Abstract

Coronary heart disease exhibits a winter peak and summer trough in incidence and mortality, in countries both north and south of the equator. In England and Wales, the winter peak accounts for an additional 20 000 deaths per annum. It is likely that this reflects seasonal variations in risk factors. Seasonal variations have been demonstrated in a number of lifestyle risk factors such a physical activity and diet. However, a number of studies have also suggested a direct effect of environmental temperature on physiological and rheological factors. We review the available evidence on seasonal variations in coronary heart disease and possible explanations for them.

Introduction

Seasonal variations have been observed in coronary heart disease (CHD), cerebrovascular disease and respiratory disease.1 These are all characterized by a winter peak and summer trough. In England and Wales, the winter peak in coronary and cerebrovascular disease accounts for an additional 20 000 deaths per annum.2 Higher winter rates of cardiac events have been demonstrated in both the northern and southern hemispheres.3–10

Consensus is lacking on whether seasonal variations in CHD mortality reflect variations in incidence or survival. Variations in admission rates and trial recruitment of patients suffering from myocardial infarction (MI) have been cited as evidence of a seasonal variation in incidence.11–13 However, seasonal variations in death are greater than those in admission,1 suggesting that survival also varies throughout the year. Although Enquselassie et al. demonstrated winter peaks in both CHD deaths and non-fatal MIs, CHD events were more likely to be fatal when the temperature was low.14 In the study by Enquselassie et al., temperature did not influence whether those deaths which did occur were sudden or occurred more than one day following the onset of symptoms.14 By contrast, Douglas et al.1 demonstrated greater seasonal variations in out-of-hospital mortality than in-hospital mortality.

The seasonal variation in CHD incidence and mortality is likely to reflect seasonal variations in one or more risk factors. The risk factors proposed by investigators have included: (i) environmental factors such as temperature and ultraviolet (UV) radiation; (ii) lifestyle risk factors such as diet, obesity, exercise and smoking; (iii) other risk factors such as blood pressure, serum cholesterol level, coagulation factors and glucose tolerance; and (iv) acute and chronic infections.

Environmental risk factors

Temperature

The geographical variation observed in CHD mortality cannot be fully explained by differences in the prevalence of known risk factors.15,16 Therefore, it has been postulated that the residual variation may be due to differences in environmental temperature. This is supported by a positive association between CHD mortality and distance from the equator.15,17,18

Rose demonstrated that temperature changes could account for practically all of the seasonal variation observed in CHD deaths.13 Furthermore, there was no evidence of a threshold effect. Fyfe et al. also demonstrated a strong negative correlation between mean monthly temperature and CHD mortality.19

In some patients, angina is known to be precipitated by exposure to cold weather. Lower environmental temperature may exert a direct effect on the heart13,20–22 or have an indirect effect via changes in blood pressure.23

Generalized cooling of the body surface of unclothed subjects has been shown to cause peripheral vasoconstriction and to increase cardiac output, blood pressure and circulating noradrenaline.24 In some subjects who suffer from angina, localized cooling of the face whilst wearing protective clothing can also cause peripheral vasoconstriction, bradycardia, an increase in forearm vascular resistance and a reduction in maximum exercise capacity.25,26 This response does not occur in normal subjects,27 nor after cooling of the abdominal skin of subjects with angina.25 The effect is thought to be mediated via the vagus nerve through a mechanism akin to the `diving reflex' found in babies and some mammals.25

Cold is associated with both a higher systolic and diastolic blood pressure.28–30 This causes an increase in oxygen consumption by the heart. In patients whose coronary circulation is already compromised this extra demand may produce myocardial ischaemia and, therefore, angina pectoris or MI. In Britain, winter blood pressures exceed summer blood pressures by around 5 mmHg.31 Sustained blood pressure differences of this order have been associated with a 21% increase in CHD events.32

A number of studies suggest that CHD mortality is more strongly associated with the amount by which temperature deviates from average rather than its absolute value.8,33,34 Also, pertinent are the speed at which temperature falls35,36 and the duration of cold weather.6,20,22,37 In addition to cold temperatures being implicated as a contributor to CHD mortality, an association with extreme high temperatures has also been demonstrated in a number of studies.33,34,38–45

It has been suggested that temperature has a dual impact on CHD mortality. Extreme cold or hot temperatures at variance with seasonal norms result in an early increase in CHD mortality which peaks between 1 and 4 days after the temperature change occurs, while the sustained low temperatures normally associated with winter result in a general increase in CHD mortality over this period.6,8,20

