Cardiovascular Disease Flashcards
What are risk factors of CVD?
Risk factors in CVD
* hypertension
* Smoking
* Alcohol misuse
* Unhealthy diet
* Physical inactivity
* Psychosocial factors
* Aging
* Gender
* Race/ ethnicity
* Genetic predisposition
* Obesity
* Diabetes
* Dyslipdaemia
What is atherosclerosis?
• Major underlying cause of CVD
• Build up of fatty material in arterial walls causing narrowing and stiffening
• Peripheral arteries
• Coronary arteries
• Cerebral atherosclerosis
• Restricted blood flow
-In heart= angina
-limb ischaemia
-stroke
What is a myocardial infarction?
Plaque rupture or blood clot occludes one or more arteries supplying the myocardium
Deprives regions of o2 and nutrients
Reduced activate area of contacting tissue during systole
What happens during circulatory collapse? How can circulation be maintained
Decreased contraction causes fall in BP and cardiac output. Immediate cardiopulmonary resuscitation (CPR) helps maintain circulation.
What are reperusion strategies?
• Clot busting drugs- thrombolytics break down fibrin
• Angioplasty- balloon catheter to restore blood flow to blocked artery
• Coronary artery bypass graft - take blood vessel from somewhere else in body usually leg and attach to heat- so bypass the heart
What are the acute effects of MI
Myocardial necrosis downstream of blockage- the cells begin to die - the longer a ligature is attached from more cellls have died
What is the immediate inflammatory response in infarct?
Pro-inflammatory response to clear necrotic cells
Release of cytokines triggers accumulation of neutrophils monocytes, macrophages
What happen during scar formation?
Reduction in pro-inflammatory signals transitions to a reparative phase
Fibroblasts differentiate into myofibroblasts speculating in producing large amounts of extra cellular matrix
Scar tissue non contractile and stiff
What’s the equations for wall stress?
Pressure X radius divided by 2 x wall thickness
What are the immediate effects of MI on the heart?
- Tissue hypoxia
Reduced rhythmic contraction
Reduced bp
Reduced cardiac output
Tissue necrosis
Inflammation in infarct region
What are the chronic effects of MI on the heart?
Widespread inflammation
Increased fibrosis
Increase ventricle stiffness
Increase hypertrophy
Increase ventricle dilation
Decrease systolic pressure
Deceased cardiac output Tissue necrosis
What is systemic hypertension?
A leading cause of CVD
Constriction of vascular smooth muscle cells
Increase cardiac output and systemic vascular resistance
How do you calculate mean arterial pressure?
Cardiac output X total peripheral resistance (TPR)
Does adding sacromeres in Paralell or series increase force generation?
In parallel
What are the hypertrophic signalling pathways?
Neuohumoral activation - insulin like growth factor-1 (IGF-1) AKt/ mTOR
Associated with physiological hypertrophy in response to exercise
Advantages and disadvantages of ECG
Advantages:
• information on electrical properties, conduction
• Low cost
• Simple
• Non-invasive- just electrodes
Limitations
• no info on contractile function or by
• Requires specialist to interpret
Advantages and disadvantages of BP monitor
Advantages
• info on systolic/ diastolic by
• Low cost
• Simple and easy to interpret
• Non invasive
Limitations
• dependent on vascular function
• Limited to systemic circulation- not pulmonary/RV function, atria - limbs
• No Ino on diastolic pressure in the heart
Ultrasound advantages and Disadavantages
Ultrasound
Advantages
• 2D/3D quantification of heart structure and contraction (stroke volume, ejection fraction, hypertrophy
• Indirect systolic pressure measurement using Doppler
• Moderate cost
• Also assess vascular function
• Fast
Disadavantages
• contraction measurements dependent on preload (ventricular filling) and afterload (vascular resistance
• No information on diastolic pressures or other phases of cardiac cycle
• Limited spatial resolution
• Image quality can be limiting- e.g obesity
Cardiac MRI advantages and disadvantages
Cardiac MRI
Advantages
* detailed 3D quantification of structure contraction and blood flow in all chambers
* Contrast techniques to measure fibrosis
Limitations
* dependent on preload (ventricular filling) and afterload (vascular resistance)
* No direct pressure measurment
* Expensive - 3k per scan
* Slow 1-2H - not real time
Pressure volume catheterisation advantages and disadvantages
Advantages
• direct systolic and diastolic pressures in all heart chambers and vessels
• Accurate volumes
• Real time throughout entire cardiac cycle Limited spatial
• Load independence measurement of heart function
Limitations
* invasive
* No info on heart structure
* No info on heart structure electrical function
What does an increase in slope of ESPV indicate?
