Cardiovascular Function

There are two types of cardiomyocytes. What?

1. Working - basis of mechanical pump

2. Electrical - basis of electrochemical impulses

Cardiomyocytes are described as…

muscle fibers

Cardiomyocytes are … nucleate

uni

Cardiomyocyte cells are joined end to end by what?

intercalated disks

What is the two main components of intercalated disks?

Desmosomes and gap junctions

What is the function of desmosomes?

Provide strong mechanical attachment between cells

What is the function of gap junctions?

Allow electrical signals to pass between cells for coordinated contraction

Inside cardiomyocytes there are…

myofibrils

Myofibrils contain the contractile filaments:

actin and myosin

In contrast to muscle cells, cardiac cells are a syncytium, what does this mean?

They are so interconnected so that they behave as a single unit. Due to the connection of the intercalated disks

What is a sacromere?

The smallest functional unit of muscle contraction within a myofibril

What structures define the boundaries of a sacromere?

Z discs

What attaches to the Z line?

Thin filaments (actin)

Where are the thick filaments (myosin) located within the sacromere?

In the center of the sacromere

What is the A band?

The region containing the full length of thick (myosin) filaments

Does the A band change lengh during contractin?

No, it stays the same

What is the I band?

The region containing thin (actin) filaments

What happens to the I band during contraction?

It shortens

How does contraction in cardiomyocytes differ from skeletal muscle?

It is involuntary and coordinated through electrical coupling

What is unique about calcium handling in cardiomyocytes?

Ca+ comes from both the sarcoplasmic reticulum and extracellular fluid

What is the M line?

Marks the midpoint of the myosin filaments

What does Myosin do?

The thick filaments that split ATP which release energy needed for moving filaments

Thin filaments are composed of…

Actin, troponin, and tropomyosin

What does Tropomyosin do?

Blocks myosin binding sites on actin at rest

Tropomyosin is regulated by what?

Troponin and Ca

The troponin complex is formed of Troponin I, Trop T, and Trop C. What does it do?

In resting muscle, tropomyosin covers myosin binding sites on actin. The troponin holds it in place. Once calcium binds to Trop C, the tropomyosin shifts to expose myosin binding sites

How to remember the molecular masses (kd) of the 3 troponins?

C - 18

I - 22

T - 37

CIT

How many cardiac isoforms does Troponin I have?

only 1

Troponin C has no … specificity

cardiac

Ok lets walk through Excitation contraction coupling

• Ca2+ binds to Troponin C

• Tropomyosin slides of actin and exposes binding sites

• myosin heads bind to actin form a cross bridge

• pushes past the actin with a “power stroke” uses ATP into ADP + P

• Pulls the actin and myosin past one another and shortens the muscle

What are the four categories fo CVD?

1. Coronary Heart Disease (CHD)

2. Cerebrovascular Disease (CVD)

3. Peripheral Artery Disease (PAD)

   1. Aortic Atherosclerotic Disease (AAD)

What are Coronary heart diseases?

Acute Myocardial infarctions, heart failure, Ischemia

What are cerebrovascular diseases?

Stroke Ischemic attack

What are peripheral artery diseases?

Intermittent claudication to arms and legs

What are aortic atherosclerotic diseases?

Aneurysms

50% of all deaths from cardiovascular diseases are due to …

coronary heart diseases

What is the primary underlying cause of coronary heart disease?

Atherosclerosis causing narrowing of coronary arteries

How does coronary heart disease lead to Myocardial Infarction?

Plaque ruptures —→ thrombus formation —→ complete blockage of coronary artery

What is a myocardial infarction?

Death (necrosis) of heart muscle due to prolonged ischemia

What is the key difference between Coronary heart disease and myocardial infarction?

CHD = chronic narrowing of coronary arteries. MI = acute blockage causing tissue death

Atherosclerosis

A condition where fatty deposits ( plaques) build up inside the walls of arteries

What is Ischemia?

A state where blood flow/oxygen to a tissue is insufficient to meet metabolic needs

What is the first step in the formation of an atherosclerotic plaque?

Endothelial injury/dysfunction, allowing LDL to enter the vessel wall and become oxidized

How does oxidized LDL (oxLDL) lead to plaque formation?

oxLDL recruits monocytes, which become macrophages that engulf more oxLDL

Macrophages that engulf oxLDL are now…

Foam cells - they create plaque (not going into detail)

What is lipoprotein associated phospholipase A2 (Lp-PLA2)?

An enzyme that circulates bound to LDL and HDL; it hydrolyzes oxidized phospholipids in lipoproteins, producing pro-inflammatory molecules

How does Lp-PLA2 contribute to atherosclerosis?

Its products promote inflammation, endothelial dysfunction, and plaque instability

What is the link between Lp-PLA2 activity and plaque vulnerability?

High Lp-PLA2 activity increases inflammatory mediators in the plaque, making it more likely to rupture and cause thrombosis —→ MI

What is lipoprotein (a)?

a lipoprotein similar to LDL but with an additional protein called apolipoprotein (a) attached

How does Lp(a) contribute to atherosclerosis?

