BSI: Cardiovascular Pathophysiology

Atherosclerosis is a condition in which fatty material collects along the walls of arteries. This fatty material thickens, hardens (forms calcium deposits), and may eventually block the arteries.

Atherosclerosis is a type of arteriosclerosis. The two terms are often used to mean the same thing.

Atherosclerosis is an inflammatory disease.

Atherosclerosis is a disease of the arteries only! It does not affect the veins because veins are so much more compliant than arteries.

The subendothelial space located in the Tunica interna of the artery.

• 1) Endothelial injury occurs
• 2) Altered expression of adhesion molecules
• 3) Migration of monocytes, T cells, and oxidized LDL to subendothelial space
• 4) Monocyte differentiation into macrophages with scavenger receptors
• 5) Macrophage endocytosis of oxidized LDL
• 6) Foam Cell formation
• 7) Foam Cell directly causes Formation of Fatty Streaks
• 8) Foam cells release cytokines
• 9) Cytokines cause smooth muscle migration and proliferation
• 10) Inflammatory ulceration of fatty streak to form plaque

• Shear stress
• - Blood flow is laminar (flat) in long axis of vessel
• - Blood flow is turbulent in regions of curvature of bifurcation (branching of vessels)

- Turbulent (chaotic, not smooth) flow can cause endothelial damage

• Hypertension
• - Increases shear stress on vessel walls

• Smoking
• - Carbon monoxide can injure endothelium
• - Increases rate of LDL oxidation

• Other causes
• - idiopathic (unknown)

The higher the LDL concentration in the blood, the longer any given LDL molecule circulates before it is removed.

Blood is an oxidizing environment.

The longer LDL circulates, the greater the fraction of oxidized LDL.

LDL suppresses activity of TGF-beta which normally functions to protect vessels against injury.

~100 mg/dL

• 1) Increases vascular smooth muscle cell proliferation
• 2) Increases macrophage engulfment of oxidized LDL
• 3) Decreases endothelial nitric oxide production
• 4) Increases the production of advanced
• glycation end-products (AGEs)

• Diabetics, who frequently have elevated glucose levels (hyperglycemia), may have the following effects from high insulin levels:
• 1) high insulin levels can stimulate the SNS
• 2) high insulin levels can increase vasoconstriction by working on smooth muscle
• 3) high insulin levels can increase intracellular Ca²⁺ in smooth muscle cells

• 1) Promote cross-linking of proteins in arterial wall leading to trapping of oxidized LDL molecules
• 2) Alters Extracellular Matrix (ECM) proteins leading to a decrease in vascular compliance
• 3) AGEs generate Reactive Oxygen Species (ROS) (which enhances neutrophil respiratory burst)
• 4) AGEs stimulate inflammatory and
• pro-thrombotic signaling in endothelial cells, macrophages, and vascular smooth muscle cells via binding to RAGE

Narrowing of artery can cause ischemia

• Plaque rupture can lead to clot formation
• - Obstruct flow of vessel
• - Clot can break off and lodge in smaller vessels

• Aneurysm
• - Weakening of vessel wall leads to dilation or “ballooning”
• - Vessel can rupture

• Hypertension (HTN) is high blood pressure. It is defined as systolic or diastolic blood pressure
• > 140/90.

• Most common cardiovascular disease
• ~50 million people in US have hypertension

• Cause unknown
• 90-95% of hypertensive patients have primary HTN

• Known cause, such as:
• - non-steroidal anti-inflammatory agents (NSAIDs)
• - caffeine
• - ephedrine
• - excessive salt intake
• - etc.

• Neuronal mechanisms
• - Overstimulation by SNS

• Peripheral autoregulatory mechanisms
• - Kidneys reset equilibrium point
• - Leads to increased blood volume

• Humoral factors
• - Increased activation of renin-angiotensin aldosterone system (RAAS)
• Insulin resistance and hyperinsulinemia

• Vascular endothelial mechanisms
• - Deficiency in local vasodilator substances (bradykinin, nitric oxide)
• - Increased production or release of vasoconstriction substances (endothelin)

Hypertension accelerates atherosclerosis

• Hypertension causes left ventricular hypertrophy
• - can lead to dysfunction of left ventricle→back up of blood into left atrium (can cause atrial enlargement)→back of blood into pulmonary system→pulmonary edema→deoxygenation of blood

• Main cause of death in hypertensive patients
• - Cerebrovascular accidents (Strokes)
• - Cardiovascular accidents (Coronary heart disease, Heart failure)
• - Renal failure ( Due to arteriosclerosis in renal arteries)

• ACE inhibitors
• Angiotensin II receptor blockers (ARBs)
• Beta-blockers
• Calcium channel blockers
• Diuretics
• Aldosterone antagonists
• Arteriolar vasodilators

The failure of the heart to pump adequate blood to satisfy the body’s needs.