If the association between temperature and CHD is causal, temperature insulation should exert a protective effect. Seasonal variations in CHD mortality differ in magnitude across Europe. Variations are least in countries such as those of Scandinavia, which have strict building regulations, and Iceland, which has ready access to plentiful natural energy resources.46,47 In a study comparing six regions in Europe, CHD mortality was independently associated with low living-room temperatures, limited bedroom heating, a low proportion of people wearing hats, gloves and anoraks, and inactivity.48

Despite the above evidence, a number of observations cast doubt on a causal association between seasonal variations in temperature and seasonal variations in CHD. Living at higher altitude is associated with both exposure to lower temperature and a reduced incidence of CHD.49–51 Also, the seasonal variations in CHD demonstrated in northern and southern hemisphere countries are also observed in equatorial countries where the temperature range is much lower.52 As a result, a number of investigators have suggested varying exposure to UV radiation as an alternative hypothesis.

Ultraviolet radiation

Most of our vitamin D is synthesized by the skin following exposure to UV radiation. Several studies have demonstrated lower levels of vitamin D metabolites in subjects with CHD.10,53,54 Higher exposure to UV radiation in summer may, therefore, protect against CHD events.

CHD patients have been shown to have significantly lower levels of 25-hydroxy-cholecalciferol (25-HCC) in both the summer53 and winter.10 However, Lund et al. demonstrated that the seasonal variations in 25-HCC present in normal subjects were less pronounced in those with CHD.53 Scragg observed some evidence of a threshold effect, with CHD risk decreasing from the bottom to second quartile of 25-hydroxyvitamin D3 level but plateauing thereafter.10 The association between vitamin D levels and CHD has been shown to be independent of smoking, body mass index, treatment for hypertension, vigorous leisure activity, total serum cholesterol and a previous history of angina or MI.10

Lifestyle risk factors

Diet and obesity

Body weight varies by season, with obesity being more common in winter months.55–57 This may in part reflect a higher fat intake in winter,55,56,58 although some investigators have demonstrated no seasonal variations in dietary fat.59 Even in those studies which have demonstrated greater fat intake in winter, this has been insufficient to account entirely for seasonal variations in weight,55,56 suggesting that lower levels of activity may also be a factor. Vitamin C intake and levels are also lower in winter than in summer.60,61

Exercise

Regular physical activity is associated with a reduced risk of CHD, but the benefits reduce within a few weeks of cessation.62–64 Many physical activities are only undertaken at certain times of the year and may, therefore contribute to the seasonal variation in CHD risk. In both sexes, overall levels of physical activity are significantly higher in summer than in winter.65

Magnus et al. demonstrated that physical activities such as walking, cycling and gardening only protect against acute coronary events if undertaken throughout the year. Activities undertaken on a seasonal basis conferred no significant benefit.66

Whilst regular exercise is beneficial, unaccustomed exertion may produce a deleterious effect. In Toronto, coronary deaths in men under 65 years increased by 85% following a snowfall.67 This was attributed to people unaccustomed to exercise being required to shovel snow. A number of studies have shown that more deaths have been associated with shovelling snow than would be expected from the time spent on this activity.68–72 Sudden deaths are more often associated with high levels of physical activity in cold temperatures than they are in warm temperatures.72

Smoking

Entrican demonstrated seasonal variations in cigarette sales, with a large increase in winter.57 However, sales may or may not be indicative of consumption.

Other risk factors

Serum cholesterol level

It has been suggested that vitamin D may simply be a confounding factor in the association between cholesterol and CHD risk. High blood cholesterol levels confer an increased risk of CHD.73–75 Furthermore, the fact that CHD risk is reduced by lowering cholesterol levels suggests that this association is causal.76,77

Cholesterol and vitamin D are structurally similar and have a common precursor: squalene.78 It has been postulated that the relative amounts of cholesterol and vitamin D produced may be influenced by exposure to sunlight, resulting in higher cholesterol levels in populations exposed to less sunlight.59 This is corroborated by the findings of a correlational study involving ten towns which demonstrated a strong positive association between latitude and mean blood cholesterol, and a strong negative association between hours of sunshine and CHD mortality.59 Further evidence is provided by the fact that a number of investigators have shown cholesterol levels are higher in winter and lower in summer.19,55,56,59,68,79–82 Keatinge et al. demonstrated that mild body surface cooling produces significant increases in both low-density lipoprotein (LDL) and total cholesterol levels.23

