Study of disease- detailed 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.
● Argument: to a large extent, studying disease allows us to identify the molecular and genetic causes of disease, the processes of which can then be extrapolated to determine normal function in healthy organisms.
● Also many studies of disease are based on animal models - which arguably do not fully replicate the complexity of human disease, and therefore may not accurately reflect normal function
(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.
● Chuvash polycythaemia, where elevated HIF activity promotes erythrocytosis and vascular remodeling, but the same pathway is also crucial for normal hypoxic adaptation, making it difficult to disentangle pathological from protective roles.
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.
● For example, CPVT highlights how subtle changes in calcium handling (RyR2 mutations) can destabilize excitation-contraction coupling, helping us understand the fine balance required for normal cardiac rhythm.
● Similarly, chronic heart failure and studies on RyR2 hyperphosphorylation demonstrate how dynamic modulation (e.g., by PKA) of channel activity is essential to physiological adaptability- and how loss of that control contributes to disease.
(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.
● Disease states like Chuvash polycythaemia or Monge’s disease (chronic mountain sickness) illustrate what happens when these adaptive mechanisms go too far, such as excessive HIF activity leading to pathological erythrocytosis.
● By studying how maladaptive responses evolve in altitude disease, we better understand where the physiological “sweet spot” lies- for example, how much erythropoiesis is adaptive vs. thrombogenic.
(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.
● Altitude sickness has revealed new insights into cerebral blood flow regulation, BBB integrity, and pulmonary vascular responses that apply broadly, even at sea level.
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.
● However, the most common mutation that causes CPVT1 is to the RyR2 channel itself.
(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.
● Under confocal line-scan microscopy, the occurrence of Ca2+ sparks was significantly higher in HEK cells transfected with CPVT-mutant RyR2 channels.
● However, the use of the embryonic kidney line raises questions as to the validity of these results in myocytes.
(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.
● One of the most promising new drugs in the treatment of CPVT is the class 1c anti-dysrhythmic, flecainide.
● Several clinical trials have shown that combination therapy of flecainide with beta blockers is effective at reducing the recurrence of tachycardias, particularly during exercise.
(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.
● Flecainide reduced the amplitude and intensity of the calcium sparks in the CPVT model.
● This was sufficient to prevent arrhythmogenic calcium waves.
(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.
● Shan et al in 2010 used a mice model of a constitutively hyperphosphorylated RyR2.
● The authors developed a RyR2 S2808D knockin mice model.
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.
● Furthermore, it may not be essential for cells to express all pacemaker currents, if these cells can be made to couple with existing pacemaker cells with connexin-43 proteins.
(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.
● The authors developed adenoviral vectors to express the HCN2 channel and GFP in the left atrium of an adult canine model, where there was direct injection of the vector.
● Electrodes were implanted to artificially stimulate vagal tone to the SAN to block endogenous pacemaker activity, whilst ECG recorded the electrical activity in the induced pacemaker region of the left atrium.
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.
● The authors transfected Chinese hamster ovary cells with cDNA for the channel, and showed the unique Iks-like properties of the channel under voltage clamp conditions.
● The authors then co-transfected the minK cDNA, and showed that coasembly of these proteins was sufficient to replicate the Iks channel properties, whereby depolarising stimuli were followed by a brief delay then a repolarising outward potassium current.
(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.
● The authors then cloned the wild-type and mutant SCN5A genes before transfecting them in COS-7 cells.
● This enabled whole-cell patch clamping of the cells, in response to depolarising steps.
Ventricular arrhythmias (SCD) subheadings (list)
Fowler 2020 and NCX exchange
Bögelholz 2016 and NCX mediated calcium extrusion
