Newsletter #280

High blood pressure has been characterized as a “silent killer,” because lots of people have hypertension without being aware of it, and the condition can lead to permanent damage throughout the body without any obvious symptoms. And it is all too common. According to the CDC, nearly half of American adults have hypertension, and risk tends to go up as we get older.

Despite its prevalence, there is reason to believe that it is not inevitable. For instance, we know that people living in certain hunter-gatherer communities have low blood pressure, and it stays that way even as they age. This suggests that we may be able to prevent it through lifestyle modification.

One such modifiable factor is sleep. Epidemiological research suggests that inadequate sleep is associated with cardiovascular disease, and this appears to be connected to blood pressure regulation. For example, an analysis of cross-sectional data from 5910 American adults found 66% higher odds of hypertension among those who slept less than six hours per night, compared to people who got 7-8 hours of sleep.

But some people might question the reliability of this sort of observational evidence. Fortunately, a couple of recent experiments were conducted which rigorously test the effects of sleep loss on blood pressure in healthy adults, and which provide us with some insight into why altered sleep has this impact. Check it out 👀

Researchers at the Mayo Clinic recruited 20 healthy young participants and put them through two 16-day inpatient trials, each separated by a period of two months. The trials went as follows, in random order:

Throughout the study periods, the participants' sleep was monitored via polysomnography, and their blood pressure was measured repeatedly. They also consumed a controlled diet designed to maintain their weight.

Compared to control sleep, the sleep restriction resulted in elevated blood pressure, and the magnitude of this effect was much greater in female participants. 24-hour systolic blood pressure and sleep systolic blood pressure increased by 8.0 mmHg and 11.3 mmHg respectively, and these increases were sustained throughout the experimental phase with no signs of adaptation.

The rise in nocturnal systolic blood pressure persisted even through the recovery period, which is concerning for two reasons. First of all, people often have curtailed sleep during the week, followed by two days of "catch-up sleep" on the weekends. This finding suggests that catching up on the weekends may not be enough to fully mitigate the deleterious effects of accumulated short sleep during the week. Secondly, nighttime blood pressure is thought to be more strongly predictive of adverse cardiovascular events, compared to daytime or 24-hour blood pressure readings.

Notably, these participants showed signs of increased sympathetic activation (higher plasma norepinephrine), as well as vascular dysfunction, the latter of which we will examine further in the next study.

In the previous study, healthy women with restricted sleep were shown to experience increased blood pressure. This was accompanied by impaired endothelial function, measured via flow-mediated dilation, which continued even after three nights of recovery sleep. Endothelial dysfunction, meaning narrowing of blood vessels, is recognized as a precursor of atherosclerosis, and independently predicts heart attacks and strokes.

To gain more insight into the molecular mechanisms driving this phenomenon, researchers at Columbia University recruited 35 women and put them through two different sleep protocols, each of which were separated by a 6 week washout period:

During each phase, participants wore devices on their wrists to objectively measure sleep and ensure that they were adhering to the protocol. To figure out what was happening inside these people's blood vessels, the researchers also harvested endothelial cells from their veins before and after undergoing each sleep condition, and exposed the cells to a special fluorogenic probe that glows when exposed to reactive oxygen species.

Sure enough, after sleep restriction, levels of endothelial oxidative stress were increased by 78%, compared to adequate sleep, based on the response of the cells to the probe. This finding, alone, isn't super surprising. In rodents and fruit flies, sleep restriction reliably results in increased oxidative stress. However, this normally is countered by an upregulation of antioxidant genes (we've discussed this a little before on the podcast).

Here's the problem: in these human participants, there was no rise in antioxidant defenses to balance the endothelial oxidative stress. When the researchers dug a little deeper, they determined that the impaired antioxidant response in the endothelium was being driven by reduced expression of DCUN1D3, a protein that plays a key role in Nrf2 antioxidant responses.

This brings us to maybe the most interesting part of the study. Growth hormone, which is primarily released in the bloodstream early in the night during sleep, apparently upregulates expression of DCUN1D3. The researchers suggest that delaying bedtime by 1.5 hours likely disrupted GH release patterns, which may have had downstream negative effects on the Nrf2-mediated antioxidant responses in endothelial cells.

Vascular oxidative stress is thought to be a key driver of hypertension, and could explain why sleep loss is associated with high blood pressure. Importantly, this appears to occur even at levels of sleep loss that are relatively common in modern societies.

💊 The soft drink 7 Up originally contained lithium.

You probably already know that the original recipe for Coca-Cola used cocaine. But, as you might expect, Coke wasn't the only beverage in the patent medicine era to incorporate drugs.

7 Up was developed by Charles Leiper Grigg in St. Louis. Back then, it was known as "Bib-Label Lithiated Lemon-Lime Soda," and contained lithium citrate, which is now used as a mood stabilizer. The product was launched in 1929, two weeks before the Wall Street Crash (perhaps fortuitous timing on their part?).

The name was eventually shortened to 7 Up, for reasons that remain unclear but might actually be a reference to lithium, which has an atomic mass of ~7.

Coconut Water

Nutrition, of course, also plays a key role in blood pressure regulation. We know that consuming more potassium in the diet helps prevent hypertension by facilitating sodium excretion through the kidneys. Unfortunately, the vast majority of the population doesn’t even come close to achieving the levels of sodium and potassium in their diet that are linked to optimal outcomes, which is why potassium has recently been characterized as “a nutrient of public health concern.”

This is my cheat code for getting enough potassium every day. One bottle of this stuff contains 810 mg of potassium, making it easy to hit that 3500 mg target. I like to drink it during (and after) workouts, because it also contains a little bit of sodium and sugar, and it is pretty refreshing when you’re sweating a lot.

(Caveat: Apparently someone became seriously ill after drinking eight 11-ounce bottles of coconut water while exercising in extreme heat. As they say, it is possible to have too much of a good thing!)

How-to Guide to Optimizing Sleep

Getting enough sleep (as well as ensuring that your sleep is high quality) is clearly key for cardiovascular health. However, achieving that can be elusive. What can you do right now to set yourself up for success?

To that end, this guide addresses five main categories for sleep optimization:

We dig deep into the literature to capture some unique research-based strategies for coaxing your body to fall asleep. The biggest takeaway from this guide is that what you do during the day may be just as important for establishing healthy sleep patterns as your nighttime routine.

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