Cardiovascular System and Terminology

• The 'cardiovascular system' includes the heart, systemic, and pulmonary circulations
• This system circulates blood throughout the body
• Blood distribution at rest:
  • 60% in systemic veins and venules
  • 15% systemic arteries and arterioles
  • 12% in the pulmonary circulation
  • 8% in the heart
  • 5% systemic capillaries

Cardiovascular Terminology

• Cardiac output (C.O.) refers to the amount of blood pumped by the left ventricle per minute
• Stroke volume is the blood volume ejected by each ventricle per heartbeat, around 70 ml per ventricle
• Venous return is the process of blood flowing back to the heart
• Inotropic affects the strength of cardiac contractions
  • Positive Inotropic actions increase the heart's force of contraction
  • Negative Inotropic actions reduce the heart's force of contraction
• Chronotropic affects heart rate
  • Positive chronotropic effects cause heart rate increase
  • Negative chronotropic effects cause heart rate decrease
• Systole is the period when the heart muscle contracts ejecting blood into the aorta and pulmonary artery
• Diastole is the period when the heart muscle relaxes and heart chambers refill via the vena cava and pulmonary vein
• Blood flow is the actual blood volume flowing through a vessel, organ, or circulatory system in a specific amount of time (ml/min or l/min)
• Blood pressure (BP) is the pressure of blood against the main artery walls
  • Normal BP is around 120/80 mmHg systolic/diastolic
  • Arterial blood pressure differential is achieved by the pumping action of the heart in systole
• Resistance is the amount of friction blood encounters as it passes through vessels
  • Peripheral resistance is common as most friction arises in vessels periphery
  • Blood viscosity, vessel length and its diameter are important factors
  • Blood flow (F) = Difference in pressure (AP) / Peripheral resistance (R)
  • Blood flow is inversely proportional to resistance and directly proportional to the pressure difference
• Blood viscosity is internal resistance to flow, and is associated with blood 'thickness'
• Increased viscosity causes increased resistance to flow
• Blood vessel length directly increases resistance
• Blood vessel diameter (calibre) has resistance that is inversely varies with the fourth power of a vessel's radius
  • Small changes in vessel calibre can greatly affect resistance and blood flow
• Poiseuille-Hagen formula relates all of this: F = APX×1×/
  • F = flow
  • AP = pressure drop
  • η = viscosity r = radius L = length
• Vascular Resistance: Large arteries close to the heart contribute little to peripheral resistance, but small calibre arterioles do. Vessel diameters can be regularly adjusted, blood flow to different areas of the body can be controlled
• Starling's Law demonstrates when a resting muscle is stretched, when it then goes to contract it will contract with greater force
  • Preload describes the blood volume in the heart's chambers at the end of diastole
  • Afterload refers to the blood volume in the heart at the end of systole.

Autonomic Control of the Cardiovascular System (CVS)

• Sympathetic nervous system triggers fight or flight responses, so enables the body expending energy
• Parasympathetic nervous system triggers resting and digesting response, which enables the body to conserve energy
• Table 1 describes the autonomic control on various receptors in the CVS:
  • Heart tissue
    • SA node: Sympathetic stimulation increases rate (β1 receptor); Parasympathetic stimulation decreases rate (M2 receptor)
    • Atrial muscle: Sympathetic stimulation increases force (β1 receptor); Parasympathetic stimulation decreases force (M2 receptor)
    • AV node: Sympathetic stimulation increases automaticity (β1 receptor); Parasympathetic stimulation decreases conduction velocity and may cause AV block (M2 receptor)
    • Ventricular muscle: Sympathetic stimulation increases force and automaticity (β1 receptor); Parasympathetic stimulation has no effect
  • Arterioles
    • Coronary: Sympathetic stimulation causes constriction (α receptor); Parasympathetic stimulation has no effect
    • Muscle: Sympathetic stimulation causes dilatation (β2 receptor); Parasympathetic stimulation has no effect
    • Viscera, skin, brain: Sympathetic stimulation causes constriction (α receptor); Parasympathetic stimulation has no effect
    • Erectile tissue: Sympathetic stimulation causes constriction (α receptor); Parasympathetic stimulation causes dilatation Salivary gland: Sympathetic stimulation causes constriction (α receptor); Parasympathetic stimulation causes dilatation (M3 receptor)

