Atherosclerosis: the Effectively Tackling and Minimizing Life-Threatening Effect

Introduction

Atherosclerosis is an immunoinflammatory disease of medium to large arteries responsible for around 50% of deaths in European civilization. It occurs when cholesterol builds up in arterial walls forming plaques that cause narrowing and restriction in blood flow. The progression of this disease may result in strokes, heart attacks, and thrombosis amongst many other life-threatening diseases. On its own, however, atherosclerosis is hardly fatal. It is the progression of the disease that results in detrimental conditions. This essay will briefly summarise atherogenesis, look at factors that increase the likelihood of this process occurring, and analyze the critical complications that may follow. An evaluation of treatment options available based on their outcomes will also be made taking into consideration their efficacy in dealing with this life-threatening disease.

Plaque Formation

The stages of atherogenesis can be grouped into five:

1. Endothelial dysfunction
2. Lipid layer formation
3. Macrophage recruitment into intima
4. Foam cell formation
5. Extracellular matrix degradation

Through the above five stages, an atherosclerotic plaque is formed. This process can also be divided into three stages:

1. Initiation
2. Adaptation
3. Disruption

Initiation

Atherogenesis begins due to the abnormal functioning of the endothelium allowing the entry and subsequent modification of lipids. This creates an environment favorable for inflammation. In this stage, the fatty streak does not significantly obstruct blood flow or occlude the arterial wall. The plaque could as a result, possibly reduce without any cardiovascular malfunction symptoms appearing. Endothelial dysfunction caused by factors such as smoking, diabetes, increased age, etc. is generally known to be the main cause of this stage. Further, into this process, macrophage migration and their transformation into foam cells can also be indirectly attributed to endothelial dysfunction.

Adaptation

After the first stage, the low-density lipoproteins (LDLs) bind to proteoglycans in the tunica intima and begin to accumulate. When chronic accumulation occurs, chemical modification follows. One modification that can occur is the reaction with pro-oxidants and reactive oxygen species. This oxidative stress results in further loss of normal endothelial and cellular function. Specialists have identified this accumulation that results in arterial stenosis and blood flow impediment as the underlying cause for atherosclerosis complications. Additionally, LDL glycation can also occur resulting in plaque that further advances inflammation in the arteries. This property is due to the presence of advanced glycation end products (AGEs) that activate inflammatory pathways. The various modifications these lipoproteins go through e.g. oxidation, leave them as molecules capable of damaging bodily tissues. This tissue damage can then initiate angiogenesis in the plaque enhancing its progression. Macrophage migration is also activated due to these changes forming foam cells in the fatty streak as they absorb more LDLs. The foam cells can then release platelet-derived growth factors (PDGF) that cause smooth muscle cells to move from the tunica media into the intima. The accumulated and confined foam cells further stimulate plaque progression by acting as proinflammatory cytokine sources.

Fibrous cap formation

The smooth muscle cells now present in the tunica intima combine with extracellular matrix constituents such as collagen and elastin to create a connective tissue referred to as the fibrous cap. This cap contains a core rich in oxidized LDLs, cholesterol, and other components of the plaque shielding it from circulating blood. At this stage, the plaque is referred to as a fibrous cap atheroma. The propensity for thrombosis is highly dependent on this fibrous cap. This is because it provides mechanical stability preventing migration of the plaque into the blood. The actual size of the cap does not have a major role in rupture; what does is the thickness. The influx, activation, and formation of foam cells thicken the thrombogenic contents of the plaque's core causing thinning and degradation. This may then result in arterial occlusion and the formation of a thrombus. This is the precedent for the development of often deadly clinical complications as blood and oxygen delivery to organs is impaired.

The nature of the cap is the basis for plaque classification of which there are two groups:

Stable atherosclerotic plaque. A thicker fibrous cap prevents rupture but increases arterial narrowing.

Unstable atherosclerotic plaque. The thinner fibrous cap predisposes plaque to rupture but is less obtrusive to the artery.

