportive evidence for these causal associations791011 The MRFIT and Framingham data711 demonstrate once again, as for BP, a strong, continuous, and graded relationship between risk for CHD and level of blood cholesterol, with a clear risk gradient above the level of 4.65mmo1/L. Much in line with MacMahon et al, another group of investigators Law MR et a112 by following up a cohort of 21 520 men, applied similar methodology and their overall findings were, that the observed difference in mortality from CHD, given a difference over time of 0.6 mmol/L in total serum cholesterol concentration, corresponded to 27% lower mortality rate from CHD.

Taken together, these results strongly support the so called ‘lipid hypothesis of atherosclerosis’. That theory encompasses the concept that the quantity and composition of the diet's fat content will alter blood total cholesterol and low-density lipoprotein levels (LDL), and this in turn will alter risk of CHD13.

Smoking:

Cigarette smoking has been consistently related in a dose-responsive manner to the development of fatal and non-fatal CHD events and the available evidence suggests that smoking may act as a triggering effect, rather than as a necessary underlying substrate for CHD14. The health hazard of cigarette smoking is now fully documented and the evidence for a causal role in cardiovascular disease is beyond any doubt15.

Diabetes Mellitus:

Diabetes accelerates atherogenesis and increases the risk of CHD, particularly in women. The age-adjusted mortality rates for CHD are 2-3 times higher for men, and 3-7 times higher for women with diabetes than among people without diabetes16. Other macrovascular sequelae are also greatly increased in diabetes. In non-insulin dependent diabetes (NIDDM) the association with heart disease is complex and is thought to be mediated through what has come to be known as ‘the insulin resistant syndrome’ (see below).

Insulin Resistance

A common clinical observation is the clustering of several risk factors in one individual. Reaven in 1988, postulated that insulin resistance and compensatory hyperinsulinaemia underlie this clustering and he coined the term “Syndrome X” (or the “insulin resistance syndrome”)17. That term entails the concept of a metabolic syndrome, wherein insulin resistance is the primary event, leading to the secondary events of hyperinsulinaemia, impaired glucose tolerance (IGT), hypertriglyceridaemia, low HDL and hypertension. Insulin resistance can be defined as a state of subnormal biological action of insulin and the defect is primary, tissue specific (mostly involving skeletal muscle) and involves reduced glucose disposal in the skeletal muscle cells18.

There is now abundant evidence that the insulin resistance syndrome predisposes individuals to develop this cluster of associated abnormalities that increase the risk of CHD19. Insulin resistance may be genetic and/or acquired. A strong genetic basis is suggested by the high prevalence of insulin resistance, diabetes (NIDDM) and cardiovascular risk in certain racial groups, although environmental factors play an important role.20–21

Obesity

Obesity has been associated with the development of insulin resistance22, but excessive calorie intake and obesity are not the sole cause, as it has been observed that 25% of non-obese individuals with normal glucose tolerance also have insulin resistance17. Kaplan23 discusses the importance of the distribution of fat (upper body obesity, or central obesity), as opposed to total body fat, as having a stronger association with the development of CHD, mediated through hyperinsulinaemia. Therefore, reference to body mass index alone as an index of obesity is inadequate because this central distribution of fat is most strongly associated with insulin resistance18.

THE MULTIPLICATIVE EFFECT OF RISK FACTORS

Using data from the MRFIT study Stamler and Neaton8 demonstrate clearly the additional impact blood pressure has on CHD risk, when other risk factors like cholesterol and smoking are present. The impact is not only additive but multiplicative. The evidence is also supported by the Framingham data. This multiplicative effect of the risk factors has important implications for preventive measures.

THE MULTIFACTORIAL GENESIS OF CVD

It is clear that CVD in general and CHD in particular are multifactorial and their clinical manifestations reflect the interaction of host and environmental factors, nature versus nurture. The WHO MONICA Project has recently published its first results regarding cross sectional surveys of cardiovascular risk factors in various populations of the developed world. The results show that there exists an enormous variation in terms of morbidity caused by these diseases in the developed countries, and that the accepted cardiovascular mortality risk factors do not reflect well the variation in mortality between populations2425. On a population level the relation of blood pressure and smoking to CHD is found to be irregular, whereas its relation to stroke is much closer, particularly for blood pressure. Regarding blood cholesterol level there is no longer a need to argue that mass CHD in a population can only occur in the presence of elevations of the mean blood cholesterol26. The MONICA Project however, does not address the developing world, whereas other recently published papers have, by studies of Asian migrants and other ethnic groups20–2127–29. The findings of these latter papers suggest that insulin resistance with clustering of diabetes, dyslipidaemia (raised triglycerides and low HDL), hypertension and obesity, in those populations, are main risk factors for an ever increasing epidemic of CHD.

