Low-density lipoprotein (LDL) is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of multiple different fat molecules, including cholesterol, within the water around cells and within the water-based bloodstream. Studies have shown that higher levels of type-B LDL particles (as opposed to type-A LDL particles) promote health problems and cardiovascular disease, they are often informally called the bad cholesterol particles, (as opposed to HDL particles, which are frequently referred to as good cholesterol or healthy cholesterol particles).^[1]

Testing[link]

Blood tests typically report LDL-C, the amount of cholesterol contained in LDL. In clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low density lipoproteins are driving progression of atherosclerosis.

Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and being available from only a couple of laboratories in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.^[2]

Biochemistry[link]

Structure[link]

Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), which circulates the fatty acids, keeping them soluble in the aqueous environment.^{[citation needed]} In addition, LDL has a highly-hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and about 1500 esterified cholesterol molecules.^{[citation needed]} This core is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) in diameter and have a mass of about 3 million daltons, but since LDL particles contain a changing number of fatty acids, they actually have a distribution of mass and size.^[3] Determining the structure of LDL has been a tough task because of its heterogeneous structure. First structure of LDL at human body temperature in native condition has been recently found using cryo-electron microscopy and it has resolution of 16 Angstrom.^[4]

LDL subtype patterns[link]

LDL particles vary in size and density, and studies have shown that a pattern that has more small dense LDL particles, called Pattern B, equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles (Pattern A). This is because the smaller particles are more easily able to penetrate the endothelium. Pattern I, for intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).^{[citation needed]} According to one study, sizes 19.0 to 20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A.^[5]

Some in the medical community have suggested the correspondence between Pattern B and CHD is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test is used more commonly. ^[6]

There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense LDL.^[7][8]

With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy,^[9] research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively-measured particle concentrations.^{[citation needed]}

Transport into the cell[link]

When a cell requires cholesterol, it synthesizes the necessary LDL receptors, and inserts them into the plasma membrane. The LDL receptors diffuse freely until they associate with clathrin-coated pits. LDL particles in the blood stream bind to these extracellular LDL receptors. The clathrin-coated pits then form vesicles that are endocytosed into the cell.

After the clathrin coat is shed, the vesicles deliver the LDL and their receptors to early endosomes, onto late endosomes to lysosomes. Here the cholesterol esters in the LDL are hydrolysed. The LDL receptors are recycled back to the plasma membrane.

Medical relevance[link]

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (April 2010)

Because LDL particles can also transport cholesterol into the artery wall, retained there by arterial proteoglycans and attract macrophages that engulf the LDL particles and start the formation of plaques, increased levels are associated with atherosclerosis. Over time vulnerable plaques rupture, activate blood clotting and produce arterial stenosis, which if severe enough results in heart attack, stroke, and peripheral vascular disease symptoms and major debilitating events.

Increasing evidence has revealed that the concentration and size of the LDL particles more powerfully relates to the degree of atherosclerosis progression than the concentration of cholesterol contained within all the LDL particles.^[10] The healthiest pattern A, though relatively rare, is to have small numbers of large LDL particles and no small particles. Having small LDL particles, though common, is an unhealthy pattern B; high concentrations of small LDL particles (even though potentially carrying the same total cholesterol content as a low concentration of large particles) correlates with much faster growth of atheroma, progression of atherosclerosis and earlier and more severe cardiovascular disease events and death. This video [5], examining autopsy specimens from an actual heart attack resulting in sudden death, shows the seqence. These videos, [6] and [7], illustrate the sequence of events and why, though the underlying process develops over decades, the symptoms are often of sudden onset.

LDL particles are formed as VLDL lipoproteins lose triglyceride through the action of lipoprotein lipase (LPL) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters [8].

A hereditary form of high LDL is familial hypercholesterolemia (FH). Increased LDL is termed hyperlipoproteinemia type II (after the dated Fredrickson classification).

LDL particles pose a risk for cardiovascular disease when they invade the endothelium and become oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debries [9] and free radicals in the endothelium.

Role in the innate immune system[link]

LDL lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding Apolipoprotein B, to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.^[11]

Lowering LDL[link]

The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component in the pathway.

Pharmaceutical[link]

• Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the blood.

