Cardiovascular System Pathophysiology Notes

Coronary Heart Disease and CAD

Coronary Heart Disease (CHD) is also known as Ischemic Heart Disease (IHD) or Coronary Artery Disease (CAD).
It's characterized by insufficient oxygenated blood delivery to the myocardium due to atherosclerotic coronary arteries.
Sequelae of CHD include:
- Angina pectoris
- Myocardial infarction
- Dysrhythmias
- Heart failure
- Sudden cardiac death

Etiology of Coronary Heart Disease

Known risk factors:
- Atherosclerosis: hardening and narrowing of coronary arteries, the cause of nearly all CHD/CAD
- Possible microcirculation abnormalities
Atherosclerosis can lead to ischemia, specifically myocardial ischemia/hypoxia.
Myocardial ischemia may lead to myocardial infarction (MI), also known as a “heart attack.”
Mechanisms:
- Thrombus formation
- Coronary vasospasm
- Endothelial cell dysfunction

Atherosclerotic Plaque

An atherosclerotic plaque is a tumor-like structure that forms between the endothelium and the smooth muscle layer of the blood vessel.
Plaque formation is a response to endothelial injury.

Risk Factors for CHD and Coronary Atherosclerosis

Non-Modifiable Risk Factors:
- Age:
  - 45+ years for males
  - 55+ years for females
- Gender: Male
- Family history: Of premature CHD in first-degree male relative <55 years old OR first-degree female relative <65 years old
Modifiable Risk Factors:
- Lipid Risk Factors:
  - Total Cholesterol > $200$ mg/dL
  - LDL Cholesterol > $130$ mg/dL
  - Triglycerides > $150$ mg/dL
  - HDL < $40$ mg/dL
- Non-Lipid Risk Factors:
  - Hypertension > $140$ mm Hg/ $90$ mm Hg
  - Cigarette Smoking
  - Thrombogenic State
  - Diabetes
  - Obesity
  - Physical Inactivity
  - Poor Diet

Lipoproteins

Dietary lipids are transported in the blood bound to proteins. These lipid-protein combinations are called lipoproteins.
Lipoproteins vary in density according to the relative amounts of protein and lipid they contain. The greater the amount of protein, the greater the density.
The protein molecules within lipoproteins are called apoproteins, abbreviated as Apo A, Apo B, etc.

Chylomicrons

Dietary lipids enter the bloodstream as chylomicrons.
Chylomicrons:
- Fed state only
- Pick up dietary lipids and cholesterol
- Transported:
  - To the tissues
  - Or liver by the hepatic portal system and are converted by hepatocytes into VLDLs and HDLs
- vLDLs travel to other tissues to drop off triglycerides. What's left is called an LDL

LDL vs HDL

LDLs:
- Major cholesterol carriers in the body
- High in cholesterol and are sometimes called “bad cholesterol.”
- They bind to receptors on cells (including coronary artery endothelial cells) and deposit cholesterol within those cells.
HDLs:
- High in protein.
- They are thought to bind excess free cholesterol from peripheral tissues and return it to the liver for removal. They are referred to as “good cholesterol”.
- Pick up cholesterol released in plasma
- Deliver to liver for excretion or tissues for steroid hormone synthesis

Mechanism of Atherosclerotic Plaque Formation

Plaques with high lipid content are fragile and can rupture.
Rupture of a plaque exposes subendothelial proteins and initiates platelet aggregation, leading to thrombus formation.
Endothelial Injury → LDLs Deposits in intima → become oxidized → activates endothelial cells → WBC receptor expression → Macrophages engulf Ox-LDL → Foam cell DIE → Lipid content released → Lipid builds in arterial wall and fibrous cap evolves.
Foam cells promote SMC proliferation and Increase collagen synthesis.
Leukocytes move to intima

Mechanisms of Coronary Atherosclerosis

Vulnerable plaques may rupture or become eroded, which stimulates clot formation on the plaque.
Vulnerable plaques have:
- Large lipid core
- Thin cap
- High shear stress
Stable plaques have:
- More collagen and fibrin
- Stable cap

Therapies to Reduce Plaque Risks

Smoking cessation
Reduce BP
- ACE inhibitors
- Exercise
Lower LDLs and raise HDLs
- Diet
- Statins- HMG-CoA reductase inhibitors
- Omega-3 (fish oil)
Prevent thrombus formation
- Aspirin
Mechanism of Statins:
$Glucose \rightarrow Acetyl-CoA \rightarrow Mevalonate \xrightarrow{HMG-CoA \, Reductase} Cholesterol$
Statins inhibit HMG-CoA reductase.

