Module 2 Studies Flashcards
(20 cards)
1
Q
Beta-2 signalling: chronotropy, inotropy (2)
A
- Hutter OF, 1956: one of the first studies to show catecholamine stimulation rises the rate of pacemaker potential (frog hearts), as a consequence of increased Ca2+ currents
- Marx, 2000: PKA phosphorylation leads to conformational changes whereby FKBP12.6 dissociates shifting the relationship between [Ca] and RyR2 open probability to the left (RyR more likely to open at lower calcium concentrations) - also FKB12.6 hyperphosphorylation in HF
2
Q
Beta-2 signalling: changes in HF (3)
A
- Paur et al: Studies with PTX (to depress Gi pathway) suppresses this negative inotropic response in takotsubo – highlighting the significance of Gi
- Nikolaev, Science 2010: in HF beta-2 found in crest and T-tubules of CM
- Froese et al, 2012: POPDC2 mutants: stress induced bradycardia, variability in HR, loss of dynamic range in adjusting HR to physiological demand (loss of linear response of HR to ISO)
3
Q
HF treatment: 1st line (5)
A
- ACEi; CONSENSUS trial – use of enalapril vs placebo in CHF (NYHA class IV) – reduction in mortality and improvement in symptoms (regression of progressive HF – relegation of NYHA class)
- ARB; ValHeFT trial – Valsartan vs placebo in HF patients – reduced combined mortality and morbidity rates, with improvement in EF, symptoms
- BB; COPERNICUS – improvement in survival with carvedilol. MERIT-HF – improved mortality outcomes with metoprolol
- MRA; RALES trial – in severe HF, in addition to standard therapy, spironolactone reduced mortality
4
Q
ARNI (2)
A
- OVERTURE trial - first looked at NEPi and ACEi. Improved HF but lots of angioedema
- PARADIGM-HF (NEPi + ARB). Superior to ACEi (20% relative and 3.7% absolute risk reduction in mortality)
5
Q
Ivabradine (4)
A
- Menown et al, 2013: All-cause mortality from HF shown to increase with HR, therefore targeting HR is important
- SHIFT trial – reduction in CHF deaths and hospital admissions with Ivabradine
- Navaratnarajah et al, 2013: reverses fibrosis in rats
- Kuwabarah et al, 2013: decreases arrhythmogenic expression of HCN channels in the ventricular myocardium in rats
6
Q
Electrical remodelling in HF (channels & calcium handling) (3)
A
- Tsuji, 2000: Ito decreased, Ik delayed rectifier reduced, Ik1 found to be decreased, increased or unchanged
- Terracciano, 2003 (using LVAD core tissue). LTCC possibly reduced in HF and may not communicate with RyR as effectively
- Marx, 2000: Stating that hyperphosphorylation of RyR regulatory protein, FKBP12.6 leads to RyR instability and greater leak
7
Q
Electrical remodelling in HF (ultrastructure - reduction in conduction velocity) (3)
A
- Smyth et al 2010 – reduced Cx43 expression in human failing hearts
- Smyth et al, 2010 – oxidative stress reduces Cx43 delivery to intercalated discs -> this translates to slowed conduction
- Akar et al, 2007 – dogs subjected to tachy pacing to mimic HF – increase in Cx43 dephosphorylation
8
Q
Hypertrophy: HCM (2)
A
- Spudich, 2015: HCM mutations clustering in the myosin mesa
- Alamo et al, 2017: myosin mutations interacting with the head motifs of the myosin mesa in the super-relaxed state
9
Q
Hypertrophy: HDACs (2)
A
- Haberland et al, 2009: HDAC9 mice KO – hypertrophy amplified to stress
- Zhang L et al, 2013: Deletion of PLC-epsilon in mice protects against stress induced hypertrophy
10
Q
CRT (4)
A
- Leclercq, 1998 – wedge pressure also decreased post CRT (improves ventricular filling)
- CARE-HF trial – CRT in HF patients (LV systolic dysfunction, NYHA class III or IV). Improved survival vs pharmacological therapy
- ECHO-CRT trial – those with narrowest QRS and worst dysnchrony actually had increased mortality risk with CRT