• Ezetimibe reduces intestinal absorption of cholesterol, thus can powerfully reduce LDL particle concentrations when combined with statins.^[12]

• Niacin (B₃), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74^[13] and HM74A or GPR109A.^[14]

• Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.^[15] Other, more recently developed and tested fibrates, e.g. fenofibric acid [10] have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.

• Some Tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.^[16] As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.

Dietary[link]

• The most effective approach has been minimizing fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body fat.^{[citation needed]} Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of Diabetes Mellitus.

• Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy.^[17] Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.^[18]

• Insulin induces HMG-CoA reductase activity, whereas glucagon diminishes HMG-CoA reductase activity.^[19] While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the digestion of carbohydrates into glucose and subsequent increase in serum glucose levels. In non-diabetics, glucagon levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.

• A ketogenic diet may have similar response to taking niacin (lowered LDL and increased HDL) through beta-hydroxybutyrate, a ketone body, coupling the niacin receptor (HM74A).^[14]

• Lowering the blood lipid concentration of triglycerides helps lower the concentration of Small LDL particles, because fat rich VLDL particles convert in the bloodstream into Small LDL particles.^[vague]

Importance of antioxidants[link]

Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals,^[20] it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.^[21][22] Studies have reported the benefits of green tea in helping to reduce LDL; some studies have focused on the antioxidant qualities of the unfermented green tea leaves^[23], others looked at green-tea compounds called catechins which are thought to decrease cholesterol absorption in the gut^[24].

Estimation of LDL particles via cholesterol content[link]

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available.

The lipid profile does not measure LDL particles directly but instead estimates them using the Friedewald equation^[8][25] by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:

Failed to parse (Missing texvc executable; please see math/README to configure.): H \approx C - L - kT

where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides, and k is 0.20 if the quantities are measured in mg/dl and 0.45 if in mmol/l.

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate.^[26] If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities are in mg/dl, may be used

Failed to parse (Missing texvc executable; please see math/README to configure.): L = C - H - 0.16T

This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer.

However, the concentration of LDL particles, and to a lesser extent their size, has a slightly stronger correlation with individual clinical outcome than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles [11]. It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is used to predict cardiovascular events, many other correlates of these clinical outcomes, such as diabetes mellitus, obesity and smoking, lose much of their predictive power.

Normal ranges[link]

In the USA, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were:^[27][28][29]

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double blind, randomized clinical trial of men with hypercholesterolemia;^[30] far more effective than coronary angioplasty/stenting or bypass surgery.

For instance, for people with known atherosclerosis diseases, the 2004 updated American Heart Association, NIH and NCEP recommendations are for LDL levels to be lowered to less than 70 mg/dL, unspecified how much lower. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and in secondary prevention as a 'reasonable further reduction'. Lack of evidence for such a recommendation is discussed in an article in the Annals of internal medicine.^[31] It should also be noted that statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels.

It has been estimated from the results of multiple human pharmacologic LDL lowering trials^{[citation needed]} that LDL should be lowered to about 50 to reduce cardiovascular event rates to near zero. For reference, from longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthood,^{[citation needed]} it has been discovered that the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not LDLipoprotein concentrations, probably not the better approach.

The feasibility of these figures has been questioned by sceptics, claiming that many members of the AHA and NIH are heavily associated with pharmaceutical companies giving them bias towards lowering cholesterol levels and such guidelines giving rise to increased use of cholesterol lowering medicine such as statins^{[citation needed]}.

A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease.^[32]

Moreover, there are publications^[33] regarding the risks of low-LDL cholesterol too.

Direct measurement of LDL concentration[link]

There are several competing methods for measurement of lipoprotein particle size although the evidence in favor of their superiority to existing methods is weak, even by the statements of proponents.^[34] Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement,^[35] as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is not widely available and is more expensive (about $98.00 US without insurance coverage) than existing tests. Furthermore the authors also said it is "...unclear whether LDL particle size measurements add value to measurement of LDL particle concentration." Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $100 US (including shipping) versus the previous costs of >$400 to >$5,000] and high accuracy. There are also other (less expensive) homogeneous assays for LDL, however most only estimate LDL.

Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who participated in the MESA trial.^[36]

Optimal ranges[link]

The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, total and large HDL particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.

