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Plaques, platelets and heart attacks
HEART attacks remain one of the most common causes of death. The good news is that over the last few decades, research has enabled us to understand the mechanism of death from heart attacks. Preventing sudden heart death starts when you are in your teenage years and having more knowledge will empower you to take proactive measures to prevent the onset of a heart attack.
Degeneration of the arteries (atherosclerosis) results in damage to the inner lining of the heart (coronary) arteries and over a period of time, repeated damage to the lining of the artery may result in weakening of the inner lining, eventually resulting in the disruption of the lining at the site of accumulation of cholesterol and/or calcium in the inner wall, exposing the underlying contents to the blood in the arterial lumen.
This may trigger a biological cascade which culminates in the formation of a blood clot at the site. It is similar to the formation of a blood clot when you cut the skin. Only this time, if the clot is big enough, it will occlude blood flow in the coronary artery and trigger a heart attack.
Initial understanding of how arterial plaques become unstable and prone to disruption is derived from limited post-mortem studies of coronary arteries and resected surgical neck (carotid) arterial specimens. The studies show that there are three separate mechanisms that precipitate the disruption of the inner arterial wall and the formation of blood clot in the arterial lumen, namely, plaque rupture, plaque erosion and calcified nodules. These findings represent a snapshot of the most advanced stage of atherosclerosis and do not provide information on the development of these lesions.
These gaps in knowledge have partially been filled by data from studies which used advanced imaging techniques to take images of the wall and lumen of the coronary arteries over a period of time. In the PROSPECT study (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), close to 700 patients were followed up for more than three years with intra-coronary artery imaging. The study identified those plaques with a thin lining with cholesterol deposits accumulated within the plaque (thin-cap fibroatheroma) as having the highest risk of precipitating a heart attack. However, only about 5 per cent of these thin-capped fibroatheroma eventually lead to a heart attack.
The search for the holy grail of atherosclerosis is on. Scientists are trying to identify blood markers which can help doctors predict plaque rupture and the risk of developing a heart attack. One common thread in research is that the presence of inflammation makes the lining of the plaque more vulnerable to rupture. Hence, finding markers that can help physicians identify inflammation of the plaque has been a key priority. The commonest marker currently used as a biological marker or biomarker for inflammation is C-reactive protein (CRP). Studies show that CRP predicts cardiovascular events and retains its predictive value even when the patient is under treatment. Other potential markers include soluble interleukin-2 receptor alpha, a marker of white cell activation, and Galectin-3, a surrogate for plaque instability.
Hemodynamics in arteries
It has been observed that plaques tend to develop at the segments of the coronary arteries where there is turbulent flow, such as at branches and curvatures. This observation is an indication that the flow characteristics in the coronary artery have an impact on the development of plaques and instability of plaques. It has been found that the cells in the lining (endothelium) act as mechanical sensors and are able to sense the impact of shear stress and turbulent flow on the wall.
With increased turbulence, the cells in the endothelium can undergo changes or send signals to adjacent tissue which will promote the development of a plaque. Higher tensile stress in the wall lining, present in the proximal segments of the heart arteries, appears to be an important triggering factor for plaque rupture. Hence, it is not surprising that plaque rupture occurs more often in the proximal rather than the more distal segments where the tensile stress is low.
Cholesterol and plaque instability
Many studies have established that "bad" or low density lipoprotein cholesterol (LDL-C) increases plaque instability. The more "soft" LDL-C accumulates under the endothelial lining and stretches it, the more unstable the plaque is. It is analogous to having the skin lifted off from its underlying tissue by accumulation of fluid during the formation of a skin blister. Treatments that can reduce the LDL-C contents of the plaque will improve plaque stability.
Studies have also shown that elevation of high-density lipoprotein cholesterol (HDL-C) has not been associated with reduction of heart attacks. One of the studies where HDL-C was increased by niacin was not translated to clinical benefit. This was because the Vitamin B, niacin, did not improve cholesterol removal from the plaque via the transporter, ABCA1 (ATP-binding cassette transporter A1).
