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.