Q J Med 2000; 93: 477-485
© 2000 Association of Physicians
Commentary papers |
The thyroid, blood flow and atheroma
Introduction
This paper aims to demonstrate how thyroid function and other conditions that affect blood flow influence the development of atheroma. Blood flow in larger vessels varies with the cardiac output. Blood flow in the capillaries is affected by viscosity changes. The mechanisms that affect the flow in large and small vessels may summate. Overt changes in thyroid function clearly affect blood flow, but are less apparent in subclinical hypothyroidism (SCH). SCH is defined as impairment of thyroid function associated with normal thyroxine (T4) and tri-iodothyronine (T3) hormone concentrations, but either a raised basal thyrotrophin (TSH) concentration or an exaggerated response of TSH to thyrotrophin-releasing hormone (TRH).
Three views have been held regarding SCH as a risk factor for coronary heart disease (CHD). Some workers have failed to find an association between the two conditions.1–4 A second view is that an association with CHD results from abnormal serum lipids found in SCH.5–10 The third view is that SCH is a risk factor for CHD unrelated to any lipid abnormality that may be present.11–13 These different views may be due to a number of problems.
Problem 1. Selective mortality. Bias is produced by selective mortality in cross-sectional studies when death from CHD is the end-point. Selective mortality also occurs when lipid studies are made in patients with a raised TSH compared with TSH measurements made in groups of patients with lipid abnormalities.7–9 Young men with thyroid antibodies and angina were reported from the town of Busselton in Western Australia14 whereas CHD and autoimmune thyroiditis is found in elderly women from Brussels.15
Problem 2. There is the paradox that more severe impairment of thyroid function leads to earlier recognition and treatment with thyroxine, whereas those with minimal impairment over a prolonged period are more likely to show an association between CHD, hypercholesterolaemia and SCH.
Problem 3. Lipid abnormalities may be subtle. One study has shown that thyroxine replacement in SCH restored a reduced concentration of high-density lipoproteins (HDL) cholesterol to normal on treatment while the total cholesterol was unchanged.16
Problem 4. It has been claimed that SCH is too uncommon to be a risk factor for CHD, but TSH concentrations even within the normal range have been shown to affect lipids and blood flow.17,18
Problem 5. Three groups of workers have shown a definite association between impaired thyroid function and CHD where the association did not appear to be related to lipid abnormalities. Bastenie's group found the association in a prospective study, after failing to do so in a cross-sectional study.11 Burgi's group did not find a high serum cholesterol in his subjects with a raised TSH, but a raised TSH was an independent risk factor for CHD more important than a high serum cholesterol.12 The third and most recent published work has been an epidemiological study in Rotterdam which confirmed SCH as an independent risk factor as important as all other risk factors for CHD.13 In none of the three studies has a reduction in blood flow in the macro-circulation been considered. Cardiac output decreases not only in overt hypothyroidism, but also in SCH.19 Changes in the micro-circulation have been suggested in the discussion of the Rotterdam study.13
The consensus of the American Thyroid Association20 and authorities in the UK now favours the treatment of SCH.21
Physiology of blood flow
Fluid flows in a columnar fashion. The most rapid flow is in the centre, and diminishes in the adjacent columns of blood until the vessel wall is reached, where shear forces are greatest. Flow closest to the vessel wall may be virtually at a standstill. The use of the term ‘friction’ is inadequate since it implies a negative process, whereas the shear forces are positive. This will be considered further under hypertension and serum lipoproteins. Resistance to flow in small vessels is related to blood viscosity. Blood behaves as a non-newtonian fluid—the relation between different shear rates and viscosity is not linear. In a homogeneous fluid, there is a linear correlation between viscosity and shear rates, with the linear slopes differing according to the fluid.
Pathology of blood flow
Impaired blood flow—cause or effect?