The theory linking sunlight exposure and CHD risk appears to be refuted by the finding that CHD mortality rates vary within relatively small geographical areas where climates are similar.83,84 Within these areas, mortality tends to be inversely associated with social class. It is usually assumed that this reflects differences in lifestyle risk factors such as cigarette smoking. However, CHD mortality is associated with social class gradient in Sweden, where cigarette consumption varies little by social class.85 Therefore, Grimes et al. proposed an alternative hypothesis that the variations in CHD mortality were, in part, due to social class differences in sunlight exposure due to differences in garden ownership, affordability of holidays and participation in outdoor recreational activities.59 Seretakis et al. suggested the complementary hypothesis that social class differences in CHD mortality reflect the inability of poorer people to control the temperature of their microclimates to the same extent.86

Coagulation factors

A number of haematological parameters vary throughout the year, including haemoglobin level, erythrocyte sedimentation rate (ESR), haematocrit, fibrinolytic activity and the percentage of adhesive platelets.87–89

In vitro and in vivo experiments suggest that a reduction in temperature results in increases in platelets, red cells, and viscosity and a reduction in plasma volume.90–93 The winter rise in fibrinogen concentrations is likely to be due to both lower temperatures and an increase in the prevalence of respiratory infections.90,93 The magnitude of rise in fibrinogen which occurs in winter is around half that attributed to smoking.90

A possible link between coagulation factors and seasonal variations in CHD is supported by the fact that seasonal variations are also evident in cerebrovascular disease and venous thromboembolic disease.46,55

Bull et al. suggested that the early increase in CHD mortality occurring within days of a fall in temperature may be mediated through thrombotic effects,21 while Keatinge et al. suggested that the sustained increases in blood pressure which occur in winter months may be attributed to increases in blood viscosity.23

Glucose tolerance

Fasting blood glucose and insulin levels are lower in normal subjects in summer than winter.94

Acute and chronic infections

Acute respiratory infections

Both CHD and respiratory infections demonstrate a winter peak. Cold temperatures increase the risk of respiratory infection through the suppression of immune responses and a direct effect on the respiratory tree.95,96

Respiratory infections have been implicated as a contributor to seasonal variations in CHD mortality through two mechanisms. Firstly, respiratory infections may increase the risk of developing or dying from CHD. Secondly, patients with CHD may be more vulnerable to developing or dying from respiratory infections, and these deaths may then be attributed to CHD.

A number of studies have demonstrated an association between acute respiratory infections, such as influenza, and CHD.97–101 It has been suggested that respiratory infections increase the risk of arterial thrombosis through an increase in plasma fibrinogen92 and endotoxin inhibition of fibrinolysis.102

Marshall demonstrated that the association between CHD and respiratory deaths was only significant in very elderly patients in whom coding of the cause of death was unlikely to be accurate.102 In many countries, CHD mortality and morbidity are between 30% and 50% higher in winter than in summer.13,20,104–106 This is of a similar magnitude to the decline in CHD mortality observed in these countries.107 Deaths due to respiratory disease have also declined but the decline has lagged behind that in CHD.108 Therefore, Cooper et al. concluded that the decline in respiratory disease was unlikely to have caused the decline in CHD mortality but may, in fact, have resulted from it, due to a decreasing number of susceptible individuals.108

Chronic infections

Studies have suggested links between CHD and a number of specific microbial agents. CHD is associated with the presence of antibodies to both Helicobacter pylori and Chlamydia pneumoniae, and both bacteria have been detected in atherosclerotic plaques.109–111 The evidence for an association with cytomegalovirus or Coxsackie virus is weaker.

Microbial agents may exert a direct effect on the endothelium or smooth muscle of the arterial wall,112–114 or have an indirect effect on plaque progression or rupture through changes in cross-reactive antibodies,115,116 lipid levels,110,117 or coagulation factors.111

The evidence that any of these agents play a role in the seasonal variations observed in CHD is weak. Helicobacter pylori is associated with the development of peptic ulceration which, as with CHD, exhibits a winter peak.118,119 Moshkowitz et al. demonstrated a winter peak in levels of Helicobacter pylori and proposed a causal link.120 However, this is refuted by some other investigators.118,119

Susceptibility rhythms

As previously mentioned, seasonal variations occur in places with very different climates. Smolensky et al. suggested that this could be explained if they resulted from susceptibility rhythms rather than environmental changes.121 He used as evidence the well-recognized hormonal and physiological changes which occur over 24-h and 28-day cycles. Some supporting evidence comes from the presence of circannual rhythms in a number of hormones including corticosteroids,122 catecholamines,23,24,123 thyroid hormones,1 and testosterone.124,125

Age and sex

Seasonal variations are not consistent across age and sex groups. Winter peaks in CHD mortality increase with age.1 This is likely to reflect a combination of factors including poorer autonomic control, lower levels of physical activity, less use of protective clothing, greater time spent at home, and poorer household heating and insulation. Younger age-groups exhibit a spring peak in addition to the winter peaks seen in other sub-groups.12,14,105 This is particularly prominent in younger men.

