Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

Background-Although pharmacological block of the slow, delayed rectifier potassium current (I Ks ) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of I Ks block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of I Ks in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results-Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mol/L) produced a Ͻ12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I Kr blockers sotalol and E-4031 markedly lengthened APD.

Background-Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanismbased approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel-related acid-sensitive K + channel-1]) 2-poredomain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results-Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage-and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions-Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.

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1 The aim of this study was to investigate the possible role of the interaction of di erent potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch-clamp techniques at 378C. 2 Complete block of I Kr by 1 mM dofetilide lengthened action potential duration (APD) by 45.6+3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 mM (a concentration which selectively blocks I Ks ) did not markedly lengthen APD (57%), but when repolarization had already been prolonged by complete I Kr block with 1 mM dofetilide, inhibition of I Ks with 10 mM chromanol 293B substantially delayed repolarization by 38.5+8.2% at 0.2 Hz (n=6). 3 BaCl 2 , at a concentration of 10 mM which blocks I Kl without a ecting other currents, lengthened APD by 33.0+3.1% (n=11), but when I Kr was blocked with 1 mM dofetilide, 10 mM BaCl 2 produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. 4 These ®ndings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin (`repolarization reserve'). However, when this normal repolarization reserve' is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a speci®c inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to de®ne the determinants of`repolarization reserve'.

BACKGROUND AND PURPOSEAt present there are no small molecule inhibitors that show strong selectivity for the Na + /Ca 2+ exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca 2+ currents and on the formation of early and delayed afterdepolarizations. EXPERIMENTAL APPROACHIon currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. KEY RESULTSORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca 2+ current or the maximum rate of depolarization (dV/dtmax), indicative of the fast inward Na + current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca 2+ current. ORM-10103 did not influence the Na + /K + pump or the main K + currents of canine ventricular myocytes, except the rapid delayed rectifier K + current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically-induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration-dependent manner. CONCLUSIONS AND IMPLICATIONSORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events. LINKED ARTICLE

It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I(to) and I(Ks) currents, and thereby may markedly enhance the risk of sudden cardiac death.

The sodium-calcium exchanger (NCX) was considered to play an important role in arrhythmogenesis under certain conditions such as heart failure or calcium overload. In the present study, the effect of SEA-0400, a selective inhibitor of the NCX, was investigated on early and delayed afterdepolarizations in canine ventricular papillary muscles and Purkinje fibres by applying conventional microelectrode techniques at 371C. The amplitude of both early and delayed afterdepolarizations was markedly decreased by 1 mM SEA-0400 from 26.672.5 to 14.871.8 mV (n ¼ 9, Po0.05) and from 12.571.7 to 5.971.4 mV (n ¼ 3, Po0.05), respectively. In enzymatically isolated canine ventricular myocytes, SEA-0400 did not change significantly the L-type calcium current and the intracellular calcium transient, studied using the whole-cell configuration of the patch-clamp technique and Fura-2 ratiometric fluorometry. It is concluded that, through the reduction of calcium overload, specific inhibition of the NCX current by SEA-0400 may abolish triggered arrhythmias.