Sunlight Has Cardiovascular Benefits Independently of Vitamin D Richard B. Weller Medical Research Council Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh , UK The most recent data from the World Health Organ- isation’s survey of the global burden of disease show that high blood pressure (BP) is the leading cause of prema- ture death and disease worldwide [1] . This risk factor un- derlies stroke and coronary heart disease, which in com- bination have an age-standardised mortality of 237 per 100,000 in the United States [2] . Measures to control hy- pertension are thus of the greatest importance. Epidemiology Active management of hypertension with effective modern drugs has led to a fall in population BP within western economies. Plotting population BP in 1980 – be- fore the availability and widespread use of effective phar- macological agents – against latitude, a clear correlation exists with around a quarter of variation in BP account- able for by latitude ( fig. 1 ). This relationship persists when the data are stratified by country income level. Seasonal changes in BP are also well described, with individual BP being lower in summer than winter in temperate latitudes [3] . Around a quarter of cardiovascular mortality within Europe can be accounted for by latitude [4] , and in a mul- ticentre observational study of risk factors correlating with atherosclerosis, latitude was found to be the stron- gest predictor of carotid artery atheroma [5] .
Biologically active vitamin D (1,25 di-hydroxy chole- calciferol) in man can be derived from the diet or syn- Key Words Ultraviolet · Skin · Nitric oxide · Blood pressure · Nitrate · Vitamin D · Sunlight · Cardiovascular Abstract Background: High blood pressure (BP) is the leading risk fac- tor for disability adjusted life years lost globally. Epidemio- logical data show a correlation between increased sun expo- sure and reduced population BP and cardiovascular mortal- ity. Individuals with high serum vitamin D levels are at reduced risk of hypertension, cardiovascular disease and metabolic syndrome, yet multiple trial data show that oral vitamin D supplementation has no effect on these end- points. Sunlight is a risk factor for skin cancers, but no link has been shown with increased all-cause mortality. Cohort studies from Scandinavia show a dose-dependent fall in mortality with increased sun-seeking behaviour. Skin con- tains significant stores of nitrogen oxides, which can be con- verted to NO by UV radiation and exported to the systemic circulation. Human studies show that this pathway can cause arterial vasodilatation and reduced BP. Murine studies sug- gest the same mechanism may reduce metabolic syndrome. Summary: Sunlight has beneficial effects on cardiovascular risk factors independently of vitamin D. Key Messages: All- cause mortality should be the primary determinant of public health messages. Sunlight is a risk factor for skin cancer, but sun avoidance may carry more of a cost than benefit for over- all good health.
Published online: January 15, 2016 Dr. Richard B. Weller, MD, FRCP(Ed)
Medical Research Council Centre for Inflammation Research University of Edinburgh, Queen’s Medical Research Institute 47 Little France Crescent, Edinburgh, EH16 4TJ (UK) E-Mail r.weller @ ed.ac.uk 0253–5068/16/0413–0130$39.50/0 Downloaded by: Ball State University 198.143.32.1 - 2/23/2016 12:51:34 PM Sunlight and Health Blood Purif 2016;41:130–134 thesised endogenously in a pathway dependent on UVB irradiation of the skin. Inadequate sun exposure with insufficient dietary intake can thus lead to deficiency (25(OH)D <20 ng/ml) and insufficiency (25(OH)D 20– 29 ng/ml). Vitamin D receptors are expressed on most cell types, and they play a well-established role in skel- etal metabolism. Additionally, in vitro mechanistic studies show vitamin D to have effects on cell differen- tiation and immune function [6] . Observational data from numerous large cohort studies, now summarised in several meta-analyses show that individuals with measured vitamin D levels in the lowest quartile have around twice the all-cause mortality of those in the up- per quartile, and are more likely to have hypertension, cardiovascular disease, metabolic syndrome, and solid organ cancers [7–9] . Clinical trials of vitamin D supple- mentation have however shown that vitamin D is of no benefit in the prevention or treatment of hypertension, cardiovascular disease, cerebrovascular disease or meta- bolic syndrome, although it is important for bone health [8] . This is further supported by a recent Mendelian ran- domisation study, which showed that patients with ge- netic polymorphisms leading to lifelong reduced vita- min D levels have a higher standardised mortality and risk of solid organ cancer, but no difference in cardio- vascular health [10] .
These apparently conflicting observations may be ex- plained by confounding; fit individuals, spending more time outside in the sun will synthesise more vitamin D, which is thus a marker for health. An alternative and non- exclusive explanation, consistent with the epidemiologi- cal data on latitude and season, is that sunlight, indepen- dently of vitamin D synthesis, has cardiovascular, cere- brovascular and metabolic benefits.