Time-trends

Seretakis et al. demonstrated a time-trend in the seasonality of disease in the USA. Between 1938 and 1991, the winter-summer total death ratio declined by about 2% per annum.86 The decline was less in the more southern states where winters were milder. Seretakis et al. suggested that this is likely to reflect improvements in indoor and vehicular heating and air-conditioning, and suggested that it may have contributed to the overall decline in CHD mortality.86

Conclusions

It is unclear whether the excess deaths which occur in winter reflect avoidable deaths or merely slightly premature deaths which would have occurred anyway within a short period of time. Identifying and rectifying those factors associated with seasonal variations will only impact on overall mortality if the former is true.

Clearly, emigration is not an option for most of those who have or are at risk of developing CHD. However, the evidence suggests that a number of simple precautions to reduce the risk of dying from CHD in winter could be taken. These include adequate indoor heating, wearing protective clothing, especially outdoor protection of the face, and avoiding unaccustomed strenuous exercise. Attempts should also be made to ensure that our lifestyles, in relation to diet, regular exercise and smoking, are at least as healthy in winter as they are in summer.

References

1
 Douglas AS, Allan TM, Rawles JM. Composition of seasonality of disease.
Scot Med J
 
1991
;
36
:
76
–82.
2
 Anon. Death in winter.
Lancet
 
1985
;
2
:
987
–8.
3
 Ahlbom A. Seasonal variations in the incidence of acute myocardial infarction I Stockholm.
Scand J Soc Med
 
1979
;
7
:
127
–30.
4
 Anderson TW, Le Riche WH. Cold weather and myocardial infarction.
Lancet
 
1970
;
i
:
291
–6.
5
 Cech I, Smolenshky M, Lane R, Halevy B, Samueloff S. Meterologic factors and temporal variations of cardiac mortality in an urban setting in a desert climatic zone.
Isr J Med Sci
 
1977
;
13
:
451
–9.
6
 Cech I, Young K, Smolensky MH, Sargent F. Day-to-day and seasonal fluctuations or urban mortality in Houston, Texas.
Int J Biometerol
 
1972
;
23
:
77
–87.
7
 Douglas AS, Allan TM, Rawles JM. Seasonal, regional and secular variations of cardiovascular and cerebrovascular mortality in New Zealand.
Aust NZ J Med
 
1990
;
20
:
669
–76.
8
 Heunis JC, Olivier J, Bourne DE. Short-term relationships between winter temperatures and cardiac disease mortality in Cape Town.
S Afr Med J
 
1995
;
85
:
1016
–19.
9
 Sakamoto-Momiyama M. Changes in the seasonality of human mortality: a medico-geographical study.
Soc Sci Med
 
1978
;
12
:
29
–42.
10
 Scragg R. Seasonal variations of mortality in Queensland.
Community Health Stud
 
1982
;
6
:
120
–9.
11
 Anon. Winter and heart-disease.
Lancet
 
1970
;
1
:
282
–3.
12
 Douglas AS, Dunnigan MG, Allan TM, Rawles JM. Seasonal variation in coronary heart disease in Scotland.
J Epidemiol Comm Health
 .
1995
;
49
:
575
–82.
13
 Rose G. Cold weather and ischaemic heart disease.
Br J Prev Soc Med
 
1966
;
20
:
97
–100.
14
 Enquselassie F, Dobson AJ, Alexander HM, Steele PL. Seasons, temperature and coronary disease.
Int J Epidemiol
 
1993
;
22
:
632
–6.
15
 Cade JE, Barker DJP, Margetts BM, Morris JA. Diet and inequalities in health in three English towns.
Br Med J
 
1988
;
296
:
1359
–62.
16
 Gyllerup S, Lanke J, Lindhom LH, Schersten B. Smoking habits, sales of fat and antihypertensives fail to explain the high coronary mortality in cold regions of Sweden.
Scot Med J
 
1991
;
36
:
165
–8.
17
 Fleck A. Latitude and ischaemic heart disease.
Lancet
 
1989
;
i
:
13
.
18
 Sinclair H. Latitude and ischaemic heart disease.
Lancet
 
1989
;
i
:
895
.
19
 Fyfe T, Dunnigan MG, Hamilton E, Rae AJ. Seasonal variation in serum lipids, and incidence and mortality of ischaemic heart disease.
J Atheroscler Res
 
1968
;
8
:
591
–6.
20
 Bull GM, Morton J. Environment, temperature and death rates.
Age Ageing
 
1978
;
7
:
210
–23.
21
 Bull GM, Morton J. Seasonal and short-term relationships of temperature with deaths from myocardial and cerebral infarction.
Age Ageing
 
