Cardiovascular disease - L8

Question 1

• Name examples of non-communicable diseases.
• Name environmental risk factors of non-communicable diseases.
• Name metabolic risk factors of non-communicable diseases.

Answer 1

• Cardiovascular disease, cancer, diabetes mellitus
• Physical inactivity, alcohol abuse, unhealthy diet, tobacco use
• Blood pressure, increased blood glucose, elevated blood lipids, obesity

Question 2

What is the relation between heart failure and ejection fraction of the heart?

Answer 2

Heart failure is where the heart is unable to pump blood effectively. The ejection fraction refers to the percentage of blood that is pumped out of heart’s left ventricle with each contraction. When the ejection fraction is reduced or preserved, this is seen as (a type of) heart failure.

Question 3

What is the difference between heart failure with reduced ejection fraction and heart failure with preserved ejection fraction?

Answer 3

• Reduced ejection fraction: the left ventricle does not eject (i.e. pump out) sufficient blood due to weakening of the heart muscle causing it to not pump properly.
• Preserved ejection fraction: the left ventricle does not fill enough blood due to heart muscle stiffening and the muscles not being able to relax. The ejection fraction is within the normal range, but due to the inability of the heart muscles to relax this leads to impaired overall cardiac function.

Question 4

Name ways how heart failure with reduced ejection fraction (HFrEF), heart failure with mid-reduced ejection fraction (HFmEF), and heart failure with preserved ejection fraction (HFpEF) can present itself in the clinic.

Answer 4

• HFrEF: myocardial infarction (atherosclerosis-related), arrhytmias, hypertrophic cardiomyopathy, acute (pericardial) myocarditis.
• HFmEF: transition phase from HFrEF to HFrEF.
• HFpEF: type 2 DM, obesity, hypertension, smoking / COPD.

Question 5

What is the difference between eccentric and concentric hypertrophy of the heart muscles?

Answer 5

• Eccentric: increase in size and volume of the left ventricle in order to accomodate a greater volume of blood. This increases stroke volume, allowing the heart to pump more blood with each contraction.
• Concentric: increase in thickness of the heart muscle walls (specifically left ventricle) in order to respond to increased pressure or resistance common in conditions like hypertension or during resistance training. This allows for more forceful contractions, allowing more effective pumping against resistance.

Question 6

Exercise-related physiological hypertrophy refers to the increase in muscle size that occurs as a result of regular and structured exercise, which can also be observed for muscles of the heart.
Explain how the muscles of the heart adapt in the following situations:
* Aerobic training
* Resistance training

Answer 6

• Aerobic training: induces eccentric cardiac hypertrophy in the left ventricle. The heart adapts by pumping more blood with each contraction (increased stroke volume) so that it can meet the increased demand for oxygen and nutrients during aerobic activities. This often leads to a lower resting heart rate, as the heart becomes more efficient at pumping blood.
• Resistance training: induces concentric hypertrophy in particularly the left ventricle (thickening of the heart muscle walls). The heart adapts by enhancing its ability to pump blood forcefully, resulting in increased cardiac output.

Question 7

Answer the following questions about how the heart adapts under regular aerobic training and resistance training:
* Volume or pressure overload as a cause of hypertrophy?
* Does chamber dilation occur as a consequence of hypertrophy?
* Do myocyte increase in length or in width?
* Fibrosis present?
* Cardiac dysfunction present?

Answer 7

Aerobic training (i.e. eccentric hypertrophy):
* Volume overload
* Chamber dilation
* Myocyte length increases
* No fibrosis
* No cardiac dysfunction

Resistance training (i.e. concentric hypertrophy):
* Pressure overload
* Without chamber dilation
* Myocyte width increases
* No fibrosis
* No cardiac dysfunction

Question 8

What is diabetes mellitus?

Answer 8

• Hyperglycemia
• Depending on etiology: reduced insulin secretion, decreased glucose utilization, and increased glucose production
• Type 1 and 2
• Insulin disorder underlie both types
• Mellitus = honey-sweet, referring to the sweet taste of urine of diabetic patients

Question 9

What is the difference between systolic and diastolic heart failure?

Answer 9

• Systolic: weakened heart muscles that cannot contract efficiently anymore, causing less blood being pumped out of the ventricles into the circulatory system.
• Diastolic: stiffened heart muscle cannot relax normally, causing less blood to fill the ventricles

Question 10

What is a different name for diastolic heart failure?

Answer 10

Heart failure with preserved ejection fraction

Question 11

Is diabetes associated with diastolic or systolic heart failure?

Answer 11

Diastolic heart failure

Question 12

What is metabolic flexibility?