For almost a century, it has been known that the ultra- violet component of sunlight is a risk factor for skin can- cer, and public health measures governing sun exposure have been largely determined by this. Skin cancer can be divided into 2 main types. Melanoma is due to malignant transformation of melanocytes. In all, 76,690 new cases occurred in 2013 in the United States with 9,480 deaths [11] . Non-melanoma skin cancer is much commoner and probably under-reported. Cases of NMSC outnumber all other cancer put together in the white-skinned popula- tions, yet the mortality is exceedingly low [12] . Of the 2 main types of NMSC, basal cell cancers are the common- est and although they can be locally destructive if untreat- ed, deaths are almost unknown. Squamous cell skin can- cers are less common than BCC, but potentially more se- rious with a measurable mortality.
For the general white-skinned population, sunlight is the major preventable risk factor for skin cancers, but the pattern of sun exposure varies with cancer type. Intermit- tent sun exposure and sunburn, particularly in childhood, increase the risk of melanoma, whereas chronic occupa- tional exposure may be protective [13] . Squamous cell skin cancer by contrast is predisposed in a dose-depen- dent fashion by chronic sun exposure. Immunosuppres- sion particularly increases the risk of developing SCC, a link first made in patients who had undergone renal transplantation, with subsequent immunosuppression. SCCs in the immunosuppressed are clinically harder to diagnose than in the immunocompetent and are more likely to metastasise. Advice on sun avoidance is thus par- ticularly important to renal allograft recipients, and these patients require regular screening, and a high index of suspicion from their dermatologist [14] .
Skin cancers can be used as a proxy measure for life- time sun exposure. A case–control study of 4.4 million Danish patients over the age of 40, showed that NMSC patients had a multi-factorially corrected OR of 0. (0.96–0.99) for all-cause mortality compared to age- and sex-matched ‘healthy’ controls. The reduction in cardio- Fig. 1. Population BP correlates with latitude. Each point repre- sents a country. Male systolic population BP is plotted against the latitude of the geographical mid-point of each country. BP values are from the MRC-HPA data in 1980.
R2 = 0.
0 2 04 06 08 0 Male systolic BP Latitude degrees N or S Downloaded by: Ball State University 198.143.32.1 - 2/23/2016 12:51:34 PM Weller Blood Purif 2016;41:130–134 vascular disease was greater, with an OR of 0.90 (0.88– 0.92) for incident myocardial infarction [15, 16] . Prospective cohort studies are less prone to confound- ing and bias than case–control studies. Two Scandinavian studies, initiated in the early 1990s, have provided valu- able information on sun exposure and all-cause mortali- ty. In the Swedish Women’s Lifestyle and Health cohort study, increased sun exposure, as recorded by the number of weeks spent on sun-bathing holidays, predicted re- duced all-cause mortality 25 years later [17] even at the expense of increased melanoma [18] . Subjects in the Mel- anoma in Southern Sweden study were asked about sun- bathing, sun-seeking holidays in summer, sun-seeking holidays in winter, and use of sunbeds to give a sun-ex- posure score of 0–4. Extensive adjustment for possible confounders was made, and subjects were re-polled 25 years after enrolment. Dose dependently, the higher the sun-seeking behaviour, the lower the all-cause mortality, with those scoring 4 having half the mortality of sun- avoiders. Extrapolating from these data, the authors cal- culate that 3% of deaths in Sweden can be accounted for by inadequate sun.
Scandinavian data on sunlight and all-cause mortality may not be generally applicable. A similar prospective de- sign of study in the United States, the NIH-AARP Diet and Health Study, showed a small increase in mortality in those who had lived in the most insolated areas [19] , al- though it showed no increase in the number of skin can- cer deaths. The study did not measure individual sun ex- posure, but instead calculated environmental sun expo- sure based on the residence of the individual at the time of enrolment. It may be that higher levels of sun exposure than those experienced by north Europeans are un- healthy, or alternatively that individuals living in the sun- niest areas adopt lifestyles that avoid the sun [20] .
The balance of epidemiological and observational data thus suggests that sunlight exposure can reduce all-cause mortality, and has particular benefits on hypertension and cardiovascular disease. These benefits are at the cost of in- creasing the risk of skin cancer incidence, although the overall benefits outweigh the risks as demonstrated by dose-dependent reductions in all-cause mortality with in- creased sun exposure. Importantly, vitamin D is not solely responsible for these proposed health benefits of sunshine. Supplementation with oral vitamin D is not adequate to reduce cardiovascular disease. Alternative mechanisms must exist to account for these benefits of sunlight. Nitric oxide has a wide range of roles, but the first de- scribed was as a vasodilator, synthesised by the actions of one of the family of 3 nitric oxide synthase (NOS) en- zymes on L-arginine. NO has a half-life of a few seconds before being oxidised to nitrite (NO 2 – ), which itself has biological actions, particularly in conditions of hypoxia and low pH, where it can be reduced to NO. Nitrite is fur- ther oxidised to nitrate (NO 3 ) and this was considered the inert end product of NO until recently. The dermis and epidermis contain significant stores of nitrogen oxides particularly nitrate, the quantity of which is about 10 times as much as in the total vascular space [21] .
