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Cardiovacular - (Show awareness of the importance of referral for ‘Red…
Cardiovacular -
Show awareness of the importance of referral for ‘Red Flag’ symptoms
Shortness of breath
Coughing or wheezing
Dizziness
Fainting
Loss of consciousness
Nausea or vomiting
Sweating
Chest pain (with or without exertion) - pressure, tightness, squeezing in the centre of ches
Pain in the arm(s), back, neck, jaw
Abdominal pain
Overwhelming sense of anxiety (similar to a panic attack)
Pain in legs like sudden cramp when walking
Being unable to lift limbs or numbness to limbs
Drooping of one side of the face or Inability to smile
Confusion
Explain the aetiology of common cardiovascular pathologies
Atherosclerosis
Dyslipidaemia * / Hypercholesterolemia
Metabolic Syndrome
Hypertension
Headline Statistics
7 million people living with cardiovascular disease (heart and circulatory) in
the UK.
• Cardiovascular disease (CVD) causes more than a quarter of all deaths in the UK
SMOKING
22,000 deaths from CVD are attributed to smoking
HYPERTENSION
Over a quarter of adults in the UK
VASCULAR COMPLIANCE
A healthy cardiovascular system is able to accommodate the increased pressure placed up it as every beat of the
heart expels blood into the aorta
Changes in arterial compliance through endothelial dysfunction can lead to stiffening of the arterial wall, this
leads to a reduction in the elastic properties of the arterial system.
Consequently the aorta is no longer able to expand to provide a buffer for the pulsatile blood flow of the heart.
Consequently the aorta is no longer able to expand to provide a buffer for the pulsatile blood flow of the heart.
Systolic pressure increases in the aorta and this pressure is distributed to distal tissues but also returns much
more rapidly through a rapid pulse wave.
The pulse wave returns to the heart even before the heart has finished its contraction and leads to a further
increase in blood pressure called augmentation.
The additional pressure delivered to the peripherial tissues can lead to events such as ischemic strokes.
INFLAMMATION
Low grade inflammation plays a crucial pathophysiological role in hypertension and cardiovascular disease.
In the vasculature, inflammation can enhance the proliferation of smooth muscle cells and plays a role in vascular
remodelling.
CRP
Six-year change in high-sensitivity C-reactive protein and risk of diabetes,
cardiovascular disease, and mortality
Single measurements of elevated high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk
of diabetes, cardiovascular disease, and mortality
INFLAMMATION AND IMMUNITY
Inflammation and immunological function and coagulation are intrinsically linked in a natural process of
protection and repair.
The issue relating to CVD and its associated conditions is the perpetual activation of what should be
a transitory event.
The primary drivers can be presented simply; oxidation, inflammation and immune dysfunction, however
consider triggers such as diet, lifestyle, nutritional deficiencies, other inflammatory conditions, and low grade
chronic infections
STRESS RESPONSE
Stress should not be ignored as a potential
driver of elevated blood pressure and CVD
Longer term stress or more correctly the
secretion of adrenalin, noradrenalin, cortisol
and aldosterone lead to a persistent
elevation of blood pressure and interaction
with the RAAS system
Incorporating therapies focused upon
moderation of the sympathetic nervous
system are an important aspect of any
therapeutic approach relating to
hypertension and cardiovascular health.
VASCULAR
REMODELLING
Traditionally, the development of coronary artery
disease (CAD) was described as a gradual growth of
plaques within the intima of the vessel
However, histologic
studies demonstrated that certain plaques do not reduce
luminal size, presumably because of expansion of the
media and EEM during atheroma development
BLOOD
Functions
Transportation
Oxygen and Carbon Dioxide
Nutrients, Hormones, Heat, Waste
Regulation
pH, Body Temperature, Cellular Hydration
Protection
Platelets - preventing blood loss
Immune Cells (White Blood Cells) to fight disease
Composition (by volume)
Blood Plasma (55%) - composed of
Water (91.5%)
Proteins (7%) - albumin, globulins, fibrinogen + others
Solutes (1.5%) - electrolytes, nutrients, gases + other
Formed Elements (45%) - formed elements per µL
Platelets (150000 - 400000)
White Blood Cells (5000 - 10000)
Red Blood Cells (4.8 - 5.4 million)
INFECTIOUS AGENTS
Seroepidemiological studies (investigations involving the identification of antibodies to specific
antigens in populations of individuals) suggest an association between several microbes and
coronary heart disease
Microbes or their structural components are found in atherosclerotic plaques
herpes viruses
Chlamydia pneumoniae
If they cause persistent infection in the vessel wall, they can directly promote a pro inflammatory,
procoagulant, and pro atherogenic environment.
