Study of disease- brief Flashcards
(55 cards)
Headings pneumonic (list)
CCHIVCAHOHTMD
Headings (list)
Introduction
Choice of topics
CPVT and heart failure (calcium/ pacemaking)
HCN mutations and sick sinus syndrome (pacemaking)
Inherited arrhythmia syndromes- SCD
Ventricular arrhythmias- SCD
Chuvash polycythaemia and HIF system (altitude)
AMS (altitude)
HACE (altitude)
Oedema formation in HACE (altitude)
HAPE (altitude)
Treatment of HAPE (altitude)
Monge’s disease/ CMS (altitude)
Difficulties in research and future (altitude)
Conclusion
Introduction subheadings (list)
Argument
Inferences are not straightforward
(Intro) Argument
● Studying disease is a common way to elucidate normal biological function, especially when experimentation in healthy organisms would be unfeasible or unethical.
● This may occur through identifying underlying genetic causes, observing functional losses or insights derived from drug therapies.
(Intro) Inferences are not straightforward
● Inferences of function are not as straightforward in certain diseases such as:
● Chronic heart failure, where RyR2 channels are modulated by intracellular kinases like PKA, making it challenging to distinguish whether pathological phenotypes result from altered phosphorylation, disease progression itself, or compensatory mechanisms.
Choice of topics subheadings (list)
Cardiovascular disease is a systemic stress test of physiology
Altitude physiology as a natural stress model
Bidirectional insights
(Topics) Cardiovascular disease is a systemic stress test of physiology
● Cardiovascular disease helps pinpoint what precise molecular interactions and feedback systems are essential for maintaining cardiac function, often before technology can detect them in healthy systems.
● The cardiovascular system integrates hemodynamics, electrophysiology, metabolism, and endocrine signaling, so its failure often reveals the importance of homeostatic mechanisms that are otherwise invisible in health.
(Topics) Altitude physiology as a natural stress model
● Altitude reveals the boundaries of adaptive physiology, and disease states help define when beneficial responses become harmful, sharpening our understanding of human limits
● Altitude represents a controlled environmental perturbation- mainly hypoxia- that allows researchers to probe how the body compensates via ventilation, hematopoiesis, and vascular remodeling.
(Topics) Bidirectional insights
● In both topics, studying disease states doesn’t just illuminate pathology- it feeds back into normal physiology:
● Heart failure and CPVT have taught us about normal calcium cycling and the role of sympathetic activation.
CPVT and heart failure (calcium/ pacemaking) subheadings (list)
Mutations to RYRs apparatus including calsequestrin and triadin
Jiang 2004
RyR2 mutations and flecainide
Hilliard 2010 and flecainide
Shan 2010 and ryanodine receptor in chronic heart failure
(CPVT and HF) Mutations to RYRs apparatus including calsequestrin and triadin
● CPTV is an inherited condition that causes cardiac arrhythmias.
● The disease is caused by a variety of different mutations in the ryanodine receptor apparatus, including calsequestrin and triadin.
(CPVT and HF) Jiang 2004
● Jiang et al in 2004 showed that these RyR2 mutations were gain of function.
● The authors transfected either wild-type or CPVT-mutant RyR2s into HEK293 cell lines and loaded them with fluo3-AM.
(CPVT and HF) RyR2 mutations and flecainide
● RyR2 mutations can increase the sensitivity of the ryanodine receptor to calcium concentrations on the cytosolic side of the SR membrane.
● The unifying feature of CPVT mutations is that their deleterious effects are only present upon sympathetic nervous system activation, often during exercise, and resulting in sudden cardiac death.
(CPVT and HF) Hilliard 2010 and flecainide
● The mechanism of action for flecainide was initially controversial, given that the drug is traditionally thought to blockade voltage gated sodium channels.
● However, Hilliard et al in 2010 identified another potential mechanism of action by comparing Wistar rats with Casq2-/- models of CPVT.
(CPVT and HF) Shan 2010 and ryanodine receptor in chronic heart failure
● The ryanodine receptor is not just affected by genetic aberrations in CPVT, instead there can be modulation by intracellular kinases.
● This can occur particularly in prolonged conditions such as chronic heart failure.
HCN mutations and sick sinus syndrome (pacemaking) subheadings (list)
Mutations and sick sinus syndrome
HCN channels, stem cells and connexin-43 proteins
Qu 2003
(HCN and sick sinus) Mutations and sick sinus syndrome
● Mutations in both membrane and calcium-handling proteins can have deleterious effects on SAN pacemaking.
● For instance, mutations in HCN proteins are commonly associated with sick sinus syndrome. Patients with this condition typically present with varied atrial arrhythmias, syncope, and fatigue.
(HCN and sick sinus) HCN channels, stem cells and connexin-43 proteins
● Despite conflicting reports as to the necessity of HCN channels for pacemaking activity, these ion channels have been described as a potential therapeutic option for delivery of a biological pacemaker.
● Other biological pacemaker avenues of research have focused on transplantation of pacemaker-like cells developed from embryonic stem cells into the SAN.
(HCN and sick sinus) Qu 2003
● Qu et al in 2003 were the first to use the HCN2 channel as a target for gene therapy.
● This channel has intermediate kinetics when compared with the HCN4 and HCN1 channels expressed in the HCN.
Inherited arrhythmia syndromes (SCD) subheadings (list)
Table 1
Sanguinetti 1996 and long QT syndrome
Kyndt 2001 and Brugada Syndrome
(Arrhythmia syndromes) Table 1- syndromes, pattern of inheritance, and gene
● Long QT syndrome, Autosomal dominant, KCNQ1, KCNH2, SCN5A
Brugada syndrome, Autosomal dominant, SCN5A
Catecholaminergic polymorphic ventricular tachycardia, Autosomal dominant/ recessive, RYR2/ CASQ2
(Arrhythmia syndromes) Sanguinetti 1996 and long QT syndrome
● Sanguinetti et al in 1996 built on work that had previously identified KvLQT1 as the ion channel mutated in LQT1.
● This channel is now known as KCNQ1.
(Arrhythmia syndromes) Kyndt 2001 and Brugada Syndrome
● Kyndt et al studied the implications of mutations on the current flow through these channels in 2001.
● The authors first identified a family of patients with Brugada syndrome, and performed exome sequencing of the SCN5A gene, before identifying a novel G1406R mutation in the gene.
Ventricular arrhythmias (SCD) subheadings (list)
Fowler 2020 and NCX exchange
Bögelholz 2016 and NCX mediated calcium extrusion