Increased contractility- indicates how easily the hear expands as it fills
Steeper ESPVR indicates resistant to filing
What are the passive determinants of relaxation?
Fibrosis, microtubules and titin
What is fibrosis?
Fibrosis
* Interstital collagen normally present at low amounts (2-4%) in myocardium
* Mostly type 1 and 111 fibrillar collagen - structured
* Increased collagen deposition by myofibroblasts
* Diffuse or localised fibrosis impairs diastolic function
* Fibres covalently cross linked by glycosylation increases stiffness
Describe microtubules
Microtubules
-cytoskeleton proteins formed by polymerisation of alpha and beta Tubulin
Dynamic structures that assemble and disassemble in minutes/ hours
Stability influenced by pot-translational modification, such as detyrosination of alpha tubulin
Describe titin
Titin
* largest known protein (3.5MDa) spans rom Z-disk to M-line of sarcomere- 1um
* Bidirectional spring- resits strength, restores length during shortening
* Two isoforms N2B and N2BA (more compliant)
* Many post-translational modifications (Phosphorylation, oxidation splice variants) after compliance
What happens during the beta adrenergic signaling cascade?
Noradrenaline and adrenaline bind to g-protein coupled beta1AR in sarcolemma
• Initiates singalling cascade leading to prodcution of cAMP by adenylyl cyclase
• CAMP activates protein kinase A (PKA) (serine specific kinases)
• Phosphate group reversible added to serine residues on target proteins modifying their function
What happens during beta1- adrenoreceptor desensitisation?
Beta1-adrenoceptor desensitisation
• heart becomes reliant on catecholamines to maintain heart function e.g following MI
• B1-AR itself becomes phosphorylated and signals it for internalisation and degradation (negative feedback)
Reduced expression of proteins in the B1-AR singalling pathway in heart failure Increases
Chronic receptor activation leads to desensitisation and reduced B-adrenergic responsiveness
Less able to increase heart rate, contraction, relaxation
What are the active determinants of relaxation?
Cystolic calcium
Myofilaments
Repolarisation
What happens during excitation contraction coupling in the hear
• action potential initiates calcium release from Intracellular store (sarcoplasmic reticulum)
• Binding to myofilaments initiates contraction
• Calcium pumped back into SR and dissociates from myofilaments
What is SERCA activity determined by?
SERCA Expression
Phospholamban expression
PLB phosphorylation
What is the major calcium removal pathway in humans?
Ca repuptake in SR
What happens to ca uptake in heart failure
Slower calcium uptake
As reduced SERCA activity
Calcium handling worsens at faster rates e.g exercise
Deceased SERCA expression in en stage heart failure
How is calcium pump regulated?
Phospholamban;a ban acts as a brake on sarco(endo)plasmic reticulum ca ATPase (SERCA), PHOHSPHORYLATION of PLB relieves SERCA inhibitions and speeds calcium uptake
What happens to phospholamban in heart failure?
No change in PLB expression
Hypophosphoylation of PLB in heart failure
What does PLB hypophosphorylation do?
• reduces Ionotrophic (contraction) and lusitropic (relaxation) response
• Mutant non-phosphorylatable PLB diminished response to beta- AR stimulation
How can family screening be used for CVD?
