Clinical human and animal models have shown clear-cut BP responses to temperature changes[13-24]. Outdoor temperatures may have differing effects on autonomic and cardiovascular systems. Antihypertensive therapy has been found to modify autonomic responses and the resulting autonomic tone, which potentially affects the presumed increase in peripheral vasomotor tone related to the colder temperatures in the winter[25]. Previous studies indicated that outdoor temperature may have stronger effects on females, due to their choice of garments or to biological differences[12,24]. Older populations may be more susceptible to the effects of outdoor temperature on BP since many cardiovascular risk factors, such as arterial stiffening, worsen with age[10-13].

SBP and DBP showed significant univariate relationships with the season (more than with temperatures)[3-12]. All other covariates [age, gender, race, region, population density, education, income, community poverty, smoking status, alcohol use, body mass index (BMI), diabetes, and current hypertensive medication status], with the exception of dyslipidemia, may be significantly related to SBP and a given season. DBP was also significantly related to the season and to all the other covariates, with the exception of alcohol use and diabetes status. Several parameters other than BP, such as, pulse, glucose, low-density lipoprotein (LDL) cholesterol levels and others vary seasonally as well[13,26].

Several studies reported on the novel finding that the time of year, characterized by season, is secondary in importance to the outdoor temperature’s association with BP[13]. The suggested etiology was that cold increases sympathetic nervous activity, as evidenced by elevated BP measurements and plasma and urinary catecholamine (noradrenaline) concentrations[25,27]. Niimi et al[27] looked into whether factors pertaining to seasonal variations exist in humans as responses of the sympathetic nervous system to the gravity-dependent BP regulation and reported that muscle sympathetic nerve activity (MSNA) has an essential role in BP regulation in humans. The lower BP in warm temperatures has been attributed to cutaneous vasodilatation, loss of water and increased sodium excretion due to sweating[15,28]. These factors have been implicated as potential mechanisms by which BP increases in cold conditions. The seasonal variation of BP in patients with chronic kidney disease seemed to have no correlation with the stage of the disease or change in body weight, but it was inversely associated with outdoor temperatures. These results suggested that volume status might not be a key mechanism for causing seasonal variation in BP[29].

Vascular wall rigidity also influences BP. Arterial stiffness is related to the BP changes between summer and winter. Pulse wave velocity (PWV), a widely used clinical indicator of arterial stiffness, was correlated with winter-summer differences in SBP (r = 0.272, P = 0.012), but not with DBP (r = 0.188, P = 0.085). Age was strongly correlated with PWV (P < 0.001)[30]. Human and animal studies have demonstrated physiological mechanisms for this response and identified factors relevant to sympathetic nervous system activation, such as isoprenaline-induced relaxation of aortae and the renin-angiotensin system (stiffness)[31,32].

Wave intensity analysis (WIA) is another modality that measures effects of sympathetic excitation and elevation of BP on mechanical (rigidity-elasticity) properties of the common carotid and femoral arteries. The diameters and arterial stiffness parameters of the right common carotid artery and the right common femoral artery in healthy young men were measured by WIA at baseline and during cold pressor testing and found to be correlated with cold[32].

BP is a product of cardiac output as well as peripheral resistance and heart rate (HR). Cardiac output and stroke volume in normotensives significantly decreased by 10% and 15% from summer to winter, respectively, (P < 0.05) whereas HR and systemic vascular resistance decreased by 5% and 11%, respectively (P < 0.05). Norepinephrine (NE), plasma renin activity (PRA), and plasma aldosterone (PA) participate in mediating hemodynamic changes[33]. PA increased by 59% from summer to winter (P < 0.05), whereas, plasma NE (PNE) plasma epinephrine and PRA increased by 19%, 2%, and 17%, respectively (P = NS for each). Across the four seasons, mean arterial pressure significantly correlated with PRA and PA (P < 0.05 and P < 0.05, respectively), whereas systemic vascular resistance significantly correlated with PNE and PRA (P < 0.05 and P < 0.05, respectively). Dramatic counter-regulatory hemodynamic and hormonal adaptations are involved in maintaining a relatively constant BP[33]. Plasma NE levels are increased, largely reflecting sympathetic nerve stimulation insofar as plasma epinephrine levels are not increased. Unfavorable effects include vasoconstriction with increased vascular resistance, myocardial damage, and reduced renal blood circulation[11,13,33].