CIRCULATORY SYSTEM
blood vessels
ARTERIES
ELASTIC Arteries have a high proportion of elastic fibres that are able store energy
and act as a pressure reservoir propelling blood from the heart, an examples of an
elastic artery is the aorta
MUSCULAR Arteries contain smooth muscle and have fewer elastic fibres.
Muscular arteries have a greater capability for vasoconstriction and vasodilation to adjust
blood flow, an examples of muscular arteries are the brachial and radial arteries in the arm
ARTERIAL ANATOMY
ENDOTHELIUM
Directly in contact with blood
The endothelium is a continuous tissue that lines the
entire cardiovascular system from the heart, through the
arteries and into the microvascular of the capillaries as
they integrate with every organ in the body until they
emerge once more into the venous system and finally
return back to the heart.
Functions of Vascular Endothelium
Maintains tone and structure via vasodilation and vasoconstriction
Regulation of cell growth and migration
Regulation of thrombotic and fibrinolytic activity
Mediation of inflammation, oxidative stress and immune mechanisms
Regulation of leukocyte and platelet adhesion to endothelial surface
Moderates oxidative processes
Regulation of endothelial permeability
Vascular tissue
is dynamic and undergoes a continual cycle
of injury and repair. If injury becomes a protracted event and
potentially multifactorial, the ability to maintain a stable and
functional vascular endothelium becomes impaired leading
to a deterioration of function.
Vascular Tone and Ion Channels
The contractile activity of smooth muscle cells in the walls of small arteries and arterioles, is the major determinant of the resistance to blood flow
vascular tone plays an important role in the regulation of blood pressure and the distribution of blood flow between and within the tissues and organs of
the body
Regulation is dependent on a complex interplay of vasodilator and vasoconstrictor stimuli from circulating hormones, neurotransmitters,
endothelium-derived factors, and blood pressure
muscle shortens when internal cellular levels of calcium increase and that this calcium movement through ion-gated channels depends
on an action potential
Closing the K+
channels keeps the membrane polarised at a certain level – a stimulus occurs leading to opening of Cl−
channels, Cl−
ions diffuse out of
the cell & the membrane depolarises, this then results in the opening of voltage-gated Ca2+ channels, allowing calcium ions into the cell =
vasoconstriction.
If the K+
channels are opened this results in diffusion of potassium out of the cells, the cell becomes hyperpolarised i.e. more negative and this inhibits
an action potential by increasing the stimulus required: the voltage-gated Ca2+ channels close, resulting in decreased intracellular Ca2
= vasodilation.
The Endothelium is the largest organ in the body covering an
area of approximately 5 tennis courts or about five times the
mass of the average sized heart.
Vascular Endothelium Receptors
an active organ with a range of
sensors to help respond to the needs of the body
Vasoconstriction and vasodilation
primarily regulated by the interaction between the receptor for Angiotensin II (ATII)
and the receptor for Bradykinin (BK)
Pattern Recognition Receptor (e.g. PRRs, TLRs)
responses
to insults (e.g. antigens, microbes, nutrients, toxins, oxidised
LDL etc) in addition to force of blood flow and blood
pressure lead to a limited range of defence responses by
the vascular tissue - oxidative stress, inflammation or an
immune response
ENDOTHELIAL DSYSFUNCTION
characterised by a shift of the actions of the endothelium toward:
Reduced vasodilation
increased pro-inflammatory state
Increased pro-thrombotic properties
associated with most forms of cardiovascular disease
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VASCULAR INFLAMMATION
An initial step in vascular inflammation
leading to atherogenesis is the ADHESION CASCADE
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OXIDATIVE STRESS
Chronic and acute overproduction of reactive oxygen species (ROS) under
pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD)
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HYPERTENSION AND ENDOTHELIAL DYSFUNCTION
Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension
Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation
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BASICALLY IT IS VERY COMPLICATED BUT A BIT LIKE A SNOWBALL EFFECT OF INFLAMMATORY, OXIDATIVE AND IMMUNE STUFF
strategically located between the wall of blood
vessels and the blood stream. It senses mechanical stimuli, such as pressure and shear stress,
and hormonal stimuli, such as vasoactive substances. In response, it releases agents that regulate
vasomotor function, trigger inflammatory processes, and affect haemostasis.
strategically located to monitor and react to events within the
vascular system that directly and indirectly affect endothelial response.
VASA VASORUM
Blood vessels also require oxygen and nutrients just like
any other tissue. Larger blood vessels have a
secondary vascular system that delivers these vital
nutrients as well as immune cells into the lining of the
larger vessels,
GlYCOCALYX
the surface layer protects endothelial
cells from the shear stress of blood flow it is composed of a
negatively charged network of proteoglycans, glycoproteins,
and glycolipids.
Another way in which the glycocalyx protects is through its
capacity to bind enzymes that scavenge oxygen
radicals, such as extracellular superoxide dismutase.
