Cold as a therapeutic strategy to improve cardiovascular risk factors

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality
in Western society. This especially accounts for the South Asian population, in
which a particularly high risk to develop CVDs is present. This may be due to
the presence of a disadvantageous metabolic phenotype in this population,
including central obesity, dyslipidemia and low-grade inflammation. The
majority of CVDs is caused by atherosclerosis (i.e. atherosclerotic (as)CVD),
for which dyslipidemia and inflammation are the main risk factors. Cold
exposure has been shown to acutely increase whole-body metabolism by
influencing both brown adipose tissue (BAT) and skeletal muscle. Cold exposure
also reshapes the immune system. Longer term highly controlled studies in
clinical research units using cold rooms or water-perfused cooling systems have
shown that cold exposure leads to improvements in cardiometabolic health
including lower fat mass. Importantly, these studies have also demonstrated
that one can get used to daily cold exposure, with less to no (thermal)
discomfort after approximately a week. However, in order to implement cold
therapy in clinical practice (for example as part of a combined lifestyle
intervention), cold should be applied in a feasible way, such as via cooling
vests or regular cold showers. We hypothesize that 6 weeks of daily bouts of
cold exposure by wearing cooling vests for 2 hours per day or by taking a cold
shower for 90 seconds per day improves cardiometabolic risk factors (i.e.
dyslipidemia, hyperglycemia and inflammation) by concomitantly increasing
thermogenic processes in BAT and skeletal muscle resulting in improved
dyslipidemia, lower (ectopic) fat accumulation and improved insulin
sensitivity. Furthermore, we hypothesize that cold treatment will reduce
inflammation through skewing of monocytes towards an anti-inflammatory
phenotype. These may be direct effects of cold following the use of cooling
vests for 2 hours per day, or more indirect effects of generating a more
healthy daily routine and *resetting* the body by taking cold showers for 90
second in the early morning.

This study will consist of three parts with three different main objectives:
- Part 1 - Pilot study;
Primary objective: To assess and compare thermal comfort upon wearing a cooling
vest, based on exposed cooling packs versus shielded cooling packs, daily for 5
days in Europid and South Asian men and women
- Part 2 and 3 - Cooling vest and cold shower studies
Primary objective: To investigate and compare the effects of 6 weeks of daily
bouts of cold exposure through wearing a cooling vest (part 2) or through cold
showers (part 3) on fat mass in South Asian versus Europid men and women (part
2) or in Europid women only (part 3)

Part 1 - Pilot study: Cross-over intervention study, in which participants
will, in random order, either wear a cooling vest with exposed cooling packs or
a vest with shielded cooling packs for two hours per day for 5 consecutive
days, with at least two weeks of *wash out* in between. Participants will daily
answer questions on comfort and practicalities. Prior to wearing either cooling
vest, a small study day will take place (e.g. two in total of approx. 1 hour
each) in which acute effects on resting energy expenditure will be assessed
(indirect calorimetry).

Part 2 and 3 - Cooling vest and cold shower studies: intervention study in
which participants will either wear a cooling vest (Part 2; e.g. the cooling
vest that appeared most suitable in Part 1) for two hours per day for 6 weeks
in total, or take daily cold showers for up to 90 seconds for 6 weeks in total
(Part 3). Before and after the intervention, a study day will take place in
which we will assess anthropometric measures (e.g. body weight, waist
circumference), fat mass (BIA), changes in white adipose tissue metabolism
(biopsy; only in Part 2), baseline blood markers for lipid and glucose
metabolism (e.g. free fatty acids, total cholesterol, LDL-cholesterol, glucose,
insulin) as well as inflammatory markers (e.g. immune cell phenotype and in
vitro response of cells to inflammatory stimuli) and stress markers (cortisol)
in blood and scalp hair. Furthermore, in part 2 we will also assess
cold-induced changes in energy expenditure (indirect calorimetry) and skin
temperature (infrared thermography), cold-induced changes in lipid metabolism
(through regular blood sampling)

Participants in the intervention group may directly and personally benefit from
participating in this research project due to the hypothesized health benefits
of cold exposure. However, little burden is expected when taking part in this
study. The intravenous cathether may cause bruising. The white fat biopsy (only
in part 2) may cause bruising, and in rare cases sensibility of the part of the
skin where the biopsy was taken may be decreased.