Week 4 - CVD reading: Flashcards
Results of a prolonged period (≥6 months) of regular intensive exercise in previously untrained individuals
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.
Exercise and cardiac remodelling:
- 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.
Upper limits of cardiac remodelling in athletes:
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.
Molecular mechanisms of physiological cardiac growth:
- 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.
The differences in cellular and structural cardiac adaptations between physiological and pathological remodelling of the heart.
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.
Flow mediated dilatation (FMD)
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
Structural changes in the arteries following endurance exercise:
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.
Optimising the CV benefits of exercise
How much exercise?
- 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.
Optimising the CV benefits of exercise.
How intense should exercise be?
- 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.
Issues with Randomised controlled trials examining the effect of exercise on disease endpoints :
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)
Modifiable risk factors for CVD:
- 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
Non-modifiable risk factors for CVD:
- 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.
Mechanisms through which physical activity can influence cardiovascular disease risk
Increased fitness and decreased body fat can affect several physiological mechanisms:
Insulin sensitivity
Lipid and lipoprotein metabolism
Blood pressure
Vascular function
Inflammation
Lipids, lipoproteins and PA:
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.
Atherogenic lipoprotein phenotype’
The combination of low HDL, elevated triglyceride concentrations and smaller denser LDL particles is termed: the ‘atherogenic lipoprotein phenotype’.
Exercise and lipoproteins
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
Physical activity and postprandial lipaemia:
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.
Mechanisms for improvements in lipid metabolism after physical activity:
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.
Blood pressure
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.
Several mechanisms have been proposed to explain the blood pressure lowering effect of exercise:
- 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.
Blood pressure categorisation for adults
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
Endothelial function:
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.
Nitric oxide (NO) - an important vasodilator released by endothelial cells
- 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.
Endothelial dysfunction
- 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.
