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Cardiovascular, Drugs - Coggle Diagram

- - - - Rapid onset
      - Short duration
      - Inability to maintain postural tone
      - Spontaneous complete recovery
  - - - SYNCOPE
        
        Neurally-mediated reflex syndromes
        
        Orthostatic hypotension
        
        Cardiac arrhythmias
        
        Structural cardiovascular disease
      - DISORDERS MIMICKING SYNCOPE
        
        With loss of consciousness, i.e., seizure disorders, concussion
        
        Without loss of consciousness, i.e., psychogenic “pseudo-syncope”
  - - - Vasovagal
      - Carotid Sinus Syndrome
      - Situational
        
        Cough
        
        Post-Micturition
        
        Defecation
    - - Drug-Induced
      - Autonomic nervous system failure
        
        Primary
        
        Secondary
    - - Brady
        
        Sinus node dysfunction
        
        Atrioventricular Block
      - Tachy
        
        VT
        
        SVT
        
        WPW
      - Long QT Syndrome
      - Brugada syndrome
    - - Acute MI
      - Aortic Stenosis
      - Hypertrophic obstructive cardiomyopathy
      - Pulmonary Hypertension
      - Aortic Dissection
  - - - Distinguish TRUE syncope from syncope MIMICS
        
        Remember syncope can result in seizure-like activity.
        
        It is important to consider serious underlying causes
        
        Syncope vs. dizziness, presyncope, drop attacks, vertigo, & seizures.
      - Determine presence of cardiovascular disease
        
        Search for structural heart disease
        
        valvular stenosis, cardiomyopathy, or myocardial infarction.
        
        This may suggest more malignant causes such as ventricular tachycardia.
        
        Critical as most important factor in prognosis and risk stratification – cardiovascular causes of syncope have the highest mortality risk.
      - Establish the cause of syncope with sufficient certainty to:
        
        Assess prognosis confidently
        
        Initiate effective preventive treatment
    - - Meticulous patient history is vital
      - Collateral/witness history should be obtained where possible
      - Review patient’s medication list: note any recent changes in medications/doses
      - Physical exam: Full examination of all systems, with particular focus on cardiovascular and neurological systems
      - Supine and upright blood pressure
      - 12 lead ECG
      - Fingerprick glucose
    - - Circumstances of collapse
        
        Eyewitness account of event if available: What happened, appearamce of patient, breathing pattern, duration, abnormal movements, incontinence etc.
        
        Circumstances prior to episode e.g. position, activity, precipitating events, recent illnesses etc.
        
        Symptoms at onset of event e.g. headache, nausea, chest pain, palpitations, aura
      - Past medical history- especially history of similar episodes, cardiac and neurological conditions
      - Medications
        
        Proarrhythmic/antihypertensives/antianginal/QT prolonging agents
        
        Illicit drug use
      - Family history
        
        Sudden cardiac death
        
        Cardiac disease, particularly arrhythmogenic heart disease
        
        Syncope
    - - Vital signs
        
        Heart rate
        
        Orthostatic blood pressure change (drop in BP on standing)
      - Cardiac examination
        
        Tachycardia, bradycardia, irregular pulse, low volume pulse, pulsus parvus et tardus
        
        Cardiac murmurs
        
        Signs of cardiac failure
      - Neurological examination
        
        Focal neurological abnormalities e.g. weakness, signs of Parkinsonism
        
        Signs of raised intracranial pressure
    - - Should be guided by history and examination
      - Laboratory investigations: FBC, renal profile, glucose, D-dimer (if suspected PE), blood alcohol level or drug screen if indicated.
      - Cardiac investigations
        
        12 lead ECG
        
        Holter monitor
        
        Echocardiogram
        
        Event Recorder/Implantable Loop Recorder
      - CT brain if seizure or other neurological cause suspected
      - Special Investigations
        
        Pacemaker check if applicable
        
        Carotid sinus massage
        
        Method
        
        Massage, 5-10 seconds
        
        Don’t occlude
        
        Monitor cardiac rhythm and BP
        
        Outcome: Positive test is defined by cardiac asystole for 3 seconds or longer, or 50 mmHg fall in systolic BP, or 30 mmHg drop in SBP with reproduction of symptoms. (ESC guidelines). Reproduction of symptoms is necessary for Carotid Sinus Syndrome diagnosis
        
        Absolute contraindications
        
        Carotid bruit
        
        known significant carotid arterial disease
        
        previous TIA/stroke in last 3 months (unless recent carotid duplex study).
        
        Complications
        
        Primarily neurological
        
        Less than 0.2%3
        
        Usually transient
        
        Head-Up Tilt Test (HUTT)
        
        Protocols vary
        
        Useful as diagnostic adjunct in atypical syncope cases
        
        Useful in teaching patients to recognize prodromal symptoms
        
        Not useful in assessing treatment
        
        Electrophysiology study (EP study)
  - - - Syncope Due to Structural Cardiovascular Disease: Principal Mechanisms
        
        Acute MI/Ischemia: Neural reflex bradycardia – vasodilatation, arrhythmias
        
        Hypertrophic cardiomyopathy: Limited output during exertion (increased obstruction, greater demand), arrhythmias, neural reflex
        
        Acute aortic dissection: Neural reflex mechanism, pericardial tamponade
        
        Pulmonary embolus/pulmonary hypertension: Neural reflex, inadequate flow with exertion
        
        Valvular abnormalities
        
        Aortic stenosis – Limited output, neural reflex dilation in periphery
        
        Mitral stenosis, atrial myxoma – Obstruction to adequate flow
    - - Brady/Tachy
        
        Bradyarrhythmias
        
        Sinus arrest
        
        High grade or acute complete AV block
        
        Can be accompanied by vasodilatation (VVS, CSS)
        
        Tachyarrhythmias
        
        Atrial fibrillation/flutter with rapid ventricular rate (eg, pre-excitation syndrome, WPW)
        
        Paroxysmal SVT or VT
        
        Torsade de pointes
        
        Drug induced
      - Long QT syndrome
      - Torsade de pointes
      - Brugada
    - - Vasovagal Syncope (VVS)
      - Carotid Sinus Syndrome (CSS)
  - - - Reassure patients about the benign nature of the syncope
      - Avoid triggers
      - Identify warning symptoms
      - Lie supine, elevate legs when symptoms start
      - Treat any underlying conditions e.g. pulmonary disease in cough syncope
      - Good fluid intake
      - Support stockings
      - Physical counterpressure manoeuvres e.g. leg crossing
    - - Fludrocortisone
      - Midodrine
    - - A Symptom, Not a Diagnosis
      - Difficult diagnosis to make – detailed history and collateral history and exam
      - Many varied causes
      - Treatment varied and depends on proper diagnosis
- - - - Viruses – CMV, Coxsackie,
      - Bacteria - Neisseria
      - Fungi - Candida
      - Protozoa – Toxoplasmosis
    - - Post – Infectious
        
        viral
        
        streptococcal
      - SLE
      - Drug hypersensitivity – eg. chemo
      - Transplant rejection
    - - Sarcoidosis
      - Giant cell myocarditis
      - Idiopathic
    - - More evidence needed especially from autopsy studies
      - Direct v Indirect Injury ?
      - So far -->
        
        Myocardial infiltration by macrophages & CD4+ T lymphocytes
        
        Myocyte damage & lymphocytic myocarditis
        
        SARSCoV-2 viral particles identified in cardiac macrophages
        
        Long term consequence awaited – Troponin – Cardiac MRI
        
        Microthrombosis – small coronary vessels
        
        Consequence of Therapy in a few ??
        Cardiac dilatation & spotty necrosis,
  - - - Myocardium oedematous
      - Lymphocytic infiltrate, mononuclear cells
      - Non ischaemic necrosis
      - Viral inclusion rarely may be seen (eg. In CMV)
    - - Myocardial fibrosis
      - Ventricular dilatation
- - - - Rate
      - Contractility
      - Tension
    - - Oxygenated blood
      - Coronary Artery Flow
    - - Angina pectoris
        
        Stable
        
        Usually chest pain caused by exercise and relieved by rest and – often not clear-cut.
        
        Reflects “Significant” vessel narrowing → atheroma
        
        One vessel > 75% stenosis or 2 > 50% …usually
        
        Assessment via angiography. Often if autopsy done → microscopic myocardial fibrosis. Why?
        
        Angina may be worsened by anaemia or increased cardiac mass i.e. hypertrophy- may reflect important non-cardiac disease
        
        Unstable
        
        Stable angina with recent progressively increasing frequency
        
        Precipitated with progressively less effort- Often occurs at rest, and tends to be of more prolonged duration.
        
        Induced by disruption of an atherosclerotic plaque (plaque rupture) and secondary thrombus.
        
        Increased risk of subsequent acute MI
      - Myocardial infarction
        
        Myocardial necrosis due to reduced blood supply
        
        Usually reflects unrelieved coronary artery occlusion evolving to tissue death - Dynamic process and can be reduced by coronary reperfusion following “stenting”
        
        Certain plaques more likely to thrombose – lipid rich with fibrous cap cracks
        
        Of note statins stabilise plaques
        
        Clinical Presentation
        
        Crushing central chest pain, unrelieved by rest; accompanied by weakness, sweating, nausea & vomiting - Radiates commonly to left shoulder and jaw
        
        May be described as indigestion
        
        Can be painless [silent] – old / diabetes
        
        Pain may be atypical e.g. abdominal.
        
