atherosclerosis

BMS 200 - Week 6 Cardiology E-learning

• Cardiomyopathies and Atherosclerosis Pathogenesis were covered in this e-learning session.
• The e-learning noted the following outcomes related to cardiomyopathies:
  • Describe the epidemiology, pathogenesis, clinical features, and prognosis of Hypertrophic cardiomyopathy, Dilated cardiomyopathy (hereditary), and Restrictive cardiomyopathy.
  • Define the pathogenesis of atherosclerosis and the generation of unstable plaques, particularly focusing on Lipoprotein A (Lp(a)) biology, Metabolic syndrome, and factors contributing to plaque instability.

Cardiomyopathies

• Cardiomyopathies are disorders targeting cardiac myocytes or extracellular tissue in the myocardium.
• Major types include:
  • Dilated Cardiomyopathies:
    • Genetic deficits in sarcomere proteins (often autosomal dominant).
    • Acquired types usually involve infectious, inflammatory, or toxic factors.
  • Hypertrophic Cardiomyopathy:
    • Genetic deficits in sarcomere proteins.
  • Restrictive Cardiomyopathy:
    • A range of causes associated with abnormal extracellular material deposition.

Hypertrophic Cardiomyopathy

• Often abbreviated as HOCM, with "O" standing for "obstructive".
• Characterized by a thickened septum (wall separating ventricles).
• Frequently leads to outflow obstruction from the left ventricle, affecting the aorta's entry.
• One of the common autosomal dominant disorders (prevalence around 1 in 500), with varying severity across patients.
• General pathogenesis:
  • Mutations within sarcomere proteins (like myosin) often lead to a gain-of-function.
  • The exact mechanism leading to hypertrophy isn't fully understood.
  • Myocytes show disorganization in orientation.

Hypertrophic Cardiomyopathy - Clinical Features

• Many cases are asymptomatic, making diagnosis challenging.
• A significant cause of sudden cardiac death or arrest, especially in athletes, due to potentially dangerous dysrhythmias.
• Symptoms like angina, dyspnea, and syncope tend to become more prominent with age.
• Syncope relates to the sudden loss of consciousness due to globally impaired cerebral hypoperfusion.
• Heart failure with preserved ejection fraction (HFpEF) can develop over time in some cases, and a subgroup may transition to HFrEF later.

Dilated Cardiomyopathy

• Often the most common type of cardiomyopathy.
• Causes are diverse, including:
  • Toxin exposure (e.g., alcohol, certain medications, stressful events).
  • Cancer treatments.
  • Peripartum events (during pregnancy or shortly after).
  • Genetic mutations (often autosomal, sometimes X-linked).
  • Inflammatory conditions (e.g., infection, sarcoidosis).
• Characterized by:
  • A massive heart despite a seemingly thin wall.
  • Typically affects the ventricles more severely than the atria.
  • Flabbiness of the heart walls.
  • Increased risk of regurgitation of AV (atrioventricular) valves.
  • A usual echocardiogram finding of HFrEF.
  • Microstructure variations (hypertrophy and atrophy/fibrosis in myocardial sections) visible in microscopy.

Dilated Cardiomyopathy - Clinical Features

• Patients can be asymptomatic until heart failure symptoms emerge.
• Typical heart failure signs include fatigue, intolerance to exercise, shortness of breath (dyspnea), and swelling in dependent areas (dependent edema).
• Great ventricular enlargement can cause mitral valve regurgitation.
• Palpitations or syncope are possible due to dysrhythmias.
• Many acquired causes show improvement if the initial injury is resolved, but significant damage may necessitate a heart transplant.

Restrictive Cardiomyopathy

• The least common cardiomyopathy type discussed.
• Characterized by restricted ventricular filling and reduced diastolic volume in at least one (sometimes both) ventricles, while systolic function and wall thickness remain normal or nearly normal.
• High mortality rate usually due to heart failure, and the condition doesn't resolve independently.
• Patients typically exhibit isolated diastolic dysfunction (HFpEF) with normal stroke volume.
• Pathogenesis can be related to conditions "outside the heart":
  • Amyloidosis.
  • Conditions like hemochromatosis or sarcoidosis that negatively impact heart function.
  • More discussion on these causes in future courses.