Cardiovascular Disease

• Definition: Cardiac and/or vascular diseases usually stemming from atherosclerosis in coronary, peripheral, or cerebral arteries
• European statistics: Cardiovascular diseases cause 47% of all deaths in Europe and premature deaths in Europe account for 38% of deaths in women and 37% of deaths in men under 75
• UK statistics (2014): Cardiovascular disease caused 27% of deaths (second biggest cause), main cause of premature death (25% men, 17% women under 75)
• UK (2013/14): 1.7 million hospital episodes for cardiovascular diseases, CCGs in England spent £4.3billion

Risk Factors for cardiovascular disease

• Smoking contains free radicals, nicotine, carbon monoxide, tar, causes increased HR, BP, lowers blood's oxygen carrying capacity
• Obesity causes more blood vessels which means the heart has to increase pressure to pump the blood further
• Diet: excess cholesterol and salt means that more water retained, which increasing blood volume and then BP
• Stress and Ageing
• Genetic predisposition (family history)
• Socioeconomic status, a chronically stressful life, social isolation, anxiety, depression, excessive alcohol consumption
• Factors grouped by modifiable or non-modifiable, modifiable factor such as lack of exercise but ageing is non-modifiable

Atheroma

• Arterial disease where atherosclerotic plaques slowly develop in luminal walls, plaques of necrotic core, lipids, cholesterol, surrounded by fibrous tissue and smooth muscle cells, this process known as atherosclerosis.
• Clinical symptoms occur in later stages when extensive narrowing of the lumen of an artery occurs through a thrombus

Lipid Transport

• Cholesterol absorbed from diet (exogenous pathway) or produced by the liver (endogenous pathway)
• Lipids and cholesterol not water soluble, transported as lipoproteins in the blood:
  • Chylomicrons- from intestinal mucosal cells to transport dietary fatty acids and cholesterol into plasma via the thoracic duct
  • VLDL- transports triglycerides and acted on by capillary lipoprotein lipase in adipose tissue and muscle
  • LDL- formed from VLDL once fatty acids extracted, rich in cholesterol, high LDL levels promote atherosclerosis ('bad cholesterol')
  • HDL- takes excess cholesterol from cells and lipoproteins to the liver ('good cholesterol')
• Cholesterol used for producing bile acids for dietary fat digestion and the production of some steroid hormones

Atherosclerosis Pathway

• Endothelial cell (EC) dysfunction/damage occurs around area of arterial bifurcations, affecting PGI2 and NO synthesis, and adhesion molecule expression
• Monocytes adhere and migrate to arterial wall, form macrophages, ECs and macrophages produce free radicals, oxidize LDL
• Macrophages take up oxidized LDL, forming 'foam cells', which cause inflammatroy cytokines
• Foam cells coalesce, forming fatty streaks, ECs, foam cells, activated platelets etc, release growth factors
• Plaques rupture forming a point for thrombus formation (thrombosis)
• Elevated plasma LDL levels are correlated with atherosclerosis development and other factors include, low HDL levels, HT, diabetes mellitus, cigarette smoking, obesity, physical inactivity

Hyperlipidaemias

• Involve raised cholesterol or triglyceride levels or both, are common with the first treatment being dietary control, followed by drug treatments
• Ideal blood cholesterol level is less than 5 mmol/L, UK average is 5.7 mmol/L, high cholesterol is 6.5 mmol/L or above
• Risk Factors include:
  • High saturated fat diet
  • Smoking
  • Lack of exercise
  • High alcohol consumption
  • Kidney or live disease
  • Genetic predisposition
• In England, over 50% of adults have raised cholesterol (that is > than 5mmol/L)
• England, 1 in 500 of the population have heterozygous familial hypercholesterolaemia and around 15% have diagnosed

