Week 4 - CVD reading:

Question 1

Results of a prolonged period (≥6 months) of regular intensive exercise in previously untrained individuals

Answer 1

Resting and submaximal exercising heart rates are typically 5–20 beats lower, with an increase in stroke volume of ∼20% and enhanced myocardial contractility.
- Structurally, all four heart chambers increase in volume with mild increases in wall thicknesses, resulting in greater cardiac mass due to increased myocardial cell size.

Question 2

Exercise and cardiac remodelling:

Answer 2

• The term ‘athlete’s heart’ refers to a constellation of adaptations that affect the structure, electrical conduction and function of the heart that facilitate appropriate increases in cardiac output during exercise. Intensive and prolonged endurance training leads to cardiac remodelling.
• Studies demonstrate dilatation of all four cardiac chambers and an increase in the maximal wall thickness in trained individuals compared with sedentary controls.

Question 3

Upper limits of cardiac remodelling in athletes:

Answer 3

In absolute terms and regardless of an athlete’s body surface area, the upper limit of physiological hypertrophy in athletes is considered ≥13 mm for maximal wall thickness and ≥65 mm for LV internal diameter in diastole.

Question 4

Molecular mechanisms of physiological cardiac growth:

Answer 4

• The best characterised signalling cascade responsible for mediating physiological cardiac growth is the insulin-like growth factor-1 (IGF-1)-PI3K(p110α)-Akt pathway.
• Increased cardiac IGF-1 expression and activation of the PI3K (p110α) pathway has been implicated in increased cardiomyocyte hypertrophy with endurance exercise in athletes.

Question 5

The differences in cellular and structural cardiac adaptations between physiological and pathological remodelling of the heart.

Answer 5

Normal Heart: This represents the baseline heart with normal-sized chambers and regular distribution of cardiomyocytes (muscle cells) and endothelial cardiac stem cells (eCSCs).

Pathological Remodelling:

Seen in conditions such as myocardial infarction (heart attack).
Structural changes: Increase in heart size and myocyte volume, but with thinning of the walls due to cell death and fibrotic replacement.
Cellular changes: Dysfunction of eCSCs leads to impaired regenerative capacity, resulting in cardiac dysfunction.
This remodelling is often considered irreversible and associated with a decline in cardiac function.
Physiological Remodelling:

Observed with endurance exercise training.
Structural changes: Enlarged heart size with proportional wall thickening and increased myocyte volume, ensuring preserved chamber function.
Cellular changes: Activation of eCSCs supports myocyte and vessel renewal, contributing to improved or maintained heart function.
This type of remodelling is typically reversible with cessation of the stressor (e.g., stopping exercise).
Overall, pathological remodelling is maladaptive and impairs cardiac function, whereas physiological remodelling represents a healthy, adaptive response to increased demands.

Question 6

Flow mediated dilatation (FMD)

Answer 6

The integrity of blood vessels function can be assessed using the technique of flow mediated dilatation (FMD), which uses an ischaemic challenge to induce changes in shear stress that stimulates vasodilation that is NO dependent
- The mechanisms responsible for reduced FDM post exercise relate to an increase in oxidative stress and/or a decline in endothelial (arginine) substrate use to cleave NO
High-intensity exercise may generate oscillatory or retrograde blood flow patterns that hinder nitric oxide (NO) production

Question 7

Structural changes in the arteries following endurance exercise:

Answer 7

Increased vessel diameter, which normalize shear rates and explain why elite athletes exhibit similar FMD to sedentary individuals despite having larger arteries and thinner walls.

Question 8

Optimising the CV benefits of exercise
How much exercise?

Answer 8

• While no optimal exercise volume or ‘dose’ has been established, low doses of casual lifelong exercise (2–3 sessions per week) do not prevent the decreased cardiac compliance and distensibility observed in healthy yet sedentary ageing.
• Research observed stiffer ventricles in casual exercisers (2–3 sessions per week) than committed (4–5 exercise sessions per week), with LV distensibility similar between casual exercisers and sedentary individuals.

Question 9

Optimising the CV benefits of exercise.
How intense should exercise be?

Answer 9

• A meta-analysis of patients with cardiometabolic diseases (ie, coronary artery disease, heart failure, hypertension, metabolic syndrome and obesity) observed significantly greater increases in VO_ 2peak following HIIT compared with Moderate intensity continuous training (MICT), equivalent to 9%, meaning that HIIT improved cardiorespiratory fitness by almost double.
• The vast majority of evidence suggests that regular (≥4 times per week), sustained (≥45 min) and intensive exercise throughout life is the most advantageous to optimise CV health.