1975
;
4
:
19
–31.
22
 Rogot E, Blackwelder WC. Associations of cardiovascular mortality with weather in Memphis, Tennessee.
Public Health Rep
 
1979
;
85
:
25
–39.
23
 Keatinge WR, McIlroy MB, Goldfien A. Cardiovascular responses to ice-cold showers.
J Appl Physiol
 
1964
;
19
:
1145
–50.
24
 Raven PB, Wilkerson JE, Harvath SM, Bolduan NW.
Can J Physiol Pharmacol
 
1975
;
53
:
293
.
25
 Hayward JM, Holmes WF, Gooden BA. Cardiovascular responses in man to a stream of cold air.
Cardiovasc Res
 
1979
;
10
:
691
.
26
 Lassvik CT, Areskog N. Angina in cold environment.
Br Heart J
 
1979
;
42
:
396
.
27
 Bullock R, Hall R. The heart in winter.
Practitioner
 
1982
;
226
:
465
–6.
28
 Dollery CT. Adrenergic drugs in the treatment of hypertension.
Br Med Bulletin
 
1973
;
29
:
158
.
29
 Kunes J, Tremblay J, Bellavance F, Harnet P. Influence of environmental temperature on the blood pressure of hypertensive patients in Montreal
Am J Hypertens
 
1991
;
4
:
422
–6.
30
 Neill WA, Duncan DA, Kloster F, Mahler DJ. Response of coronary circulation to cutaneous cold.
Am J Med
 
1974
;
56
:
471
.
31
 Wilmshurst P. Temperature and cardiovascular mortality.
Br Med J
 
1994
;
309
:
1029
–30.
32
 MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. I: prolonged differences in blood pressures: prospective observational studies corrected for the regression dilution bias.
Lancet
 
1990
;
335
:
765
–74.
33
 Curwen M, Devis T. Winter mortality, temperature and influenza: has the relationship changed in recent years?
Population Trends
 
1988
;
54
:
17
–20.
34
 Tout DG. Biometerology.
Prog Phys Geog
 
1987
;
1
:
474
–86.
35
 Macfarlane A. Daily mortality and environment in English conurbations a: air pollution, low temperature, and influenza in Greater London.
Br J Prev Soc Med
 
1977
;
31
:
54
–61.
36
 Macfarlane A, Walker RE. Short-term increases in mortality during heatwaves.
Nature
 
1976
;
264
:
434
–6.
37
 Oaechsli FW, Beuchly RW. Excess mortality associated with three Los Angeles September hot spells.
Environ Res
 
1970
;
3
:
277
–84.
38
 Alderson M. Season and mortality.
Health Trends
 
1985
;
17
:
87
–96.
39
 Burch GE, Miller GC. The effects of warm, humid environment on patients with congestive heart failure.
S Afr Med J
 
1969
;
62
:
816
–22.
40
 DePasquale NP, Burch GE. The seasonal incidence of myocardial infarction in New Orleans.
Am J Med Sci
 
1961
;
242
:
468
–74.
41
 Ellis FP. Mortality from heat illness and heat-aggravated illness in the United States.
Environ Res
 
1972
;
5
:
1
–58.
42
 Leithead CS, Lind AR. Heat Stress and Heat Disorders. London, Cassell, 1964.
43
 Lye M, Kamal A. Effects of a heatwave on mortality rates in elderly inpatients.
Lancet
 
1977
;
I
:
529
–31.
44
 Lyster WR. Death in summer.
Lancet
 
1976
;
2
:
469
.
45
 Schuman SH. Patterns of urban heat-wave deaths and implications for prevention: data from New York and ST Louis during July 1966.
Environ Res
 
1971
;
5
:
59
–75.
46
 McKee CM. Cold at heart.
Lancet
 
1989
;
2
:
564
–5.
47
 McKee CM. Deaths in winter: can Britain learn from Europe?
Eur J Epidemiol
 
1989
;
5
:
178
–82.
48
 Eurowinter Group. Cold exposure and winter mortality from ischaemic heart disease, cerebrovascular disease, respiratory disease, and all causes in warm and cold regions of Europe.
Lancet
 
1997
;
349
:
1341
–6.
49
 Fabsitz R, Feinleib M. Geographic patterns in country mortality rates from cardiovascular diseases.
Am J Epidemiol
 
1980
;
111
:
315
–28.
50
 Mortimer EA, Monson MD, MacMahon B. Reduction in mortality from coronary heart disease in men residing at high altitude.
N Engl J Med
 
1977
;
296
:
581
–5.
51
 Voors AW, Johnson WD. Altitude and arteriosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States.
J Chronic Dis
 