Answer 12

The ability to respond or adapt according to changes in metabolic or energy demans as well as prevailing conditions or activities. It is an interplay between optimal substrate sensing, transport, storage, and utilization and is required to integrate energy production and demand and to maintain energy homeostasis and cardiac contractility.

Question 13

Describe the difference in substrate oxidation regarding fatty acid oxidation, glucose oxidation, and BCAA & ketone oxidation in the heart during:
* Diabetes
* Heart failure with reduced ejection fraction (HFrEF)

Answer 13

• Diabetes: increased use of fatty acid oxidation, less use of glucose oxidation.
• HFrEF: increased use of glucose oxidation, less use of fatty acid oxidation.

BCAA & ketone oxidation is not different between the two conditions.

Question 14

Describe the insulin signal transduction pathway that occurs in skeletal muscle.

Answer 14

Insulin is released when a rise in blood glucose levels is detected by the pancreas. Insulin then binds to its (tyrosine kinase receptor), leading to phosphorylation of intracellular substrates.

• Two of these substrates are Cbl and CAP that interact with each other. When CAP is phosphorylated, the Cbl-CAP complex disassociates from the insulin receptor and stimulates translocation of glucose transporters GLUT4 to the plasma membrane so that glucose can be taken up.
• Interaction of insulin with its receptor also has its own downstream effects: two other substrates of the insulin receptor are Shc and IRS proteins. When these substrates are phosphorylated and activated, they can stimulate cell growth, protein synthesis, glycogen synthesis, and glucose transport.

Question 15

How does a high supply of fatty acids and circulating lipoproteins in Type 2 diabetes mellitus affect insulin signal transduction? And what else is affected by this high supply of fatty acids and lipoproteins?

Answer 15

• Type 2 diabetes mellitus -> high amounts of fatty acids from adipose tissue and circulating lipoproteins.
• Increased fatty acid supply -> lipid overload and lipotoxicity in cardiomyocytes (characterized by accumulation of long-chain acyl-CoA, acylcarnitines, ceramides, and DAGs).
• The accumulation of these substances hinder insulin receptor phosphorylation and intracellular insulin signaling.
• This results in a reduction of glucose uptake and oxidation in cardiomyocytes.
• Circulating pro-inflammatory cytokines further reinforce the detrimental effects on insulin signaling and glucose metabolism.
• The high levels of fatty acids are stored in the form of triglycerides, broken down into fatty acids, and then these fatty acids are re-synthesized into triglycerides without energy being produced. This disrupts the functioning of mitochondria (mitochondrial uncoupling), which alltogether impairs the functioning of the heart muscle, leading to a reduction in cardiac efficiency.
• In addition, changes in (mitochondrial) membrane lipid composition and ROS production contributes to supercomplex destabilization (oxidative phosphorylation) and disturbances in fission/fusion dynamics of mitochondria.
• Lastly, there is altered cytosolic calcium handling, which causes changes in mitochondrial calcium concentration and activities.

Question 16

Besides dysregulated insulin signaling and dysfunctioning mitochondria caused by fatty acid accumulation in T2 diabetes mellitus, what else is a consequence of fatty acid accumulation?

Answer 16

Cardiac hypertrophy, steatosis, and fibrosis.

NF-kB pathway is important here.

Question 17

What else causes cardiac hypertrophy, steatosis, and fibrosis besides fatty acid accumulation?

Answer 17

Activation of the NLRP3 inflammasome, which promotes myocardial remodeling.

Question 18

Endotoxin LPS is a component of the outer membrane of Gram-negative bacteria. In the context of obesity, there is evidence to suggest that increased levels of circulating LPS may contribute to chronic low-grade inflammation, a condition often associated with obesity and insulin resistance. When LPS enters the bloodstream, it can trigger an inflammatory response by activating immune cells, particularly through toll-like receptor 4 (TLR4) signaling.

Describe the pathway between endotoxin LPS, NLRP3 inflammasome and how these two can be linked to decreased muscle growth and mitochondrial dysfunction.

Answer 18

• LPS binds to TLR4, where a signaling cascade is initiated that activates the NF-κB pathway, resulting in the production of IL-6.
• Activation of the NF-κB pathway also results in the activation of the NLRP3 inflammasome.
• NLRP3 activates caspase-1 that results in the activation of IL-1β.
• IL-1β results in decreased muscle growth and also has an effect on mitochondria, resulting in ROS production.
• IL-6 can lead to reduced protein synthesis, which also leads to reduced muscle growth.
• Mitochondrial dysfunctioning/ROS production also leads to decreased muscle growth

Question 19

Obesity and adipocyte inflammation are correlated with each other. Describe this relationship in the following situations with regard to inflammation, metabolic control, and vascular function:
* Lean with normal metabolic function
* Obese with mild metabolic dysfunction
* Obese with full metabolic dysfunction

Answer 19

• Lean with normal metabolic function: everything in balance (presence of M2 macrophage and CD4+ T cells).
• Obese with mild metabolic dysfunction: increased inflammation, lowered metabolic control, balanced vascular function (resulting in presence of M1 macrophages and CD8+ T cells).
• Obese with full metabolic dysfunction: highly increased inflammation, highly decreased metabolic control, lowered vascular function (resulting in nectrotic adipocytes and production of pro-inflammatory adipokines).