Virchow believed that intimal damage in arteries was followed by infiltration of lipid into the vessel wall which leads to narrowing, impaired flow and subsequently the development of thrombosis. Harland22 points out that Rokitansky and Duguid believed that the initial lesion was thrombus which became incorporated into the intima to produce the atheromatous lesion. In other words, the impaired flow was the initial cause of the atherosclerotic lesion, against the view that the impaired flow was the consequence rather than an initiator of atherogenesis. Virchow's opinion is usually accepted, but an initial impairment of flow may be of critical importance and influenced by thyroid function. The two views are not mutually exclusive.
Distribution of atheroma
Atheroma tends to develop where the blood flow is relatively sluggish. The greater curvature of the transverse thoracic aorta is relatively free of atheroma and increased on the inner curvature where flow is sluggish.23 The effect of stasis has also been shown by the advanced atheroma in false channels of chronic aortic dissection (with no atheroma in the true lumen) of patients with normal serum cholesterol concentrations.24 Lesions in the right coronary arteries are concentrated on the inner wall of the curvatures.23
Altered blood flow
Conditions with increased and decreased rates of blood flow are listed in Table 1
. Conditions with a reduced blood flow tend to have more atheroma while those with an increased flow have less.
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Thyroid status
The association of SCH with CHD and peripheral arterial disease has already been discussed. Patients who have been on adequate doses of thyroxine do not develop CHD de novo,25 even when there has been no significant change in the total serum cholesterol levels. In some of these patients, there may have been an increase in HDL cholesterol without any change in total cholesterol on thyroxine replacement for SCH.16 SCH also reduces the cardiac output, which returns to normal on replacement therapy.19 Autoimmune thyroiditis, as demonstrated by the presence of circulating thyroid antibodies, tends to increase with age. It is significant that they were absent in a group of centenarians studied by Pinchera and his colleagues.26 Pinchera had already shown earlier that one third of subjects with hypercholesterolaemia had an exaggerated response of TSH to thyrotrophin-releasing hormone (TRH).27 Within the normal range of TSH concentrations, a correlation has been shown between cholesterol and TSH.17 A correlation between TSH and blood flow has also been demonstrated.18
The infrequency of CHD in thyrotoxicosis has been noted.28 The general apathy on this subject has been aptly demonstrated by leading textbooks of cardiology and thyroidology citing this reference but mis-quoting it by replacing the ‘infrequency’ by the ‘frequency’ of CHD in thyrotoxicosis.
Exercise
Reduced serum cholesterol and increased blood flow is common to exercise, hyperthyroidism and anaemia. In a study of the leisure activity of 15 171 men, heavy leisure activity was associated with lower levels of coronary heart disease, lower blood pressure and lower mean serum cholesterol levels.29 Amongst 16 882 male executive civil servants, the risk of developing CHD was about one third in men recording vigorous exercise compared with men who did not.30 Physical activity increased the level of HDL cholesterol and plasma lipids were favourably altered in both men and women after a programme of moderate exercise.31
Obesity
Obesity occurs when energy intake in the form of food is greater than expenditure in the form of exercise. One third of the daily energy used by a sedentary worker goes into muscular activity, but with hard work or exercise as much as three quarters is used up. In obesity, expenditure may be balanced by intake, but there must have been a period in the past when an imbalance led to the weight gain. The majority of patients with non-insulin-dependent diabetes and insulin resistance are also obese. The diabetes gives rise to vascular complications which will be discussed later. The unaffected action of insulin in non-insulin-dependent diabetes is the ability to convert carbohydrate to fat. When the fat stores are filled to capacity, hyperglycaemia and glycosuria occur.
Very strict dietary regimes with no emphasis on exercise can be counterproductive in the treatment of obesity. If a subject is taking virtually no calories, fat stores are consumed, leading to hypercholesterolaemia as seen in some subjects with anorexia nervosa.