• disorder of coronary arteries (atherosclerosis)
• hypertension (high blood pressure)
• cardiomyopathy
• heart valve disorder (stenosis = narrowing of a valve, ie mitral valve stenosis)
• abnormal heart rhythm (arrhythmias)
• decreased filling
• decreased contractility

• The SNS activates in an attempt towards compensation during heart failure:
• - Increases heart rate and contractility
• - Increases vasoconstriction
• - Increases venous tone which increases venous return

• The RAAS also activates in an attempt to compensate during heart failure:
• - Decreased perfusion through kidneys
• results in activation of RAAS
• - Results in increased salt and water retention, vasoconstriction, and increased contractility

• Ventricular remodeling is changes in myocytes and extracellular matrix that result in:
• - changes in size of heart
• - changes in shape of heart
• - changes in structure of heart
• - changes in function of heart

• Ventricular remodeling could be due to:
• - myocyte loss
• - hypertophy
• - lengthening
• - fibrosis in extracellular matrix

Ventricular remodeling will eventually lead to a decline in systolic and/or diastolic function, and therefore lead to heart failure.

The body's attempt to maintain cardiac output by activating the SNS and RAAS.

Compensation by the SNS and RAAS can lead to ventricular remodeling and progressive damage of the heart.

• - In the short term, compensation is beneficial in that it maintains Cardiac Ouput (CO)
• - In the long term the heart progressively weakens and the body can no longer compensate enough to maintain an adequate CO

• Vasoconstriction increases afterload
• Increases contractility (increases work of the heart)
• Stimulates ventricular remodeling

• Retention of salt/water leads to volume overload
• Overstretching of the heart, thus weakening the heart even more
• Pulmonary edema occurs causing:
• - deoxygenation of blood
• - Leads to positive feedback loop
• - Most common cause of death in heart failure patients
• Edema in peripheral tissues

Stimulates ventricular remodeling

Causes arrhythmias

Because there can be so much fluid accumulation in the tissues that it interferes with gas exchange; therefore, oxygen can not readily get to the tissues.

Increased contractility increases oxygen demand of the heart

Vasoconstriction increases afterload

• Chronic exposure of norepinephrine is toxic to myocardial cells
• - necrosis or apoptosis

Norepinephrine can induce arrhythmias

Norepinephrine (NE)

The treatment depends on the stage of the disease.

• Treatments in the compensated stage are:
• 1) Inhibit actions of SNS
• - β-blockers
• 2) Inhibit actions of RAAS
• - ACE inhibitors
• - ARBs
• - Aldosterone antagonists

• 3) Other Treatments
• - Diuretics
• - Decrease salt and water intake

Pericarditis is an inflammation of the pericardium (the fibrous sac surrounding the heart).

Excess fluid places extra pressure on the heart, squeezing it and limits its ability to pump blood.

Pericarditis is fairly common and is most often caused by viral, bacterial or fungal infections.

The pressure from pericarditis that limits ventricular filling.

Referred pain

MAP = (SV x HR) x TPR

Everything in the above equation, including MAP will increase with pericarditis.

• Thickened heart muscle
• Hard for blood to leave the heart
• The heart will work harder to pump the blood

• The 1st sign of HCM may be Sudden Cardiac Death!
• Dyspnea (shortness of breath)
• Angina (chest pain)
• Arrhythmias
• Syncope (fainting)
• Cardiac failure

Hypertrophic cardiomyopathy

• Mutants affect the function of the contractile unit of the myofilaments by becoming incorporated into the sarcomere altering:
• 1) myosin-actin crossbridge formation
• 2) the force and movement generated by the thick and thin filaments

• Pharmacologic Goals
• 1) ↓ contractility
• 2) improve diastolic function
• 3) ↓ ischemia
• 4) suppress arrhythmias

• Treatment options
• β- blockers: inhibit SNS stimulation of the heart → reduce heart rate, decrease contractility, and stress
• on the myocardium
• Calcium Channel Blockers (mainly Verapamil): blocks calcium from entering the myocardium → reduction in contractility and has a negative chronotropic effect