Metabolic Disorders and Pharmacotherapies Flashcards
What metabolic disorders lead to increased risk of cardiovascular disease?
- Hypercholesterolemia.
- Dyslipidemia.
- Obesity.
- Insulin resistance.
- Type II Diabetes.
- Glucose dysregulation.
What other disorders can lead to increased risk of cardiovascular disease?
- Type I Diabetes (autoimmune disease).
What is the connection between diabetes and risk of CV disease?
- Diabetes is associated with increased incidence of all-cause and CV mortality, in individuals with and without previous CV disease.
- This is true even when adjusting for age, sex, race, ethnicity, BMI, cholesterol, BP and smoking status
- This incidence shows a dose-dependent effect as HbA1c increases.
- WHO states that in 2021 1.6 million people died with diabetes as the direct cause and almost half the deaths were under 70 years of age.
What is artheroscleorsis?
- Greek words: - athero (gruel or paste) & sclerosis (hard).
- Atherosclerosis is the most common cause of heart attacks and strokes - caused by clot forming on atherosclerotic plaque or clot/plaque sloughing off.
What is the connection between diabetes and artherosclorosis?
- Obesity & Type II diabetes associated with dyslipidemia, the major risk factor for atherosclerosis.
Describe plaque formation in atherosclerosis.
- Focal accumulations of lipids in inner lining of large & medium-sized arteries.
- Functional effects extend into microcirculation.
- Partially or totally block blood flow, compromise ability of artery to constrict or dilate.
- Rupture of plaque – clot formation.
- Usually silent (can start as early as childhood), accelerates rapidly over 50 years of age.
Describe the mechanism of plaque formation.
- Endothelial damage: Expression of adhesion molecules, recruitment of
monocytes & macrophages, generation of free radicals, take up oxidized LDL to form foam cells. Accumulation of connective & elastic tissue, cell debris, cholesterol crystals & Ca2+ - Migration of muscle cells
- Inflammatory fibro-proliferative response
- Formation of dense fibrous cap over lipid-rich core - atheroma.
What can damage the endothelium?
- High blood glucose.
- High blood pressure.
What happens after plaque formation?
- Bleeding into the plaque.
- Formation of a blood clots
- Rupture due to plaque instability.
- Plaque may occlude blood blow.
- A ruptured plaque/clot may slough off into the circulation.
What factors increase the risk of stroke or MI?
- Obesity, T2D.
- HTN, high cholesterol, inflammation.
- Systemic inflammation (obesity, metabolic syndrome).
- High LDL, HTN, necrotic lipid core, T2D.
Describe the roadmap to stroke or MI?
- Hyperlipidemia increases circulating lipids.
- Due in part to endothelial dysfunction, lipids like LDL accumulate along the arterial lining.
- LDL is oxidized and Immune cells (monocytes, macrophages) are recruited and take up the oxidized LDL.
- Foam cells are formed by immune cells that took up LDLox, and cell death can occur
- Inflammation triggers vascular smooth muscle cell migration and proliferation.
- Accumulated VSMCs, foam cells and extracellular matrix components form a fibrous cap over the lipid-dense core.
- A plaque has now formed, interfering into the luminal space and reducing blood flow
- The plaque is susceptible to rupture, forming a thrombus and leading to downstream CV events.
What is ischemia?
- Lack of blood supply.
What is infraction?
- Full obstruction of blood supply.
What does myocardial ischemia lead to?
Infraction
What does cerebral ischemia lead to?
Stroke.
What does peripheral ischemia lead to?
Gangrene and amputation.
What does renal ischemia lead to?
Impaired filtration and renal failure.
What caused the “Atherosclerosis epidemic”?
- High-fat diet.
- Obesity.
- Physical inactivity.
- Diabetes.
- Disorders of lipoprotein metabolism (dyslipidemia), which can be genetic or acquired.
________ ‘kills more than obesity‘
Inactivity ‘kills more than obesity‘
_______ is a “modifiable risk factor” for cardiovascular disease.
Dyslipidemia is a “modifiable risk factor” for cardiovascular disease.
What can dyslipidemia be modified by?
- Diet and exercise.
- Drugs.
What factors lead to decreased systemic inflammation?
What factors increase systemic inflammation?
- Mainly obesity, but aging, smoking, alcohol, environmental pollution, infection, chronic disease and poor sleep and also increase systemic inflammation.
What are the symptoms of metabolic syndrome?
- Dyslipidemia.
- Hypertension.
- Hyperglycemia and Insulin resistance.
- Platelet aggregation.
- This all leads to atherosclerosis.
What drugs are used to reduce dyslipidemia?
- Statins.
- Fibric acid derivatives.
- Thiazolidinediones.
What drugs reduce hypertension?
- ACE inhibitors.
- Angiotensin receptor blockers.
- Beta-blockers.
- Calcium chain blockers.
- Diuretics.
What drugs reduce hyperglycemia and insulin resistance?
- Insulin.
- Metformin.
- Thiazolidinediones.
- Sulfonylureas.
- Nonsulfonylurea.
- Secretagogues.
What drugs reduce platelet activation and aggregation?
- Aspirin.
- Clopidogrel.
- Ticlopidine.
How does diabetes mellitus lead to atherogenesis?
What is the Framingham Heart Study?
- Studies cardiovascular disease throughout generations.
What have been the most important discoveries of the Framingham Heart Study?
- High blood pressure and high cholesterol levels shown to increase the likelihood of heart disease.
- Physical activity found to reduce the risk of heart disease and obesity to increase the risk of heart disease.
- Association between age of adult menarche and adult BMI and select genetic variants.
What where the findings on the effects of sex hormones and genetic variation on the heart?
- This study using FHS participants of the second and
third generation identified 2
genetic and 4 environmental trait pairs that showed sex-
specific differences - These data highlighted ways in
which genes and environment
interact to affect CV structure
and function differently in men
vs women.
What is the Framingham risk score?
- Based on findings from the study you can use your serum lipids, (more on these later…) blood pressure, age, diabetes status and family history to predict your risk of developing cardiovascular disease.
What is the connection between lifestyle and drugs?
- Diet and lifestyle changes SHOULD always accompany any pharmacotherapy.
- Often just diet/exercise alone can result in very beneficial changes – first line therapy
- Issues with this include adherence…why?
- Many reasons!! What can we recall?
- No “magic bullet” drug.