1979
;
32
:
157
–62.
52
 Seto TB, Mittleman MA, Davis RB, Taira DA, Kawachi I. Seasonal variation in coronary artery disease mortality in Hawaii: observational study.
Br Med J
 
1998
;
316
:
1946
–7.
53
 Lund B, Badskjaer J, Lund B, Soerensen OH. Vitamin D and ischaemic heart disease.
Horm Metab Res
 
1978
;
10
:
553
–6.
54
 Vik T, Try K, Thelle DS, Forde OH. Tromso heart study: vitamin D metabolism and myocardial infarction.
Br Med J
 
1979
;
2
:
176
.
55
 Gordon DJ, Hyde J, Trost DC, et al. Cyclic seasonal variations in plasma lipid and lipoprotein levels: the lipid research clinics coronary primary prevention trials placebo group.
J Clin Epidemiol
 
1988
;
41
:
678
–89.
56
 Gordon DJ, Trost DC, Hyde J, et al. Seasonal cholesterol cycles: the Lipid Research Clinics Coronary Primary Prevention Trial placebo group.
Circulation
 
1987
;
76
:
1224
–31.
57
 Entrican JH, Douglas AS. Circannual rhythm of arterial and venous thromboembolic disease.
Scot Med J
 
1979
;
24
:
273
–8.
58
 Van Staveren WA, Deurenberg PD, Burema J, De Groot LCPGM, Hautvast JGA. Seasonal variation in food intake, pattern of physical activity and change in body weight in a group of young adult Dutch women consuming self-selected diets.
Int J Obes
 
1986
;
10
:
133
–45.
59
 Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease.
QJM
 
1996
;
89
:
579
–89.
60
 Gale CR, Martyn CN, Winter PD, Cooper C. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people.
Br Med J
 
1995
;
310
:
1563
–66.
61
 Khaw KT, Woodhouse P. Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease.
Br Med J
 
1995
;
310
:
1559
–63.
62
 Mann GV, Garrett HL, Farhi A, et al. Exercise to prevent coronary heart disease; an experimental study of the effects of training on risk factors for coronary disease in men.
Am J Med
 
1969
;
46
:
12
–27.
63
 Roskamm H. Optimum patterns of exercise for healthy adults.
Can Med Assoc J
 
1967
;
96
:
895
–900.
64
 Saltin B, Blomqvist G, Mitchell JH, et al. Response to exercise after bed rest and after training; a longitudinal study of the effects of training on risk factors for coronary disease in men.
Am J Med
 
1969
;
46
:
12
–27.
65
 Dannenberg AL, Keller JB, Wilson PW, Castelli WP. Leisure time physical activity in the Framingham Offspring Study. Description, seasonal variation, and risk factor correlates.
Am J Epidemiol
 
1989
;
129
:
76
–88.
66
 Magnus K, et al. Walking, cycling or gardening, with or without seasonal interruption, in relation to acute coronary events.
Am J Epidemiol
 
1979
;
110
:
724
–33.
67
 Anderson TW, Rochard C. Cold snaps, snowfall and sudden death from ischemic heart disease.
Can Med Assoc J
 
1979
;
121
:
1580
–3.
68
 Glass RI, Wiesenthal M, Zack MM, Preston M. Risk factors for myocardial infarction associated with the Chicago snowstorm of Jan 13–15, 1979.
JAMA
 
1981
;
245
:
164
–5.
69
 Kavanagh T, Shephard RJ. The immediate antecedants of myocardial infarction in active men.
Can Med Assoc J
 
1973
;
109
:
19
–22.
70
 Shephard RJ. Ischaemic heart disease and exercise. Chicago, Year Book Medical, 1981:428.
71
 Whittington RM. Snow shovelling and coronary deaths.
Br Med J
 
1977
;
1
:
577
.
72
 Vuori I, Suurnakki T, Surrnakki L, Pasanen M. Lampolitan, tuulen nopeuden ja fyysisen kuormituksen yh-teydet akillisiin sydankuolemiin. Kylmatuktimus-sym-posiumi.
Kuopio
 
1986
;
4
:
15
–16.
73
 Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361662 men.
Lancet
 
1986
;
ii
:
933
–6.
74
 Rose G, Shipley M. Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study.
Br Med J
 
1986
;
293
:
306
–7.
75
 Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction.
N Engl J Med
 
1990
;
323
:
1112
–19.
76
 The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
Lancet
 
1994
;
344
:
1383
–9.
77
 Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia.
N Engl J Med
 