        May be “silent” present as heart failure (esp in elderly) arrhythmia – confusion – weakness.
        
        Need a high index of suspicion.
        
        Pathology
        
        Coronary atheroma --> plaque rupture and subsequent thrombosis initiates ischaemia – possibly reversible for 6 – 12 hours.
        
        Necrosis of myocardium begins 30 mins after occlusion and progresses from the subendocardial myocardium through the full thickness of the myocardium to the pericardial zone. (Transmural infarct)
        
        Why is it subendocardial?
        
        Most untreated episodes of ischaemia cause --> Transmural infarction.
        
        NB Subendocardial (AKA Non ST-elevation MI--NSTEMI) infarction more likely in incomplete artery occlusion or may develop in prolonged shock.
        
        Schematic representation of the progression of myocardial necrosis after coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the center of the ischemic zone. This entire region of myocardium (shaded) depends on the occluded vessel for perfusion and is the area at risk. Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle. The end result of the obstruction to blood flow is necrosis of the muscle that was dependent on perfusion from the coronary artery obstructed. Nearly the entire area at risk loses viability.
        
        Pathogenesis of Coronary Artery Occlusion
        
        Plaque rupture / fissure
        
        Exposure of lipid, smooth muscle foam cells
        
        Thrombin generation and fibrin platelet aggregates
        
        Thrombus in the atheromatous plaque with repair
        
        Plaque rupture with secondary thrombosis- can cause a myocardial failure or a fatal arrhythmia
        
        Diagnosis
        
        Clinical
        
        ECG (EKG): quick, easy and gives information about site and vessel involved as well as information about arrhythmias.
        
        Lab Evaluation : Troponin-I (TNI) and Troponin-T used most commonly. Also MB fraction of creatine kinase (enzyme) cardiac specific structural proteins
        
        Cardiac Troponins- Regulatory proteins of actin filaments in cardiac muscle – engage with calcium.
        
        Troponin Advantages
        
        Stays elevated for 7-14 days.
        
        Enzyme levels give some idea of extent of infarct, latter depending on location of obstruction, significance of vessel, degree of myocardial hypertrophy and presence of a collateral coronary circulation.
        
        More specific.
        
        Certain subtypes of troponin (I and T) are indicators of damage to the myocardium and can be measured in the blood by immunoassay techniques. Must be repeated to look for a rise
        
        Troponin levels are not specific Other conditions associated with raised troponins (any cause of myocardial necrosis)
        
        Cardiac surgery
        
        Cardiac contusion
        
        Myocarditis
        
        HOCM
        
        Cardiomyopathy
        
        Chemotherapy
        
        Renal disease
        
        Poly/dermatomyositis
        
        i.e. Troponins are a marker of all heart muscle cell necrosis
        
        - myocarditis
        
        Microscopic & Gross Pathology
        
        Up to 10 hours no microscopic change in myocardium
        
        Day 1: Myocardium. Coagulation necrosis with hypereosinophilia and wavy fibres. Dead vessels – haemorrhage.Macroscopically - Dark Red Firm
        
        Day 1 Coagulative necrosis on left characterised by non-nucleated wavy fibres with oedema causing widened space between fibres – rare neutrophils also present. Microscopic features of myocardial infarction and its repair. One-day-old infarct showing coagulative necrosis along with wavy fibers (elongated and narrow), compared with adjacent normal fibers (at right). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils.
        
        Day 2 – 7: Beside necrotic area – inflammation – neutrophils and oedema. If marked can get fever and raised WCC (bad prognosis).Macroscopically – Soft yellowish/tan tissue.
        
        Day 2-7 Necrotic myocardium with polymorphs
        
        Day 7 Soft yellow Myocardium [Cross section of left ventricle]:
        
        Day 7 – 14: Ongoing repair process with resorption of dead tissue and granulation tissue at edges. Macroscopic – depressed area with red edges.
        
        Week 2-8: Evolving fibrosis and decreasing vascularity. Macroscopic – grey white tissue
        
        Week 8: Dense fibrosis. Macroscopic depressed thinned myocardium and scar.
      - Chronic ischaemic heart disease
  - - - Sudden large coronary thrombosis on a ruptured atheromatous plaque
      - Secondary to an arrhythmia in chronic ischaemic heart disease as defined above.
      - 50% dead before arrival in hospital
- - - - Decreased valvular diameter – i.e. Aortic stenosis
      - Inadequate valve seals – i.e. aortic or mitral regurgitation
  - - - Insult [Index Event] – Compensation – Decompensation
      - Index Event - Reduces contractility or compliance
      - Compensation
        
        May mask severity – disease advanced at presentation
        
        Adrenergic and Renin angiotensin aldosterone systems
      - Decompensation
        
        Characterised by remodelling
        
        Myocyte hypertrophy - contractility – desensitisation - loss – replacement
        
        Ventricular wall – perfusion – papillary muscle – AV ring
    - - Heart failure --> complex clinical syndrome resulting from: Impairment of :
        
        Ventricular filling- e.g. with poor venous return, poor volume, Starling’s law
        
        Ventricular ejection e.g. of blood from the left ventricle (pump function)
      - Heart failure occurs when the heart is unable to pump blood at a rate [cardiac output] sufficient to meet the metabolic demands of the tissue
    - - NB – Pathologists often use anatomical / morphological classifications e.g.
        
        Left ventricular failure V Right Ventricular Failure
        
        Lobar pneumonia V Bronchopneumonia
        
        Small cell carcinoma V Non-small cell carcinoma
      - Clinicians often use clinical classifications e.g.
        
        Reduced Ejection Fraction failure V Preserved EF failure
        
        Community acquired V Hospital acquired pneumonia
        
        Primary lung carcinoma V Metastatic lung carcinoma
    - - Left ventricular failure (LVF)
        
        Reduced ejection fraction (EF) (systolic HF) Vs Preserved EF (diastolic HF) filling
        
        Causes of The Index Event
        
        Ischaemic heart disease - Muscle failure and therefore pump failure
        
        Hypertension - Increased pressure to pump against [remember BP = CO x PR]
        
        Aortic & Mitral valve diseases
        
        Aortic Stenosis Increased - pressure to pump against
        
        Aortic & Mitral regurgitation Increased volume to pump
        
        Mitral Stenosis - decreased filling
        
        Other Cardiac muscle diseases eg cardiomyopathy or myocarditis
        
        Arrhythmia- Rate too fast to empty ventricle at each beat or to slow [remember CO = SV x HR)
        
        Remember Heart failure can be present in High Output state
        
        “Congestion” of the pulmonary venous circulation → pulmonary oedema & dyspnoea
        
        Hypo-perfusion of systemic tissue →organ dysfunction e.g. mesenteric ischaemia or renal failure
        
        main manifestations of left heart failure
        
        Dyspnoea which may limit exercise tolerance - (pulmonary oedema - orthopnoea / nocturnal cough /paroxysmal nocturnal dyspnoea)
        
        Fatigue - Low output from left ventricle with peripheral hypoperfusion
        
        Right ventricular failure due to pulmonary venous hypertension – peripheral stasis
        
        Why does the patient have dyspnoea?Fluid retention in left heart causes pulmonary venous hypertension, which may lead to pulmonary oedema and reduced ability to aerate the lung alveoli with consequent reduced oxygenation of blood
        
        Macro & Micro Heart Findings in LVF
        
        Gross Examination of heart:
        
        Findings reflect the underlying disease process / index event (e.g. Infarction; valve abnormality)
        
        Left ventricle is often hypertrophied or dilated.
        
        Left atrium may be dilated eg mitral stenosis– risk of atrial fibrillation and thrombus.
        
        Microscopy of the heart:
        
        Fibrosis [localised] due to previous infarction
        
        Non-specific myocyte hypertrophy; diffuse fibrosis
        
        Inflammation of myocardium e.g. if the heart is failing due to viral myocarditis
        
        Pulmonary oedema & congestion produces heavy, wet lungs.
        
        Accumulation of oedema fluid in alveolar spaces
        
        Reduced air entry into alveolar spaces
        
        Reduced oxygen transfer into pulmonary capillaries
        
        Dyspnoea on exertion, later at rest
        
        Wet lungs are prone to Infection
        
        Decreased Peripheral Perfusion
        
        Kidney- Decreased renal perfusion activates renin angiotensin system with expansion of blood Volume --> Can contribute to pulmonary oedema
        
        Brain- Hypoxic encephalopathy in advanced heart failure
        
        Mesenteric or hepatic ischaemia
        
        Left Ventricular Hypertrophy and failure
        
        Initial insult causing myocardial injury.
        
        Pathologic remodelling causing left ventricular hypertrophy +/- dilatation.
        
        Compensatory adaptations initially maintain cardiac output, however ultimately result in cellular changes, fibrosis and pump failure.
        
