Cardiac Pharmacology Flashcards
(14 cards)
Physiological hypertrophy
- caused by pregnancy or exercise
- eccentric growth
- increased cardiac function
- increase in myocyte length is greater than increase in width
Pathological hypertrophy
- in hypertension or aortic stenosis
- increase in myocyte width is greater than increase in length
- re-expression of fetal stress genes (ANF)
- increased arrhythmias
Hypertrophy
- hypertrophy = reduced chamber volume and thickened muscle wall
- dilated heart = larger chambers, myocytes grow in length, harder to pump (Laplace)
- arrhythmias = additional pacemakers develop which aren’t in rhythm with the SAN
- specific SNPs increase the risk of arrhythmias
Cardiac adaptation
cardiac function acutely modulated to meet the needs of the organism
heart adapts over time
- heart size increases through the lifetime to increase CO
- but has no increase in proliferation
myocytes are terminally differentiated and cease to proliferate soon after birth
- cut the apex of a 1-day-old mouse = fibroblasts invade
- cut the apex of a 7-day-old mouse = fibroblasts invade and remain (fibrosis)
- can we recapitulate the neonatal regenerative properties in the adult heart?
Hypertrophic growth
- differential changes in gene expression between pathological and physiological hypertrophy
- re-expression of fetal stress genes ANF and alpha-MHC = attempt of heart to promote natriuresis and reduce stress on heart in pathological hypertrophy
Asymmetric septal hypertrophy
asymmetric septal hypertrophy with obstruction
- asymmetric septum prevents valves working
- mitral valve presses against septum, causing obstruction
- systolic anterior motion of mitral valve
can also have asymmetrical septal hypertrophy without obstruction if mitral valve is in the correct position
Aging
- aging is the greatest risk factor for cardiac pathologies
- age-related differences in expression of proto-oncogenes and contractile protein genes in response to pressure overload in rats
- older rats are less able to adapt to aortic constriction by e.g. increased calcium ATPase activity
- aging population with increased obesity = increased cardiovascular disease
Role of calcium in disease
phenotype = reduced contractility and increased arrhythmia
causes:
- modification of calcium transient
- defect in EC coupling
- increased SR calcium leak/elevated diastolic calcium = increased NCX activity = DAD and APs
- altered contractile apparatus
- alterations in SR function in cardiac remodelling
- SERCA expression negatively correlated with severity of disase
- ANF expression correlated with hypertrophy
- as hypertrophy progresses to failure, calcium cycling at the level of the SR store deteriorates
Evidence of calcium defects in disease
- pacing model of chronic left ventricular dysfunction in degeneration induced by tachypacing of right ventricle
- myocyte size increases
- calcium reduced in hypertrophy and heart failure
Caffeine
- sensitises RyR to calcium
- stimulates opening
- calcium leaves
- not taken up by SERCA
- extruded by NCS
- indication of increased calcium in normal over hypertrophic heart
- NCX current reduced in disease
- shows SR store reduced in disase
Calcium and heart failure
- calcium sparks reduced in amplitude and increased in frequency in heart disease
- SR calcium load reduced in heart failure
- shown by low affinity calcium indicator loaded into SR
- calcium store and rate of refilling in heart failure
- luminal calcium depleted in disease
- RyR sensitivity increased in heart failure
RyR defects in disease
- RyRs hyperphosphorylated
- hypersensitive in heart failure
- PKA increases activity of RyR
- chronic SNS activation in early stages of heart failure
- RyR function regulated by CaMKII over PKA
- CaMKII = phosphorylates RyR at S2814
- enhances spontaneous events
- calcium spark, leak and arrhythmias
- CaMKII activity enhanced in disease
- phosphorylates phospholamban
RyR dysregulation
- contributes to arrhythmias
- increases spontaneous release
- on a background of reduced SERCA/calcium clearance, diastolic calcium increases
- spark coupling increased to produce a calcium wave through propagation
- increased diastolic calcium via leaky RyRs
- NCX electrogenic and increased in HF
- increased store loading not required in HF due to altered RyRs
RyR mutations and arrhythmia
- RyR2 mutations underlie arrhythmia generation
- catecholamine stress causes catecholamine polyventricular tachycardia
- patients diagnosed in teenage years and often post-mortem
- RyR2 mutations increase spontaneous calcium release
- increased calcium entry and increased SERCA = overloading SR
- calcium release in stress = death due to calcium spillovers = arrhythmia