Question 10

Issues with Randomised controlled trials examining the effect of exercise on disease endpoints :

Answer 10

very large sample sizes and long durations of follow-up are needed to detect statistically significant effects on these outcomes (e.g., heart attack and stroke)

Question 11

Modifiable risk factors for CVD:

Answer 11

• Dyslipidaemia: elevated total cholesterol or low-density lipoprotein cholesterol concentrations, depressed high-density lipotropin cholesterol concentration, elevated triglyceride concentrations
• Hypertension
• Cigarette smoking
• Obesity (particularly central/ abdominal obesity)
• Hyperglycaemia or T2 diabetes

Question 12

Non-modifiable risk factors for CVD:

Answer 12

• Family history: risk is increased in first-degree relatives of people with premature atherosclerotic disease (<60 years)]]]
• Age: higher risk in older individuals
• Sex: higher risk in men
• Ethnicity: higher risk in individuals with South Asian ethnicity
• Socio-economic status: higher risk with greater deprivation
• Existing diseases/ conditions: higher risk in individuals with T1 diabetes, chronic kidney disease, rheumatoid arthritis, atrial fibrillation or familial hypercholesterolaemia.

Question 13

Mechanisms through which physical activity can influence cardiovascular disease risk

Answer 13

Increased fitness and decreased body fat can affect several physiological mechanisms:
Insulin sensitivity
Lipid and lipoprotein metabolism
Blood pressure
Vascular function
Inflammation

Question 14

Lipids, lipoproteins and PA:

Answer 14

Chylomicrons and VLDL are lipoproteins involved in the transport of triglycerides. Chylomicrons carry dietary triglycerides, while VLDL transports triglycerides synthesized in the liver. Both are referred to as triglyceride-rich lipoproteins because they primarily consist of triglycerides. LDL, on the other hand, primarily carries cholesterol in the bloodstream. Elevated levels of chylomicrons, VLDL, and LDL are considered atherogenic, meaning they promote the formation of fatty deposits in the arteries, contributing to cardiovascular disease (CVD).

In contrast, HDL is protective against CVD by facilitating the process of “reverse cholesterol transport,” where excess cholesterol is transferred from tissues to the liver for excretion. Triglyceride-rich lipoproteins are hydrolyzed by lipoprotein lipase (LPL) in capillary beds of adipose tissue and skeletal muscle. This hydrolysis releases non-esterified fatty acids (NEFA) for storage or oxidation and transfers phospholipid surface material and cholesterol to HDL.

High LPL activity can increase HDL levels by promoting the transfer of surface material to HDL. If triglyceride clearance is slow, there is a neutral lipid exchange between triglyceride-rich lipoproteins and HDL, leading to an inverse relationship between plasma triglyceride and HDL concentrations. This process affects the size and composition of both triglyceride-rich lipoproteins and HDL particles.
Considering the role of HDL in reverse cholesterol transport, low HDL concentrations are a risk factor for CVD.
Equally, low HDL concentration may be a marker for defective metabolism of triglyceride-rich lipoprotein.
The combination of low HDL and elevated triglyceride concentrations is also associated with circulating LDL particles that are smaller and more dense than normal.

Question 15

Atherogenic lipoprotein phenotype’

Answer 15

The combination of low HDL, elevated triglyceride concentrations and smaller denser LDL particles is termed: the ‘atherogenic lipoprotein phenotype’.

Question 16

Exercise and lipoproteins

Answer 16

The most consistent findings are of an increase in the concentration of protective HDL and reduced concentrations of plasma triglycerides and the triglyceride-rich lipoproteins chylo-microns and VLDL.

Well-designed randomised controlled intervention trials have shown that exercise training causes reductions in VLDL triglyceride and increases in HDL.
* In addition to demonstrating reductions in VLDL triglyceride and increases in HDL with eight months of exercise training in previously inactive, overweight men and women, these studies also found reductions in small LDL particles which are particularly atherogenic.
* The amount of exercise was found to be more important than its intensity for changing lipoprotein concentrations

Question 17

Physical activity and postprandial lipaemia:

Answer 17

Repeated and excessive postprandial lipaemia (increased blood triglycerides after eating) leads to lower HDL levels and more small, dense LDL particles. This situation increases clotting risk, damages endothelial function, and promotes systemic inflammation, all of which contribute to atherosclerosis. Studies show that endurance-trained athletes have a lower postprandial triglyceride rise compared to sedentary individuals.
A single aerobic exercise session can reduce postprandial hypertriglyceridemia.
Exercise intensity and duration both influence this effect.
However, if the energy expended through exercise is replaced by increased food intake, the triglyceride-lowering effect is diminished, highlighting the importance of the energy deficit from exercise.
Additionally, resistance exercise and short-duration high-intensity interval exercise have also been shown to effectively lower postprandial triglyceride levels.