- Nijjer et al, 2012 - changes in EF variability in measurements and correlation, trial bias (external monitoring, blinding) and correlation
11
Q
His-Bundle Pacing (2)
A
- Arnold et al, 2018: better ventricular resynchronisation seen in HF patients with LBBB compared to conventional CRT, with greater improvement in haemodynamic parameters
- HOPE-HF trial - trial ongoing
12
Q
Cardiac dysfunction -> HF: cellular/microscopic changes (2)
A
- Gorelik group, 2009: Z-groove index lowered in HF (de-tubulation, contraction amplitude decreases, spark frequency increasing)
- Nikoloaev et al, 2010: beta2 T-tubules global cAMP signalling (crest and T-tubules)
13
Q
DCM (1)
A
- Wilkinson et al 2015: Thin filament mutation uncoupling TnI phosphorylation with decreased calcium sensitivity. This blunts the adrenergic response (reduced EF, CO, contractility)
14
Q
Endogenous cardiac stem cells (5)
A
- Noseda et al, 2015: combination of SP and PDGRF-alpha progenitor cells have great cloning ability in the adult murine myocardium. Good sarcomeric organisation, poor long term engraftment
- Loffredo S et al, 2011: Cre-Lox and fate mapping - 50% of cells in infarct border zone are non-myocytes
- Ellison et al, 2013: cKit+ restore cardiac function by regenerating CM, ablation of the CSCs abolishes regeneration
- Wallner et al, 2016: No cKit derived myocardial recovery of CMs following acute injury with ISO administration
- CADUCEUS trial – phase 1 trial, administration of cardiosphere derived cells following MI – LVEF not changed
15
Q
hESC: advantages & disadvantages (2)
A
- Chong et al 2014 – hESC derived CM shown to regenerate non-human primate heart. Cells electrically coupled with host. Extensive durable engraftment, even 12 weeks post MI
- Sartiani, 2007 – presence of immature CM: ventricular cells having pacemaker potential, IK1 failing to develop
16
Q
iPSC: disadvantages (2)
A
- Shiba et al, 2016 – allogeneic iPSC derived CM transplantation into primate hearts . Increase in EF, FS, even at 12 weeks. However, significant incidences of VT
- Ong et al, 2015 – transplantation of human iPSC-CM into mouse following acute MI. Improvement in LV function, but poor retention of cells (therefore perhaps paracrine actions)
17
Q
Paracrine: growth factors and cardiprotection (2)
A
- Ong et al, 2015 – transplantation of human iPSC-CM into mouse following acute MI. Improvement in LV function, but poor retention of cells (therefore perhaps paracrine actions)
- Takahashi et al, 2006 – cytokines produced by bone marrow cells contributing to cardioprotection. Supernatant injected in acute MI model in rat - decrease in fibrotic area
18
Q
Paracrine: mesenchymal stem cells (2)
A
- Gnocchi et al, 2006: Akt-MSC conditioned medium injected into rat infarcted hearts – reduction in infarct size and improved ventricular function
- Mangi et al, 2003: genetically engineered overexpression of Akt-1 in MSC – reduced myocardial inflammation, hypertrophy and normalised systolic/diastolic cardiac function
19
Q
Paracrine: ECM homeostasis (1)
A
- Xu et al, 2005: MSC and ECM changes post-MI
Expression of collagen and TGF-beta decreased by MSC transplantation, acting to inhibit cardiac fibrosis
20
Q
ECM: pathological changes and therapeutic options (3)
A
- Cameletti et al, 2004 – fibroblasts electrically coupling via connexins to rabbit sino atrial node CMs in cell culture
- Mukherjee et al, 2003 – Broad spectrum MMP inhibition attenuates post MI LV dilatation in pigs
- PREMIER trial – RCT looking at selective MMP inhibition to prevent ventricular remodelling post-MI. Failure to improve outcomes or reduce remodelling. What is the explanation?