See also[link]

Footnotes[link]

External links[link]

• Fat (LDL) Degradation: PMAP The Proteolysis Map-animation
• Adult Treatment Panel III Full Report
• ATP III Update 2004
• Roland_Stocker
• Cromwell WC, Otvos JD (September 2004). "Low-density lipoprotein particle number and risk for cardiovascular disease". Current Atherosclerosis Reports 6 (5): 381–7. DOI:10.1007/s11883-004-0050-5. PMID 15296705. 
• O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). "Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal". Journal of the American College of Cardiology 43 (11): 2142–6. DOI:10.1016/j.jacc.2004.03.046. PMID 15172426. 

Myocardial infarction
Classification and external resources
Diagram of a myocardial infarction (2) of the tip of the anterior wall of the heart (an apical infarct) after occlusion (1) of a branch of the left coronary artery (LCA), right coronary artery = RCA
ICD-10	I21-I22
ICD-9	410
DiseasesDB	8664
MedlinePlus	000195
eMedicine	med/1567 emerg/327 ped/2520
MeSH	D009203

Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids (cholesterol and fatty acids) and white blood cells (especially macrophages) in the wall of an artery. The resulting ischemia (restriction in blood supply) and ensuing oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death (infarction) of heart muscle tissue (myocardium).

Classical symptoms of acute myocardial infarction include sudden chest pain (typically radiating to the left arm or left side of the neck), shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety (often described as a sense of impending doom).^[1] Women may experience fewer typical symptoms than men, most commonly shortness of breath, weakness, a feeling of indigestion, and fatigue.^[2] A sizeable proportion of myocardial infarctions (22–64%)^[3] are "silent", that is without chest pain or other symptoms.

Among the diagnostic tests available to detect heart muscle damage are an electrocardiogram (ECG), echocardiography, cardiac MRI and various blood tests. The most often used blood markers are the creatine kinase-MB (CK-MB) fraction and the troponin levels. Immediate treatment for suspected acute myocardial infarction includes oxygen, aspirin, and sublingual nitroglycerin.^[4]

Most cases of myocardial infarction with ST elevation on ECG (STEMI) are treated with reperfusion therapy, such as percutaneous coronary intervention (PCI) or thrombolysis.^[5] Non-ST elevation myocardial infarction (NSTEMI) may be managed with medication, although PCI may be required if the patient's risk warrants it.^[6] People who have multiple blockages of their coronary arteries, particularly if they also have diabetes mellitus, may benefit from bypass surgery (CABG),^[7][8]. The European Society of Cardiology guidelines in 2011 proposed treating the blockage causing the myocardial infarction by PCI and performing CABG later when the patient is more stable.^[7] Rarely CABG may be preferred in the acute phase of myocardial infarction, for example when PCI has failed or is contraindicated.^[7]

Ischemic heart disease (which includes myocardial infarction, angina pectoris and heart failure when preceded by myocardial infarction) was the leading cause of death for both men and women worldwide in 2004.^[9] Important risk factors are previous cardiovascular disease, older age, tobacco smoking, high blood levels of certain lipids (low-density lipoprotein cholesterol, triglycerides) and low levels of high density lipoprotein (HDL) cholesterol, diabetes, high blood pressure, lack of physical activity and obesity, chronic kidney disease, excessive alcohol consumption, the abuse of illicit drugs (such as cocaine and amphetamines), and chronic high stress levels.^[10][11][12]

Classification[link]

There are two basic types of acute myocardial infarction based on pathology:

• Transmural: associated with atherosclerosis involving a major coronary artery. It can be subclassified into anterior, posterior, inferior, lateral or septal. Transmural infarcts extend through the whole thickness of the heart muscle and are usually a result of complete occlusion of the area's blood supply.^[13]
• Subendocardial: involving a small area in the subendocardial wall of the left ventricle, ventricular septum, or papillary muscles. The subendocardial area is particularly susceptible to ischemia.^[13]

In the clinical context, a myocardial infarction can be further subclassified into a ST elevation MI (STEMI) versus a non-ST elevation MI (non-STEMI) based on ECG changes.^[14]

The phrase heart attack is sometimes used incorrectly to describe sudden cardiac death, which may or may not be the result of acute myocardial infarction. A heart attack is different from, but can be the cause of cardiac arrest, which is the stopping of the heartbeat, and cardiac arrhythmia, an abnormal heartbeat. It is also distinct from heart failure, in which the pumping action of the heart is impaired; however severe myocardial infarction may lead to heart failure.^[7]

