Myocardial infarction (MI): 

MI is the most common cause of mortality in developed countries. It is a multifactorial disease that involves atherogenesis, thrombus formuation and propagation. Thrombosis can result in complete or partial occulsion of coronary arteries. The luminal narrowing or blockage of coronary arteries reduces oxygen and nutrient supply to the caridac muscle (cardiac ischemia), leading to myoardial necrosis and/or stunning.

Causes of MI: 

Atherosclerosis is the leading cause of heart disease as well as stroke in the developed world. Atherosclerosis is characterized by the accumulation of lipid particles and cells of the immune system in subendothelial regions, leading to narrowing of the arterial lumen and, following plaque rupture, to thrombosis. Many components of the immune system are involved in the pathologic processes including macrophages that develop into foam cells, T cells, autantibodies, autoantigens which are components of vessel walls and cholesterol partciles and cytokiens that are secreted by cells within atherosclerotic plaques.

Arrhythmias often occur due to slowing of conduction of the electrical impulse through the heart. Rapid impulse conduction is needed for the heart to beat in a steady rhythm. When this is disturbed, the patient may experience a life-threatening cardiac arrhythmia. Among others, conduction slowing and arrhythmias can occur in patients who suffer from a heart attack, heart failure, or from a genetic cause.

The gene, named SCN10a-short (S10s), was identified in the search for a one-off gene therapy that could improve heart function and prevent cardiac arrhythmias.

Risks: 

Genetics plays an important role in MI risk. Families with a positive family history of MI account for 14% of teh general population, 72% of premature MIs, and 48% of all MIs.

Diagnosis and Assays Used to Determine the Risk of Coronary Artery (CAD) and/or Coronary Heart Disease:

Ultrasound: Carotid atherosclerosis can be measured non-invasively by ultrasound and is closely related to all major cardiovascular risk factors and generally accepted to be a strong predictor of clinical cardiovascular disease.

Nuclear Magnetic Resonance (NMR): NMR uses the characteristic signals broadcast by lipoprotein subclasses of different size as the basis of their quantification. Each subclass signal emanates form the aggregate number of terminal methyl groups on the lipids contained within the particle, with the cholesterol esters and triglycerides in the particle core each contributing 3 methyl groups and the phospholipids and unesterified cholesterol in the surface shell each contributing 2 methy groups. The total number of methyl groups contained within a subclass partcile is, to a close approximation, dependent only on the partice’s diameter and is substantially uanffected by differences in lipid composition arising from such sources as varaibility in the rleative amounts of cholesterol ester and triglyceride in the particle core, varying degress of unsaturation of the lipd fatty acyl chains, or varying phospholipd composition. For this reason, the methy NMR signal emitted by each subclass serves as a direct measure of the particle concentraiton of that subclass.

Mechanisms of Action and Pathogenesis:

Mathematical formuals: CHD risk is also known to be contributed to independently by high number of “bad” LDL particles and low numbers of “good” HDL particles. LDL particles can create atherosclerosis by entering the artery wall, becoming oxidized, and then being ingested by macrophages to create cholesterol-rich foam cells, which grow into the atherosclerotic plaque. HDL particles can enter the artery wall and prevent or reverse this process by 1) inhibiting the oxidation of LDL particles and 2) removing cholesterol from the foam cells and delivering it back to the liver – a process called reverse cholesterol transport.

The overal risk of CHD depends on the balance between the bad and good particles. CHD and CAD has conventionally been assed based on measurements of cholesterol content of a patient’s LDL and HDL particles (LDL-C, HDL-C). Treatment decisions may thereafter be made to reduce the “bad” cholesterol (LDL-C) or increase the “good” cholesterol (HDL-C) A convenient combined risk factor is the ratio of LDL-C/HDL-C or the ratio of Total Cholesterol/HDL-C which is almost the same thing.

Treatment Options:

Protein Targets:

–-Propertein covertase substilisini Kexin type 9 (PCSK9): has been implicated as a mjaor regulator of plasma LDL-c and has emerged as a promising target for prevention and treatment of coronary heart disease. Human genetic studies identified gain of function mutations, which were associated with elevated serum levels of LDL-C and premature incidences of caronary heart diseases, whereas loss of function mutaitons were associated with low LDL-C and reduced risk of coronary heart disease. Antiboides to PCSK9prevent the degradation of LDLP receptor, thus lowering serum levels of LDL cholesterol and potently reducing serum cholesteroal in mice and monkeys (Chaparro-Riggers, J. Biological Chemistry, 287(14), 2012, 11090-11097.

Foods to Lower Cholesterol:

Oats: combats contain a fiber called beta-glucan which is known for its cholesterol lowering properties.

Fish Oils (omega-3 fatty acids):

–Vascepa (Amarin) is an icosapent, ethyl, an ethyl ester of an omega-3 fatty acid commonly found i fish oils under the brand name Vascepa. In 2012, the FDA approved Vascepa for the treatment of severe hypertriglyceridemica, a condition in which a patient’s blood triglyceride level is at least 500 mg/dL. In 2019, following the success of Amerin’s additional research, the FDA approved Vascepa for a second use: as a treatment to reduce cardiovascular risk (i.e., mycardial infarction, stroke, coronary revascularization and unstable angina requing hospitalization in patients having blood triglyceride leves of at elast 150 mg/dL. (See US Patent Nos: 9,700,537, 10,568,861).