Question 18

Mechanisms for improvements in lipid metabolism after physical activity:

Answer 18

Prior exercise appears to reduce postprandial lipaemia by increasing triglyceride clearance from the circulation, rather than reducing hepatic triglyceride production.
* There are several factors that may contribute to this improvement in triglyceride clearance, including:
a) Increased muscle LPL activity as the rate-limiting step in triglyceride
b) Increased blood perfusion towards skeletal muscle after exercise thereby increasing the exposure of triglyceride-rich lipoproteins to LPL for the stimulation of lipolysis and consequent reductions in plasma triglycerides.

Exercise improves postprandial lipaemia primarily by positively influencing very-low-density lipoprotein (VLDL) production and metabolism. After exercise, the liver releases larger, more triglyceride-rich VLDL particles, which are more efficiently broken down. This effect is enhanced by increased lipoprotein lipase (LPL) activity and greater muscle blood flow during exercise recovery. Together, these mechanisms improve VLDL packaging in the liver and triglyceride clearance in the muscles, leading to reduced postprandial triglyceride levels.

Question 19

Blood pressure

Answer 19

Hypertension is another major risk factor for CVD which is influenced by exercise.

Among the Harvard alumni studied by Paffenbarger and colleagues (1983), men who did not report engaging in vigorous sports were 35% more likely to develop hypertension during the 6– 10-year follow-up than those who did.
It is now well document that even a single session of aerobic exercise causes a transient lowering of blood pressure. This has been termed post-exercise hypotension.

Question 20

Several mechanisms have been proposed to explain the blood pressure lowering effect of exercise:

Answer 20

• Reductions in total peripheral resistance due to reduced sympathetic nerve activity and increased responsiveness to vasodilators such as nitric oxide
• Exercise may also invoke structural changes to arteries and veins, leading to increases in cross-sectional area (hence, less resistance to blood flow).
• The stimulation of sustained vasodilation from acute aerobic exercise appears to be primarily due to increases in the vasodilator histamine and resetting of the baroreceptor reflex and sympathetic withdrawal after exercise.
  In contrast, resistance exercise may reduce systemic vascular conductance; subsequently the hypotension experienced after resistance exercise is more likely the result of central mechanisms such as reductions in cardiac output.

Question 21

Blood pressure categorisation for adults

Answer 21

Normal:
Systolic: Less than 120 mm Hg
Diastolic: Less than 80 mm Hg

Prehypertension:
Systolic: Between 120–139 mm Hg
Diastolic: Between 80–89 mm Hg

Stage 1 Hypertension:
Systolic: Between 140–159 mm Hg
Diastolic: Between 90–99 mm Hg

Stage 2 Hypertension:
Systolic: 160 mm Hg or higher
Diastolic: 100 mm Hg or higher

Question 22

Endothelial function:

Answer 22

Endothelial function refers to the ability of the endothelium (the thin layer of cells lining blood vessels) to interact with vascular smooth muscle to influence blood flow.
Endothelial cells exert their effects by secreting various agents that diffuse to the adjacent vascular smooth muscle and induce either vasodilation or vasoconstriction.

Question 23

Nitric oxide (NO) - an important vasodilator released by endothelial cells

Answer 23

• This is released continuously in the basal state, but its secretion can be rapidly increased in response to exercise.
• NO secretion is also elevated in response to increases in shear stress (the force exerted on the endothelium by blood flow).
• This would result in flow-induced arterial vasodilation, thereby allowing the blood to flow freely and preventing undue increases in BP.

Question 24

Endothelial dysfunction

Answer 24

• contributes to all stages of atherosclerosis
• Endothelial injury/ dysfunction increases permeability to lipoproteins and promotes the adhesion of monocytes to the endothelium to progress the initial stages of atherosclerosis.
• Once atherosclerotic plaques are formed within blood vessels, endothelial dysfunction is also associated with these plaques becoming particularly vulnerable to rupture which increases the risk of adverse cardiovascular events.
• Vulnerable plaques are characterised by the presence of a large lipid pool inside the plaque, a thin fibrous cap, increased macrophage infiltration and apoptosis (cell death) within the cap which results in the growth of a necrotic core.
• The rupture of coronary atherosclerotic plaques is the major mechanism of coronary thrombosis (the formation of a blood clot within a blood vessel of the heart) which can restrict blood flow within the heart and cause myocardial infarction.