A 2007 consensus document classifies myocardial infarction into five main types:^[15]

• Type 1 – Spontaneous myocardial infarction related to ischaemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection
• Type 2 – Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension
• Type 3 – Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischaemia, accompanied by new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood
• Type 4 – Associated with coronary angioplasty or stents:
  • Type 4a – Myocardial infarction associated with PCI
  • Type 4b – Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy
• Type 5 – Myocardial infarction associated with CABG

Signs and symptoms[link]

Rough diagram of pain zones in myocardial infarction; dark red: most typical area, light red: other possible areas; view of the chest

Back view

The onset of symptoms in myocardial infarction (MI) is usually gradual, over several minutes, and rarely instantaneous.^[16] Chest pain is the most common symptom of acute myocardial infarction and is often described as a sensation of tightness, pressure, or squeezing. Chest pain due to ischemia (a lack of blood and hence oxygen supply) of the heart muscle is termed angina pectoris. Pain radiates most often to the left arm, but may also radiate to the lower jaw, neck, right arm, back, and epigastrium,^[7][17] where it may mimic heartburn. Levine's sign, in which the patient localizes the chest pain by clenching their fist over the sternum, has classically been thought to be predictive of cardiac chest pain, although a prospective observational study showed that it had a poor positive predictive value.^[18]

Shortness of breath (dyspnea) occurs when the damage to the heart limits the output of the left ventricle, causing left ventricular failure and consequent pulmonary edema. Other symptoms include diaphoresis (an excessive form of sweating),^[1] weakness, light-headedness, nausea, vomiting, and palpitations. These symptoms are likely induced by a massive surge of catecholamines from the sympathetic nervous system^[19] which occurs in response to pain and the hemodynamic abnormalities that result from cardiac dysfunction. Loss of consciousness (due to inadequate cerebral perfusion and cardiogenic shock) and sudden death (frequently due to the development of ventricular fibrillation) can occur in myocardial infarctions.^[7]

Women and older patients report atypical symptoms more frequently than their male and younger counterparts.^[20] Women also report more numerous symptoms compared with men (2.6 on average vs 1.8 symptoms in men).^[20] The most common symptoms of MI in women include dyspnea (shortness of breath), weakness, and fatigue. Fatigue, sleep disturbances, and dyspnea have been reported as frequently occurring symptoms that may manifest as long as one month before the actual clinically manifested ischemic event. In women, chest pain may be less predictive of coronary ischemia than in men.^[21]

At least one-fourth of all myocardial infarctions are silent, without chest pain or other symptoms, ^[22][3] with silent myocardial infarcations being more common in younger people. These cases can be discovered later on electrocardiograms, using blood enzyme tests or at autopsy without a prior history of related complaints. Estimates of the prevalence of silent myocardial infarctions vary between 22 and 64% ^[3]. A silent course is more common in the elderly^[3], in patients with diabetes mellitus^[23] and after heart transplantation, probably because the donor heart is not fully innervated by the nervous system of the recipient.^[24] In people with diabetes, differences in pain threshold, autonomic neuropathy, and psychological factors have been cited as possible explanations for the lack of symptoms.^[23]

Any group of symptoms compatible with a sudden interruption of the blood flow to the heart are called an acute coronary syndrome.^[25]

The differential diagnosis includes other catastrophic causes of chest pain, such as pulmonary embolism, aortic dissection, pericardial effusion causing cardiac tamponade, tension pneumothorax, and esophageal rupture. Other non-catastrophic differentials include gastroesophageal reflux and Tietze's syndrome.^[26]

Causes[link]

Heart attack rates are higher in association with intense exertion, be it psychological stress or physical exertion, especially if the exertion is more intense than the individual usually performs.^[27] The period of intense exercise and subsequent recovery is associated with about a 6-fold higher myocardial infarction rate (compared with other more relaxed time frames) for people who are physically very fit.^[27] For those in poor physical condition, the rate differential is over 35-fold higher.^[27] One observed mechanism for this phenomenon is the increased arterial pulse pressure stretching and relaxation of arteries with each heart beat, which, as has been observed with intravascular ultrasound, increases mechanical "shear stress" on atheromas and the likelihood of plaque rupture.^[27]

Acute severe infection, such as pneumonia, can trigger myocardial infarction. A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis.^[28] While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive as to whether it can be considered a causative factor.^[28] Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.^[29]