1995
;
333
:
1301
–7.
78
 Myant NB. The Biology of Cholesterol and Related Steroids. London, William Heinmann Medical Books, 1981.
79
 Paul O, Lepper MH, Phelan WH, et al. A longitudinal study of coronary heart disease.
Circulation
 
1963
;
28
:
20
–31.
80
 Thomas CB, Holljes HWD, Eisenberg FF. Observations on seasonal variations in total serum cholesterol level among healthy young prisoners.
Ann Intern Med
 
1961
;
54
:
413
–30.
81
 Van Gent CM, Van der Voort H, Hessel LW. High-density lipoprotein cholesterol, monthly variation and association with cardiovascular risk factors in 1000 forty-year-old Dutch citizens.
Clin Chim Acta
 
1978
;
88
:
155
–62.
82
 Doyle JT, Kinch SH, Brown DF. Seasonal variation in serum cholesterol concentration.
J Chron Dis
 
1965
;
18
:
657
–64.
83
 Blackburn, Hyndburn and Ribble Valley Health Authority. Public Health Report, 1992.
84
 Marmot MG, Shipley MJ, Rose G. Inequalities in death—specific explanations of a general pattern?
Lancet
 
1984
;
ii
:
1003
–6.
85
 Rosengren A, Wedel H, Wilhelmsen L. Coronary heart disease and mortality in middle-aged men from different occupational classes in Sweden.
Br Med J
 
1988
;
299
:
822
–5.
86
 Seretakis D, Lagiou P, Lipworth L, et al. Changing seasonality of mortality from coronary heart disease.
JAMA
 
1997
;
278
:
1012
–14.
87
 Renbourn ET. Variation, diurnal and over longer periods of time, in blood haemoglobin, haematocrit, plasma protein, erythrocyte sedimentation rate and blood chloride.
J Hygiene
 
1947
;
45
:
455
–67.
88
 Semenko IF. Seasonal changes in the fibrinolytic system of the blood of patients with coronary atherosclerosis.
Kin Med
 
1973
;
51
:
57
–63.
89
 Touitou Y, Touitou C, Bogdan A, et al. Differences between young and elderly subjects in seasonal and circadian variations of total plasma proteins and blood volume as reflected by haemoglobin, haematocrit and erythrocyte counts.
Clin Chem
 
1986
;
32
:
801
–4.
90
 Elwood PC, Beswick A, O'Brien JR, et al. Temperature and risk factors for ischaemic heart disease in the Caerphilly prospective study.
Br Heart J
 
1993
;
70
:
520
–3.
91
 Keatinge WR, Coleshaw SR, Cotter F, et al. Increases in platelet and red cell counts, blood viscosity, and arterial pressure during mild surface cooling: factors in mortality from coronary and cerebral thrombosis in winter.
Br Med J
 
1984
;
289
:
1405
–8.
92
 Neild PJ, Syndercombe-Court D, Keatinge WR, et al. Cold-induced increases in erythrocyte count, plasma cholesterol and plasma fibrinogen of elderly people without a comparable risk in protein C or factor X.
Clin Sci
 
1994
;
86
:
43
–8.
93
 Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease.
Lancet
 
1994
;
343
:
435
–9.
94
 Fahlen M, Oden A, Bjorntorp P, Tibblin G. Seasonal influence on insulin secretion in man.
Clin Sci
 
1971
;
41
:
453
–8.
95
 Ophir D, Elad Y. Effects of steam inhalation on nasal patency and nasal symptoms in patients with the common cold.
Am J Otolaryngol
 
1987
;
3
:
149
–53.
96
 Tyrrell D, Barrow I, Arthur J. Local hyperthermia benefits natural and experimental common colds.
Br Med J
 
1989
;
298
:
1280
–3.
97
 Bainton D, Jones GR, Hole D. Influenza and ischaemic heart disease—a possible trigger for acute myocardial infarction.
Int J Epidemiol
 
1978
;
7
:
231
–9.
98
 Alling DW, Blackwelder WC, Stuart-Harris CH. A study of excess mortality during influenza epidemics in the United States 1968–1976.
Am J Epidemiol
 
1981
;
113
:
30
–43.
99
 Clifford RE, Smith SWG, Tillet ME, Wherry PJ. Excess mortality associated with influenza in England and Wales.
Int J Epidemiol
 
1977
;
6
:
115
–28.
100
Rogot E, Padgett SJ. Associations of cardiovascular and stroke mortality with temperature and snowfall in selected areas of the United States, 1962–1966.
Am J Epidemiol
 
1976
;
103
:
565
–75.
101
Spodik DH, Flessas AP, Johnson RN. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients.
Am J Cardiol
 
1984
;
53
:
481
–2.
102
Biemond BJ, Levi M, Cate HT, et al. Plasminogen activator and plasminogen activator inhibitor. I. release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades.
Clin Sci
 