        Reduced cardiac output causes organ hypoperfusion and pulmonary venous congestion and pulmonary oedema
        
        Pattern of hypertrophy reflects the nature of the stimulus
        
        Pressure - overload hypertrophy e.g. Hypertension / Aortic stenosis
        
        Concentric increase in wall thickness
        
        Volume - overload dilatation & hypertrophy
        
        Ventricular dilatation
        
        Wall thickness increased, normal or decreased
        
        New sarcomeres in series with existing sarcomeres
      - Right ventricular failure (RVF)
        
        Cor pulmonale / Pulmonary Hypertension
        
        PURE* Right Heart Failure – Causes
        
        Parenchymal diseases of the lung e.g. cor pulmonale [pulmonary heart disease]
        
        Diseases of pulmonary vasculature - primary pulmonary hypertension, recurrent pulmonary thromboembolism
        
        *Left Heart failure will cause secondary right heart failure when the latter is severe
        
        increased Pulmonary artery pressure [pulmonary vascular bed] - increased RV afterload – RV remodelling
        
        symptoms
        
        Peripheral pedal oedema (ankle swelling)
        
        Pleural effusions
        
        Ascites
        
        Hepatosplenomegaly
        
        Pathology Findings
        
        Right atrial dilatation
        
        Right ventricular dilatation + /- hypertrophy; AV Ring stretching – Tricuspid Incompetence
        
        Hepatic congestion & --> cirrhosis [cardiac sclerosis -->cirrhosis]
        
        Congestion around central vein --> portal vein --> etc.
        
        Pleural effusions
        
        Pericardial effusions
        
        Ascites
        
        Pedal & lower limb and subcutaneous oedema
      - Acute & chronic
        
        Acute V Chronic LVFsymptoms differ
        
        Chronic eg chronic angina- Pulmonary congestion and often mild dyspnoea and oedema
        
        Acute eg acute MI
        
        Systemic organ failure due to cardiogenic shock eg
        
        Hypoxic cerebral damage/encephalopathy
        
        Pulmonary oedema and severe breathlessness
      - Left-sided or right-sided heart failure can occur independently and failure of one side can produce strain in the other causing global heart failure
    - - Cardiac Output [CO] = HR x SV [L/min]
      - Stroke Volume [SV] = End diastolic Volume [EDV] – End systolic Volume [ESV]
        
        Factors include Preload / Afterload / Contractility
      - Ejection Fraction = SV / EDV e.g 70/120 ~ 58% [n >/= 50%]
        
        HF with reduced or preserved EF
      - HFrEF [systolic HF]
        
        Index Event
        
        reduced Contractility
        
        reduced ESV reduced SV reduced CO reduced EF
        
        increased ESV increased EDV increased Pul Cap We
      - HFpEF [diastolic HF]
        
        Index event
        
        increased LV Wall thickness
        
        reduced LV compliance – wall is stiff
        
        reduced LV Filling - reduced EDV - reduced SV
        
        But Contractility Maintained
        
        ∴ small amount of blood is emptied from chamber i.e EF preserved BUT CO is low
    - - Cardiac output dependant on: Heart rate & stroke volume
        
        Heart rate = beats per minute, Autonomic influences on sinoatrial node
        
        Stroke volume = amount of blood pumped by ventricle during each cardiac contraction and is dependant on
        
        Venous return
        
        Sympathetic activity
        
        Pumping ability of left ventricle
    - - 1) increased venous return
      - 2) increased ventricular filling (end diastolic volume) and increased preload (initial stretching of cardiac myocyte prior to contraction)
      - 3) increased force of contraction and increased stroke volume
      - More volume, better pump…up to a certain point !
      - Other ways to increase stroke volume
        
        Increase Sympathetic activity to the heart
        
        increased contractility of heart (better pump action)
        
        vasoconstriction (which increases venous return
        
        Both ↑ stroke volume
        
        Retain salt and water (RAAT- Renin Angiotensin Aldosterone System)- Expand blood volume , increases stroke volume
        
        Inotropes deployed in severe pump failure
        
        Release noradrenaline- Increases heart rate, augments myocardial contractility & vascular resistance
        
        (ANP levels are a good serum marker of heart failure in clinical practice)
        
        Vasodilatory peptide that may offset peripheral vasoconstriction
    - - Non-inflammatory causes
        
        Increased hydrostatic pressure (fluid leaves vessels)
        
        Reduced plasma [ protein ] oncotic pressure (fluid leaves vessels)
        
        Sodium & water retention
        
        Lymphatic obstruction
      - Oedema in Heart Failure
        
        Site of oedema: Transudate
        
        Left heart failure → pulmonary oedema.
        
        Right heart failure → lower extremities and ascites.
    - - Lifestyle- Salt and fluid restriction decreases intra vascular volume
      - Pharmacologic approaches:
        
        Relieve fluid overload → Diuretics
        
        Block renin-angiotensin-aldosterone axis → ACE inhibitors
        
        Lower adrenergic tone → β-blockers
      - Non-pharmacologic: - for end stage cardiac failure
        
        Non-pharmacologic: - for end stage cardiac failure
        
        Implantable defibrillator
        
        Left ventricular assist device
        
        Transplantation
- - - - Dilated [CMD]
        
        Primary
        
        Progressive cardiac hypertrophy & subsequent dilation
        
        Gradual cardiac failure
        
        Four chamber hypertrophy and dilatation, often of unknown cause
        
        Aetiology
        
        Most 2° ischaemia
        
        25% genetic
        
        Impairment of cardiac muscle force production or transmission
        
        Disturbance of myocellular Ca++ metabolism
        
        Listed CMD1A-Z followed by CMD1AA – CMD 1 NN etc
        
        Acquired
        
        Possible pathological myocardial insults:
        
        Alcohol
        
        Previous myocarditis – e.g. coxsackie-virus B
        
        Drugs – e.g. chemotherapy (eg, doxorubicin, trastuzumab)
        
        Immunologic reaction
        
        Polymorphisms in Genes know to cause Genetic Cardiomyopathy may pre-dispose to acquired disease
        
        Early: Impaired left ventricular contractility
        
        End stage: Ejection fraction of 25%
        
        normal EF: 50-75%
        
        Most common form of cardiomyopathy (90% of cases)
        
        Occurs at any age, most common age 20-60yrs
        
        Slowly developing heart failure
        
        May be sporadic or familial [genetic]
        
        Men>Women
        
        Fundamental defect is ineffective ventricle contraction and poor cardiac output
        
        50% of patients die within 2 years
        
        25% survive longer than 5 years
        
        Death due to progressive cardiac failure, or complications such as arrhythmias
        
        Heart transplantation frequently necessary
        
        Pathology
        
        Heart - heavy, flabby & large, hypocontractile (Poor pump)
        
        Dilatation of all 4 chambers
        
        Weight exceeding 900g What is normal ? average 280 to 312 g with ranges from 250 to 346 g
        
        Thinning of the ventricular wall
        
        Mural thrombi are common – risk of emboli. Why? Mural thrombi may form due to stasis of blood once chamber dilation and dysfunction are significant.
        
        Functional mitral regurgitation Why?
        
        Coronary arteries are usually not obstructed
        
        microscopic:
        
        Individual cardiac muscle cells vary in size
        
        Myocyte hypertrophy
        
        Interstitial fibrosis Do you know what this means?
        
        Scant mononuclear inflammatory infiltrate
      - Hypertrophic [CMH]
        
        Hypertrophic Obstructive (HOCM)
        
        Myocardial hypertrophy
        
        Abnormal diastolic filling
        
        Intermittent ventricular outflow obstruction: Left ventricular outflow tract obstruction (LVOTO) is a complex congenital cardiac defect that interferes with the ejection of blood from the left ventricle into the ascending aorta.
        
        In contrast to DCM, powerful hyperkinetic contractions that rapidly excel blood from ventricles
        
        But, stiff walled ventricles – diastolic filling impaired
        
        Remember SV = EDV-ESV
        
        Aetiology
        
        Familial in 50% of cases (Autosomal dominant trait)
        
        Mutations in genes encoding sarcomeric contractile proteins
        
        Prognosis varies with the genetic defect
        
        Related to inefficiency of ATP utilization
        
        Reduced ATP: Interferes with Ca++ reuptake
        
        Triggers Ca++ dependent hypertrophy & arrhythmia
        
        Genes involved in
        
        Sarcomeric contractile proteins
        
        Z-disk proteins
        
        Calcium-induced calcium release
        
        ATP generation systems
        
        Membrane & Basal lamina components e.g. Duchenne MD
        
        Mitochondrial Function
        
        25 CMH genetic Subtypes !!
        
        Clinical
        
        Angina-nMyocardial ischaemia common, without coronary artery disease – why ?
        