There is an association of an increased incidence of a heart attack in the morning hours, more specifically around 9 a.m.^[30][31][32] Some investigators have noticed that the ability of platelets to aggregate varies according to a circadian rhythm, although they have not proven causation.^[33]

Risk factors[link]

Myocardial infarction results from atherosclerosis.^[7] Risk factors for myocardial infarction include:

• Age^[10]
• Gender: At any given age men are more at risk than women, particularly before the menopause,^[27] but because in general women live longer than men ischemic heart disease causes slightly more total deaths in women.^[10]
• Diabetes mellitus type 1 or Diabetes mellitus type 2 ^[34]
• High blood pressure^[35]
• Dyslipidemia/hypercholesterolemia (abnormal levels of lipoproteins in the blood), particularly high low-density lipoprotein, low high-density lipoprotein and high triglycerides^[35]
• Tobacco smoking, including secondhand smoke^[35]
• Short term exposure to air pollution including: carbon monoxide, nitrogen dioxide, and sulfur dioxide but not ozone.^[36]
• Family history of ischaemic heart disease or myocardial infarction particularly if one has a first-degree relative (father, brother, mother, sister) who suffered a 'premature' myocardial infarction (defined as occurring at or younger than age 55 years (men) or 65 (women).^[10]
• Obesity^[37] (defined by a body mass index of more than 30 kg/m², or alternatively by waist circumference or waist-hip ratio).
• Lack of physical activity.^[10]
• Psychosocial factors including, low socio-economic status, social isolation, negative emotions and stress increase the risk of myocardial infarction and are associated with worse outcomes after myocardial infarction. Socioeconomic factors such as a shorter education and lower income (particularly in women), and unmarried cohabitation are also correlated with a higher risk of MI.^[38]
• Alcohol — Studies show that prolonged exposure to high quantities of alcohol can increase the risk of heart attack.
• Oral contraceptive pill – women who use combined oral contraceptive pills have a modestly increased risk of myocardial infarction, especially in the presence of other risk factors, such as smoking.^[39]
• Hyperhomocysteinemia (high homocysteine)in homocysteinuria is associated with premature atherosclerosis^[40], whether elevated homocysteine in the normal range is causal is contentious.^[41]

Inflammation is known to be an important step in the process of atherosclerotic plaque formation.^[42] C-reactive protein (CRP) is a sensitive but non-specific marker for inflammation. Elevated CRP blood levels, especially measured with high-sensitivity assays, can predict the risk of MI, as well as stroke and development of diabetes.^[42] Moreover, some drugs for MI might also reduce CRP levels.^[42] The use of high-sensitivity CRP assays as a means of screening the general population is advised against, but it may be used optionally at the physician's discretion in patients who already present with other risk factors or known coronary artery disease.^[43] Whether CRP plays a direct role in atherosclerosis remains uncertain.^[42] Inflammation in periodontal disease may be linked to coronary heart disease, and, since periodontitis is very common, this could have great consequences for public health.^[44] Serological studies measuring antibody levels against typical periodontitis-causing bacteria found that such antibodies were more present in subjects with coronary heart disease.^[45] Periodontitis tends to increase blood levels of CRP, fibrinogen and cytokines;^[46] thus, periodontitis may mediate its effect on MI risk via other risk factors.^[47] Preclinical research suggests that periodontal bacteria can promote aggregation of platelets and promote the formation of foam cells.^[48][49] A role for specific periodontal bacteria has been suggested but remains to be established.^[50] There is some evidence that influenza may trigger an acute myocardial infarction.^[51]

Baldness, hair greying, a diagonal earlobe crease (Frank's sign^[52]) and possibly other skin features have been suggested as independent risk factors for MI.^[53] Their role remains controversial; a common denominator of these signs and the risk of MI is supposed, possibly genetic.^[54]

Calcium deposition is another part of atherosclerotic plaque formation. Calcium deposits in the coronary arteries can be detected with CT scans. Several studies have shown that coronary calcium can provide predictive information beyond that of classical risk factors.^[55][56][57]

Many of these risk factors are modifiable, so many heart attacks can be prevented by maintaining a healthier lifestyle. Physical activity, for example, is associated with a lower risk profile.^[58] Non-modifiable risk factors include age, sex, and family history of an early heart attack, which is thought of as reflecting a genetic predisposition.^[27] To understand epidemiological study results, it is important to note that many factors associated with MI mediate their risk via other factors. For example, the effect of education is partially based on its effect on income and marital status.^[38]