Lipid Lowering Drugs

• Statins, 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase reversibly inhibits hepatic HMG CoA reductase, key enzyme in synthesis of mevalonic acid
  • Mevalonic acid goes on to farnesol, which becomes cholesterol
• Inhibition of HMG-CoA reductase lowers cholesterol levels, by restriction of mevalonic acid supply
• To compensate, liver expresses more HMG CoA reductase so cholesterol synthesis is restored
  • Statins induce increased expression of hepatic LDL receptors, increasing uptake of LDL, increase clearance of cholesterol from plasma
  • Side effects include: Gastrointestinal problems (constipation, diarrhoea, flatulence), nausea and rashes. Patients complain of muscle soreness and rhabdomyolysis may occur as statins affect muscle cellular systems
• These problems are reversible reducing dose or stopping administration.
• Products from breakdown of muscle proteins toxic to kidneys, if allowed to build up
• Contraindications: Pregnancy and breastfeeding, as cholesterol is needed during fetal development, Liver disease as statins extensively metabolized by hepatic cytochrome P450's
• Orally Administered

Fibrates

• Oral; Bezafibrate and gemfibrozil
• Reduce Triglycerides (~30%) LDL (~10%) and Increase HDL (~10%)
• Thought to works by stimulating a lipoprotein lipase- reducing triglyceride content of VLDLs and chylomicrons as well as stimulate hepatic LDL receptor expression.
• Formulations are given as sustained release
• Side Effects include: Intestinal disturbances and myosistis like Syndromes (imflammatory muscular degeneration).

Bile Acid Sequestrants

• Bile Acid Binding, Basic Anion Exchange Resins and Oral
• Drugs such as colestyramine, colestipol and colesevelam. These are orally administered drugs that bind to intestinal bile acids and prevent their reabsorption.
• Promotes conversion of cholesterol into more bile acids so hepatic increases LDL receptor -This enhances plasma cholesterol.
• Given as a divided Powder
• Side effects: Mostly confined to intestines, examples are bloating abdominal discomfits and diarrhea due to interferance with absorption of fat soluble vitamins .
• Contraindications: Complete Biliary obstruction,

Nicotinic Acid

• Inhibits hepatic VLDL formation
• Reduces LDL production so lowers cholesterol levels by ~10-20%
• Gram Quantities
• Side effects: flushing, dizziness, headaches, palpitations, nausea and vomiting.

Ezetimibe

• inhibits cholesterol absorption in the intestine
• It is used in Combinations with statins and dietary measures
• Leads to a decrease in the amount of intestinal Cholesteral delivered into the Liver.

Hypertension (HT)

• Elevated arterial blood pressure above the expected range (140/90- 160/95mmHg borderline)
• Primary or 'essential' HT (~90% of cases) maybe of unknown cause but small sympathetic activity increases cardiac output and peripheral resistance, so increases BP.
• Genetics and environmental factors. may play role too. 'Secondary' HT has a known cause such as kidney or Endocrine diseases.
• Patients should be screened and pharmacits take a key role in screening as well as in hypertension screening

Risk Factors

• Genetic dispositions (family history)
• Aging: Blood vessels lose flexibility,
• Gender: Men are up to the age of 45
• Lack of excersie, Obesity, Diet.
• Smoking and Stress
• Public England Estimates suggest that the Diseased caused by hyperextension costs the National health serivice 2 billion.

Treatments

• starting points includes reduction in body weight salt/ smoking
• NICE guidelines show step wise drug treatment.s
  • Step 1: Asian and Caucasian patients under the age of 55 are likely to have high renin HT
• 2: combining one drug from each
• 3 ; tripple theropy where three drugs are ben
• 4. If tripple theropy

Vasodialating Drugs

• Drugs such as ACE Inhibitors ARAS Calcuim channel Blocks lowere blood or reduce peripheral blood.
• ACE Inhibitiors RAS a Pyhsologcal mechanism that tries to maintain BP And NA l
• They can help perffrusion of blood thought the kindney
• Rememin( not the same enmziyme) Is a released from the Juxta Apparatus

1. Acton Angiostensen

• If Rass is inappropaitally active so then it inhibits
• It is needed can canse hypertension
• Same as above For example: Enalprill Etto OC NH CH3 h00C

2. Angiotensin Receptor Antagosnists / Blockers ( ara) or ARBS

• Ace inhibotors side effect it cam ben difficult tio

So Ras can ben affted By anginosiingAt

1. ACE Inhibitors
2. Beta-Blockers
3. Calcuum Channel Antagonistics

Overview of the cardiovascular system, including systemic and pulmonary circulations. Cardiac output refers to the amount of blood pumped by the left ventricle per minute. Positive Inotropic actions increase the heart's force of contraction, while Negative Inotropic actions reduce the heart's force of contraction.