Question 25

Exercise training improves endothelium-dependant vasodilation:

Answer 25

• Exercise training improved vasodilation in response to acetylcholine infusion and increased blood flow in the left internal mammary artery after adenosine infusion.
• These findings were supported by significantly greater in vitro endothelium-dependent vasodilation and approximately double the levels of endothelial nitric oxide synthase mRNA and protein content in the trained group compared with the control group.
• The rise in endothelial NO synthase expression is most likely mediated by increases in sheer stress during exercise training and this is thought to be largely responsible for the associated in vivo improvements in vasodilatory responsiveness.

Question 26

The ‘gold-standard’ measure of vascular function

Answer 26

assess the change in coronary artery diameter in response to acetylcholine function
- Invasive procedure
- Alternative approach: involves the examination of flow-mediated dilation of a peripheral conduit artery (based on the principle that an increase in blood flow due to reactive hyperaemia can enhance shear stress induced NO production)

Question 27

Methods for assessing flow-mediated dilation (FMD):

Answer 27

• Flow-mediated dilation measures changes in the diameter of a conduit artery in response to an increase in shear stress induced by a surge in blood flow. This is most commonly measured using the brachial artery (located close to the inside of the elbow).
• A surge in blood flow is stimulated by reactive hyperaemia whereby a cuff is inflated either above or below the conduit artery to induce ischemia of the distal tissues. The rapid release of the inflated pressure cuff then stimulates an increase in blood flow to these distal tissues, with the increase in shear stress stimulating flow-mediated vasodilation of the conduit artery. The change in artery diameter is measured using ultrasound.

Question 28

Potential mechanism responsible for exercise-induced improvement in endothelial function:

Answer 28

• Increases in nitric oxide production
• A decrease in oxidative stress
• Increased production of extracellular superoxide dismutase (an antioxidant enzyme which prevents the premature breakdown of NO)

Question 29

Insulin resistance and glucose tolerance:

Answer 29

Glucose enters the circulation from the absorption of exogenous CHO’s across the small intestine after a meal, and from the liver as a result of liver glycogen breakdown and/ or gluconeogenesis. It leaves the blood by uptake into various tissues (brain, liver muscle).
Skeletal muscle contractions during exercise stimulate an increase in glucose uptake independently of insulin signalling.
- Increases in transport into the muscle occurs as a result of GLUT-4 translocation to the cell membrane which is stimulated by muscle contraction
This is further supported by the utilisation of and depletion of muscle glycogen concentrations during exercise, which reduce the accumulation of intramuscular glucose-6-phospahte and subsequently increase the use of intramuscular glucose for energy. Consequently, free glucose concentration in the muscle are reduced.
The insulin-independent increases in muscle glucose uptake during exercise demonstrate the potential benefits of physical activity as a nonpharmacological method by which to decrease hyperglycaemia in insulin resistant states.

Question 30

Glucose Clamp Techniques:

Answer 30

• The most accurate (gold-standard) method for determining the blood glucose response to insulin is the euglycaemic clamp technique. This involves intravenous (via a vein) infusion of insulin to produce the same plasma insulin concentration in all individuals. Simultaneously, glucose is infused intravenously to obtain euglycaemia (equal blood glucose concentration). The greater the quantity of glucose required to produce euglycaemia, the more insulin sensitive (less insulin resistant) the individual.
• An alternative glucose clamp technique is the hyperglycaemic clamp which involves continuous intravenous glucose infusion to maintain a stable level of elevated blood glucose concentrations (hyperglycaemia). The measurement of insulin secretion in response to the glucose infusion provides a measure of beta-cell function, while the requirement of a greater quantity of glucose to maintain a constant level of hyperglycaemia indicates higher levels of glucose metabolism by the body’s tissues

Question 31

HbA1c

Answer 31

Represents a form of haemoglobin which is covalently bound to glucose and provides a marker of average blood glucose concentrations from the previous two to three months. Therefore, improvements in HbA1c are indicative of medium-term improvements in blood glucose concentrations.

Question 32

Training adaptions that may facilitate improved glucose and NEFA delivery and metabolism:

Answer 32

• Increased capillary density and blood flow
• Increased muscle GLUT4 content
• Increased activity of enzymes involves in glucose (hexokinase, glycogen synthase) and oxidative metabolism (citrate synthase, succinate dehydrogenase)
• Reductions in body fact (improves glucose tolerance as a result of reduced NEFA flux to the liver and muscles).