        Arrhythmia – ventricular
        
        Death – sudden. Athletes especially
        
        Pathology - Gross
        
        Massive myocardial hypertrophy
        
        Disproportionate ventricular septal thickening
        
        LV outflow obstruction
        
        Heart weight excess 800g
        
        Left atrium may also be dilated
        
        Extensive myocyte hypertrophy
        
        Most prominent in the left ventricle and interventricular septum
      - Restrictive
        
        Primary decrease in ventricular compliance -->
        
        Diastolic relaxation impeded
        
        Impaired LV ventricular filling during diastole
        
        LV systolic function unaffected
        
        Ventricles are of normal size
        
        Remember SV = ESV - ESV
        
        Less common than DCM, HCM
        
        Majority patients >60yrs
        
        Caused by any process that reduces myocardial compliance
        
        Non-infiltrative
        
        Familial (genetic factors less well defined)
        
        Idiopathic
        
        Infiltrative
        
        Amyloidosis
        
        Sarcoidosis
        
        Metastatic tumour
        
        Storage e.g. Haemochromatosis
        
        Radiation Fibrosis
        
        Pathology Gross & Microscopic
        
        Stiff thickened LV wall
        
        Massive L Atrial Dilatation
        
        Endo-myocardium replaced by amorphous
        
        Pink and exhibits apple-green birefringence when stained with Congo – Red and examined under polarised light to indicate presence of Amyloid
        
        Heart stained with PERL’s stain to show massive Iron accumulation in Heart – appearances of Haemochromatosis
    - - Selective right ventricular – arrythmogenic [ARVD]
      - Ventricular Fibrillation [Brugada Syndrome]
      - Metabolic
      - Long QT [Romano-Ward]
- - - - significant complications + potentially fatal;
      - easily missed; need a high index of suspicion.
    - - Rheumatic fever important in resource-poor countries;
      - IV devices often the risk factor in well resourced countries
    - - Native valve endocarditis
      - Prosthetic valve endocarditis
        
        No health care contact
        
        Nosocomial endocarditis
        
        Healthcare-related endocarditis resulting from invasive procedures
      - Endocarditis in persons who inject drugs: often right-sided (Tricuspid valve)
      - Other categorisation by
        
        Causative organism: Staphylococcal, streptococcal, fungal, etc.
        
        Onset: “subacute”, “acute” - terms are rarely used now
    - - Prosthetic valve surgery
      - IV drug use (persons who inject drugs)
      - Resource rich countries: the mean age of patients with endocarditis has increased:
      - Why? The population has aged &
        
        rheumatic fever has declined in incidence
        
        increasing use of implantable cardiac devices and heart valves
    - - Procedure
        
        Investigations of, or procedures (e.g. surgery) involving, the gastrointestinal, genitourinary or upper respiratory tracts
        
        Indwelling devices (IV lines, pacemakers)
        
        Dental, e.g. tooth extraction
        
        Tonsillectomy
        
        Other
        
        Intravenous drug use
        
        Animal exposure/pets
      - Patient factors
        
        Heart lesion
        
        Prosthetic valve
        
        Previous endocarditis
        
        Patent ductus arteriosus
        
        Aortic +/or mitral regurgitation or stenosis
        
        Chronic diseases
        
        particularly dialysis patients
        
        chronic liver disease
        
        malignancy
        
        Advanced age
        
        Corticosteroid use
        
        Poorly controlled diabetes
        
        Immunocompromised state (including HIV infection).
    - - Usually there is a defect/lesion causing turbulence in blood flow resulting in damage to the endocardial surface with platelets/fibrin aggregated on the surface
      - Bloodstream infection following dental or other procedure (large numbers of bacteria in the blood)
      - Platelets/fibrin on the surface act as a nidus for bacteria
      - Bacteria adhere to clot/aggregate & a vegetation develops: layers of platelets/fibrin, bacteria, platelets/fibrin/bacteria etc.
      - Infective, immunological & embolic complications follow
      - Valve lesion/ Bloodstream infection/ Platelets/fibrin --> Damaged Endocardium --> Vegetations -->
        
        Bloodstream infection, fevers, rigors,
        
        Emboli e.g. gangrene
        
        Tissue damage i.e. valve rupture
        
        Immune activation, vasculitis, acute glomerulonephritis
    - - Others- 4%
        
        Chlamydia, Q fever, brucella, legionella, mycoplasma, bartonella (diagnosis using serology or PCR)
        
        HACEK organisms - fastidious (require prolonged incubation (grow slowly on culture plates) ~2%
        
        Fungi 1-2%
      - No organism identified 5-10%
      - 80%
        
        Staphylococci (increasing) >40%
        
        S. aureus 25%
        
        Coagulase –ve 15%
        
        Streptococci (decreasing) <40%
        
        ‘viridans’ (oralis, mutans, mitis, bovis) 20-25%
        
        enterococci 10%
        
        other 5%
    - - HISTORY: Non-specific symptoms Malaise, fatigue, weight loss, arthralgia/ myalgia
      - EXAMINATION
        
        Fever - often low grade; chills, rigors, night sweats
        
        Heart - new or changing murmur; +/- other cardiac signs
        
        Abdomen- Splenomegaly
      - Immunological phenomena
        
        Hands + feet: Osler’s nodes (painful red raised lesions)
        
        Eyes: Roth Spots (retinal haemorrhages)
      - Unexplained embolic phenomenon
        
        Hands: splinter haemorrhages
        
        Arterial emboli (white leg), ‘stroke’, pulmonary infarcts (drug users)
    - - Occurs in a minority, 5-10% of cases
      - Associated with
        
        Persons who inject drugs
        
        Cardiac device infections,
        
        Central venous catheters,
        
        HIV & congenital heart disease
      - The tricuspid valve is often affected
      - There may be signs of sepsis, respiratory symptoms (emboli), lung abscess(es)
      - The outcome is generally good however there may be poor compliance amongst persons who inject drugs
    - - Blood cultures- Ideally three sets taken before starting antibiotics at least one hour apart
      - Echocardiography- (+other imaging) transoesophageal (TOE) if available, is superior to transthoracic (TTE)
      - Other investigations include serology (e.g. Q fever), PCR, ESR/CRP (non specific), urinalysis, FBC
      - Culture/PCR of excised valves after surgery
      - The Modified Duke criteria are predictive of IE
    - - Blood cultures- Ideally three sets taken before starting antibiotics at least one hour apart
      - Echocardiography- (+other imaging) transoesophageal (TOE) if available, is superior to transthoracic (TTE)
      - Other investigations include serology (e.g. Q fever), PCR, ESR/CRP (non specific), urinalysis, FBC
      - Culture/PCR of excised valves after surgery
      - The Modified Duke criteria are predictive of IE
      - Recent advances in imaging techniques have resulted in an improvement in identification of endocardial involvements and extracardiac complications of infective endocarditis.
        The addition of the results of these imaging modalities may improve the sensitivity of the modified Duke criteria
    - - Management - 1
        
        Unless the patient is very ill, confirm the aetiology first before starting antibiotics
        
        Liaise with clinical microbiology regarding diagnosis, optimal therapy & follow-up
        
        Combination antibiotic therapy is usually required for 4-6 weeks; shorter courses are now increasingly being considered
        
        Early consultation with a cardiac surgeon if complications (e.g. recurrent emboli) occur or if there is failure to respond to treatment: up to 40% require surgery
      - Management – 2
- - - - “Late potentials” are surface representation of areas of slow conduction in ventricular myocardium Slow conduction may be due to myocardial scar or ischemia
  - - - Calcium channelopathy
      - 5 / 10,000, more common in Asia
      - 8-10 x men vs. women
    - - Usually at night - SIDS
  - - - Premature ventricular contractions: 10 to 93 percent
      - Ventricular tachycardia: 3 to 39 percent
      - Ventricular fibrillation: 4 to 20 percent
  - - - Class Ib drugs – “fast”
        
        1b – block inactivated channels
        
        Class Ib: Lignocaine, mexiletine
        
        Mexiletine, oral treatment of ventricular arrhythmia
        
        Lidocaine
        
        Standard treatment for ventricular arrhythmias associated with AMI and cardiac surgery
        
        Acts preferentially on ischaemic myocardium
        
        Administered IV only
        
        Rapidly metabolized /Half-life = 30 mins
        
        Side effects: High plasma levels cause drowsiness, paresthesia and seizure activity
        
        Phenytoin, treatment of seizure disorders.
        
        Lignocaine (old) & lidocaine (INN) – same drug.
        
        Reduce height of AP peak, as blocking INa during the AP, but will have dissociated before the next AP.
        
        Paresthesia refers to a burning or prickling sensation that is usually felt in the hands, arms, legs, or feet.
        
        Class 1b prefer desensitized state, frequently found in ischaemic tissue
      - Class Ic drugs – “slow”
        
        1c – dissociate slowly
        
        Class Ic: Propafenone, flecainide
        
        Flecainide
        
        No effect on action potential duration
        
        Use in life threatening VT and in SVT
        
        Given orally
        
        Major SE: Proarrhythmic, given by electrophysiologist
        
        Propafenone
        
        Treatment of life threatening arrhythmias
        
        Given orally
        
        SE: Exacerbation of lung disease (COPD, asthma) due to partial beta blocking action
        
        The Cardiac Arrhythmia Suppression Trial (CAST) identified that flecainide (and by extension propafenone) increased mortality. It was abandoned.
        
        Markedly inhibits conduction through the His–Purkinje system.
        
        Overdose – extended QRS period – toxic!
      - class 1a
        
        1a – block open channels, Ia show an intermediate rate of dissociation.
        
