Our cardiovascular system is a complex network of vessels, carrying life-sustaining blood throughout our bodies. The health of our arteries plays a vital role in our overall well-being. Arterial stiffness, a concept that is not so familiar to many, is gaining attention as a crucial factor in our cardiovascular health. In this article, we will explore what arterial stiffness is, its relationship to cardiovascular disease, why it's a known independent predictor of cardiovascular events, and the drugs currently being tested to ameliorate it.
What is Arterial Stiffness?
Arterial stiffness refers to the reduced ability of your arteries to expand and contract as blood flows through them. Our arteries should have some elasticity, allowing them to absorb the pressure generated by the heart's contractions and release it gradually. Think of them as shock absorbers for your blood. However, due to different risk factors (we will discuss them in a minute) our arteries can lose this flexibility, becoming stiffer.
Image generated with DALL-E
Which are the key factors of arterial stiffness?
1. Age: Arterial stiffness tends to increase with age. As people grow older, their arteries naturally become less flexible due to changes in the composition of the extracellular matrix, increased collagen deposition, and alterations in the structure of elastin fibers.
2. Hypertension (High Blood Pressure): High blood pressure is a major contributor to arterial stiffness. Chronic exposure to elevated blood pressure leads to structural changes in the arterial walls, including increased collagen deposition and vascular remodelling, resulting in reduced elasticity.
3. Atherosclerosis: Atherosclerosis is the buildup of fatty plaques in the arteries, which can lead to inflammation and changes in the arterial wall structure. Atherosclerotic plaques and the inflammatory response they trigger can contribute to arterial stiffness.
4. Diabetes: Diabetes, especially poorly controlled diabetes, can lead to increased arterial stiffness. Hyperglycemia, oxidative stress, and the formation of advanced glycation end products (AGEs) all play roles in this process.
5. Lifestyle factors, such as smoking, obesity, physical inactivity, and poor diet can all increase the risk of arterial stiffness. Smoking damages blood vessels and promotes inflammation, obesity leads to metabolic changes and inflammation, physical inactivity contributes to stiffness, and an unhealthy diet with high saturated fats and processed foods can also impact arterial health negatively.
6. Genetics: Genetic factors can influence an individual's susceptibility to arterial stiffness. Some people may have a genetic predisposition that makes them more vulnerable to developing stiff arteries.
7. Inflammation: Chronic systemic inflammation, whether due to autoimmune diseases or other inflammatory conditions, can contribute to arterial stiffness by affecting the structure and function of blood vessels.
What are the molecular mechanisms behind arterial stiffness?
Arterial stiffness involves a range of intricate molecular mechanisms that affect the flexibility of blood vessel walls. One prominent mechanism is the increased deposition of collagen and alterations in the extracellular matrix. The extracellular matrix, housing vital components like collagen and elastin fibers, plays a pivotal role in preserving arterial elasticity. In conditions such as atherosclerosis and the natural aging process, collagen accumulates and the composition of the extracellular matrix undergoes changes, leading to heightened stiffness. For instance, individuals with essential hypertension experience elevated large artery stiffness due to the heightened pressure loading on the vessel walls, which leads to the accumulation of stiff materials like collagen. This biomechanical fatigue results from the repetitive pulsatile stress exerted on the arterial walls. Furthermore, the activation of the renin-angiotensin system contributes to structural alterations in the arterial wall by stimulating vascular smooth muscle cell (VSMC) proliferation, fostering low-grade inflammation, increasing collagen content, and promoting the formation of advanced glycation end products.
Another mechanism that impacts arterial stiffness is the degradation of elastin fibers. Elastin, a protein responsible for imparting elasticity to arterial walls, can be degraded by enzymes like matrix metalloproteinases (MMPs), ultimately reducing arterial flexibility.
Endothelial dysfunction is a third crucial factor. The endothelium, the innermost layer of blood vessels, produces nitric oxide (NO), a molecule that facilitates vessel dilation and promotes vascular relaxation. However, conditions such as hypertension and atherosclerosis can lead to endothelial dysfunction, resulting in reduced NO production and impairing the flexibility of arteries.
Chronic inflammation also contributes to arterial stiffness. Inflammatory cytokines and immune cells have the potential to disrupt the structure and function of blood vessel walls. Furthermore, oxidative stress can damage blood vessels, including elastin and collagen fibers, causing them to become stiffer due to the action of reactive oxygen species (ROS).
An additional example is found in chronic kidney disease, where arterial stiffness is partly attributed to calcification of the large artery wall. This process involves a sequence of molecular events, commencing with the loss of expression of inhibitory proteins by vascular smooth muscle cells (VSMCs) and culminating in the expression of proteins associated with chondrocytic, osteoblastic, and osteoclastic functions. These proteins collectively orchestrate the vascular calcification process, contributing to arterial stiffness.
These various molecular mechanisms interact and, in some cases, amplify one another, leading to the overall loss of arterial elasticity, a key characteristic of arterial stiffness.