The European Society of Cardiology and the European Association for Cardiovascular Prevention and Rehabilitation have developed an interactive tool for prediction and managing the risk of heart attack and stroke in Europe. HeartScore is aimed at supporting clinicians in optimising individual cardiovascular risk reduction. The Heartscore Programme is available in 12 languages and offers web-based or PC version.^[59]

Pathophysiology[link]

A myocardial infarction occurs when an atherosclerotic plaque slowly builds up in the inner lining of a coronary artery and then suddenly ruptures, causing catastrophic thrombus formation, totally occluding the artery and preventing blood flow downstream.

Drawing of the heart showing anterior left ventricle wall infarction

Acute myocardial infarction refers to two subtypes of acute coronary syndrome, namely non-ST-elevated myocardial infarction and ST-elevated myocardial infarction, which are most frequently (but not always) a manifestation of coronary artery disease.^[14] The most common triggering event is the disruption of an atherosclerotic plaque in an epicardial coronary artery, which leads to a clotting cascade, sometimes resulting in total occlusion of the artery.^[60][61] Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue in plaques in the wall of arteries (in this case, the coronary arteries), typically over decades.^[62] Blood stream column irregularities visible on angiography reflect artery lumen narrowing as a result of decades of advancing atherosclerosis.^[63] Plaques can become unstable, rupture, and additionally promote a thrombus (blood clot) that occludes the artery; this can occur in minutes. When a severe enough plaque rupture occurs in the coronary vasculature, it leads to myocardial infarction (necrosis of downstream myocardium).^[60][61]

If impaired blood flow to the heart lasts long enough, it triggers a process called the ischemic cascade; the heart cells in the territory of the occluded coronary artery die (chiefly through necrosis) and do not grow back. A collagen scar forms in its place. Recent studies indicate that another form of cell death called apoptosis also plays a role in the process of tissue damage subsequent to myocardial infarction.^[64] As a result, the patient's heart will be permanently damaged. This myocardial scarring also puts the patient at risk for potentially life threatening arrhythmias, and may result in the formation of a ventricular aneurysm that can rupture with catastrophic consequences.

Injured heart tissue conducts electrical impulses more slowly than normal heart tissue. The difference in conduction velocity between injured and uninjured tissue can trigger re-entry or a feedback loop that is believed to be the cause of many lethal arrhythmias. The most serious of these arrhythmias is ventricular fibrillation (V-Fib/VF), an extremely fast and chaotic heart rhythm that is the leading cause of sudden cardiac death. Another life-threatening arrhythmia is ventricular tachycardia (V-Tach/VT), which may or may not cause sudden cardiac death. However, ventricular tachycardia usually results in rapid heart rates that prevent the heart from pumping blood effectively. Cardiac output and blood pressure may fall to dangerous levels, which can lead to further coronary ischemia and extension of the infarct.

The cardiac defibrillator is a device that was specifically designed to terminate these potentially fatal arrhythmias. The device works by delivering an electrical shock to the patient in order to depolarize a critical mass of the heart muscle, in effect "rebooting" the heart. This therapy is time dependent, and the odds of successful defibrillation decline rapidly after the onset of cardiopulmonary arrest.

Diagnosis[link]

The diagnosis of myocardial infarction can be made after assessing patient's complaints and physical status. ECG changes, coronary angiogram and levels of cardiac markers help to confirm the diagnosis. ECG gives valuable clues to identify the site of myocardial damage while coronary angiogram allows visualization of narrowing or obstructions in the heart vessels.^[65] At autopsy, a pathologist can diagnose a myocardial infarction based on anatomopathological findings.