        Class Ia: Disopyramide, quinidine, procainamide
        
        side effects:
        
        Procainamide: Given PO, IV or IM. Associated with N+V, Rash, Arthralgia, Lupus like syndrome occurs more frequently and earlier in patients who are slow acetylators of procainamide.
        
        Quinidine: administered orally, GI side effects. Cinchonism CNS S/E tinnitus, hearing loss, visual disturbances, confusion and psychosis. Antibody induced thrombocytopenia
        
        Disopyramide: Anticholinergic effects: Nausea,vomiting, dry mouth, urinary retention
        
        Procainamide – short-term use only
        
        Quinidine and similar drugs
        
        Used for atrial fibrillation
        
        Used less and less
        
        They are proarrhythmic in that they prolong the QT interval and by depressing conduction may promote reentry
        
        There are no large-scale outcome trials that demonstrate that class I agents decrease mortality
      - Target the sodium channel
      - All class 1 drugs extend the QRS period
        As sodium channel blockers, many have local anaesthetic effects
      - Use-dependent channel block is this characteristic that enables all class I drugs to block the high-frequency. Excitation of the myocardium that occurs in tachyarrhythmias, without preventing the heart from beating at normal frequencies. Class I drugs bind to channels most strongly when they are in either the open or the inactivated state, less strongly to channels in the resting state. Their action therefore shows the property of ‘use dependence’ (i.e., the more frequently the channels are activated, the greater the degree of block produced).
    - - Metoprolol, carvedilol and bisoprolol
      - Heart b1*, lungs and blood vessels b2
      - 2.3 x, 1/4.5 x, 13.5 x selective for b1
      - Act on SA and AV nodes predominantly
      - Treat SVT and ventricular arrhythmias
      - S.Es: Bronchoconstriction, heart block, heart failure
      - Prevent/reverse ventricular remodelling
      - Why are beta blockers used in the treatment of angina and heart failure?
      - Decrease heart rate and automaticity – ability to create a cardiac potential.
      - They have been shown to improve survival (MERIT-HF, CIBIS II and US-Carvedilol Trials). A careful uptitration of dosages is achievable with a low rate of side effects. The mechanism of beta-blocker effects in heart failure are cardiac protection from beta1-adrenoceptor overstimulation, antiarrhythmic effects, reduction in heart rate and positive energetic effects or a combination thereof.
      - Initial treatment can worsen the condition, with improvements being seen after a few days. Therapeutic window is small, even smaller for those with heart failure.
    - - Class III: Amiodarone, bretylium, sotalol
        
        Amioderone
        
        Amiodarone mainly effects the purkinje fibres and ventricular muscle cells
        
        After absorption distributes slowly but extensively to adipose tissue
        
        Very slow elimination that is up to 6 months
        
        Lipid soluble, extensively distributed in the body
        
        Excreted through lachrymal glands, skin and biliary tract
        
        Lung scarring main cause of toxicity (10% fatal)
        
        Amiodarone contains iodine
        
        Amiodarone also blocks sodium, calcium channels, alpha and beta receptors
        
        Dronedarone
        
        Electrophysiological effect resembles amiodarone
        
        Structural changes to reduce lipohilicity thus shorten half life and reduce accumulation in tissue
        
        Changes made to reduce risk of amioderone-associated thyroid-related and pulmonary disease
        
        Large trial 4,628 patients, dronedarone reduced the incidence of cardiovascular events or death in patients with atrial fibrillation
        
        Less toxic, no iodine. However:
        
        Dronedarone is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or New York Heart Association (NYHA) class IV heart failure. Dronedarone doubles the risk of death in these patients.
        
        “Dronedarone is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, dronedarone doubles the risk of death, stroke, and hospitalization for heart failure.
        
        Bretylium – not available in US
        
        Essentially used in ICU setting in patients who have recurrent and refractory ventricular tachyarrythmias
        
        Short-term use only – 3-5 days
        
        Hypotension main side effect
        
        “Consider only as last-resort medication”
        
        Sotalol
        
        -alol means mixed alpha and beta blocker.
        
        Non-selective beta blocker, K+ channel blocker
        
        Still considered Class 3
        
        Exerts negative inotropic effect only thru b-blocking action
        
        Used to treat ventricular arrhythmias
        
        Main SE: prolong QT interval, beta blocker SE
      - Act by slowing repolarisation (phase 3), prolonging the action potential duration
      - Rx: SVT and Ventricular arrhythmias
      - Used in life threatening cases, iv load followed by oral
      - S.Es: Thyroid disorders, photosensitivity, liver damage and pulmonary alveolitis
    - - Verapamil and Diltiazem- Non-dihydropyridines
      - Block the L subtype of Ca++ channels
      - Act on AV node (NB: Ca++ influx only)
      - Treatment of SVT (Supraventricular tachycardia) only
      - S.Es: CHF (Congestive heart failure) , interacts with beta blockers
      - Calcium Channel Blockers (Nondihydropyridine) may enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Risk C: Monitor therapy (uptodate.com)
  - - - Cardiac glycosides initially described by Withering in 1775
      - Digoxin, extracted from the foxglove plant has two main effects:
        
        It is a positive inotrope- in the failing heart the Frank-Starling ventricular function curve is shifted down and to the right. Digoxin shifts this curve up and to the lefteffect – increase force of contraction – inhibition of Na/K/ ATPase. Increase intracellular Na, leads to Na/Ca exchange and increase in intracellular Ca.
        
        It reduces the electrical activity of the heart- slows SA node firing rate, and slows conduction through the AV node
      - Used to treat HF and atrial fibrillation
      - Monitor frequently
      - Increases circulating K.
    - - By inhibiting the Na/K/ ATPase, CGs raise intracellular calcium, required for muscle contraction
      - Ca-activated proteins, e.g., troponin-C – drive muscle contraction
      - Ca is toxic to the cell – pumped out in exchange for Na.
      - Na even worse! NaK ATPase exchanges it for K - all is good.
      - Block NaK ATPase, now Na accumulates in the cell. Not good (see above!)
      - Now Na/Ca exchange works in the opposite direction – Na out, Ca in. Muscle cell fires.
- - - - COX-1 pathway: thromboxane production
        
        Aspirin- Block thromboxane signalling
        
        Mechanism of Action :
        
        Inhibits COX-1 converting arachidonic acid to TxA2
        
        Aspirin irreversibly* acetylates COX-1 at amino acid serine 529
        
        When PGH2 synthase is inhibited, TxA2 cannot be formed
        
        Platelets have reduced capacity to activate, thus preventing platelet aggregate formation
        
        *This is why aspirin works – only COXI that has this effect. Other NSAIDs if taken with aspirin will reduce these effects!
        
        Specificity of aspirin
        
        COX is a ubiquitous enzyme involved in PG synthesis in nearly every cell in the body
        
        Prostaglandins in CNS regulate vascular tone and body temp
        
        Prostaglandins in stomach regulate acid secretion
        
        Aspirin inhibits COX activity
        
        Therefore we can expect several side effects!
        
        Nausea
        
        Bleeding in the Gastrointestinal tract (GIT)
        
        However, we can avoid these side effects by regulating the mode by which we administer aspirin:
        
        Platelet life-span is 10-12 days- 10% of platelet population is replaced daily
        
        Platelets are anucleate i.e., have no nucleus- They are therefore unable to synthesise new proteins
        
        Aspirin inhibits COX irreversibly. Therefore, aspirin treatment irreversibly inhibits platelet COX for the remaining life of the platelet. However, non-platelet COX can recover within 4-8 hours as all other cells can regenerate new COX protein in this time
        
        We can achieve platelet-specific action of aspirin by pharmacokinetic manipulation
        
        Manipulating aspirin dosage to achieve platelet specificity
        
        325mg Aspirin
        
        Will inhibit all prostaglandin formation in body
        
        Most cells, except platelets, will recover within 4-8 hours by de novo synthesis of COX
        
        Repeated administration is likely to cause gastric ulceration and other side effects
        
        75mg Aspirin
        
        Will inhibit all prostaglandin synthesis by 10-20%
        
        Most cells will recover within 4-8 hours
        
        Platelets will remain inhibited for their lifespan
        
        Daily dosage will cumulatively inhibit all platelet COX but non-platelet COX will only be minimally affected
        
        Gastric ulceration (and other side effects) is less likely to occur
        
        Cyclooxygenase (COX) inhibitor - aspirin
        
        Benefit of ASA is achieved at low doses (75-100 mg daily) (25% >40 y.o., USA)- Reduced mortality by 25%
        
        Indications for use
        
        Prophylaxis for thromboembolism (prevention of TIA, MI)
        
        Prevention of ischemic events in patients with unstable angina
        
        Can be used in combined with other antiplatelet drugs (clopidogrel)
      - ADP - P2Y12 pathway: thrombin production
        
        Ubiquitous expression of P2Y1 receptors in other tissues of the body – lack of specificity, many trials ongoing
        
        P2Y12 receptors highly expressed on the platelet surface – clopidogrel (P2Y12 antagonist) - most widely used as an antithrombotic agent - recommended in many published guidelines
        
        Indications for use
        
        Secondary prevention of stroke, TIA, MI
        
        Unstable angina
        
        Percutaneous Coronary Intervention (angioplasty with stent)
        
        Coronary artery bypass surgery
        
        Mechanism of Action
        
        Clopidogrel
        
        Covalent binding to cysteine sulphydryl residues, irreversibly blocks the P2Y12 ADP receptor
        
        Effect lasts for the lifetime of the platelet (7-10 days)
        
        Blocking the P2Y12 receptor prevents the amplification of the signal that results in a larger aggregate and inhibits TxA production
        
        Clopidogrel is a prodrug which is metabolised by hepatic cytochrome P450 enzyme CYP2C19 in a 2-step oxidation process*
        
        Prasugrel
        
        Prasugrel is also a prodrug, requires single oxidation step for biological activity activated by CYP 3A5 (CYP 2B6, minor)
        
        More rapid onset of action after oral administration preferred in ACS
        
        Same MoA as clopidrogrel
        
        Achieves greater and more consistent platelet inhibition in individual patients (less inter-individual variability)
        
        Higher cost limits its widespread clinical use
        
        Higher risk of bleeding; contraindicated after stroke and TIA, >75 y.o.
        