Question 20

Which cytokines stimulate the differentiation of a macrophage into M1? And which cytokines stimulate the differentiation of a macrophage into M2?

Answer 20

• M1 (pro-inflammatory): TNF-a, IL-17
• M2 (anti-inflammatory): IL-13, IL-4

Question 21

What is often a cause of heart failure with reduced ejection fraction?

Answer 21

Atherosclerosis

Question 22

Describe the pathophysiology of atherosclerosis.

Answer 22

• LDL accumulation in the arterial wall that undergo chemical changes.
• Endothelial cells are stimulated to display adhesion molecules for monocytes.
• Monocytes mature into active macrophages and ingest LDL.
• Macrophages that ingest LDL become foam cells that result in the formation of the fatty streak (initiation of atherosclerosis).

Question 23

How does the presence or absence of M1 or M2 macrophages influence whether atherosclerosis can progress?

Answer 23

• M2 macrophage (anti-inflammatory) results in prevention of macrophage necrosis, clearance of apoptotic macrophages, and ultimately resolution of inflammation.
• M1 macrophage (pro-inflammatory) results in apoptosis, postapoptotic necrosis, necrotic core, increasing plaque vulnerability.

Question 24

During initiation of atherosclerosis, a positive feedback loop is present that can enhance the progression of atherosclerosis. Describe this process.

Answer 24

After initiation of atherosclerosis (formation of fatty streak), endothelial cells upregulate adhesion molecules and pro-inflammatory cytokines (e.g. ICAM-1, VCAM-1, selectins). Adipocytes also release molecules such as leptin, TNF-a, and IL-6, which further activate endothelial cells and contribute to inflammation. The activated endothelial cells, in turn, enhance the recruitment of immune cells such as monocytes, leading to M1 macrophage differentiation and further progression of the plaque.

Question 25

A study investigated the effect of exercise volume vs. intensity and the progression of coronary atherosclerosis. What did the study find?

Answer 25

That both exercise volume and intensity showed less progression of coronary atherosclerosis. this was not the case when exercise intensity was very vigorous.

Question 25

Another study investigated the benefits and risk of long-term exercise on coronary function, morphology, and atherosclerosis.
What was found in this study?

Answer 25

• Higher life expectancy
• Lower risk of plaque rupture
• Less consequences of stenosis
• Increased risk of coronary atherosclerosis

Question 25

Name potential explanations for the increased risk of coronary atherosclerosis in athletes.

Answer 25

• Altered coronary hemodynamics
• Increased inflammation
• Imbalanced diet
• Psychological stress
• Genetics
• Performance enhancing drugs
• Immune-modulating medication
• Increased systolic blood pressure
• Increased mechanical stress
• Disrupted laminar flow
• Decreased vitamin D intake/uptake
• Decreased magnesium intake/uptake
• Increased parathyroid hormone

Question 26

What conclusion was made based on a study where they measured glucose tolerance after 1 week of exercise in patients with mild type 2 diabetes mellitus?

Answer 26

After 1 week of exercise, improvements were observed in glucose tolerance of these patients. Therefore, no single medication for type 2 diabetes mellitus is as good as exercise.

Question 27

What is the difference between white and brown adipose tissue?

Answer 27

• Brown fat breaks down blood glucose and fat to create heat and maintain body temperature. It contains lots of mitochondria. For example, cold temperatures activate brown fat, which leads to various metabolic changes in the body.
• White fat is used for energy storage and is made up of big droplets of lipids, or fatty acids.

Question 28

What effect do myokines have on white adipose tissue?

Answer 28

• Decreases inflammation
• Increases insulin sensitivity
• Increases lipid oxidation
• Increases browning of fat
• Increases thermogenesis

Question 29

Describe how transdifferentiation of white adipose tissue into brown adipose tissue occurs as a result of exercise.

Answer 29

Exercise leads to the upregulation of PGC-1a (key regulator of mitochondrial biogenesis). Through a signaling cascade, where PGC-1a activates FNDC5 (precursor of irisin), which is then cleaved into irisin. Irisin stimulates the upregulation of UCP1 in white adipose tissue. This results in increased oxygen consumption and decreased expression of white adipose tissue genes, ultimately leading to the browning of the adipose tissue.