Atherosclerosis - Pathogenic Mechanisms

• A multifaceted disorder varying across individuals due to environmental and genetic influences.
• Key factors include:
  • Systemic and local inflammation.
  • Dyslipidemia (especially elevated lipoprotein A (Lp(a))).
  • Metabolic syndrome and diabetes.
  • Hypertension.

Atherosclerosis - Review

• Starts with fatty streaks and progresses through oxidized LDL deposition, macrophage migration/activation, and calcification.
• Foam cell development results from cholesterol accumulation.
• Accumulation of extracellular matrix within the intima leads to a variably-stable fibrous cap over necrotic tissue and immune cells.
• The lumen narrows (stenosis) impairing blood flow.

Review - Risk Factors and Atherosclerosis Development

• Smoking, high blood pressure, and oxidative stress increase endothelial damage.
• Elevated Lp(a) likely contributes to increasing endothelial damage by improving immune cell recruitment at the plaque.
• Diabetes and dyslipidemia (including metabolic syndrome) potentially make LDL more likely to be incorporated into the intima (particularly when considering age-related changes and oxidation).
• Age-related modifications may increase overall inflammation contributing to oxidative stress.

More on Lp(a)

• Everyone has some Lp(a).
• The liver produces Lp(a), and production can increase with acute phase responses (triggered by cytokines like IL-6).
• Women generally produce more Lp(a) than men, although higher levels are linked with a greater risk for cardiovascular events.
• Similar structure to LDL but important differences are highlighted in structural diagrams.
• Lp(a) binds oxidized phospholipids, and this is thought to be central to its pathogenic role.

More on Lp(a) (cont)

• Lp(a) can contribute to atherosclerosis by initiating coagulation, increasing unstable plaque development, activating monocytes in the arterial wall, and promoting pro-inflammatory cytokine/adhesion molecule expression.
• Elevated IL-6 levels are linked with increased Lp(a) and seem to contribute most to atherogenic effects.

More on Plaque Types

• Unstable plaques have vulnerable fibrous caps, susceptible to rupture and release of thrombogenic molecules, thereby increasing cardiovascular risk.
• Factors affecting plaque stability include the quantity of collagen in the fibrous cap
• Activated platelets support collagen production and deposition, although the initial trigger for activation may have involved endothelial cell damage.
• Activated macrophages contribute by producing metalloproteinases, which degrade collagen and decrease plaque stability.

Unstable Plaques and ACS

• Harrison's video is a valuable resource regarding unstable plaques and acute coronary syndromes.
• The Atlas of Atherosclerosis from Harrison's Principles of Internal Medicine provides a more detailed description.
• The chapter highlights unstable plaques and acute coronary events (ACS).

More on Plaque Types - FYI

• Plaque erosion is a separate pathophysiological pathway from plaque rupture and can also lead to ACS.
• Eroded plaques have a more stable fibrous cap and overlying thrombus, with a different inflammatory profile than ruptured plaques.
• In eroded plaques, neutrophils are major contributors to creating a complex matrix (NET).
• Although plaque erosion contributes significantly to ACS, it's less well-understood than rupture.

Diabetes and the Metabolic Syndrome

• Conditions related to the metabolic syndrome influence atherosclerosis development
• Elevated VLDL is linked with increased circulating LDL, which fuels atherogenesis.
• Increased visceral fat is associated with insulin resistance, increased free fatty acids (FFAs), and increased pro-inflammatory cytokines production.
• AGEs accumulate in the basement membrane, including the tunica intima
• AGEs on LDL increase the likelihood of pro-inflammatory cell activation and foam cell development.

This e-learning session covers critical aspects of cardiomyopathies and atherosclerosis pathogenesis. Students will learn about the epidemiology, pathogenesis, clinical features, and prognosis of various types of cardiomyopathies, alongside the underlying mechanisms of atherosclerosis and plaque instability. Prepare to explore these vital topics in cardiovascular health.