THE BENEFITS OF RISK REDUCTION

High blood pressure:

To see whether the observed benefit of lowering DBP by 5-6 mmHg, shown in MacMahon's overview6 could be translated into similar results in the known clinical trials at that time, the same group headed by Collins R30 undertook a similar overview of 14 randomised trials of antihypertensive drugs. It included 37,000 individuals, mean treatment duration 5 years and mean difference in DBP 5-6 mmHg. The result showed that the expected reduction of stroke incidence was borne out by a reduction of 42%, but regarding CHD the expected reduction of 20-25% was only reduced by 14%. Thus the large hypertension intervention trials of the past 20 years have demonstrated a disappointing effect in terms of lowering cardiovascular risk, except for stroke. Several possible explanations for this have been put forward. Firstly, the adverse effects of the antihypertensive agents used in these trials (mainly betablockers and diuretics) on the blood lipid profile and other metabolic variables such as glucose and potassium31–32. Secondly, the multifactorial effect of the insulin resistance syndrome17. Thirdly, a delay of the full benefit of the antihypertensive treatment given is possible, given too short a follow up period of the trials.33

High blood cholesterol:

In order to estimate whether lowering of blood cholesterol could actually reproduce the results of their earlier overview, Law et al pooled the results of 10 large prospective (cohort) studies, three international prospective (epidemiological) studies and 28 randomised controlled (interventive) studies34. The 10 cohort studies included 494,804 men and recorded 18,811 CVD events, whereas the 28 randomised clinical trials included 46,254 men and recorded 4241 events. The analysis of the 10 cohort studies concluded that a 10% (0.6 mmol) reduction in total cholesterol translates into a 50% reduction in the risk of CHD at the age of 40, successively diminishing in benefit as age increases, to 40% at 50 years and 30% at 60 years of age. The overall results of 27% from their earlier study12 was largely borne out by their pooled analysis.

Insulin resistance:

If the present observational epidemiologic evidence regarding the joint risk effect of the metabolic consequences of insulin resistance and obesity hold true, then the rationale of reducing central obesity and increasing physical activity becomes obvious182127. But to that end there do not exist any controlled clinical interventive trials to this day.

The excess cardiovascular risk associated with cigarette smoking has been shown to decrease markedly after quitting smoking, in primary as well as secondary prevention14–15.

Regression of atherosclerosis:

What is the evidence for regression of atherosclerosis? Adequately controlled, serial coronary angiographic studies have been appearing in the literature since 1984. Most of them have focused on lipid modification by drugs, although a few have dealt with life style changes. In a recent overview of eight key serial angiographic trials relating to lipid intervention Howes LG et al show that stabilisation or regression of atherosclerosis does occur with the use of lipid-regulating therapy.35–36 These authors also state that some trial results show that this may translate into improved clinical outcomes.

PREVENTIVE STRATEGIES

Rose G37 came forward with the terms of ‘population strategy’ versus ‘high-risk strategy’. The variance between populations in terms of population average demonstrates how the distribution curve of the various risks within each population is simply a function of its population mean and those individuals who deviate are simply the tail of the population's own distribution. From this line of reasoning it follows that preventive measures can be laid out as a two-pronged strategy, shifting the whole distribution curve downwards, to the left, or shifting high-risk individuals out of the danger zone (see diagram).

There is now a converging consensus internationally that the two-pronged preventive strategy, as outlined by Rose, is the most cost-effective strategy available today.

International and national bodies have identified primary health care (PHC) as the appropriate setting in which to implement this strategy38–40. The personnel in PHC are well placed in order to use the opportunities of clinical contacts to identify individuals, who are at special risk for future disease. Rose G41 argues that the implication of this is an uncomfortable one for many countries; namely, the effective delivery of preventive medicine to individuals requires an efficient system of PHC.

RISK ASSESSMENT

Putting the high risk strategy into action entails sorting out those who are high risk cases. Apart from deciding on the appropriate cut-off level between cases and non-cases in terms of a specific risk factor, we are faced with the dilemma of assessing the individual's actual risk of future disease. It has been high-lighted recently how imperative it is to assess cardiac risk in terms of overall risk, taking into account the multiplicative effects of the known risk factors, as well as aiming for those with the highest risk323942–45

CONCLUSION AND RECOMMENDATIONS

An account has been given of the cumulative and the impressive evidence of the major cardiovascular risks. The major risk factors have been delineated and evidence given for their continuous and graded effect on CVD risk. The common occurrence of clustering of these major risk factors in the individual has been pointed out, as well as their joint multiplicative deleterious effect in terms of increased incidence of CVD.

The overall strategy in combating the cardiovascular diseases has been portrayed as a population versus high-risk strategy. Heart disease incidence depends on how people live, and so it follows that progress in prevention depends on social, economic, and political decisions; as well as on the successful communication of our medical knowledge. By sound impartial advice, physicians can guide and assist in those decisions. Primary health care is well suited as a venue to that end. The need for a multifactorial approach is stressed, as well as an assessment of the overall cardiovascular risk in as much a quantitative and real terms as possible.

Many of the developing countries, like those of the Middle East, have experienced rapid socioeconomic changes over the last two decades and most of the aforementioned risk factors have become highly prevalent. For instance, obesity, high blood pressure, high blood cholesterol and diabetes are increasingly encountered. The prevalence of diabetes is among the highest in the world in the Arabian peninsula46–47 Apart from excessive caloric intake and sedentary life-style, cigarette smoking is an important health hazard issue to address.

An effective infrastructure within primary health care, along with population-wide health counselling is of primary importance, in regard to counteracting the deleterious long-term effects and premature death of cardiovascular disease.

In a second paper the present author will describe how, the department of Family and Community Health at the Sultan Qaboos University in Oman, addresses the practicalities of implementing a preventive strategy along the lines presented in this review.