Disruption and rupture

The inflammatory cytokines present from modified LDLs encourage the release of matrix metalloproteinases (MMP) from foam cells to break down the elastin and collagen of the fibrous cap as illustrated in Figure 2. This greatly weakens the fibrous cap reducing its ability to provide mechanical stability. Smooth muscle cells sensitized to apoptosis by cytokines may also have a role in plaque disruption and rupture. As smooth muscle cells synthesize the majority of vascular collagen, their death takes away a component essential for cap stability increasing the risk of rupture. The angiogenesis initiated in LDL modification poses a serious clinical threat if this stage is reached in a patient. The rupture of formed vasa vasorum within the plaque may also end up in plaque hemorrhage which can cause sudden death in the individual emerging from clotting and thrombi formation.

Risk Factors

The following are certain factors which when in place increase the chance of an individual developing this disease:

• Diabetes. Impaired insulin effectiveness allows a high level of sugar to circulate in the blood and contributes to atherosclerosis development.
• Smoking. Smoke constituents increase blood pressure and cholesterol levels and also tighten and damage vessels. This increases the formation, progression, and destructive effects of atherosclerotic plaques respectively.
• Sedentary lifestyle. Plaque constituents such as fats and cholesterol are not used up with this lifestyle but are allowed to accumulate and may go on to cause serious harm.
• Family history of cardiovascular disease - Specific genes linked to atherosclerosis remain unidentified, however, it has been observed that a family history of atherosclerosis does increase an individual's chances of acquiring the disease.
• Older age. Lifestyle and genetic factors that contribute to atherogenesis increase with age potentially to a stage where serious harm can occur.
• High levels of triglycerides and or low-density lipoprotein (LDL) in the blood.
• High fat, sugar, and salt (HFSS) foods. Increases plaque constituents circulating in the blood.
• High blood pressure. Places a higher amount of force on arterial walls making them more vulnerable to narrowing and damage.

Clinical Complications of Atherosclerosis

Features of atherosclerotic lesions that result in fatal consequences include smooth muscle cells, inflammation, thin fibrous caps, and a large lipid pool. Looking back to atherogenesis, these are all characteristics that can appear as the process continues. It is therefore evident that the clinical complications of atherosclerosis can be attributed to the progression of the disease not simply the appearance of the disease itself. There are various complications that can arise as atherosclerosis progresses and many different viewpoints about which ones are the most malignant. Complexity is further increased as complications are dependent on the size and location of affected vessels, the specific type of plaque, and the length of the atherogenesis process. The following developments also represented in Figure 3 have been identified as the four main clinical consequences of atherosclerosis due to the debilitating effect they can have:

1. Acute narrowing of the lumen. If the atherosclerotic plaque ruptures, pro-coagulants are released into the blood leading to thrombus formation and occlusion of the vessel by activating blood clotting. Blood and consequently oxygen flow to organs is therefore restricted resulting in fatal diagnoses such as; gangrenes, ischemic necrosis, myocardial infarction, strokes, etc.

2. Chronic occlusion. Gradual occlusion of the arterial lumen as atherosclerosis progress can severely damage affected vessels as the plaque takes up the route of oxygen, blood, and nutrients depriving organs of these essential substances. This deficit in organs can possibly result in chronic ischemia, angina pectoris, organ atrophy, intermittent claudication, etc.

3. Embolism. After a plaque ruptures, thrombi fragments can be distributed to various vascular locations. At these sites, the fragments can become embedded in the vessel preventing oxygen, blood, and other required nutrients from reaching those organs resulting in the grave manifestations of oxygen-deprived tissues e.g. gangrenes, etc.

Cholesterol crystal emboli can also form. These appear when the atherosclerotic plaque ruptures releasing its contents which travel through the blood and form emboli in vessels. This obstruction further aggravates the conditions associated with atherosclerosis.