Although nitrate has been considered to be biologi- cally inactive, it is now apparent that an alternative mech- anism of NO synthesis involves sequential reduction of nitrate to nitrite and then NO [22] . This occurs on the skin surface, where nitrate-reducing bacteria generate ni- trite from sweat nitrite. The nitrite in turn is reduced to NO in the slightly acidic conditions of the skin surface [23] . Bacterial nitrate reductases allow the use of nitrate as an electron acceptor in respiration in the absence of oxygen. Nitrate reductase enzymes have also been de- scribed in mammalian tissues [24] . Photochemical reduc- tion of nitrate also occurs with ultraviolet wavelengths, and is enhanced in the presence of thiols [25] . Thiol-rich cysteine is a major component of keratins, the key struc- tural components of skin.
Human skin brings together nitrate, thiols, environ- mental ultraviolet radiation, and a rich dermal vascular plexus giving access to the systemic circulation. Irradia- tion of healthy human volunteers with physiologically relevant doses of ultraviolet A radiation (which does not synthesise vitamin D) produces a fall in systemic BP and rise in heart rate, independently of temperature change, and concurrent with a rise in circulating nitrite (a marker for NO levels) and fall in nitrate [26, 27] . Forearm pleth- ysmography studies in which UVA irradiation of the arm occurs simultaneously with intra-brachial artery infusion of a NOS antagonist, show arterial vasodilatation, con- firming that this effect is independent of NOS [26] .
While these human in vivo studies are recent, the ob- servation that sunlight and ultraviolet could directly di- late the arterial vasculature was made by Robert Furch- gott almost 40 years before his Nobel prize for the discov- ery that ‘endothelium derived relaxant factor’ was NO. Following a chance observation in the laboratory where organ baths were intermittently exposed to daylight on a cloudy day, he showed that isolated arterial smooth mus- cle from which the endothelium had been removed di- lated in response to ultraviolet radiation [28] . The ab- sence of endothelium in these experiments differentiated these results from his later classic Nobel Prize–winning work, where he demonstrated an acetyl choline–driven Downloaded by: Ball State University 198.143.32.1 - 2/23/2016 12:51:34 PM release of a diffusible vasodilator from endothelial cells. The mechanism of NO synthesis differs in these 2 exper- imental set ups, but NO is the active mediator in both [29] .
UV-induced release of NO from the skin may have more widespread cardiovascular actions than BP reduc- tion. Oral nitrate reduces oxygen cost during exercise [30] due to an improvement in mitochondrial efficiency [31] . We have shown that the combination of UVA irra- diation and oral nitrate supplementation produces an ad- ditive improvement in exercise performance with re- duced oxygen demand in elite cyclists [32] .
Metabolic syndrome and type 2 diabetes have a lower prevalence in summer than in winter. In a mouse model of diabetes, mice fed with a high-fat diet developed weight gain, impaired glucose and insulin tolerance, fatty livers, and gonadal fat deposition [33] . Irradiation of the mouse with a sub-erythemal dose of UV twice weekly reduced weight gain and development of markers of metabolic syndrome, but addition of oral vitamin D supplementa- tion had no effect. Applying a topical NO donor to the dorsal skin of the mice reproduced the effects of UV, and treating the mice with an NO scavenger on the back blocked the beneficial effects of the UV [33] .
Ultraviolet therapy might well have a therapeutic role beyond the treatment of skin disease. It should be avoid- ed in those with particular risk factors, such as the im- munosuppressed transplant patient, but as a non-phar- macological intervention it has several potential benefits. Hypertension, metabolic syndrome and diabetes are three of the major morbidities of our age. The mechanis- tic and early trial data I have outlined suggest that these may be amenable to a form of phototherapy. Hyperten- sion is clearly a risk factor that must be treated. In pa- tients with impaired renal function, pharmacological choices are reduced and phototherapy offers potential as an adjunctive therapy. The reduced oxygen demand demonstrated in athletes treated with UVA and nitrate supplementation suggests benefit in patients with heart failure and other conditions where oxygen delivery is compromised.
Public health advice on sunlight exposure is at the crossroads. Almost a century of data has confirmed the carcinogenic effects of UV radiation on the skin, and de- lineated the mechanisms by which this occurs. There is however a remarkable absence of any evidence that UV reduces lifespan, in sharp contrast to other risk factors (e.g. hypertension, smoking, alcohol) on which we advise. A substantial body of evidence shows that sunlight has health benefits and that these are independent of vitamin D and thus cannot be reproduced by oral supplementa- tion. The UV-induced reduction of cutaneous nitrate and its export to the systemic vasculature, which I have helped delineate, is an additional mechanism by which sunlight may exert beneficial effects on health, but other mecha- nisms surely exist. All-cause mortality and its reduction should be the primary aim of physicians, not the narrow avoidance of skin cancer.
Disclosure Statement Richard B. Weller research is supported by the British Heart Foundation, the Royal Society and the Foundation for Skin Re- search. He has no conflicts of interest.