Atherosclerosis: Inflaming hearts all over the world
11 May 2017
It has long been hypothesised that low-density lipoprotein (LDL) plaques are the primary driver in the development of atherosclerotic disease. Research across multiple branches of cardiovascular medicine has highlighted the correlation between elevated plasma LDL cholesterol and a narrowing of the arterial lumen through plaque build-up. What is now being recognised in addition to this, is that a critical inflammatory process runs parallel to the traditional lipid-centric model in atherosclerosis progression. Whilst current therapeutics have been successful in addressing the hyperlipidaemia component, targeting vascular inflammation therapeutically is the next step in reducing the morbidity and mortality attributable to this condition.
The inflammation in atherosclerosis is the result of a complex network of cellular processes and interactions. In early stages of the disease, lipids accumulate in the subendothelial layer of the arterial wall. Nearby vascular cells are triggered to instigate an immune response, which attracts monocytes, T cells and other leukocytic cells to the area. This leads to the development of lipid-laden macrophages that go on to form atherosclerotic plaques. It is estimated that over 65% of all acute myocardial infarcts occur following destabilisation of these plaques. The plaque ruptures, triggering a modulating inflammatory process that leads to platelet aggregation at the rupture site. This thrombosis can block the artery to such an extent that blood flow is severely reduced and a major adverse cardiovascular event occurs. Histological investigations have shown that unstable plaques have not only a higher propensity to rupture but higher levels of inflammatory markers and mediators (including leukotrines and cytokines) in comparison to stable plaques.
So what does this mean for cardiovascular drug development? Data from prior clinical trials has demonstrated that statins, the gold standard in hyperlipidemia treatment, also appear to have some ability to inhibit the inflammatory process. However, they only help to delay disease progression. Given that cardiovascular disease is still the leading cause of death across the world, therapeutic advances that target vascular inflammation directly should be considered the ultimate development goal.
Dedicated to the memory of James Bechaz
11th May 1947 – 12th November 2015