Anaemia
Anaemia, like hyperthyroidism and exercise, both increases blood flow and reduces serum cholesterol levels.32 Patients with iron-deficiency anaemia, haemolytic anaemia and pernicious anaemia all have low serum cholesterol levels which rise on correction of the anaemia.32 Serum cholesterol levels in women under the age of 50 are directly related to the risk of CHD33 so that anaemia may account for the relative freedom from CHD of pre-menopausal women with menstrual blood loss. It may also explain the low instance of CHD in underdeveloped countries, where iron deficiency anaemia is common due to inadequate intake and loss due to hookworm infestation, probably the commonest disease in the world. The protection from CHD in post-menopausal women on hormone replacement therapy may well be due to withdrawal bleeding.
Gallerani and his colleagues34,35 have shown in 4401 subjects with the thalassaemia trait that CHD is very significantly reduced in men but not women. Although most causes of anaemia increase the macro-circulation by an increase in cardiac output and the micro-circulation by a decreased viscosity, thalassaemia is associated with an increase in red cell rigidity, thereby increasing viscosity.36 Clearly, the first of these two effects is predominant in subjects with heterozygote thalassaemia. If a mild reduction in the haematocrit is protective against CHD, it would be expected that a significant effect might be confined to men compared to premenopausal women in whom a reduced haematocrit is normal. Gallerani did not find either a lower serum cholesterol level or lower blood viscosity to account for the protection given to these subjects. An associated genetic effect protecting heterozygote genotype in males was suggested. The protective role of an increased blood flow was not considered.
In eastern Finland, 2682 men who donated blood were shown to be protected from CHD.47 The possible prevention of CHD in anaemic patients may be due in part to the changes in the serum lipids but more to the increased blood flow. The increased blood flow is due primarily to the increased cardiac output but also to decreased blood viscosity. The haemodynamic effect of increased cardiac output and arteriolar dilatation is an effort to compensate for the tissue hypoxia resulting from the anaemia. Decreased capillary flow in polycythaemia gives the tissues more time to take up the extra available oxygen. It is with good reason that athletes train at altitude to develop a polycythaemia or even auto-transfuse in order to obtain the advantage of polycythaemia. What is good for present physiological efficiency is not necessarily advantageous later. Numerous studies have shown that a high haematocrit is associated with an increased incidence of CHD.38–40
Diabetes mellitus
Both insulin-dependent and non-insulin-dependent diabetes develop vascular complications of the disease, but it is particularly non-insulin-dependent diabetes associated with hypertension and obesity that develops atheroma. The lipid abnormalities are probably not as severe as those seen in SCH. Increased viscosity occurs due to osmotic changes with fluctuations in the blood sugar and episodes of dehydration. Autoimmune thyroiditis is frequently associated with diabetes mellitus.41 In summary, the blood flow in non-insulin-dependent diabetes is reduced by a combination of haemodynamic forces, increased viscosity and lipid abnormalities. LDL cholesterol also increases viscosity.
Paget's disease (osteitis deformans)
In a study of thirty nine subjects with Paget's disease of bone, five had evidence of coronary artery disease, and only these five had a low or normal cardiac output, compared with the rest who had a high cardiac output.42
Smoking
One cigarette can temporarily decrease the blood flow in the leg, and smoking is a significant factor for CHD.43–46 When other risk factors are absent, CHD is uncommon despite heavy cigarette smoking. There is no significant evidence to suggest that hypercholesterolaemia results from cigarette smoking, but the profound vasoconstrictive effects of cigarette smoking decreasing blood flow may not be the only mechanism increasing the risk of CHD.47 There is an activation of platelets that adhere to the blood vessel wall, decreasing blood flow. In southern parts of Europe, where there is little relationship between smoking and CHD, warmth, by increasing the blood flow, may counteract the ill-effects of smoking, in contrast to its great influence in cold northern parts of Europe such as Glasgow and East Finland.