Lp (a) promotes cholesterol deposition, inflammation, and inhibits fibrinolysis, increasing risk of plaque formation and thrombosis

Why is Lp(a) considered an independent cardiovascular risk factor?

Its levels are genetically determined and high Lp (a) increases risk of coronary artery disease regardless of LDL levels

What are the 3 criteria for the diagnosis of MI?

1. History of cardiac disease

2. ECG (electrocardiogram)

3. serum cardiac markers (Enzymes, Troponin I and T, myoglobin, inflammation markers)

What is the most specific and sensitive biomarker for diagnosing MI?

Cardiac troponins (I and T)

How soon after myocardial injury do troponins typically rise?

3-6 H after onset of symptoms

How long can troponins remain elevated after an MI?

7-10 days

Which biomarker rises and falls fastest, often used to detect reinfarction?

Creatine kinase MB (CK-MB)

True or false: CK-MB is completely specific to cardiac muscle

False - CK MB is mostly cardiac but can rise in skeletal muscle injury

What is myoglobin, and why is it not used alone for MI diagnosis?

Myoglobin is an early rising, non specific marker; it rises 1-4 H post-MI but is not cardiac-specific

What is the typical pattern of biomarker rise in MI?

Myoglobin rises first, then CK-MB and troponins, with troponins staying elevated longest

Which of the biochemical markers are most specific for myocardial injury?

Cardiac troponins

What are treatment methods of MI?

Oxygen administration, fibrinolytic agents, etc

Markers of Myocardial necrosis are…

CK-MB, Myoglobin, Cardiac troponins

Markers of Myocardial Ischemia are…

Ischemia Modified Albumin (IMA)

What is Ischemia modified Albumin (IMA)?

IMA is produced when circulating albumin comes in contact with ischemic tissue in the heart or other organ

What causes the formation of Ischemia-modified albumin?

Ischemia (low oxygen) leading to oxidative stress and modification of albumin’s N terminus —→ albumin can no longer bind metals like cobalt

IMA is a VERY EARLY marker for ischemia (not infarction) so what does this mean?

It does not require tissue death

How is IMA measured?

By the Albumin Cobalt Binding (ACB) test

What happens in the ACB test?

cobalt is added to the patient’s serum, the unbound cobalt is what is measured. Altered albumin will bind less cobalt so less unbound cobalt = less IMA. more unbound cobalt = more IMA (Ischemia)

What is Heart type fatty acid binding protein (H-FABP)?

small cytosolic protein in cardiac muscle that transports fatty acids

How soon does H-FABP rise after a Myocardial infarction?

within 1-3 hours

How does H-FABP rise quickly after myocardial injury?

because it is small and located in the cytoplasm, so it is released rapidly when cells are damaged

Is H-FABP more specific than troponin for diagnosing MI?

NO

Which rises earlier in myocardial injury: H-FABP or troponin?

H-FABP rises earlier

What are Natriuretic peptides?

regulatory diuretic natriuretic substances responsible for salt and water homeostasis. Incudes ANP, BNP, CNP

What stimulates the release of BNP from the heart?

Ventricular stretching due to increased pressure or volume

What is BNP and what is its function?

B-type natriuretic peptide; it promotes vasodilation, natriuresis, and diuresis to reduce cardiac workload

From which part of the heart is BNP primarily released?

The ventricles

What is the precursor molecule to BNP?

proBNP

Into what two substances is precursor molecule, proBNP, split into?

BNP (active) and NT-proBNP (inactive)

How do BNP levels change in heart failure?

They increase due to ventricular stretch

BNP is specific for Myocardial infarction: true or false

False —→ reflects stress/stretch not infarction specifically

What type of process is coronary artery disease (CAD)?

An inflammatory process that progresses along with atherosclerosis.

How does CRP contribute to CAD?

CRP stimulates macrophages, which increase LDL deposition in atherosclerotic plaques

Again, what is the role of macrophages in atherosclerosis?

They ingest oxidized LDL, becoming foam cells, which contribute to plaque formation and inflammation

How does inflammation make plaques dangerous?

Inflammatory cells weaken the fibrous cap, making plaques more likely to rupture —→ thrombosis —→ MI

What is CRP and when is it produced?

An acute phase reactant produced in response to any inflammatory reaction

Does a CRP measurement indicate the location of inflammation?

No- it reflects the presence of inflammation, not where it occurs

What is the cardiovascular risk associated with high normal CRP levels (0.15 - 10 mg/L)?

Individuals at the high end of normal CRP have a 1.5 - 4x higher risk of myocardial infarction compared with those at the low end

What is hsCRP and why is it used?

High sensitivity CRP; measures low levels of CRP for cardiovascular risk assessment, especially in moderate risk individuals

Does lowering CRP levels reduce cardiovascular risk?

No evidence supports that lowering CRP alone decreases risk

How is homocysteine related to cardiovascular disease?

Elevated homocysteine is an independent risk factor for: atherosclerotic vascular disease and venous thrombosis

How does homocysteine contribute to atherosclerosis?

It has a toxic change on the endothelium, promoting plaque formation and arterial damage