In cold conditions, neurohumoral responses help increase heart function and maintain BP and organ perfusion, but chronic activation of these responses is detrimental to the normal balance between myocardial-stimulating and vasoconstricting hormones and between myocardial-relaxing and vasodilating hormones[3,11,13,24-26,33-37]. The heart contains many neurohumoral receptors (α₁, β₁, β₂, β₃, angiotensin II type 1 and type 2, muscarinic, endothelin, serotonin, adenosine, cytokine), but the role of these receptors is not yet fully defined. In patients with heart failure, β₁ receptors (which constitute 70% of all cardiac β receptors) are down-regulated, probably in response to intense sympathetic activation. The result of down-regulation is impaired myocyte contractility and increased HR.

Hormonal changes are known to have more chronic effects than neural sympathetic changes. The data on seasonal hormonal regulation are controversial. Radke et al[33] reported that anti-diuretic hormone (ADH) is released in response to a fall in BP (in the summer) via various neurohormonal stimuli. Increased ADH decreases renal excretion of free water, possibly contributing to hypervolemia and hyponatremia. Atrial natriuretic peptide is released in response to increased atrial volume and pressure, while brain (B-type) natriuretic peptide is released from the ventricle in response to ventricular stretching[33]. In contrast, Hirvonen et al[34] showed insignificant changes in catecholamines. While mean plasma noradrenaline concentrations diminished significantly from autumn to spring, and even more in the winter-summer group, there was no statistically significant difference between the groups. Adrenaline levels also showed a trend to decrease, and that change became significant when calculated by using the combined means of both groups. Plasma homovanillic acid and β-endorphin values were on the same level in all seasonal samples in both groups. By the spring, plasma serotonin levels decreased by about 50% in both groups. Hirvonen et al[34] showed a correlation with BP and anxiety in the autumn (r = 0.367), while endorphins and hysteria had a negative correlation in the winter (r = 0.370) and 5-hydroxy indole acetic acid and obsession had a positive correlation in the spring (r = 0.351).

Seasonal changes in HR and BP and FiO₂ were shown to be associated with autonomic nervous system control. In the winter, the HR is higher and the oxygen consumption is lower, although training can increase vagal control and lower the HR and BP[35].

It has been posited that other seasonal variables, such as sunlight, may have an effect on BP. However, a number of studies have shown that atmospheric pressure (which can be used as a proxy for sunny weather), rainfall, and humidity were not related to BP[36-40]. Other factors that vary with the time of year, such as exercise, stress levels (e.g., summer holidays), mood (bipolar disorders), cognitive function, various health behaviors and biological processes, have all been shown to influence BP[29,35,41]. Other risk factors of hypertension and stroke, such as BMI (weight gain), are higher in the winter months. One study reported that the mean increase in SBP/DBP in the winter was significantly higher in underweight individuals than in individuals who were normal/overweight/obese (P < 0.05)[42]. Levels of inflammatory biomarkers (e.g., CRP and ICAM-1) are also associated with colder outdoor temperatures[43-45]. BP, preprandial glucose, A1C, and LDL cholesterol varied seasonally in patients with diabetes, with higher values in the winter and lower values in the summer[26].

Many studies showed increased all-cause and cardiac mortalities in the winter compared to the other seasons (Figures 1 and 2)[1,11,13,49-67]. Cold weather generally showed a delayed health effect up to several weeks. The same trend was observed even in the most developed societies[1,52-60]. Healy’s analysis of data from 1988 to 1997 indicated that a relative excess of winter mortality was highest in southern Europe, Ireland, and the United Kingdom, where seasonality in mortality was estimated as being between 18%-28%[53]. He also noted that the Scandinavian and other northern European countries were relatively unaffected by the problem[53]. The cold-stressed heart and other organs produce tumor necrosis factor α (TNFα)[44]. This cytokine increases catabolism and is possibly responsible for cardiac dysfunction, which may accompany severely symptomatic HF as well as other detrimental changes. The failing heart also undergoes metabolic changes with increased free fatty acid utilization and decreased glucose utilization. These changes may become therapeutic targets[13,33]. Harmful effects include vasoconstriction with decreased preload and after-load, direct myocardial damage (including apoptosis), reduced coronary and renal blood flow, and activation of other neurohumoral systems (including ADH system)[11,13,33]. Patients with HF and cold-induced stress have endothelial dysfunction. They produce fewer endogenous vasodilators (e.g., nitric oxide, prostaglandins) and more endogenous vasoconstrictors (e.g., endothelin), thus increasing afterload, all of which factors predispose to coronary and cerebrovascular events.

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Figure 1 Excess of winter mortality in general populations for a period of 10 years[53,71].

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Figure 2 Excess of cardiovascular mortality and stroke[54-57,70].

