Arrhythmias

A pictorial representation of adjacent cardiomyocytes illustrating the genes implicated in Mendelian forms of atrial fibrillation and the presumed mechanism of action of the mutations.

Mahida S et al. Cardiovasc Res 2011; 89:692-700 - Click here to view the abstract

The majority of mutations have been identified in ion channel subunit genes and lead to either gain-of-function or loss-of-function effects. Gain-of-function potassium channel mutations have been identified in KCNQ1, KCNE2, KCNE5 and KCNJ2. KCNQ1, KCNE2 and KCNE5 encode subunits of the cardiac I_KS channel while KCNJ2 encodes a subunit of the I_K1 channel. A loss-of-function potassium channel gene mutation has been reported in KCNA5, which encodes a subunit of the I_Kur channel. Both gain-of-function and loss-of-function mutations have been identified in SCN5A, which encodes the α subunit of the cardiac sodium channel. Loss-of-function mutations have also been reported in SCN1B and SCN2B, genes encoding β subunits of the cardiac sodium channel.

Non-ion channel gene mutations have also been implicated in familial AF. These include mutations in NUP155, GJA5 and NPPA. NUP155 encodes a nucleoporin, which is a molecular component of nuclear pore complexes. GJA5 encodes connexin-40, an atrial gap junction protein which plays a role in cell-to-cell electrical coupling. The reported NPPA mutation is associated with markedly elevated levels of mutant atrial natriuretic.

Altered Subcellular Ca²⁺ Handling Protein Expression and Phosphorylation in Atrial Fibrillation-induced Remodeling

Greiser M et al. Cardiovasc Res 2011; 89:722-733 - Click here to view the abstract

Altered Subcellular Ca<sup>2+</sup> Handling Protein Expression and Phosphorylation in Atrial Fibrillation-induced Remodeling

Schematic drawing depicting changes in function, expression, and phosphorylation levels of key Ca²⁺ handling proteins in human atrial fibrillation (AF), with arrows denoting direction of change. Dephosphorylation of channel subunits due to increased activities of phosphatases 1 and 2 (PP1, PP2) contributes to the reduction of L-type Ca²⁺ current (I_CaL), which is a hallmark of AF-induced remodeling (Inset). However, locally increased phosphorylation of (PP1)-inihibitor-1 (I-1) prevents dephosphorylation of Ca²⁺ release channels (Ryanodine receptors, RyR2) of the sarcoplasmic reticulum (SR), resulting in their hyperphosphorylation by protein kinase A (PKA) and Ca²⁺/calmodulin–dependent kinase II (CaMKII) in AF. Contribution of this hyperphosphorylation to initiation and perpetuation of AF is currently debated. Inositol 1,4,5-trisphosphate type 2 receptor (IP₃R) protein expression is increased in AF, although little is known regarding its functional relevance. Upregulation of Na⁺/Ca²⁺ exchanger (NCX) function and expression is a constant finding in AF and might contribute to cellular proarrhythmic mechanisms (triggered activity). The pump rate of the SR Ca²⁺-ATPase (Serca2a) is increased by phosphorylation of its regulatory protein phospholamban (PLB). Similar to RyR2, PLB is hyperphosphorylated in AF at PKA and CaMKII sites (Ser16 and Thr17, respectively).

Upregulation of Na⁺/Ca²⁺ exchanger (NCX) function and expression is a constant finding in AF and might contribute to cellular proarrhythmic mechanisms (triggered activity). The pump rate of the SR Ca²⁺-ATPase (Serca2a) is increased by phosphorylation of its regulatory protein phospholamban (PLB). Similar to RyR2, PLB is hyperphosphorylated in AF at PKA and CaMKII sites (Ser16 and Thr17, respectively). Regional alterations in Ca²⁺ handling protein expression and phosphorylation show the importance of differential regulation of subcellular Ca²⁺ handling domains in AF.
MyBP-C, myosin-binding protein C; P, phosphate group.
*changes in MyBP-C phosphorylation are controversial in the literature.