Statins- HMG-CoA reductase inhibitors

Statins inhibit HMG-CoA reductase, a key enzyme for the synthesis of cholesterol in the liver.
Examples: Atorvastatin, Lovastatin, Pravastatin, and Simvastatin
Decrease LDL, decrease VLDL, and increase HDL
Used for CHD prevention
Side effects include muscle toxicity and liver enzyme elevation
Rated category X in pregnancy

Pathophysiology of Ischemia

Ischemia: oxygen supply insufficient to meet metabolic demands
Coronary perfusion can be altered by:
- Large, stable atherosclerotic plaque
- Acute platelet aggregation and thrombus
- Vasospasm
- Failure of autoregulation by the microcirculation
- Poor perfusion pressure

Myocardial Ischemia/Angina Pectoris

Myocardial Ischemia: Increased $O<em>2$ demand and/or decreased $O</em>2$ supply.
Angina Pectoris: chest pain associated with intermittent myocardial ischemia

Angina Pectoris

Angina Pectoris:
1. Stable (typical) angina
2. Prinzmetal (variant) angina
3. Unstable (crescendo) angina
Burning, crushing, squeezing, choking, or referred pain.
May result in inefficient cardiac pumping with resultant pulmonary congestion and shortness of breath.
No permanent myocardial damage occurs.
Types of Angina Pectoris
- Stable (typical) Angina
  - Most common
  - Due to coronary atherosclerosis
  - Occurs in response to increased myocardial workload
  - “Effort” angina: Triggered by physical or emotional exertion
  - Relieved by rest and nitroglycerin (vasodilator)
- Prinzmetal (variant) Angina
  - Occurrence is unpredictable
  - Due to vasospasm
  - Relieved by calcium channel blockers (inhibit smooth muscle contraction)

Acute Coronary Syndromes (ACS)

Acute Coronary Syndromes (ACS):
- Unstable angina and MI are difficult to distinguish thus lumped together as ACS.
Characterized by:
- Chest pain is more severe and long-lasting than typical angina
- Plaque rupture and acute thrombosis are thought to occur
- Unstable Angina: occlusion is partial or thrombus dissolves before myocardial cell death occurs
- Myocardial Infarction: occlusion is complete and thrombus persists long enough to cause myocardial cell death

Myocardial Infarction

MI is due to complete occlusion of a coronary artery.
- 40-50% of MIs are due to occlusion of the LAD aka anterior interventricular artery.
MI causes myocardial cell death by both apoptosis and necrosis.
- Necrotic cell death leads to inflammation of myocardial tissue surrounding the infarct (dead tissue).
Dead myocardial tissue cannot regenerate. It is eventually replaced by connective tissue (scar tissue).

Diagnosis of MI

MI diagnosis based on 3 primary indicators:
- Signs and symptoms (symptom set may vary in women)
  - Severe chest pain radiating to neck, jaw, shoulder, arm, back
  - Nausea, vomiting
  - Diaphoresis (sweating)
  - Shortness of breath
- Electrocardiographic changes
  - ECG is inspected for the presence of ST-segment elevation
  - Large Q wave and inverted T wave may occur
- Elevations in the levels of specific marker proteins in the blood
  - Blood serum is inspected for the presence of protein indicators of myocardial cell death.
  - Used to make a final diagnosis
  - Myoglobin, Creatine kinase (CK)-MB, Troponin
    ECG changes and serum markers allow clinical distinction between acute angina and MI

MI Electrocardiographic Changes

MI Electrocardiographic changes:
- ST elevation: acute cellular injury, ischemia and diagnostic for MI. Ventricle walls are not coordinating the depolarization order (R wave is meeting the T). Ischemia is indicative of tissues necrosing. Ongoing and may be reversible over time

MI Serum Marker Changes

Markers:
- Myoglobin
- Creatine kinase (CK)-MB
- Troponin- Most commonly used
Increase in concentration suggests leakage from fatally damaged cells that have lost plasma membrane integrity

