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What Causes Cardiovascular Disease? The Response to Injury Hypothesis, Part 4

ByDr. Malcolm KendrickDecember 2, 2019

Reducing the risk of cardiovascular disease

Viewing cardiovascular disease (CVD) as a response-to-damage process means reducing risk relies on doing at least one of three things, and ideally all three:

  • Protecting the endothelium from damage
  • Reducing blood coagulability
  • Improving the healing processes

Protecting the endothelium from damage

There are some obvious things that can be done to protect the endothelium that are already well recognized.

Exercise is important. It reduces blood pressure and CVD risk. While there are many different mechanisms to explain this, perhaps the most important is that exercise induces nitric oxide (NO) synthesis, which is the key molecule for maintaining endothelial health.

Another well-recognized way to improve endothelial health is to stop smoking. As highlighted in a previous article, it is clear that smoking kills endothelial cells.

Air pollution also damages and kills endothelial cells. As C. A. Pope et al. explain, “Episodic PM2.5 (fine particulate matter air pollution) exposures are associated with increased endothelial cell apoptosis (cell death).” Therefore, smoking and exposure to fine particulate air pollution (car exhaust/diesel exhaust) should be reduced and/or avoided as much as possible. Indeed, any air pollution is damaging to the cardiovascular system.

It is also important to maintain the glycocalyx, the “forest” of glycoproteins that lines and protects the endothelium. This is more important for those who have diabetes or other conditions that tend to result in a thinned glycocalyx — e.g., those with chronic kidney disease, the elderly, those on various medications, and those with lower levels of protein/albumin in the bloodstream. It is increasingly recognized that damage or degradation of the endothelial glycocalyx is a key step in CVD development, so it is important to maintain the glycocalyx. This is why protein supplementation with chondroitin sulphate (CS) can be beneficial in certain groups (CS is often used in arthritis). It provides some of the building blocks needed to keep the glycocalyx healthy. The authors of a 2018 study in Thrombosis and Haemostasis conclude, “The data presented herein add insight into how CS interferes with the progression of atherogenesis and support the rationale of considering CS as pharmacologic mediation of atherosclerosis initiation and progression for prevention of cardiovascular events.”

Another factor that can have an impact on the glycocalyx and endothelial health is long-term periodontal disease (chronic infections in the teeth). The causal mechanism is almost certainly that bacteria release exotoxins that damage the glycocalyx and thus endothelial cells. This means good dental health is important.

An additional factor that is highly beneficial though more controversial is sunlight. It has been found that sunlight stimulates nitric oxide production, thus lowering the blood pressure (BP), and can reduce mortality. R. B. Weller writes, “Cohort studies from Scandinavia show a dose-dependent fall in mortality with increased sun-seeking behaviour. Skin contains significant stores of nitrogen oxides, which can be converted 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 suggest the same mechanism may reduce metabolic syndrome (often called pre-diabetes).”

It is also probable that the positive impact of sunlight on vitamin D production is important in reducing CVD. Diane Wallis et al. claim, “Vitamin D deficiency links to cardiovascular disease can be found in a number of studies demonstrating a 30% to 50% higher cardiovascular morbidity and mortality associated with reduced sun exposure caused by changes in season or latitude. Conversely, the lowest rates of heart disease are found in the sun-drenched Mediterranean coast and in southern versus northern European countries. Cardiac death has been reported to be the highest during winter months.” This may be at least in part due to the benefit of vitamin D on endothelial cell production. As Roberto Negro explains, “Vitamin D deficiency has been associated with depletion of EPCs (endothelial progenitor cells) and endothelial dysfunction, and in vitro vitamin D supplementation improved EPCs [sic] capacity to form colonies and increase their viability.”

Essentially, any factor that can improve endothelial health or function will have a benefit with regard to CVD. From a drug/medication perspective, this should theoretically include any drugs that stimulate nitric oxide production:

  • ACE-inhibitors (widely used to control raised blood pressure)
  • Viagra (this stimulates nitric oxide production)
  • Statins
  • Nitrates such as nitroglycerine (GTN), isosorbide dinitrate, etc. (usually only used to treat people with angina)

In general, it would be advisable only to take medications if you already have CVD and/or high blood pressure that cannot be controlled in other ways.

From a supplementation perspective, the supplements that can increase nitric oxide production are:

  • L-citrulline
  • L-arginine
  • Flavinoids
  • Nitrates – found in beetroot, spinach, etc.

One thing to be careful about is salt restriction. Salt restriction can activate the physiological system required to keep the blood pressure up and stop the kidneys from excreting sodium. This system is referred to as the renin-aldosterone-angiotensin system (RAAS). As Maricica Pacurari et al. explain, “The renin-angiotensin-aldosterone system (RAAS), one of the most important hormonal systems, oversees the functions of cardiovascular, renal, and adrenal glands by regulating blood pressure, fluid volume, and sodium and potassium balance.” An activated RAAS system is a significant risk factor for CVD, primarily because the hormones angiotensinogen and aldosterone are inhibitors of nitric oxide. While activation of this system keeps the blood pressure up, it damages the endothelium.

The most effective way to stop activation of the RAAS system while keeping the blood pressure under control is to increase potassium consumption. Sodium and potassium have a complex interplay in all human systems. However, in simple terms, the balance between sodium and potassium is key. In a 2017 study in the American Journal of Physiology, Alicia McDonough et al. conclude, “The findings suggest that public health efforts directed toward increasing consumption of K+-rich natural foods would reduce BP and, thus, cardiovascular and kidney disease.” Therefore, it seems, rather than reducing sodium intake and risk firing up the RAAS system, we should increase potassium intake.


KendrickMalcolm Kendrick is a family practitioner working near Manchester in England. He has a special interest in cardiovascular disease, what causes it, and what may prevent it. He has written three books: The Great Cholesterol ConDoctoring Data, and A Statin Nation. He has authored several papers in this area and lectures on the subject around the world. He also has a blog,, which stimulates lively debate on a number of different areas of medicine, mainly heart disease.

He is a member of THINCS (The International Network of Cholesterol Sceptics), which is a network of doctors and scientists who believe that cholesterol is not the main underlying cause of heart disease. He remains a proud Scotsman, whisky drinker, and failed fitness fanatic who loves a good scientific debate — in the bar.

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