Schematic diagram of cardiac fibrogenesis cascade and its contribution to atrial fibrillation (AF)

Yue L et al. Cardiovasc Res 2011; 89:744-753 - Click here to view the abstract

In response to a variety of stimuli, cardiac fibroblasts proliferate, differentiate, synthesize extracellular matrix (ECM) proteins, and produce cytokines like transforming growth factor-beta (TGFβ) and interleukin-6 (IL6) that in turn stimulate fibroblasts, thereby providing positive feedback that amplifies and perpetuates the fibrogenesis cascade. ECM accumulation causes fibrosis that favours the occurrence and maintenance of AF. There are two types of fibrosis, responsive and reparative, that can be caused by many common stimuli, with reparative fibrosis being particularly involved in repairing tissues after cardiomyocyte death. Fibrosis promotes AF by acting as a conductive barrier that impedes impulse propagation and/or via proarrhythmic cellular interactions between cardiomyocytes and fibroblasts. Intracellular Ca²⁺ signals mediated by transient receptor potential (TRP) channels, in particular TRP melastatin-related 7 (TRPM7) channels, are critical for fibroblast proliferation, differentiation, and ECM production in fibroblasts from AF patients. Ca²⁺ release may affect fibroblast function via the modulation of gene expression through Ca²⁺-dependent transcription factors (TFs). Fibroblast Ca²⁺ signalling may be an effective target for the prevention of fibrogenesis and could be a novel approach to AF therapy.

Expression of skeletal muscle sodium channel (Nav1.4) or connexin32 prevents reperfusion arrhythmias in murine heart

Anyukhovsky E P et al. Cardiovasc Res 2011; 89:41-50-Click here to view the abstract

Overexpressing the acidosis-resistant connexin32 (Cx32) maintains normal conduction in myocardium exposed to a low pH environment. Intracellular acidification induced by acute myocardial ischemia can close pH-sensitive Cx43 gap junctions and contribute to conduction slowing and reentrant arrhythmias. We studied right ventricular epicardium from mice whose hearts had been injected 4 days earlier with either adenoviral Cx32 or naked adenovirus. We simulated acidosis using a low pH solution containing Na-acetate. This decreased intracellular pH (measured with pH-sensitive microelectrodes) from 7.0 to 6.4. At pH 6.4, most Cx43 gap junctions are closed, while significant numbers of Cx32 junctions should remain open and support conduction.

In representative maps of conduction times (A – D) the pacing site is marked with a cross and isochrones are drawn at 3 ms intervals. Low pH had no effects on maximum diastolic potential (MDP) (E) and maximum upstroke velocity of the action potential (Vmax) (F) in both groups. Acidosis induced a significant decrease in conduction velocity (CV) in Shams and had no effect in Cx32 (G). As a result, at low pH, CV was higher in Cx32-expressing mice. *P<0.05 vs. pH 7.4 in the same group, +P<0.05 vs. Sham at the same pH (n=8 for both groups).

Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation

De Jong A M et al. Cardiovasc Res 2011; 89:754-765 - Click here to view the abstract

A schematic representation of the calcium homeostasis and events that may take place due to calcium overload induced by AF. Depolarization of the cardiomyocyte leads to inflow of calcium into the cell via (i) L-type Ca²⁺-channels, (ii) reverse mode Na⁺/Ca²⁺-exchanger, and (iii) T-type Ca²⁺-channels. This induces calcium-induced-calcium release from the sarcoplasmic reticulum via ryanodine receptors (RyR) into the cytoplasm. Calcium, subsequently, binds to contractile elements and initiates contraction. In the diastole, calcium leaves the cytoplasm via sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), which is regulated by phospholamban (Pln), and via the Na⁺/Ca²⁺-exchanger and plasma membrane Ca²⁺-ATPase.

Ions can also leave and enter the cell via stretch-activated channels (SAC). During AF calcium overload can contribute to an altered signal transduction. Activation of Ca²⁺-dependent proteins such as calpain, calcineurin, and calcium/calmodulin-dependent protein kinase II (CaMKII) may be increased. Activation of calpain may result in degradation of muscle proteins (myolysis). Increased calcineurin activation activates NFAT (nuclear factor of activated T-cells) by dephosphorylation and CaMKII activates myocyte enhancer factor 2 (MEF2) signalling. Both lead to altered gene expression such as increased ANP and BNP expression and hypertrophy. Calsarcin, a stretch-sensitive protein localized to the Z-disk, is an inhibitor of calcineurin. The plasma membrane calcium-ATPase fine tunes diastolic calcium levels and inhibits calcineurin via direct binding.