A chest radiograph and routine blood tests may indicate complications or precipitating causes and are often performed upon arrival to an emergency department. New regional wall motion abnormalities on an echocardiogram are also suggestive of a myocardial infarction. Echo may be performed in equivocal cases by the on-call cardiologist.^[66] In stable patients whose symptoms have resolved by the time of evaluation, Technetium (99mTc) sestamibi (i.e. a "MIBI scan") or thallium-201 chloride can be used in nuclear medicine to visualize areas of reduced blood flow in conjunction with physiologic or pharmacologic stress.^[66][67] Thallium may also be used to determine viability of tissue, distinguishing whether non-functional myocardium is actually dead or merely in a state of hibernation or of being stunned.^[68]

WHO criteria^[69] formulated in 1979 have classically been used to diagnose MI; a patient is diagnosed with myocardial infarction if two (probable) or three (definite) of the following criteria are satisfied:

1. Clinical history of ischaemic type chest pain lasting for more than 20 minutes
2. Changes in serial ECG tracings
3. Rise and fall of serum cardiac biomarkers such as creatine kinase-MB fraction and troponin

The WHO criteria were refined in 2000 to give more prominence to cardiac biomarkers.^[70] According to the new guidelines, a cardiac troponin rise accompanied by either typical symptoms, pathological Q waves, ST elevation or depression, or coronary intervention is diagnostic of MI.

Prevention[link]

The risk of a recurrent myocardial infarction decreases with strict blood pressure management and lifestyle changes, chiefly smoking cessation, regular exercise, a sensible diet for those with heart disease, and limitation of alcohol intake. People are usually commenced on several long-term medications post-MI, with the aim of preventing secondary cardiovascular events such as further myocardial infarctions, congestive heart failure or cerebrovascular accident (CVA). Unless contraindicated, such medications may include:^[71][72]

• Antiplatelet drug therapy such as aspirin and/or clopidogrel should be continued to reduce the risk of plaque rupture and recurrent myocardial infarction. Aspirin is first-line, owing to its low cost and comparable efficacy, with clopidogrel reserved for patients intolerant of aspirin. The combination of clopidogrel and aspirin may further reduce risk of cardiovascular events, however the risk of hemorrhage is increased.^[73]
• Beta blocker therapy such as metoprolol or carvedilol should be commenced.^[74] These have been particularly beneficial in high-risk patients such as those with left ventricular dysfunction and/or continuing cardiac ischaemia.^[75] β-Blockers decrease mortality and morbidity. They also improve symptoms of cardiac ischemia in NSTEMI.
• ACE inhibitor therapy should be commenced 24–48 hours post-MI in hemodynamically stable patients, particularly in patients with a history of MI, diabetes mellitus, hypertension, anterior location of infarct (as assessed by ECG), and/or evidence of left ventricular dysfunction. ACE inhibitors reduce mortality, the development of heart failure, and decrease ventricular remodelling post-MI.^[76]
• Statin therapy has been shown to reduce mortality and morbidity post-MI.^[77][78] The effects of statins may be more than their LDL lowering effects. The general consensus is that statins have plaque stabilization and multiple other ("pleiotropic") effects that may prevent myocardial infarction in addition to their effects on blood lipids.^[79]
• The aldosterone antagonist agent eplerenone has been shown to further reduce risk of cardiovascular death post-MI in patients with heart failure and left ventricular dysfunction, when used in conjunction with standard therapies above.^[80] Spironolactone is another option that is sometimes preferable to eplerenone due to cost.
• Evidence supports the consumption of polyunsaturated fats instead of saturated fats as a measure of decreasing coronary heart disease.^[81] Omega-3 fatty acids, commonly found in fish, have been shown to reduce mortality post-MI.^[82] While the mechanism by which these fatty acids decrease mortality is unknown, it has been postulated that the survival benefit is due to electrical stabilization and the prevention of ventricular fibrillation.^[83] However, further studies in a high-risk subset have not shown a clear-cut decrease in potentially fatal arrhythmias due to omega-3 fatty acids.^[84][85]

Blood donation may reduce the risk of heart disease for men,^[86] but the link has not been firmly established.

A Cochrane review found that giving heparin to people with heart conditions like unstable angina and some forms of heart attacks reduces the risk of having another heart attack. However, heparin also increases the chance of suffering from minor bleeding.^[87]

Management[link]

An MI requires immediate medical attention. Treatment attempts to salvage as much myocardium as possible and to prevent further complications, hence the phrase "time is muscle".^[88] Oxygen, aspirin, and nitroglycerin may be administered. Morphine was classically used if nitroglycerin was not effective; however, it may increase mortality in the setting of NSTEMI.^[89] A 2009 and 2010 review of high flow oxygen in myocardial infarction found increased mortality and infarct size, calling into question the recommendation about its routine use.^[90][91] Other analgesics such as nitrous oxide are of unknown benefit.^[6] Percutaneous coronary intervention (PCI) or fibrinolysis are recommended in those with an STEMI.