        Ticagrelor
        
        Ticagrelor is metabolically active (not a pro-drug) does not require cytochrome P450 enzyme activation
        
        Rapidly absorbed and directly and reversibly inhibits the platelet P2Y12 receptor through allosteric modulation
        
        Short half-life of approximately 7 hours, ticagrelor requires a twice daily dosing
        
        Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker (irreversible / reversible) is indicated for acute high-risk patient with ACS and in those undergoing coronary stenting
      - PAR-1: the thrombin receptor
    - - GPIIb /IIIa receptor binds to RGD motifs on fibrinogen to cross-link platelets & promote aggregation
      - Arginine, Glycine, Aspartic Acid
      - Mechanism of action: Ligands mimic the RGD site and bind GPIIb/IIIa, preventing interaction with fibrinogen
      - GPIIb/IIIa receptor antagonists
        
        Administered in IV formulation+ Used for unstable angina and as an adjuvant to PCI with stent application + Side effects: Thrombocytopenia and increased risk of bleeding
        
        Abciximab is composed of 7E3 Fab fragments - Chimeric human / murine monoclonal antibody
        
        Tirofiban (small molecule inhibitor)- Synthetic mimetic of the RGD sequence of fibrinogen
      - Eptifibatide- a peptide mimic of the RGD sequence
        
        Longer half-life, reversible?*
        
        Administered in IV formulation
        
        Used for acute cardiac ischemic events in patients with angina, myocardial infarction
        
        Side effects: Severe bleeding, hypotension, Cardiovascular failure, arrhythmias, fibrillation. = peptide effects at several sites
      - *Eptifibatide t ½ 2.5 hours
      - Abciximab t ½ (plasma) 2 hours. However, 29 & 13% of bound remains on the receptor after 8 & 15 days.
      - Tirofiban t ½ 2 hours. Back to baseline within 8 hours.
      - Peptide, so inactive orally. Requires IV injection
    - - Thromboxane receptor antagonists
      - Serotonin/5-HT receptor antagonists
      - GPIb alpha receptor antagonists
      - Signalling molecule inhibitors (PI3 kinase)
  - - - Thrombopoietin
      - Interleukin (IL) 3 and 6
  - - - PF4 exerts its angiostatic effect via inhibition of binding of different growth factors such as FGF and VEGF to cells
      - RBCs 6-8 µm diameter, 1.5-2.5 µm thick
      - Anucleated cellular fragments/thrombocytes (not true cells)
      - Fragments of cytoplasm that are derived from the megakaryocytes
      - Discoid in shape, very small - 2-4 μm
      - Contain internal cytoskeleton including actin and myosin proteins and microtubules; essential for platelet activation and spreading
      - Contains two types of granules:
        
        Alpha granules (vWF, Fibrinogen, Factor V, PF4/CXCL4)
        
        Delta / Dense granules (ADP, Ca2+, serotonin/5-HT)
    - - Life-span ~ 10 days
      - Normal platelet count: 150,000 – 400,000/μl blood
      - Under normal healthy conditions platelets circulate as quiescent cells, survey vascular integrity
      - Undergo rapid activation upon vessel wall damage, contribute to clot formation to arrest blood loss
      - Under laminar flow environments, platelets are pushed to the periphery by larger white and red blood cells. Consequently, they remain in close proximity to the blood vessel wall where they can quickly respond to any vascular damage.
    - - Vascular System- Controls rate of blood flow
      - Platelet System- Interaction of vasculature and platelets form a temporary plug
      - Coagulation System- Clotting factors form a stable insoluble fibrin plug
      - Fibrinolytic System- Fibrin lysing
      - Dysregulation in any component can result in thrombosis/bleeding
      - Haemostasis: Primary vs. Secondary
        
        Primary haemostasis
        
        Platelet plug formation
        
        Dependent on normal platelet function and von Willebrand Factor – tethers platelets to site of injury
        
        Serves as platform for secondary haemostasis
        
        Secondary haemostasis
        
        Activation of coagulation clotting factors, resulting in thrombin generation
        
        Deposition of fibrin mesh network which traps red cells
    - - Platelets express GPCRs: initiate signal transduction pathways and function.
        
        -protease-activated receptors (PARs).Thrombin cleaves autoregulatory domain.
        
        -ADP receptors (P2Y1, P2Y12). P2Y12 is a G-protein–coupled receptor consisting of a single polypeptide chain with 7 transmembrane α-helices associated with multiple functionally different G proteins that elicit specific intracellular responses to ADP resulting in the activation
        
        Surface Glycoprotein (GP) receptors:
        
        GP VI
        
        GP Ib-IX-V complex
        
        GP IIb-IIIa complex
      - 1) Platelet adhesion at damaged vessel wall, mediated by release of vWF from endothelial cells and collagen exposure
      - 2) Platelet activation and spreading via ADP, thrombin secretion from granules - amplification
      - 3) Platelet aggregation; release of thromboxane and ADP promotes platelet recruitment and aggregation
      - 4) Thrombus formation via thrombin release, coagulation activation and fibrin mesh deposition
      - GPIIb/IIIa activation
        
        Platelet activation (by thrombin, TXA2 or collagen) causes platelet membrane activation of glycoprotein complex IIb/IIIa (open conformation)
        
        Inside-out signalling
        
        An important platelet receptor for fibrinogen
        
        Acts to cause platelet aggregation and crosslinking
    - - Within seconds of adhesion - change in shape
        
        Spherical
        
        Pseudopodia
      - Reorder of actin and tubulin polymers of cytoskeleton
        
        Dense Granules- Ca2+ / ADP / ATP / serotonin – chemical messengers that promote further platelet activation and aggregation
        
        Alpha Granules - vWF / fibrinogen / factor V / PF4
    - - Release of soluble agonists (autocrine and paracrine signalling) amplify platelet activation and recruit further circulating platelets
      - ADP: secreted from dense granules
      - binds to P2Y12 and P2Y1 on the platelet surface
      - inducing platelet TxA2 synthesis, shape change, granule release, activation of GPIIb/IIIa.
      - Thromboxane A2 is generated by the activity of thromboxane synthase on prostaglandin H2
      - Prostaglandins (PG) key cellular mediators that regulate platelet function, inflammation, muscle tone
      - Act on GPCRs on variety of tissues
      - Short half-life and synthesized in response to stimuli
        
        -Prostacyclin (PGI)
        
        -Thromboxane/TxA2 (Platelet aggregation)
        
        -Prostaglandins (D, E, F)
        
        -Leukotrienes (allergic response, bronchial smooth muscle contraction)
        
        PGI2 (prostacyclin) is released from healthy endothelial cells
        
        PGD2 is released from mast cells – inflammatory marker
        
        PGE2 has varied effects (constriction, dilation, hyperalgaesia, pyrexia, decreased acid release into stomach)
      - Platelet signalling: prostaglandin production
        
        Prostaglandins and thromboxane are produced by:
        
        Sequential oxygenation of arachidonic acid,
        
        by cyclooxygenases (COX-1 and COX-2) to produce intermediate prostaglandin H2
        
        Action of prostaglandin synthases or thromboxane synthase
        
        PGI2 or prostacyclin; released by endothelial cells, inhibits platelet activation and aggregation, promotes vasodilation
        
        PGD2 produced by mast cells with roles in inflammation
        
        PGE2 produced by smooth muscle cells macrophages and activated platelets, role vary depending on receptor
      - Platelet signalling: Thromboxane
        
        Thromboxane A2 (TxA2) is the predominant prostanoid generated in activated platelets
        
        it acts locally via its receptor to
        
        activate platelets
        
        stimulate platelet shape change
        
        release platelet granule contents
        
        promote platelet aggregation
      - Platelet structure-function: disorders
        
        Adhesive: Bernard-Soulier Syndrome – defective GPIb
        
        Amplification / secretion: Gray platelet syndrome – defective granule secretion
        
        Aggregation: Glanzmann Thrombasthenia – defective GPIIb/IIIa
        
        BSS – increased bleeding (1 in 1 million)
        