4. Aneurysm. After a long period of time, as the plaque progresses it can travel from the tunica intima into the tunica media. This leads to a reduction in the size of the medial layer and elastic tissue loss producing arterial weakness and dilation. Besides this, the presence of smooth muscle cells in the medial layer will further increase the damaging properties of the plaque. The very probable sudden rupture of these formed aneurysms releases blood into the intracranial space and damages brain cells by clotting possibly resulting in death.

Treatment

From the associated complications above, it is evident that atherosclerosis is a disease that can have deadly effects if unmanaged. Most treatment options have four main goals:

• Slowing or stopping the atherogenesis process
• Reducing the probability of clot formation and associated diseases
• Increasing the diameter of narrowed arteries
• Reducing risk factors

The late manifestation of clinical symptoms in atherosclerosis after plaques have probably reached a significant stage is the reason why treatment is aimed at distinct areas and not the root cause.

The following are some courses of action that can be undertaken to achieve this:

1. Lifestyle Changes

As earlier discussed, many elements that increase the likelihood of developing atherosclerosis are lifestyles and attitudes adopted. It is consequently apparent that tackling these issues could possibly slow down or stop the continuance of atherogenesis. Some of the changes that can be implemented include:

• Smoking cessation
• Moderating alcohol consummation
• Adopting a healthy diet
• Undertaking frequent exercise
• Getting to and maintaining a healthy weight

2. Medication

This treatment option is highly dependent on the individual factors in their life that led them to develop atherosclerosis and their current stage. Some medication options include:

• Statins. Block the hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA) enzyme to lower cholesterol formation thereby reducing the rate of plaque progression.
• Blood pressure medications. Lower blood pressure to reduce the damaging effects on arteries.
• Blood sugar and cholesterol medications. Lower blood sugar levels so fewer elements are present in blood that contribute to plaque progression. This has been proven to reduce subsequent cardiac complications and death rates.
• Anticoagulants. Slow down clotting that leads to deadly strokes and heart attacks.
• Anti-inflammatory drugs. Counters inflammation that has been seen to encourage plaque growth and weaken fibrous caps resulting in rupture.

3. Surgery

The above two methods of atherosclerosis management may have beneficial effects on the individual. However, there are some situations where a more aggressive approach is required. For instance, in patients where plaque progression has reached an advanced stage and poses an imminent threat to life. Surgical options are not limited to but include:

• Coronary Artery Bypass Grafting. Diverts blood around occluded or narrowed arteries ensuring organs receive blood and oxygen required and may reduce or prevent the appearance of fatal clinical complications earlier discussed.
• Carotid Endarterectomy. Removes plaques from carotid arteries in the neck restoring blood and oxygen flow to the brain and possibly preventing deadly strokes.
• Coronary AngioplastyPercutaneous Coronary Intervention. Opens narrowed or blocked arteries restoring the flow of oxygen and blood possibly preventing the life-threatening states aforementioned. Stents may also be used to keep arteries open after surgery.

Conclusion

The complete atherogenesis process is still not fully understood. When this process does occur, stable plaques are comparatively harmless because they do not rupture or form emboli as easily. However, the gaps in the knowledge available do not allow certainty that every plaque formed will be stable. Some plaques will be vulnerable and likely to thromboembolic or rupture leading to the unambiguously accepted grave and life-threatening consequences this disease can have. Early identification of atherosclerosis can allow the slowing stopping treatment options we have available be implemented and increases their chances of effectiveness. There is now much more information on atherogenesis and plaque disruption. Rupture has also now been acknowledged as the origin of deadly atherosclerosis complications. This information has led to the awareness of specific interventions that are likely to be successful e.g. anti-inflammatory drugs and statins. This insight into atherosclerosis and plaque rupture aetiopathogenesis that continues to improve with new research, combined with target-directed therapies allows novel advances to be made in effectively tackling this critical disease and minimizing as best as possible its life-threatening effect.