Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness

Today’s post is based on the following review published in American Heart Association’s Hypertension Journal (September 2018, Vol 72, Issue 3).

screenshot-2018-09-09-at-8-04-12-pm

Here is the link to the article:

https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.118.11065

I chose this review for analysis today because I think it is very pertinent to the pathophysiology of hypertension and will greatly help us understand the processes leading up to the development of hypertension.

It has long been known that increased arterial stiffness has a very important role in the pathogenesis of hypertension. Increased arterial stiffness is demonstrated by an increase in pulse wave velocity. A pulse wave velocity of 12m/sec is indicative of increased arterial stiffness.

This review sheds light on the renin-angiotensin-aldosterone system (RAAS) and its role in facilitating arterial stiffness which leads to the development of hypertension.

Three major groups of population are at increased risk of tissue RAAS mediated arterial stiffness.

  1. Diabetics: The hyperinsulinemia and hyperglycemia activate tissue RAAS which leads to the development of arterial stiffness. It is also interesting to note that diabetics have been shown to have increased arterial wall stiffness even in the absence of arterial wall thickness.
  2. Obese: Adipose tissue directly synthesizes and releases angiotensin II and aldosterone especially visceral adipose tissue. It has been shown that skinfold thickness is directly related to the degree of arterial stiffness.
  3. Elderly: Aging also leads to increased activation of tissue RAAS promoting arterial stiffness.

Now let us discuss the exact pathologic mechanisms by which tissue RAAS causes arterial stiffness. Two main cell types are involved. Vascular smooth muscle cells (VSMC) and endothelial cells (EC). Multiple pathways are implicated.

  1. Sympathetic Nervous System (SNS): Under normal circumstances, angiotensin II does not cross the blood brain barrier. However, elevated angiotensin II levels increase the permeability of blood brain barrier and activate the SNS, which results in activation of RAAS.
  2. Oxidative Stress: The most important enzyme involved in generating reactive oxygen species is nicotinamide adenine dinucleotide phosphate oxidase (NADPO). This enzyme is activated by angiotensin II and aldosterone. Activation of NADPO inactivates nitric oxide (NO) which impairs vascular relaxation thus contributing to stiffness.
  3. Inflammation: Angiotensin II and aldosterone increase the expression of several proinflammatory cytokines. These include factor 𝜅B (NF-𝜅B), toll-like receptor 4 (TLR4), monocyte chemoattractant protein-I (MCP-1), T-lymphocytes and T-cell derived cytokines and CD11b.
  4. Vascular and cardiac fibrosis: Angiotensin II and aldosterone cause fibrosis by increasing growth factor β1, transglutaminase 2, lysyl oxidase and tumor necrosis factor receptor-associated factor 3 (TRAF3).
  5. Sodium hemostasis and the endothelial cell sodium channel: Endothelial cells (EC) have EnNac (endothelial cell sodium channel) which is a channel through which Na enters the cell under the influence of RAAS. ECs have a well developed glycocalyx that limits the access of Na to the endothelial nitric oxide synthase (eNOs) but under the influence of overactive RAAS, the enzyme responsible for the degradation of EnNaC is impaired which leads to accumulation of these channels in the cell membrane. This increases Na entry manifold which overwhelms the ability of the glycocalyx to protect eNOs. Therefore, G-actin in the glycocalyx is polymerized to F-actin which impairs endothelial nitric oxide synthase (eNOs) resulting in decreased NO mediated vascular wall relaxation and increased stiffness. This is clearly shown in Figure 1 in the article.

So what is the significance of all this?

As things stand right now, anti-hypertensive drug therapy is only recommended to be started after hypertension is diagnosed. Before the diagnosis of hypertension, risk factor modification can be undertaken to prevent the development of hypertension. This risk factor modification may include eating a low salt diet, exercising regularly, losing weight, stopping smoking but drug therapy is only recommended after hypertension is diagnosed.

Now this review says arterial wall thickness predates the development of clinical hypertension. Pulse wave velocity can be measured and we can identify those patients who are at risk of developing hypertension before they even develop the disease.

So, here is my question.

Are we looking at a time where we will diagnose patients with increased arterial stiffness and start them on angiotensin converting enzyme inhibitors/angiotensin receptor blockers/mineralocorticoid receptor blockers before the onset of clinical hypertension? If this review is to be believed, patients with diabetes mellitus type 2, hyperinsulinemia, hyperglycemia, obesity and the elderly will definitely benefit from this therapy. This will probably be called drug prophylaxis of hypertension.

If so, are the insurers going to be willing to pay for it?

Please share your viewpoint on this issue by posting your comments.

Thank you for reading my analysis of this review.

 

 

 

 

2 thoughts on “Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness

  1. Thanks for the review ,I have now understood the mechanism why age, obesity and diabetes, etc. ,are also risks factors for SHTN…It was really worth the time.

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    1. Thank you for reading my post and liking it. Please stay tuned for more informative articles in the days to come. Please let your friends and family also know about subscribing for free on my website. This way they can benefit from the information too.

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