Events underlying myocardial infarction

MI resuts from blockages of the coronary arteries in the heart. These arteries supply blood to the heart tissue and originate from the aorta. Commonly blockages can occur in more places in the left coronary artery than the right coronary artery. Blockages can be a result of plaque build from atherosclerosis. 

Coronary heart disease is second to coronary artery disease is the most common causeof death in the UK. It causes 26% of all deaths. Using 2015 CHD mortality data for the UK estimates that there are about 160K a year. Prevalence, which varies across the UK, increases with age; it is estimated that ~2.65 million people in the UK have CHD. There are over 300,000deaths per year in 1961. 

90% (men) and 93% (women) of MI were attributed to modifiable risk factors such as: smoking; diet; obesity; physical activity; alcohol; dyslipidaemia; hypertension and diabetes. 

Smoking increases the risk of CHD. The long term risk of smoking to individuals has been quantified in a 50-year cohort study of british doctors. The study found that mortality from CHD was ~60% higher in smokers (and 80% higher in heavy smokers) than in non-smokers. Regular exposure ti second-hand smoke increases the risk of CHD by ~25%. It is estimated that smoking caused about 31,000 deaths from CVD in 2000 in the UK. Overall, around 1 in 8 deaths from CVd were attributed to smoking. A higher proportion of premature deaths from CVD, around 1 in 5, were attributed to smoking. 

Diet. The world health report 2002 estimated that around 4% of all disease burdenin the developed countries were caused by low fruit and veg consumption, and that just under 30% of CHD and almost 20% of stroke in developed countries was due to fruit and veg consumptio levels below 600g/day. 

Physical activity.Recent research from the World Health Organization highlighted the importance of physical inactivity as a major risk factor for CHD. The 2002 World Health Report estimated that around 3% of all disease burden in developed countries was caused by physical inactivity, and that over 20% of CHD and 10% of stroke in developed countries was due to physical inactivity (less than 2.5 hours per week moderate intensity activity or 1 hour per week vigorous activity).

Alcohol The World Health Report 2002 estimates that over 9% of all disease burden in developed countries is caused by alcohol consumption and that 2% of CHD and almost 5% of stroke in men in developed countries is due to alcohol. However, the impact of alcohol consumption in women in developed countries is estimated to be positive – if no alcohol were consumed, there would be a 3% increase in CHD and a 16% increase in stroke.

Hypertension. More recently the INTERHEART study estimated that 22% of heart attacks in Western Europe and 25% of heart attacks in Central and Eastern Europe were due to a history of high blood pressure, and that those with a history of hypertension were at just under twice the risk of a heart attack compared to those with no history of hypertension.

Dyslipidemia.  (INTERHEART) estimated that 45% of heart attacks in Western Europe and 35% of heart attacks in Central and Eastern Europe are due to abnormal blood lipids, and that those with abnormal lipids are at over three times the risk of a heart attack compared to those with normal lipids.

Obesity. (INTERHEART) 63% of heart attacks in Western Europe and 28% of heart attacks in Central and Eastern Europe were associated with abdominal obesity (a high waist to hip ratio), and those with abdominal obesity were at over twice the risk of a heart attack compared to those without. This study also found that abdominal obesity was a much more significant risk factor for heart attack than BMI.

Diabetes. (INTERHEART) estimated that 15% of heart attacks in Western Europe and 9% of heart attacks in Central and Eastern Europe are due to diagnosed diabetes, and that people with diagnosed diabetes are at three times the risk of a heart attack compared to those without.

Its estimated to cost the UK economy 30.7 billion pounds per year. Of the total cost of CVD: 47% is due to direct health care costs; 27% to productivity losses and 26% to the informal care of people with CVD.

Stable angina - a plaque forms but does not occlude the blood vessel.

Unstable angina - an unstable plaque forms and ruptures causing blood to coagulate and form a thrombus, blocking the blood vessel. 

Pain - substernal radiating to left arm neck and/or jaw.

Plasma markers increase due to damage to myocytes. Creatine Kinase MB (1970’s), (4-8 hrs after MI, peak at 24h, elevated for 2-3 days). Cardiac Troponin T (cTnT) (1990’s), Rise approx. 4 hrs after MI, peak at 18-24h after onset, elevated for  7-10 days. Copeptin (C terminal portion of the AVP precursor peptide), Elevated before cTnT decline 3-5 day later. Cardiac myosin binding protein C, Elevated within 20 min.

Normal ECG and changes (STEMI), ST-segment elevation myocardial infarction (STEMI) is the term cardiologists use to describe a classic heart attack. It is one type of myocardial infarction in which a part of the heart muscle (myocardium) has died due to the obstruction of blood supply to the area. The ST segment refers to the flat section of an electrocardiogram (ECG) reading and represents the interval between jagged heartbeats. When a person has a heart attack, this segment will no longer be flat but will appear abnormally elevated.