Geography
The British Regional Heart study showed that after adjustment for other factors, cardiovascular mortality was highest in the west of Scotland and lowest in southeast England.48 The highest mortality from coronary heart disease is in Glasgow and east Finland, whilst the lowest in Europe is in south Spain and south Italy. Populations that are relatively poor, as in Greece and Portugal, have a lower mortality rate from CHD than Finland and the UK. Warm countries will be associated with an increased cardiac output at rest and more opportunities for exercise. Grimes and his colleagues49 point out that death from coronary artery disease is more common with increasing distance of residence from the equator. Their highest figures are from northwest Scotland and northern Scandinavia. They believe that the mortality risk is related to the amount of sunshine. It is argued that sunlight deficiency could increase serum cholesterol by allowing squalene metabolism to progress to cholesterol synthesis rather than to Vitamin D. A simpler explanation is that the population closer to the equator is warmer and probably more active. The poorer countries such as in Africa may well be suffering from iron-deficiency anaemia resulting from inadequate intake and increased blood loss from hookworm infestation. The warmth, the exercise and the anaemia all causing increased blood flow is a more likely explanation than the amount of sunlight for the different mortality figures.49 Weather changes are also a rational explanation for the increased incidence of CHD in ethnic Africans and Indians resident in Europe and the USA. Grimes49 also showed that outdoor activities such as gardening are associated with a lower concentration of blood cholesterol in the summer but not in the winter, which he attributes to sunshine and vitamin D synthesis, but could equally be due to exercise and warm weather. The PRIME study could not explain the several-fold difference in risk of coronary heart disease between France and Northern Ireland. Amongst the many factors considered, there was no mention of blood flow.50 The so-called French paradox may be explained in several ways. The French diagnostic code may differ from the UK. In France, many more cardiac deaths are attributed to heart failure, while cardiac deaths in the UK are usually labelled CHD. The difference may be due to increased flow reducing CHD, but increased cardiac output leading eventually to death by heart failure. In Albania, the mortality from CHD is double in the cold northeast compared with the warm southwest but again is considered an effect of the ‘Mediterranean lifestyle’.51 Separate risk factors may summate—for example, the effects of cold are less likely to be combated by the poor, and infection is more common when poorer subjects are crowded together.
Seasonal variations in coronary heart disease
Blood flow to the skin can vary from virtually nil to 30% of the total cardiac output. Seasonal variations of CHD may again be related to the associated cold, diminished physical activity during the winter and more chance of infection. The decrease in haemodynamic flow in cold weather summates with the decrease in blood flow due to increased viscosity, often associated with infection. The increased viscosity leading to CHD appears to be associated with high packed cell volumes and platelet counts.52 Koenig and his colleagues53 compared the plasma protein pattern that causes the difference in plasma viscosity between the high levels in the west of Scotland and the low levels of viscosity in southern Germany. They suggest that this difference in the flow is a plausible explanation for the altered rates of CHD in these areas. In Taiwan, which is a subtropical area, poor thermoregulation in older people may precipitate CHD.54 The picture is made more complicated because cold causes a temporary increase in blood pressure, related to increase peripheral resistance, which in turn leads to diminished flow.55
Death from CHD is more common at night, when again blood flow is decreased.
