Background— Spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR) can generate afterdepolarizations, and these have the potential to initiate arrhythmias. Therefore, an association may exist between spontaneous SR Ca 2+ release and initiation of atrial fibrillation (AF), but this has not yet been reported. Methods and Results— Spontaneous Ca 2+ release from the SR, manifested as Ca 2+ sparks and Ca 2+ waves, was recorded with confocal microscopy in atrial myocytes isolated from patients with and those without AF. In addition, the spontaneous inward current associated with Ca 2+ waves was measured with the use of the perforated patch-clamp technique. The Ca 2+ spark frequency was higher in 8 patients with AF than in 16 patients without (6.0±1.2 versus 2.8±0.8 sparks/mm per second, P <0.05). Similarly, the spontaneous Ca 2+ wave frequency was greater in patients with AF (2.8±0.5 versus 1.1±0.3 waves/mm per second, P <0.01). The spontaneous inward current frequency was also higher in 10 patients with AF than in 13 patients without this arrhythmia (0.101±0.028 versus 0.031±0.007 per second, P <0.05, at a clamped potential of −80 mV). In contrast, both the Ca 2+ released from the SR and the Na + -Ca 2+ exchange rate induced by a rapid caffeine application were comparable in patients with and without AF. Conclusions— The observed increase in spontaneous Ca 2+ release in patients with AF probably is due to an upregulation of the SR Ca 2+ release channel activity, which may contribute to the development of AF.

PDE4 is critical in controlling cAMP levels and thereby Ca(2+) influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24 −/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24 −/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.Hutchinson-Gilford progeria syndrome | progerin | prelamin A | connexin43 | calcium handling T he LMNA gene encodes A-type lamins (lamin A and lamin C), key components of the mammalian nuclear envelope with important structural and regulatory functions that affect signaling, transcription, and chromatin organization among other processes (1). Mature lamin A is produced from the precursor prelamin A through a series of posttranslational modifications, consisting of sequential farnesylation at the cysteine in the Cysteine-SerineIsoleucine-Methionine motif, cleavage of the Serine-IsoleucineMethionine residues, carboxymethylation of the newly accessible cysteine, and a final proteolytic cleavage by the zinc metallopeptidase STE24 (ZMPSTE24, also called FACE-1) (2).Mutations in the human LMNA gene or defective processing of prelamin A cause a group of diseases termed laminopathies, including the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS), a very rare genetic disorder with an estimated prevalence of 1 in 21 million people (www.progeriaresearch.org). SignificanceDefective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson-Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in proger...

Atrial fibrillation patients show increased A(2A)R expression that may account for the high baseline level of spontaneous SR calcium release seen in myocytes from these patients, and the ability of A(2A)R antagonists to reduce this abnormal calcium release points to the A(2A)R as a novel molecular target in AF.