Atherosclerosis is an inflammatory disease. Atherosclerosis involves the cellular infiltration of several cell types, including monocytes, T lymphocytes, and perhaps even mast cells.  Monocytes interact with the endothelial layer, attach firmly to the endothelium, and migrate into the subendothelial space, where the monocytes differentiate into macrophages.  Macrophages release a variety of chemicals, including cytokines, and also take up lipids, becoming foam cells.  Macrophages and foam cells secrete growth factors, which lead to cell proliferation and matrix production, as well as metalloproteinases, which lead to matrix degeneration.  Thus, macrophages and foam cells both contribute to lesion growth and may contribute to instability and thrombotic events.

Macrophages and foam cells express growth factors and proteinases. Once the macrophage has taken up lipid and been converted into a foam cell, all the cell types necessary for the inflammatory process that leads to atherosclerosis are present.  Macrophages and foam cells produce not only cytokines but also a variety of growth factors that lead to cell proliferation and matrix production, and metalloproteinases that lead to matrix degeneration.  Thus, macrophages and foam cells both contribute to lesion growth and may contribute to instability and thrombotic events.

In summary, the evidence that atherosclerosis is an inflammatory disorder is overwhelming and now accepted by virtually all investigators in the field.  It is also widely accepted that LDL are subject to a variety of proinflammatory modifications that may play a large role in their atherogenicity.  In addition, the protective effect of HDL is now recognised as having at least some anti-inflammatory components. LDL=Low density lipoprotein HDL=High density lipoprotein

Merck Statins: late 1980s- early 1990s introduced. Potent inhibitors of cholesterol synthesis. 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) reductase inhibitors

First 5-6 years of use. Decrease LDL-C by 25% lowers coronary heart disease by 30-40%

The definitive treatment for MI is reperfusion of the ischemic tissue to limit infarct size and preserve cardiac muscle function. - by administration of anti-platelet therapy or surgical procedure to “open” vessel. If even a short period of acute ischemia is followed by reperfusion- tissue necrosis occurs  much more rapidly and the extent is very much greater.

This is called ischemia-reperfusion injury.Ischemia-reperfusion injury is defined as “the pathology that is extended, accelerated or expressed beyond that observed during ischemia alone, resulting from events occurring after reperfusion”Occurs in all vascular bedsAnimal models of I-R MI suggest that reperfusion injury may account for up to 50-65% of the injury. Activated EC’s resulting from reperfusion produce more ROS (superoxides) and less NO following reperfusion – This imbalance results in subsequent inflammatory responses

Histological studies (1933) showed that following MI neutrophil infiltration was an early event. Until recently it was widely assumed that neutrophils were involved in tissue repair. Acute myocardial infarction shows wavy cardiac muscle cells that represent dead or necrotic cells. Inflammation due to necrosis is also evident by the presence of numerous immune cells, especially neutrophils

Animal studies

Little tissue necrosis associated with ischemic tissue. Necrotic tissue seen shortly after reperfusion with oxygenated blood. Not with blood saturated with nitrogen. Reperfusion with O2 associated with generation of superoxide. This study shows the importance of oxygenated blood in causing ischemia-reperfusion injury (IR)

Endothelial adherence via Selectins  and Integrins

Transmigration

Chemotaxis to affected myocyte

Identification of target myocyte

Adhesion to myocyte

Induction of myocyte cell death

These are the steps of how neutrophils mediate myocyte cell death.

Pro-inflammatory mediators induce expression of selectins on the endothelial surface.

This leads to tethering and rolling of circulating neutrophils (leukocytes)

Rolling neutrophils exhibit integrin activation which results in firm adhesion.

Neutrophils then crawl towards endothelial junctions and transmigrate between pericytes.

Neutrophils then release proteases and ROS and bind to and kill myocytes

APC is a plasma serine protease that is vitamin K dependent. It down-regulates the processes of clotting and inflammation. It decreases apoptosis of cardiomyocytes and inhibits inflammatory mediators after heart muscle death due to ischaemia following MI. Wang et al, published a paper in 2011 detailing the mechanism that allows this to happen. They compared wildtype APC to mutant APC that either lacked anti-coagulant effects or signalling activity to prevent apoptosis. It was determined that the anti-coagulative properties of APC reduced the size of the MI and not the signalling mechanism. It also found that APC directly interacts with cardiomyocytes to activate the AMPK pathway as well as modulating the NF-kappaB (it suppressed cytokines and prevents leukocytes from crossing the endothelium through inhibiting this pathway)  and JNK pathways. APC cleaves factors Va and VIIIa in the blood clotting process when activated by a thrombin/thrombomodulin complex. 

This paper, however, used a 1 and 2 way ANOVA to analyse there results and it should only have been a 2 way ANOVA and the post-hoc analysis tests were not reported questioning the robustness of the results reported.