These enzymes help reduce the oxidative stress and
maintain NO bioavailability, and so prevent endothelial
dysfunction
Antioxidant therapy and avoiding hyperglycaemia are
protective of the glycocalyx
.
ARTERIOLES
Arterioles are almost microscopic and help to regulate the flow of blood to capillaries by
contraction and relaxation of arteriole smooth muscle
CAPILLIARIES
Capillaries are microscopic vessels connecting arterioles to venules and are responsible
for the exchange of nutrients and waste products from blood and tissue cells through
interstitial fluid. The more metabolically active a tissue or organ is the greater the size
of the capillary network in order to ensure adequate oxygen and nutrient delivery.
VENULES
A venule is a unification of several capillaries which collect blood from capillaries and drain
it into the veins. The tissue structure like capillaries has very few smooth muscle cells.
VEINS
Veins have very few elastic fibres or smooth muscle cells but are still able to distend
sufficiently to allow for variations of blood volume and blood pressure. Blood pressure is
much lower in the venous system than the arterial system and blood flowing back to the
heart can slow or pool. In order to avoid this occurring many veins contain internal valves
which inhibit blood from flowing backwards.
OXIDISED LDL and ATHEROGENESIS
The oxidative
modification
hypothesis of
atherosclerosis
predicts that low
-density
lipoprotein (LDL)
oxidation is an
early event in
atherosclerosis
and that
oxidised LDL
contributes to
atherogenesis.
DRIVERS OF VASCULAR DISEASE
OXIDATIVE STRESS
The number of pathways in which oxidative stress
can lead to endothelial dysfunction are numerous
but ultimately all lead to changes in
1) nitric oxide production
2) alterations to adhesion and migration factors
(e.g.ICAM-1 and VCAM-1)
leads to vasoconstriction and an
increased immunological response.
ENDOTHELIAL FUNCTION AND OXIDATIVE STRESS
vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin
and endothelium derived hyperpolarizing factor, as well as vasoconstrictors.
NO plays an important role in the regulation of vascular tone, inhibition of platelet aggregation, and suppression
of smooth muscle cell proliferation
Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis.
Cardiovascular diseases are associated with endothelial dysfunction
It is well known that the grade of endothelial function is a predictor of cardiovascular outcomes
Either reduced production of NO or increased production of reactive oxygen species, mainly superoxide,
may promote endothelial dysfunction.
One mechanism by which endothelium-dependent vasodilation is impaired is an increase in oxidative
stress that inactivates NO
NITRIC OXIDE AND PEROXYNITRITE
NO is not just an endothelial-derived relaxing facto
it is a fundamental signalling device regulating virtually every critical
cellular function
It also functions as a potent mediator of cellular damage in a wide range of conditions though most of the cytotoxicity
attributed to NO is rather due to Peroxynitrite, produced from the diffusion-controlled reaction between NO and another free
radical, the superoxide anion
Peroxynitrite interacts with lipids, DNA, and proteins to trigger cellular responses ranging from subtle modulations of cell
signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. Peroxynitrite can also inhibit the
mitochondrial electron transport chain by altering the permeability of the mitochondrial outer membrane resulting in a state of
cellular energy deficiency
peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke,
myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer,
and neurodegenerative disorders.
This combination of superoxide and NO produces a necessary and short lived immune reaction. As superoxide levels
become disproportionate to NO, the level of perioxynitrate increases at a rate of 10 x perioxynitrate for 1x superoxide.
Perioxynitrate is implicated in many chronic diseases and is one reason to caution the supplementation of L-Arginine (a
precursor to NO) unless there is an absolute deficiency and is the known reason behind NO deficiency
WHAT IS NITRIC OXIDE (NO)?
a potent vasodilator
produced via the stimulation of the B₂
(Bradykinin Receptor) from its precursor
L-arginine.
Stimulation of the AT-1 receptor via ATII
(angiotensin II) induces a
vasoconstrictive reaction in part due to the
inhibition of NO
NO is inhibited by ATII via the release
of the first oxidative radical in a series
of radicals called superoxide anion.
RAAS, ANGIOTENSIN II and NITRIC OXIDE
Reduced NO production
Platelet aggregation and adhesion
Vasoconstriction
Stimulation of NF-Kb
Decreased BH4 (required for NO)
Mitochondrial oxidative stress increase
Premature vascular ageing
Atherosclerosis
Up regulation of RAAS
Increase in ACE and Angiotensin II signalling
Angiotensin II induces oxidative stress
Angiotensin II induces inflammation
Increased endothelial dysfunction
Reduced NO production
Evaluate orthodox medical approaches to cardiovascular disease
Explain the application of nutritional therapy in optimising the
cardiovascular system