Etiologies- Diagnostic Distinction Among Acute Coronary Syndrome (ACS) Types

STEMI- ST elevation heart attack
- Usually happens due to total blockage of one of the main coronary arteries that provides blood flow to the heart
NSTEMI- None ST elevation heart attack
- Happens usually due to partial coronary artery blockage or blockage in a branch off of the main coronary artery
- Some electrical pattern changes can be visible, but often they are not as distinctive, making other tests much more important in diagnosing

Myocardial Ischemia at the Cellular Level

Decreased cardiac output due to MI causes sympathetic nervous system activation and increased heart rate. This makes things worse for the myocardium!

MI Compensatory Response

Compensation
- Mechanisms for acute loss:
  1. Sympathetic activation
  2. RAAS
- Chronic activation of these mechanisms worsens heart failure

Treatment of Myocardial Ischemia

Decrease myocardial oxygen demand:
- Rest and control pain
- Reduce effects of sympathetic response
- Reduce heart rate
- Reduce systemic blood pressure (afterload)
Increase myocardial oxygen delivery:
- Thrombolysis (tPA)
- Angioplasty
- Coronary bypass grafting

Treatments For Coronary Artery Occlusion

Thrombolysis: lyse the thrombus with drugs
- Streptokinase
- Tissue plasminogen activator
Plaque disruption with angioplasty, followed by anticoagulation or stent placement to open lumen and prevent reocclusion
Coronary artery bypass grafting: surgical placement of a new conduit to bypass the occlusion

Angioplasty

A catheter with a balloon or stent at its leading end is threaded into the femoral or brachial artery and into the aorta. At the base of the aorta, it is threaded into the occluded coronary artery.

Coronary Bypass Surgery

The thoracic cavity is opened.
A piece of a blood vessel from elsewhere in the body is grafted into the aortic wall at the base of the aorta.
Its distal end is grafted into the wall of the occluded vessel--distal to the area of occlusion.

Heart Valve Stenosis

Narrow valve causes a pressure gradient to develop across the abnormal open valve
Over time, affected chamber compensates à myocardial hypertrophy

Heart Valve Insufficiency

Heart valve insufficiency causes blood to backflow (regurgitate) through the abnormal closed valve
This causes turbulent blood flow

Heart Valve Disease

Murmur: Abnormal auscultated sound (turbulent blood flow) produced by a stenotic or regurgitant valve
Assessment of murmur can identify valvular abnormality

Mitral Valve Stenosis

Valve leaks during diastole producing murmur
Blood accumulates in the left atrium producing a pressure gradient across the valve.
Decreased stroke volume of the left ventricle because of deficient filling

Mitral Valve Stenosis Cont.

Leads to atrial fibrillation
Left atrial and pulmonary congestion may result
If uncorrected, mitral stenosis may result in chronic pulmonary hypertension, right ventricular hypertrophy, and right-sided heart failure
Atrial Fibrillation is common due to excessive atrial volume (dilation)

Mitral Valve Regurgitation

Valve leaks (regurgitates) during systole causing a murmur
Valve fails to close during LV systole
Blood regurgitates into the LA during LV systole while LA is still being filled with normal incoming blood
Extra blood in the left atrium leads to increased pressure and pulmonary edema

Mitral Valve Prolapse

Valve flaps balloon upward abnormally into the left atrium
A prolapsed mitral valve often causes some regurgitation
This condition is quite common in women over 40 years of age
Majority of affected persons have no symptoms, and most are unaware of their condition

Aortic Valve Stenosis

Aortic valve opening is narrowed causing resistance to flow
Flow through the valve is impeded during systole causing a murmur
Less blood enters the aorta and it enters slowly
The afterload for the left ventricle is increased
Eventually, this causes hypertrophy of the left ventricle

Aortic Valve Regurgitation

Blood leaks back into the left ventricle from the aorta during diastole causing a murmur
The EDV for the left ventricle is increased due to regurgitant blood and normal LA blood entering
More contractile force is generated
Hypertrophy and dilation
Eventually, high volume work leads to heart failure

Treatments

Surgery
Valve Replacement: Valve replaced with mechanical, animal, or cadaver valve