Measurements of maximal oxygen intake and muscle strength commonly show parallel seasonal changes. However, potential effects upon body mass and body fat that increase in the winter may be counteracted by changes in food intake[14]. In developed societies, body fat commonly increases during the winter, with parallel changes in blood lipids, BP and blood coagulation - changes that are not always fully reversed during the following summer[11,13,52,61-66,68-72]. Health consequences of seasonal variations in physical activity, including an increased vulnerability to cardiac catastrophe and a year-by-year increase in total body fat, seem most likely to occur if the average level of physical activity for the year is low[14].

Exposure to decreased temperature is associated with an increase in the inflammation marker levels of CRP, soluble VCAM-1 and soluble ICAM-1 among elderly men, suggesting that inflammation markers are part of intermediate processes, which may lead to cold-related but not to heat-related cardiovascular deaths[44]. Other inflammatory markers, such as the white blood cell count, TNFα, interleukins-1β, -6 and -8, were not associated with cold and cardiovascular mortality[44].

Many studies report a seasonal pattern to stroke (Figure 2), which has a strong relationship with BP[2,48,51,55-61,67,70-72]. Stroke-prone rats have been found to have exaggerated BP responses to cold exposure[49]. Tienviboon et al[50] proposed that cold windy winter weather was the predisposing factor for the attack of reversible cerebral vasoconstriction syndrome (RCVS). RCVS has reversible multifocal narrowing of the cerebral arteries, as demonstrated on magnetic resonance angiography studies, in addition to brain edema and infarcts[50]. The consistent effect across various human demographic groups suggests that this is a real physiological phenomenon and not an artifact of living conditions[50].

Seasonal changes have implications in physical activity for fitness and human health[14]. Photosensitivity and nutrient shortages mediate animal hibernation via the hypothalamus and changes in leptin and ghrelin concentrations. Opportunities for hunting and crop cultivation determine seasonal activity in underdeveloped human societies, but temperature and rainfall are dominant factors in developed societies, usually over-riding innate rhythms. Both questionnaire data and objective measurements show that many groups of all ages increase their physical activity from winter to spring or summer. For example, the prevalence of being overweight, sedentary behavior and age were found to be inter-related among shift workers[14]. Most developed societies show increased all-cause mortality, including cardiac mortalities, in the winter[10,11,13,52-54,61-66,68-70]. Health consequences of seasonal variations in physical activity, including an increased vulnerability to cardiac catastrophe and a year-by-year increase in total body fat, seem most likely if the average level of physical activity for the year is low. Public health recommendations should emphasize the importance of maintaining physical activity during adverse environmental conditions by adapting clothing, modifying behavior and exploiting any available air-conditioned indoor facilities[14,52]. Improved protection against cold temperatures could lead to a reduction in the winter excess of cardiovascular mortality[12,24,53-57]. It has been postulated that people who are habitually involved in physical activity are better able to tolerate the cold stresses and are generally healthier than those who do not exercise[24]. BP and plasma catecholamine and serotonin levels decrease while practicing winter physical activities[14,24]. People who are involved in winter sports develop physiological adaptations: changes in their humoral status (e.g., decreased levels of serotonin) and enhanced vagal control either suggest adaptation or reflect seasonal variation from autumn to spring and show less significant seasonal BP changes[35]. Although it is generally advantageous for older people to be physically active in order to prevent circulatory disease, there may be a rationale for advising that that they should avoid intense activity at certain times of the day, especially in the winter[52]. Not uncommonly, patients need to increase the dose of antihypertensive medications or add another group of antihypertensive medicines during the winter months[10].

Many studies report a seasonal pattern to stroke, which is strongly related to BP[43]. The risk for stroke and transient ischemic attack increases exponentially with age, and BP is a potent modifiable target for reducing the risk for stroke in the elderly. In elderly patients with isolated systolic hypertension and in those with intracranial atherosclerotic disease, the lowering of BP has consistently been shown to be well tolerated and effective in reducing the risk for stroke and its complications. Evidence suggests that ambulatory BP monitoring may provide a more sensitive means of detecting patients at risk as well as for monitoring the therapeutic effect. The association of BP with season and outdoor temperature was examined in the Three-City Study, a population-based longitudinal study on 8801 subjects who were 65 years of age or older[11]. Outdoor temperature and BP were strongly correlated, especially in patients who were 80 or older. It was suggested that careful monitoring of BP and antihypertensive treatment during periods of extreme temperatures could contribute to reducing the consequences of BP variations and their complications in the elderly[24]. Preferable medications are agents that modify the renin-angiotensin system, particularly angiotensin receptor blockers, while calcium channel blockers may confer additional benefit in stroke protection alongside BP lowering[11,13,52,56,57].