The Relationship between Arterial Stiffness and Cardiovascular Disease
Arterial stiffness, though it may not sound concerning, is closely tied to heart and vascular health, and these issues are leading causes of death worldwide. When your arteries lose their natural flexibility, it can lead to several problems. Firstly, stiff arteries make your blood pressure go up, putting extra strain on your heart, which is a well-known risk for heart disease and strokes. Secondly, stiff arteries can restrict the flow of blood to different parts of your body, including your heart, potentially harming your heart muscle and raising the risk of heart attacks. Thirdly, arterial stiffness can make blood flow less smoothly in your arteries, which can cause turbulence and place stress on the artery walls, which in turn increases the chance of dangerous plaque build-up. Finally, stiff arteries can hinder the exchange of oxygen and nutrients between your blood vessels and the tissues they supply, which can have a broader impact on your overall health.
Arterial Stiffness as an Independent Predictor of Cardiovascular Events
Arterial stiffness is not merely a symptom or secondary concern; it's a substantial and independent predictor of cardiovascular events. This means that even in the absence of other apparent risk factors like high blood pressure or elevated cholesterol levels, increased arterial stiffness alone can significantly raise your risk of experiencing cardiovascular problems such as heart attacks and strokes. In clinical settings, several techniques are employed to monitor arterial stiffness
Pulse Wave Velocity (PWV): This method gauges the speed at which pressure waves travel through the arteries. Stiffer arteries transmit these waves more rapidly. It's a straightforward and non-invasive test that can offer valuable insights into arterial stiffness.
Augmentation Index (AIx): This approach examines how pressure waves in the arteries are reflected, providing information about arterial stiffness. It's often measured using a device called a tonometer, which is placed on the skin's surface.
Carotid-Femoral Pulse Wave Velocity (cfPWV): This is a specific type of PWV that measures the time it takes for a pulse wave to travel between the carotid artery in the neck and the femoral artery in the groin. It's considered the gold standard for assessing arterial stiffness.
Ultrasound Imaging: Doppler ultrasound can assess the stiffness of specific arteries, such as the carotid artery, providing a direct view of the arterial wall and its function.
Magnetic Resonance Imaging (MRI): In some cases, MRI can be employed to evaluate arterial stiffness, offering comprehensive information about the structure and function of blood vessels.
The University of Antwerp and Arterial Stiffness
Cédric Neutel, from the University of Antwerp's Physiopharmacology lab, is delving into the biomechanics of large blood vessels and their response to cardiovascular diseases. His research aims to not only enhance our understanding of these vessels but also explore the potential reversibility of vascular function changes through pharmacological treatments. In one study, Neutel found that the SGLT2 inhibitor empagliflozin, administered for 7 weeks at 15 mg/kg/day, reduced age-related stiffness in the aorta of elderly mice with normal blood glucose levels. Interestingly, the effect varied in different parts of the aorta, with a decrease in collagen type I and TGF-β (a protein responsible for increasing the amount of collagen and accelerating the degradation of elastin) deposition in the abdominal infrarenal section but not in the thoracic descending aorta. Notably, empagliflozin couldn't prevent elastin fragmentation. Despite these nuances, the study suggests that SGLT2 inhibition, specifically with empagliflozin, holds promise in alleviating arterial stiffness associated with aging. However, more research is needed to uncover the underlying, potentially region-specific, mechanisms at play.
Graphical abstract of the study conducted by Cédric Neutel.
The De-Stiffening Therapy?
There is a growing interest in whether reducing arterial stiffness can have real benefits for stroke management and prevention. Treatment to make arteries less stiff is emerging as a promising way to decrease the occurrence of strokes and improve the outlook for those affected. While we often focus on managing risk factors, like high blood pressure, it's essential to address the structure of our blood vessels too. Exercise is a simple and effective way to make your arteries more flexible.
In terms of medication, certain drugs that lower blood pressure can also help with arterial stiffness. For example:
- ACE inhibitors (like lisinopril) and ARBs (like losartan) are known to be particularly effective at reducing arterial stiffness by reversing changes in the vessel walls.
- Calcium channel blockers, such as amlodipine, can also help, although they might not be as effective as ACE inhibitors or ARBs.
- Beta-blockers, like metoprolol, are less helpful for arterial stiffness. Some newer ones, such as nebivolol and carvedilol, show promise, but more research is needed.
However important questions still remain open:
1. **Targeting Arterial Stiffness (AS):**
- *Can medications that lower blood pressure also reduce stiffness?* While lowering blood pressure does ease the stress on arterial walls, it might not change the fundamental properties of the tissues.
- *Should we look for more specific ways to target AS (i.e. one specific biological target)?* This remains uncertain at the moment.
2. **Reversing Arterial Stiffness and Related Problems:**
- *Does reversing stiffness help with associated health problems?* Increased stiffness often leads to reduced heart function and, sometimes, hypertension. While studies show that reducing stiffness can improve these conditions, we're not certain if it fully reverses the damage. Can we only slow down the disease's progression by reducing AS? Unlike atherosclerosis, where some treatments have shown plaque reduction, the reversibility of AS remains unclear.
Key articles:
Article written by Lorenzo Cianni, Cédric Neutel and edited by Christien Bowman
コメント