        GPS – around 60 cases reported
        
        Glanzmann – around 1 in 1 million
        
        All: bruise easily and have an increased risk of nosebleeds (epistaxis). They may also experience abnormally heavy or extended bleeding following surgery, dental work, or minor trauma. Women often have irregular, heavy periods (menometrorrhagia).
  - - - endothelial damage and/or artherosclerotic plaque rupture
      - platelet rich due to the high shear stress
      - Arterial “white thrombi”, platelet-rich
    - - form at lower shear
      - associated with stasis near valves
      - result from TF exposure and triggering the clotting cascade
      - fibrin-rich
      - Venous “red thrombi”, erythrocyte/fibrin-rich
    - - Common primary feature - systemic thromboembolism in the late stages in critically ill patients
      - DVT ̴ 58% of cases (late stage)
      - PE = direct cause of death in 33% of cases
    - - Antiplatelet drugs
      - Anticoagulants
        
        Heparins
        
        Warfarin
        
        DOACs
        
        Target specific clotting factors
      - Fibrinolytic agents
        
        Tissue-Plasminogen activator (t-PA)
        Lyse freshly-formed clots
    - - 1) Conversion from ‘quiescent’ state to active ‘haemostatic’ state
      - 2) Initial platelet tethering is mediated as von Willebrand factor, deposited in the subendothelial matrix of the damaged vessel wall, interacts with GPIbα of the GPIb-IX-V complex
      - 3) Particularly important at high shear rates supporting platelet translocation (decelerating platelets and keeping them in close contact with the endothelium) over the subendothelium, but not stable adhesion
- - - - Angina symptoms
        
        Clinical presentation
        
        Pressure-like
        
        may radiate down arm or into neck
        
        occurs with exertion and relieved by rest
        
        Retrosternal discomfort
        
        Pathophysiology
        
        Usually associated with the presence of significant obstructive coronary disease (stable disease)
        
        unstable disease associated with plaque rupture
      - Angina occurs when the oxygen supply to the myocardium is insufficient for its needs
        
        Cardiac myocytes rely on aerobic metabolism
        
        If the supply of oxygen remains below a critical value, a sequence of events leads to cell death
        
        Clinically determined by an elevations of circulating troponin (a biochemical marker of myocardial injury), and of cardiac enzymes (e.g., the cardiac isoform of creatinine kinase) and changes in the surface ECG
      - The pain has a characteristic distribution in the chest, arm and neck, and is brought on by exertion, cold or excitement.
      - Three kinds of angina are recognised clinically:
        
        Stable - no change in symptoms over previous weeks
        
        Predictable chest pain on exertion
        
        Caused by an increased demand on the heart
        
        usually caused by fixed narrowing(s) of the coronary arteries by atheroma, Narrowing of the aortic valve (‘aortic stenosis’) can also cause angina by reducing coronary blood flow even in the absence of coronary artery narrowing.
        
        Symptomatic therapy is directed at reducing cardiac work with
        
        organic nitrates
        
        β-adrenoceptor antagonists
        
        and/or calcium antagonists
        
        together with treatment of the underlying atheromatous disease, usually including a statin, and prophylaxis against thrombosis with an antiplatelet drug, such as aspirin
        
        Unstable - abrupt pattern change typically at rest
        
        This is characterised by pain that occurs with less and less exertion, culminating in pain at rest.
        
        The pathology is similar to that involved in myocardial infarction, namely platelet–fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel.
        
        Treatment is similar to that for myocardial infarction and includes imaging and consideration of revascularisation procedures.
        
        Antiplatelet drugs (aspirin and/or an ADP antagonist such as clopidogrel or prasugrel) reduce the risk of myocardial infarction in this setting,
        
        and antithrombotic drugs add to this benefit at the cost of increased risk of haemorrhage.
        
        Organic nitrates (see later) are used to relieve ischaemic pain.
        
        and variant - usually stress related, patients develop coronary spasm
        
        This is relatively uncommon. It can occur at rest and is caused by coronary artery spasm, often in association with atheromatous disease.
        
        Therapy is with coronary artery vasodilators
        
        (e.g., organic nitrates, calcium antagonists)
      - Arterial Endothelial Function: Role of Renin Angiotensin System (RAS)
        
        In a stressed heart, the renin-angiotensin system is activated due to reduced tissue perfusion.
        
        Angiotensin I is converted by Angiotensin Converting Enzyme (ACE) to Angiotensin II expressed on the surface of the endothelium. ACE also inactivates bradykinin- an inducer of pain
        
        Ang II causes vasoconstriction (increased afterload) and releases aldosterone, which causes Na+ and water retention (congestion/oedema).
        
        Ang II causes increased release of noradrenaline
        
        Ang II effect mediated via the AT1 receptor
    - - Myocardial oxygen supply
        
        Coronary blood flow
        
        Oxygen content
      - Coronary circulation has a very high basal oxygen consumption
      - Also has a very high oxygen extraction rate, therefore increased demand must be met by increased flow
      - Most of the oxygen demand must be met in diastole
    - - Synthesis and actions of nitric oxide in Endothelial cells
        
        NO has a wide range of biological functions that contributes to the regulation of vascular homeostasis
        
        modulation of vascular dilator tone
        
        regulation of local cell growth
        
        protection of the vessel from injurious consequences of platelets activation
        
        Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive enzyme nitric oxide synthase (NOS).
      - Arterial Endothelial Function: Role of Nitric Oxide (NO)
        
        Mitochondrial aldehyde dehydrogenase (ALDH2)
        
        NO activates guanylyl cyclase
        
        cGMP enables smooth muscle relaxation and vasodilation
        
        Reduced NO leads to:
        
        Enhanced expression of chemo-attractants
        
        Enhanced expression of cell adhesion proteins on endothelial cells-enabling monocyte adhesion
        
        Enhanced oxidation of LDL
        
        Enhanced Platelet activation
        
        Hypertension, hypercholesterolemia, smoking, diabetes mellitus and heart failure are associated with diminished local synthesis of nitric oxide
      - Organic Nitrates for treatment of Angina
        
        Nitroglycerin, used for over 150 years, is a potent vasodilator in the treatment of angina pectoris and chronic heart failure, and, in its extended release forms, it still remains first-line drug therapy for many patients.
        
        Organic nitrates are metabolised with release of NO
        
        Most of the antiischemic efficacy of nitrates pertains to their ability to decrease myocardial oxygen demand as a result of systemic vasodilatation rather than any activity as a coronary vasodilator
        
        Nitrates do not have a direct effect on cardiac chronotropy or inotropy.
        
        Nitrates also have significant antiplatelet and antithrombotic properties
        
        Tolerance to nitrates
        
        Repeated administration of nitrates to smooth muscle preparations in vitro can result in tolerance
        
        This leads to a diminished vascular relaxation in response to each dose
        
        It is usual to require a nitrate free period of 10-12 hours in each 24 hours
        
        Tolerance to the anti-anginal effect of nitrates does not occur to a clinically important extent with ordinary formulations of short-acting drugs (e.g. glyceryl trinitrate)
        
        but tolerance does occur with longer-acting drugs (e.g. isosorbide mononitrate)
        
        or when glyceryl trinitrate is administered by prolonged intravenous infusion or by frequent application of slow-release transdermal patches
        
        It is usual to require a nitrate free period of 10-12 hours in each 24 hours
        
        Side effects of nitrates
        
        Include: postural hypotension* and a throbbing headache
        
        Transient episodes of hypotension - may be exacerbated by alcohol
        
        Excessive use can also result in the formation of methaemoglobin**, an oxidation product of haemoglobin that is ineffective as an oxygen carrier
        
        Danger of additive effect with PDE 5 Inhibitors e.g., sildenafil
        
        Clinical uses
        
        Myocardial infarction
        
        Heart failure
        
        Hypertensive crises
        
        Stable angina
        
        Unstable angina
        
        Postural Hypotension is a failure of the a vasoconstricting reflex to occur when a person changes from lying to sitting, or sitting to standing. As a result blood pools in dilated blood vessels and the patient may faint.
        *Formation of methhaemoglobin seldom occurs when nitrates are used clinically but is induced deliberately with amyl nitrite in the treatment of cyanide poisoning , because methaemoglobin binds and inactivates cyanide ions.
      - Methods of administration of nitrates
        
        Sublingual (tablets and spray) – first line of therapy
        
        Nitroglycerin (glyceryl trinitrate, GTN), metabolised in liver
        
        Peak concentration in 4 mins, half-life of 40 mins
        
        Isosorbide dinitrate – 2-5 minutes
        
        Oral
        
        Isosorbide dinitrate, peak 6 minutes
        
        Half life 2-5 hrs. (mononitrate longer half life*)
        
        Cutaneous- Transdermal patch (GTN)
        
        Intravenous
        
        *Isosorbide mononitrate also available in oral form
        
        Extended release – up to 24 hours
        
        GTN, dinitrate available for IV
        
        Nitrates, usually in the form of a sublingual preparation, are the first-line therapy for the treatment of acute anginal symptoms. Patients should be instructed to use them at the onset of angina or for prophylaxis of anginal episodes
    - - Angina is managed by using drugs that improve perfusion of the myocardium or reduce its metabolic demand, or both
      - The main anti-anginal drugs are vasodilators and produce both these effects
        
        calcium antagonists
        
        Calcium antagonists (CAs) reduce angina by inhibiting inward calcium currents through the cell membrane in many tissues, including the myocardium, cardiac conduction tissues, and vascular smooth muscle cells in both coronary arteries and peripheral vessels. They are also called Calcium Channel Blockers Intracellular calcium deprivation relaxes smooth muscle cells, causing vasodilation in the peripheral and coronary beds and increased coronary blood flow.
        