1995
;
88
:
587
–94.
103
Marshall RJ, Scragg R, Bourke P. An analysis of the seasonal variation of coronary heart disease and respiratory disease mortality in New Zealand.
Int J Epidemiol
 
1988
;
17
:
325
–31.
104
Anderson TW, Le Riche WH. Seasonal variation in ischaemic-heart-disease mortality.
Lancet
 
1970
;
2
:
1140
.
105
Dunnigan MG, Harland WA, Fyfe T. Seasonal incidence and mortality of ischaemic heart-disease.
Lancet
 
1970
;
2
:
793
–7.
106
Sotaniemi E, Vuopala U, Huhti E, Takkunen J. Effect of temperature on hospital admissions for myocardial infarction in a sub-arctic area.
Br Med J
 
1970
;
4
:
150
–1.
107
Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialized countries since 1950.
World Health Stat Q
 
1988
;
41
:
155
–78.
108
Cooper R, Tsong Y, Hoeksema R, Liu K. Is the recent decline in coronary disease mortality in the United States attributable to lower rates of influenza and pneumonia?
Prev Med
 
1980
;
9
:
559
–68.
109
Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?
Lancet
 
1997
;
350
:
430
–6.
110
Mendall MA, Goggin PM, Molineaux N, et al. Relation of Helicobacter pylori infection and coronary heart disease.
Br Heart J
 
1994
;
71
:
437
–9.
111
Patel P, Mendall MA, Carrington D, et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors.
Br Med J
 
1995
;
311
:
711
–4.
112
Epstein SE, Speir E, Zhou YF, et al. The role of infection in restenosis and atherosclerosis: focus on cytomegalovirus.
Lancet
 
1996
;
348(Suppl I)
:
S13
-17.
113
Gill EA, McIntyre TM, Prescott SM, Zimmerman GA. Mechanisms of vascular injury in the pathogenesis of infectious disease.
Curr Opin Infect Dis
 
1992
;
5
:
381
–8.
114
Vallance P, Collier J, Bhagar K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?
Lancet
 
1997
:
349
:
1391
–2.
115
Leinonen M. Pathogenetic mechanisms and epidemiology of Chlamydia pneumoniae.
Eur Heart J
 
1993
;
14(Suppl K)
:
57
–61.
116
Birnic D, McKay IC, Hood S, McColl EKJ, Hillis WS. Association between antibodies to mycobacterial heat shock protein 65 and coronary atherosclerosis: possible mechanism of action of Helicobacter pylori in increasing cardiovascular risk.
Heart
 
1996
;
75(Suppl 1)
:
64
.
117
Niemala S, Kartrunen T, Korhonen T, et al. Could Helicobacter pylori infection increase the risk of coronary heart disease by modifying serum lipid concentrations?
Heart
 
1996
;
75
:
573
–5.
118
Savarino V, Mela GS, Zentilin P, et al. Are duodenal ulcer seasonal fluctuations paralleled by seasonal changes in
24
 hour gastric acidity and Helicobacter pylori infection?
J Clin Gastroenterol
 
1996
;
22
:
178
–81.
119
Lam SK. Aetiological factors of peptic ulcer: perspectives of epidemiological observations this century.
J Gastroenterol Hepatol
 
1994
;
9(Suppl)
:
S93
-8.
120
Moshkowitz M, Konikoff FM, Arber N, et al. Seasonal variation in the frequency of Helicobacter pylori infection: a possible cause of the seasonal occurrence of peptic ulcer disease.
Am J Gastroenterol
 
1994
;
89
:
731
–3.
121
Smolensky M, Samueloff S, Halevy B, Macdonald E, Reinberg A. Circannual rhythm of cardiac mortality. An attempt to identify possible endogenous and exogenous factors.
Isr J Med Sci
 
1976
;
12
:
818
–27.
122
Watanabe GI. Seasonal variations of adrenal cortex activity.
Arch Environ Health
 
1964
;
9
:
192
.
123
Wilkerson JE, Raven PB, Bolduan NW, Horvath SM. Adaptations in man's adrenal function in response to acute cold stress.
J Appl Physiol
 
1974
;
36
:
183
–9.
124
Reinberg A, Lagoguey M, Chauffournier JM, Cesselin F. Circannual and circadian rhythms in plasma testosterone in five healthy young men.
Acta Endocrinologia
 
1975
;
80
:
732
.
125
Smals AGH, Kloppenborg PWC, Bernard TJ. Circannual cycle in plasma testosterone levels in man.
J Clin Endocrin Metab
 
1976
;
42
:
979
.