ABCA1 is the main cholesterol remover in plaque-causing cells called macrophages. Hence, HDL increase with niacin in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) was not associated with beneficial clinical outcomes.
There is clinical data to show that increased capacity for removal of cholesterol from the plaque is associated with lower likelihood of developing significant narrowing in the coronary and carotid arteries. Cholesterol-lowering drugs such as statins have been shown to be able to reduce plaque size by significant reduction of blood cholesterol.
Bleeding into the coronary plaques or intra-plaque bleeding is a key factor that increases the vulnerability of the plaque to rupture. The coronary artery wall has microscopic vessels and rupture of micro-circulatory vessels can cause bleeding within the wall of the coronary artery. The damaged blood cells release enzymes that increase inflammation and they also degenerate into soft necrotic material which enhances the instability of the plaque.
The net effect is an arterial lining "weakened" by inflammation, beneath which there is a pool of soft "mushy" debris comprising dead cells and cholesterol. It is like an expanded skin blister with a soft liquid interior and a thinned-out lining which can tear any time.
There have also been studies that demonstrated that increased blood pressure is associated with intra-plaque bleeding in carotid plaques in slightly more than one-fifth of patients. With ageing, the arterial wall becomes less elastic and is stiffer. This increased stiffness has been associated with more intra-plaque bleeding.
Platelets are the component of our blood which helps to ensure the formation of clots to stop bleeding and to cover the ruptured linings of damaged arterial walls. The blood platelets play an important role in heart attacks. Adhesion of blood platelets to inflamed linings of coronary arteries results in movement of cholesterol-containing macrophage cells into the wall of the coronary arteries.
In addition, clumping of platelets plays a critical role in the formation of a blood clot occluding the residual lumen of a narrowed heart artery segment. Hence, anti-platelet medication is an effective measure in the reduction of cardiovascular risk by preventing platelet clumping during plaque rupture.
It has been shown that plaques that are highly vulnerable to rupture have many white blood cells of the type known as monocytes/macrophages, especially at the edges of the thin linings of the plaques. These macrophages release chemicals which increase inflammation of the lining. Experimental evidence has shown that blocking the effects of chemicals that attract monocytes virtually stops the development of plaques.
Stabilisation of the plaque
Preventing disruption of plaques is key to avoiding the sudden occlusion of the coronary artery by a blood clot. Hence, if you have been told by your doctor that you have blockage of your heart arteries, take the following measures to prevent a sudden heart attack:
- Lower your LDL-C to as low as possible, preferably less than 70 mg/dl. Lowering of LDL-C is of paramount importance in preventing the development of plaque rupture and statins are currently the most commonly used drugs.
- Do not exercise just to raise the HDL-C. Elevation of HDL-C was not associated with reduction of heart attacks as it does not result in net removal of cholesterol from the plaque. Vigorous exercise can precipitate a heart attack if you have an unstable plaque.
- Treating high blood pressure to achieve a normal blood pressure level can reduce the likelihood of bleeding in the plaques in the carotid arteries and reduce the progression of atherosclerosis in the coronary arteries.
- Commencement of blood-thinning medication such as aspirin will reduce the likelihood of sudden clot formation.
- Monitoring of CRP may help to identify those at high risk of plaque rupture.
- Cessation of smoking can prevent further damage to the wall of the coronary arteries.
- If you have diabetes mellitus, good control is necessary to prevent plaque progression and deposition of calcium in the walls of coronary arteries.
Religious adherence to these measures may make the difference between life and death.
- Dr Lim is medical director at the Singapore Heart, Stroke & Cancer Centre. He is a professor at Fudan University, Shanghai and vice-president of both the World Chinese Doctors Association and the World Federation of Chinese Cardiovascular Physicians. He is also founding editor of Heart Asia, a journal of the British Medical Journal Publishing Group
- This series is brought to you by Heart, Stroke and Cancer Centre. It is produced on alternate Saturdays.
- To read more of Dr Lim's previous health-related articles, visit: http://www.btinvest.com.sg/specials/shscc