Families may have a history of sudden death, can then identify a pathological gene variant in the patient, and do genetic screening of family member that turn up asymptomatic but are carriers of the mutant alleles
What are cardiomyopathies?
They broadly affect the structure and function of muscle cells or structure of the myocardium
What is hypertrophic cardiomyopathy?
Is thickening o the heart
What can hypertrophy be mistaken for on ECG?
Athletes heart
What are thw two genes essential for cross bridging that has predominantly autosomal dominant mutations in causing hypertrophic cardiomyopathy?
MYH7
MYBPC3
What type of mutuation usually occurs in MYH7?
Missense single nucleotide polymorphisms
What type of mutation occurs in MYBPC3?
Nonsense, resulting in premature stop codon and truncated protein
Where do MYH7 mutation occur? What effects does it have on cross-bridge cycling?
In head and neck region of B-MHC with ATPase and motor activity.
Lead to increased/ deceased myosin ATPase activity
Altered Ca2+ binding/ release from TnC
What does HCM cause and lead to?
HCM usually causes hypercontractile cellular phenotype, leading to increased interactive between actin and myosin proteins
Increased force development, but slower relaxation
Increased myofilaments Ca2+ sensitivity
What causes the symptoms of dyspnea and heart failure?
Septal hypertrophy obstructs the LV outflow tract so reduced cardiac output
What is the septal myomectomy technique?
Removing a Chunk of the septum so allows blood flow
What are the current treatments of cardiomyopathy?
Current treatments include
beta-blockers or Na channel inhibitor to slow heart rate and make it less
excitable
implantable cardioverter defibrillator (ICD)
Septal myectomy for obstructive HCM
New myofilament desensitising drugs (e.g. Mavacamten) provide
symptomatic relief
reduce myofilament Ca2+ sensitivity
Lifestyle interventions may help reduce arrhythmias
What are channelopathies?
They occur due to mutations in ion channels that regulate the electrical properties of the heart
What is long QT syndome and what are symptoms?
Prolonged QT interval caused by delayed Repolarisation of the ventricle- develop anting, palpitations and sudden cardiac arrest
What are the major genes encoding ion channels that are responsible for over 90% of LTQS
KCNQ1
KCNH2
SCN5A
What does longer action potential increase the likelihood of? What does this trigger?
Early afterdepolarisations - can trigger premature ectopic beats and disrupt normal electrical conduction through the heart
Rapid uncoordinated contraction causes cardiac output to fall
What are the treatments and lifestyle alive to treat QT syndrome?
Treatments include
beta-blockers
Late sodium current blockers
implantable cardioverter defibrillator
left cardiac sympathetic denervation
Lifestyle advice
Avoiding strenuous swimming LQT1
Avoiding loud noises LQT2
Correcting electrolyte imbalance (e.g.
increasing potassium intake bananas,
vegetables, pulses)
What can cause acquired LQTS?
Result of drugs e.g antibiotics, antihistamines, antidepressants anti-arrhythmics
Ikr very susceptible to inhibition by different drugs
Ikr block is specifically screened for during new drug development
What can people with CPVT experience?
Severe arrhythmias during physical or emotional stress bought on by adrenaline
What are the majority of cases of CPVT caused by? How does it work?
SNPs causing missense mutations in RYR2 gene. RYR2 is a Ca2+ channel located inside muscle cells in the membrane of Intracellular Ca2+ store. During systole, RYR2 channels open allows Ca2+ to pass into cytosol for muscle contraction
RYR2 normally remain closed in diastole- CPVT cases RYR2 to become leaky
What are the symptoms of CPVT?
Not present at rest but usually provoked by stress, emotional and physical activity
Adrenaline increases Ca2+ loading in hear and overload Ca2+ store - when threshold in exceeded the store empties resulting in Ca2+ waves - Leaky RYR2 have a lower threshold
Treatment of CPVT?
beta-blockers to suppress adrenergic stimulation
flecainide (Na channel inhibitor that may also inhibit
RYR2)
left cardiac sympathetic denervation
implantable cardioverter defibrillator