        Therapeutically important calcium antagonists act on L-type channels.
        
        L-type calcium antagonists comprise three chemically distinct classes:
        
        dihydropyridines (e.g., nifedipine, amlodipine)
        
        Properties: Peripheral and coronary vasodilators, negative inotropic action
        
        Drugs: Amlodipine, nifedipine, felodipine, isradipine, nicardipine, nisoldipine
        
        Nifedipine, slow release
        
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        Amlodipine
        
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        Felodipine, sustained rel
        
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        Isradipine, sustained rel
        
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        Nicardipine
        
        Duration of action: Short
        
        Usual dose: 20-40mg (3 times a day)
        
        Common side effects: Headache, oedema, dizziness, flushing
        
        Non-dihydropyridines (non-DHPs)
        
        benzothiazepines (e.g., diltiazem)
        
        Properties: Additional negative chronotropic and inotropic actions
        
        Diltiazem, slow release
        
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        Diltiazem, immediate release
        
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        Verapamil, immediate release
        
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        Verapamil, slow release
        
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        phenylalkylamines (e.g., verapamil)
        
        Properties: Additional negative chronotropic and inotropic actions
        
        Most dihydropyridines (e.g., nifedipine) cause dilatation of smooth muscle
        
        Verapamil preferentially affects the heart
        
        Diltiazem is intermediate in its actions
        
        In the heart they cause a decrease in contractility
        
        They can favourably alter the ratio of supply and demand in chronic stable angina
        
        Verapamil and diltiazem, slow sinoatrial (SA) and atrioventricular (AV) nodal conductions to reduce heart rate and depress contractility under physiological conditions.
        
        In the periphery they cause relaxation of vascular smooth muscle. They reduce arteriolar pressure (afterload)
        
        Calcium channel blockers
        
        These drugs lower the frequency of angina, lower the need for nitrates, increase treadmill walking time, and improve ischaemic ST-segment changes on exercise testing and electrocardiographic monitoring.
        
        Calcium antagonists have been shown to be equally effective as beta-blockers in the management of stable angina.
        
        ESC guidelines on stable coronary artery disease for the management of stable angina consider either a beta-blocker or a CA as appropriate first-line treatment.
        
        Dihydropyridines (DHPs) lower BP and myocardial wall tension to reduce myocardial oxygen consumption.
        
        A rise in coronary blood flow further contributes to correcting myocardial oxygen imbalance.
        
        All calcium channel blockers can be used
        
        Most common: longer-acting forms of diltiazem and verapamil, amlodipine, or felodipine.
        
        Good oral absorption Many have low bioavailability due to hepatic first-pass metabolism, primarily by CYP3A4.
        
        Calcium blockers should be tried in patients who cannot tolerate beta-blockers.
        
        Side effects
        
        Headache
        
        Dizziness
        
        Flushing
        
        Hypotension
        
        Peripheral oedema/ankle swelling
        
        Bradycardia
        
        Constipation
        
        Precipitate heart failure
        
        Drugs Interactions
        
        Other negative chronotropic or inotropic agents to produce bradycardia, heart block, or HF has been reported.
        
        Some statins (atorvastatin and simvastatin), macrolide antibiotics, cimetidine and grapefruit juice may raise the effective level of Cas
        
        ACE Inhibitors
        
        Angiotensin Receptor Blockers: Mechanism of Action
        
        Angiotensin II is a potent vasoconstrictor.
        
        Mediates its affect by binding to AT1 receptors to cause:
        
        Vasoconstriction, especially marked in efferent arterioles of the renal glomeruli
        
        Increased noradrenaline release, reinforcing sympathetic effects
        
        Proximal tubular reabsorption of Na+
        
        Secretion of aldosterone from the adrenal cortex
        
        2 types of Drugs affect Angiotensin:
        
        ACE Inhibitors
        
        Angiotensin-converting enzyme inhibitors (ACEi’s) lower total peripheral resistance by blocking the actions of ACE, the enzyme that converts angiotensin I to angiotensin II
        
        There are three subclasses of ACE inhibitors:
        
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        Block the formation of angiotensin II
        
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        Patients with stable angina pectoris who have diabetes, hypertension, proteinuria, or chronic renal disease or those with impaired left ventricular systolic function (left ventricular ejection fraction <40%) and all post-MI patients should also be treated with an ACE inhibitor
        
        Angiotensin Receptor Antagonists
        
        Block the activation of angiotensin II at AT1 receptors in smooth muscle cells of blood vessels, cortical cells of the adrenal gland, and adrenergic nerve synapses.
        
        Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone*, among other actions. The combined effect reduces blood pressure.
        
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        Losartan, Valsartan, Candesartan
        
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        Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have known benefits for a subset of patients with hypertension, diabetes mellitus, decreased left ventricular ejection fraction (less than 40 percent), or chronic kidney disease
        
        All patients with stable vascular disease are likely to derive some benefit from these drugs, to a degree approximately proportional to the level of baseline risk.
        
        Can either block formation (ACE inhibitors) or actions (AT2 R1 antagonists)
        
        Renin-Angiotensin System (RAS)
        
        ACE converts Ang I into Ang II the active vasoconstrictor
        
        ACE 2 enzyme – trans membrane enzyme found in lung epithelium, endothelium, heart, GI tract- converts Ang II into Ang 1-7
        
        Ang 1-7 is vasodilator, raises NO, it is a counter balance to Ang II
        
        COVID virus attaches to ACE 2 and reduces its function
        
        organic nitrates and
      - Another group of anti-anginal drugs slow the heart and hence reduce metabolic demand - β-adrenoceptor antagonists
    - - Sympathetic activity, acting through β 1 adrenoceptors, increases heart rate (+ Chronotropic effect), contractility (+Inotropic effect) and automaticity but reduces cardiac efficiency (in relation to oxygen consumption).
      - The β 1 adrenoceptors act by increasing cAMP formation, which increases Ca 2+ currents.
      - β-Adrenoceptor antagonists (beta blockers), slow the heart rate & decrease the force of contraction
      - They therefore reduce the oxygen demand of the heart and reduce the frequency of angina attacks
      - Current guidelines recommend beta blockers as first-line treatment in patients with angina either on their own or in combination with a calcium channel blocker
      - ACEIs and ARBs also reduce cardiac work and improve survival, as does opening the coronary artery (with angioplasty or thrombolytic drug) and antiplatelet treatment.
        Automaticity is the property of cardiac cells to generate spontaneous action potentials
      - β-Adrenoceptor antagonists (Beta-blockers)
        
        Adrenoceptor antagonists are the cornerstone of therapy in chronic stable angina.
        
        They block the action of adrenaline/noradrenaline on the beta- adrenergic receptors
        
        They are important in prophylaxis of stable angina, and in treating patients with unstable angina, acting by reducing cardiac oxygen consumption
        
        They reduce the myocardial oxygen demand by:
        
        Reducing the HR (chronotropic effect)
        
        Decrease contractility (inotropic effect)
        
        Decrease the blood pressure (afterload)
        
        They reduce mortality and re-infarction in post-myocardial infarction patients
        
        Since beta blockers reduce the heart rate-blood pressure product during exercise, the onset of angina or the ischemic threshold during exercise is delayed or avoided.
        In patients who cannot tolerate a beta blocker, alternative initial therapies include calcium channel blockers or long-acting nitrates.
        
        These drugs act on the heart, not the vasculature. Any effects on coronary vessel diameter are of minor importance
        
        Cardioselectivity refers to selectivity at beta-1 site and is “dose-dependent”. Most beta-blockers in clinical use are “cardioselective”*, however:
        
        Metoprolol 2.3-fold selectivity for β1 over β2
        
        Atenolol 4.7-fold selectivity for β1 over β2
        
        Carvedilol is a non-selective beta blocker that has vasodilating properties as a result of selective alpha-1 antagonism
        
        β-Adrenoceptor antagonists are avoided in variant angina because of the theoretical risk that they will increase coronary spasm
        
        Side effects
        
        Bronchoconstriction: block beta-2 mediated smooth muscle relaxation in the bronchi. Thus relatively contra-indicated in reversible airways disease e.g., asthma
        
        Mask symptoms of hypogylcaemia Hypoglycaemia: beta blockers inhibit adrenaline-induced glucose synthesis in liver
        
        May precipitate heart failure
        
        Bradycardia
        
        Exacerbate peripheral vascular disease
        
        Somnolence, depression
        
        Impotence
        
        Adversely alter lipid profile
        
        Clinical uses
        
        Angina- stable and unstable
        
        Heart Failure, arrhythmias
        
        Myocardial infarction
  - - - Diltiazem, teratogenic in animals, use if needed
      - Nifedipine – OK
      - Dihydropyridines – OK