Effect of vasodilators on CHD
Alcohol
The balance of benefit and harm from alcohol consumption, wine and other alcoholic drinks, differs between countries. The marked increase in mortality in Eastern Europe has been attributed to the increase in alcohol consumption.56 There is suggestive evidence that light drinking has a protective if slight effect on mortality from CHD.57 The explanations for this beneficial effect include an increase in high-density lipoproteins,58 antioxidants,59 stress and concomitant use of monounsaturated fat, i.e. olive oil. The obvious increased flow by a direct haemodynamic effect on the cardiovascular system is not mentioned, but there are reports of haemostatic mechanisms with reduction of platelet aggregation60 and a relaxant effect on micro-vessels.61
Nicotinic acid
Until the introduction of the statins for reducing abnormal lipids, the only cholesterol-reducing drug which had a significant effect on CHD and general mortality was nicotinic acid.59 A crucial difference between the other drugs used at that time to lower serum cholesterol and nicotinic acid was that nicotinic acid was a vasodilator and increased blood flow. The effect of nicotinic acid on the blood lipids was no more impressive than the other drugs used at that time. D-thyroxine, contaminated with L-thyroxine, was tried and abandoned. Since L-thyroxine has about five times the potency of D-thyroxine, it is not surprising that the varying thyroid effect caused alarming and dangerous symptoms.63
Other vasodilator drugs
Mortality has been reduced in hypertension by the use of ACE inhibitors, and more recently these drugs have become a recognized accepted treatment for heart failure, where mortality has again been reduced. Vasodilator drugs have been used for the treatment of angina for many years, but again they have been found to be effective in reducing heart failure mortality. The commonest cause of left ventricular failure is CHD, and vasodilator drugs may therefore have both a direct effect on heart failure and an indirect effect on CHD. The mortality reductions in several large trials have been compared by Struthers.64 He compared a 31% mortality reduction in the Consensus I trial using enalapril with a 38% mortality reduction using the vasodilator hydralazine combined with isosorbide. Data in the text conflicts with that shown in Table 2, but there is no doubt regarding the benefit of both groups of vasodilator drugs in reducing mortality rates.
The Heart Outcome Prevention Evaluation (HOPE) Study has shown the dramatic effect of an ACE inhibitor on risk of death, CHD, stroke and heart failure in high-risk patients with pre-existing disease.65 An editorial referring to the benefits of ACE inhibitors makes an illuminating statement66—‘It is overly simplistic to label these drugs vasodilators. They appear to have effects on the vasculature, heart and kidneys that go far beyond their rather small blood pressure-lowering effects’. This suggests a misapprehension by equating blood pressure with blood flow. Flow depends solely on the difference in pressure at two ends of a tube and not on any particular level of pressure at any place along that tube. An ACE inhibitor may have a profound effect on the vasculature, heart and kidneys related to an increased blood flow without any significant blood pressure changes. It is also relevant that the beta-adrenergic-blocking drugs were contraindicated in heart failure, but carvedilol has a vasodilatory effect which improves the left ventricular ejection fraction, and is now used in the treatment of heart failure.
Viscosity
Changes in the cardiac output particularly affect the blood flow in the arteries, while changes in viscosity affect the flow in capillaries. The effects are interrelated and may both be influenced by changes in thyroid function. TSH levels even within the reference range are correlated with blood flow.18
Plasma viscosity is determined by various macromolecules such as fibrinogen, immunoglobulins and lipoproteins.67 Koenig and his colleagues68 have shown that after adjustment for all the usual risk factors, the relative risk of heart attacks for men in the highest quintile for viscosity was more than three times as much as in the lowest quintile. Accepted coronary risk factors can only account for about one third of myocardial infarctions. Viscosity, particularly that due to fibrinogen may be a major independent cardiovascular risk factor.69,70 White blood cell count was also positively associated with the incidence of CHD.67 This leads to a possible mechanism for those who believe that CHD is related to infection or antibodies. The subject has been extensively reviewed by Koenig and his colleagues.67
Serum lipoproteins affect blood viscosity. This was first shown with clofibrate affecting blood viscosity in subjects with intermittent claudication.71 Initially, statins were thought only to reduce low-density lipoprotein cholesterol, but pleiotropic effects of statins include an effect on viscosity and probably improve the endothelial dysfunction which occurs in hypercholesterolaemic patients.72 This is especially apparent in non-insulin-dependent diabetes. Patients suffering from anginal pain get relief from statins much earlier than could be expected by any regression of atheromatous plaques.