Question 33

The potential mechanisms underlying an anti-thrombotic effect of exercise training include:

Answer 33

• A reduction in platelet activation (a trigger for the formation of clots)
• Lower circulating levels of procoagulant (or clotting) factors
• Increased fibrinolysis activity (the enzymatic breakdown of blood clots).

Question 34

Clustering of cardio-metabolic risk factors:

Answer 34

• Dyslipidaemia (specifically, high trigly¬cerides and low HDL)
• Insulin resistance
• Impaired glucose regulation or diabetes
• Obesity (particularly visceral obesity)
• Hypertension
• Systemic low-grade inflammation.
  Diabetes and obesity are twice as common among people with hypertension as among those with normal blood pressure.
  The common cause’ of the clustering of risk factors is likely due to a combination of abdominal (particularly visceral) adiposity, insulin resistance and chronic low-grade inflammation.

Question 35

Metabolic syndrome

Answer 35

Clinically defined as a combination of three or more of the following factors: elevated waist circumference, raised triglycerides, low HDL, raised blood pressure and raised fasting glucose.

Question 36

The relationship between central obesity, insulin resistance and cardio-metabolic disease risk factors

Answer 36

Obesity and Insulin Resistance: Insulin resistance is linked to enlarged and “full” adipocytes, which disrupt fat storage and metabolism, leading to metabolic dysfunction.
Fat Spillover: Overfilled adipocytes cannot store excess fat effectively, increasing circulating NEFA and triglycerides, which are deposited in liver and muscle tissues. This leads to lipid intermediates (e.g., ceramides) accumulating, which impairs insulin signaling.
Muscle Metabolism: Increased NEFA oxidation in muscles reduces carbohydrate usage, slowing glucose breakdown and lowering glucose uptake due to decreased insulin sensitivity.
Visceral Fat: Visceral fat is particularly harmful because it delivers excess fat to the liver via the portal vein, worsening insulin resistance.
Hypoxia and Inflammation: Large adipocytes suffer poor oxygenation, triggering cell death and macrophage infiltration. Macrophages release pro-inflammatory cytokines, increasing insulin resistance and systemic inflammation.
Inflammatory Feedback Loop: Pro-inflammatory cytokines from visceral fat intensify insulin resistance in liver and muscle, creating a cycle of inflammation and resistance.
Progression to Diabetes: Persistent insulin resistance raises blood glucose, forcing the pancreas to release more insulin. Some maintain this compensatory response, while others develop type 2 diabetes as pancreatic function deteriorates.

Question 37

Abnormalities associated with insulin resistance and chronic low-grade inflammation

Answer 37

• Diabetes or impaired fasting glucose/impaired glucose tolerance
• Hyperinsulinaemia
• Raised blood pressure
• Atherogenic dyslipidaemia, e.g. raised triglycerides, low HDL-cholesterol, high levels of ¬apolipoprotein B and C-III, small dense LDLs
• High levels of postprandial lipaemia
• Endothelial dysfunction
• Pro-thrombotic factors, e.g. high fibrinogen and plasminogen activator inhibitor-1 (PAI-1), high viscosity
• Microalbinuria (abnormally high albumin in urine indicative of vascular damage to glomeruli of kidney
• High uric acid (abnormally high uric acid in blood resulting from defects in insulin action on renal tubular reabsorption of uric acid)
• Non-alcoholic fatty liver disease

Question 38

Summary:

Answer 38

• Change in risk factors provide casual inferences for the association between physical activity levels and cardio-metabolic disease observed in epidemiological studies
• Acute bouts of physical activity improve post prandial lipid metabolism which may contribute to the improvements in lipoprotein profile observed with exercise training
• Increasing physical activity can reduce blood pressure in populations with normal blood pressure, hypertension or resistant hypertension
• Improvements in endothelial function in response to physical activity may stimulate arterial modelling (increased arterial size)
• Physical activity can improve glucose tolerance through insulin-dependent and insulin-independent mechanisms
• Interactions between visceral obesity, insulin resistance and chronic low-grade inflammation can cause ‘clustering’ of cardiometabolic risk factors, including: glucose intolerance, dyslipidaemia, high blood pressure, endothelial dysfunction and thrombosis.
• Physical activity has a preventive and therapeutic role in ameliorating multiple cardio-metabolic disease risk factors