Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two-AF exacerbates heart failure causing a significant increase in heart failure ...symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.
Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. ...Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart's response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition.
Large animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could ...predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF.
Healthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF.
Eighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 95% confidence intervals 0.2-52.0
= 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 95% confidence intervals 0.59-1.04
= 0.04).
The critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals.
Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and ...triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content.
Key points
Heart failure is a pro‐arrhythmic state and arrhythmias are a major cause of death.
At the cellular level, Ca2+ waves resulting in delayed after‐depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+.
We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure.
We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves.
The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content.
The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.
figure legend Raising external Ca2+ (1) leads to a background Ca2+ influx via TRPC6 channels (2). This Ca2+ is pumped into the sarcoplasmic reticulum via SERCA leading to a rise in SR Ca2+ content (3). When SR Ca2+ content reaches a threshold, spontaneous Ca2+ release leads to propagating Ca2+ waves (4). In heart failure, the background Ca2+ influx is increased and SR threshold decreased, resulting in a greater propensity to Ca2+ waves.
Background Atrial fibrillation ( AF ) is common in the elderly, but rare in the young; however, the changes that occur with age that promote AF are not fully understood. Action potential ( AP ) ...alternans may be involved in the initiation of AF . Using a translationally relevant model, we investigated whether age-associated atrial vulnerability to AF was associated with susceptibility to AP alternans. Methods and Results AF was induced in conscious young and old sheep using 50 Hz burst pacing. Old sheep were more vulnerable to AF . Monophasic and cellular AP s were recorded from the right atrium in vivo and from myocytes isolated from the left and right atrial appendages. AP alternans occurred at lower stimulation frequencies in old sheep than young in vivo (old, 3.0±0.1 Hz; young, 3.3±0.1 Hz; P<0.05) and in isolated myocytes (old, 1.6±0.1 Hz; young, 2.0±0.1 Hz; P<0.05). Simultaneous recordings of Ca
and membrane potential in myocytes showed that alternans of AP s and Ca
often occurred together. However, at low stimulation rates Ca
alternans could occur without AP alternans, whereas at high stimulation rates AP alternans could still be observed despite disabling Ca
cycling using thapsigargin. Conclusions We have shown, for the first time in a large mammalian model, that aging is associated with increased duration of AF and susceptibility to AP alternans. We suggest that instabilities in Ca
handling initiate alternans at low stimulation rates, but that AP restitution alone can sustain alternans at higher rates.
Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca
waves which activate a Na
-Ca
exchange (NCX) current, leading to delayed after-depolarisations and ...triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca
content reaches a threshold and are commonly induced experimentally by raising external Ca
, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca
was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca
content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca
induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca
content was smaller in HF due to a lower threshold. Raising external Ca
had no effect on total influx via the L-type Ca
current, I
, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca
entry which sustains Ca
efflux during waves in the steady state. Wave frequency and background Ca
entry were decreased by Gd
or the TRPC6 inhibitor BI 749327. These agents also blocked Mn
entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca
induces waves via a background Ca
influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca
waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca
waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca
. We investigate the mechanism by which raising external Ca
causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca
influx via the TRPC6 channel is responsible for SR Ca
overload and Ca
waves. The increased propensity for Ca
waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca
waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.
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