Plasma viscosity and the components related to plasma viscosity have been studied in a group of 472 healthy patients referred for hyperlipidaemia of whom 40 were found to have primary hypothyroidism. The results showed that a low free T4 was associated with increased viscosity. The results suggested that free T4 may play a physiological role in the regulation of the haemostatic equilibrium in hyperlipidaemic patients, and that the low levels of free T4 are associated with a hypercoagulable state.73
HDL and LDL cholesterol
Raised total cholesterol levels are associated with an increased risk of atheroma. It is the LDL cholesterols and the triglycerides which are responsible for the development of atheroma, while HDL is protective. The HDL, because of its increased weight, will flow down the centre of the arterial stream, while the LDL will be adjacent to the lining of the vessel. The energy produced by the product of rate and weight will increase the force of the central columnar flow and influence the rate even adjacent to the vessel wall. The faster the LDL travel, the less will be their absorption by the intima. A simple analogy is the effect of a bullet on the dusty inner wall of an air-gun barrel. A high-density lead pellet will clean the barrel of dust; a low-density bread pellet will be scattered and become partially adherent to the wall. A separate but important other difference between the HDL and LDL is related to the increased resistance to flow due to the viscosity of LDL.
Effect of endothelium on blood flow
Local mechanisms only dilate small microvessels. Much of the resistance to blood flow is in upstream arterioles and small arteries. A mechanism is needed to dilate these vessels in response to increased flow in the microvessels. Increased flow from any cause will bend the endothelium in the direction of the flow, thereby releasing nitric oxide (NO) which dilates the proximal vessels. NO synthesis is diminished in essential hypertension74 and this might be primary or secondary to the rise in blood pressure. Impaired release of NO also occurs with age, smoking, hypercholesterolaemia and diabetes, for which the common denominator is atheroma.75 The varying NO secretion is probably the mechanism responsible for the flow changes described in this paper that influence the development and retardation of atheroma.
Blood flow changes due to both cardiovascular dynamic forces and viscosity will summate. It is probable that flow changes associated with varying thyroid function are a more important influence than the lipid changes which are also present with varying degrees of impaired thyroid function.
Hypertension
Although it is a major risk factor for atheroma, hypertension has been considered last because it is the only condition in which the atheroma is not obviously associated with a decrease in flow. In fact, the increased blood pressure on the vessel wall increases shear, so that while the central areas of flow are particularly fast, the flow adjacent to the vessel wall is virtually at a standstill. Sustained hypertension is due to increased peripheral resistance, but is often associated with plasma volume contraction and haemoconcentration, which also reduces flow in the microcirculation.
Future action
Evidence has been produced here to suggest that impaired blood flow in the macro and microcirculations may well be responsible directly or indirectly for the development of atheroma. In 1998, the Medical Research Council76 in a randomized trial produced the unexpected finding that warfarin significantly reduced fatal heart attacks, while aspirin significantly reduced non-fatal heart attacks. A US physician's trial77 gave similar results. Professor Born78 believes that the results were due to differences in plaque fissure size. A simpler explanation is that with impaired flow in the macrocirculation, thrombus formation is likely to occur and can be successfully treated with warfarin, preventing fatal heart attacks, whereas decreased flow in the microcirculation, usually due to increased viscosity, will lead to unstable angina, and the effect of aspirin on platelet stickiness in this group of patients will be more effective than warfarin in reducing non-fatal angina.
Warfarin has caused an increased number of fatal subdural haematomas due to trivial trauma over the past few years. Thyroxine, by increasing flow in the macrocirculation, would be a more physiological and certainly safer alternative. A large double-blind trial is needed where aspirin 75 mg daily and L-thyroxine 75 mcg daily are given together to counteract the effects of impaired blood flow in the micro and macrocirculations, respectively. Attempts in the past to initiate this research have been limited.79 CHD, the commonest cause of death in men and women, might become a rare event at very little cost.
Notes
Address correspondence to Dr P.B.S. Fowler, Shirley Holms, South Park Drive, Gerrards Cross, Bucks SL9 8JH 
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