Prognosis[link]

The prognosis post myocardial infarction varies greatly, depending on a person's health, the extent of the heart damage and the treatment given. For the period 2005–2008 in the United States, the median mortality at 30 days was 16.6% with a range from 10.9% to 24.9% depending on the hospital.^[92] Using variables available in the emergency room, people with a higher risk of adverse outcome can be identified. One study found that 0.4% of patients with a low-risk profile died after 90 days, whereas in high-risk people it was 21.1%.^[93]

Some of the more reproduced risk-stratifying factors include: age, hemodynamic parameters (such as heart failure, cardiac arrest on admission, systolic blood pressure, or Killip class of two or greater), ST-segment deviation, diabetes, serum creatinine, peripheral vascular disease and elevation of cardiac markers.^[93][94][95] Assessment of left ventricular ejection fraction may increase the predictive power.^[96] The prognostic importance of Q-waves is debated.^[97] Prognosis is significantly worsened if a mechanical complication such as papillary muscle or myocardial free wall rupture occurs.^[98] Morbidity and mortality from myocardial infarction has improved over the years due to better treatment.^[99]

Complications[link]

Complications may occur immediately following the heart attack (in the acute phase), or may need time to develop (a chronic problem). Acute complications may include heart failure if the damaged heart is no longer able to adequately pump blood around the body; aneurysm or rupture of the myocardium; mitral regurgitation, in particular if the infarction causes dysfunction of the papillary muscle; and arrhythmias, such as ventricular fibrillation, ventricular tachycardia, atrial fibrillation and heart block. Longer-term complications include heart failure, atrial fibrillation, and the increased risk of a second myocardial infarction.

Epidemiology[link]

Myocardial infarction is a common presentation of ischemic heart disease/coronary artery disease. The World Health Organization estimated in 2004, that 12.2% of worldwide deaths were from ischemic heart disease;^[9] with it being the leading cause of death in high or middle income countries and second only to lower respiratory infections in lower income countries.^[9] Worldwide more than 3 million people have STEMIs and 4 million have NSTEMIs a year.^[100]

Rates of death from ischemic heart disease have slowed or declined in most high income countries, although cardiovascular disease still accounted for 1 in 3 of all deaths in the USA in 2008.^[101] In contrast, ischemic heart disease is becoming a more common cause of death in the developing world. For example in India, ischemic heart disease had become the leading cause of death by 2004 accounting for 1.46 million deaths (14% of total deaths) and deaths due to ischemic heart disease were expected to double during 1985–2015.^[102] Globally it is predicted that disability adjusted life years (DALYs) lost to ischemic heart disease will account for 5.5% of total DALYs in 2030, making it the second most important cause of disability (after unipolar depressive disorder), as well as the leading cause of death by this date.^[9]

Legal implications[link]

At common law, in general a myocardial infarction is a disease, but may sometimes be an injury. This has implications for no-fault insurance schemes such as workers' compensation. In general, a heart attack is not covered;^[103] however, it may be a work-related injury if it results, for example, from unusual emotional stress or unusual exertion.^[104] In addition, in some jurisdictions, heart attacks suffered by persons in particular occupations such as police officers may be classified as line-of-duty injuries by statute or policy. In some countries or states, a person having suffered from a myocardial infarction may be prevented from participating in activity that puts other people's lives at risk, for example driving a car or flying an airplane.^[105]

Research[link]

Patients who receive stem cell treatment by coronary artery injections of stem cells derived from their own bone marrow after a myocardial infarction (MI) show improvements in left ventricular ejection fraction and end-diastolic volume not seen with placebo. The larger the initial infarct size, the greater the effect of the infusion. Clinical trials of progenitor cell infusion as a treatment approach to ST elevation MI are proceeding.^[106]

There are currently 3 biomaterial and tissue engineering approaches for the treatment of MI, but these are in an even earlier stage of medical research, so many questions and issues must be addressed before they can be applied to patients. The first involves polymeric left ventricular restraints in the prevention of heart failure. The second utilizes in vitro engineered cardiac tissue, which is subsequently implanted in vivo. The final approach entails injecting cells and/or a scaffold into the myocardium to create in situ engineered cardiac tissue.^[107]

References[link]