Stroke and atrial fibrillation: risks, prevention and therapy in the elderly.

Atrial fibrillation (AF) represents a high risk of systemic embolism, particularly of stroke (S). This is true not only when AF is associated with an organic cardiopathy, but also in the so-called nonvalvular AF (NVAF). Not all cases of AF are of the same S-risk; such risk is higher for rheumatic AF and lower for NVAF. Therefore, a risk stratification is important in order to decide long-term antithrombotic prophylaxis. Five major trials have recently examined the thromboembolic prophylaxis in this group of patients. These randomised prospective open studies showed a significant reduction of S and systematic embolism in patients receiving low dose of warfarin (W), even in the elderly, as compared to placebo, and the incidence of hemorrhagic complications was also very low. Significant benefits of aspirin (ASA) were observed only in one trial in patients, except those older than 75 years. In a double blind, randomised trial indobufene was found effective resulting in 67% reduction of S and systematic embolism in patients with various cardiac diseases in AF or sinus rhythm. Consequently, a reasonable policy would be to treat patients with NVAF (also old ones) with anticoagulants unless contraindications or lone atrial fibrillations are present; in the latter cases ASA and indobufene should be considered. In the secondary prevention of ischemic S, W has given good results, whereas ASA and indobufene seem to be promising.

Simultaneous measurement of Ca2+, contraction, and potential in cardiac myocytes.

A system is described that can simultaneously record cytosolic Ca2+ concentration ([Ca2+]i), cell length, and either membrane potential or current in single cardiac myocytes loaded with the fluorescent Ca2+ indicator indo-1. Fluorescence is excited by epi-illumination with 3.8-microsecond flashes of 350 +/- 5 nm light from a xenon arc. Indo-1 fluoresence is measured simultaneously in spectral windows of 391-434 nm and 457-507 nm, and the ratio of indo-1 emission in the two bands is computed as a measure of [Ca2+]i for each flash. With cells loaded with the permeant acetoxymethyl ester of indo-1, quantitation of [Ca2+]i is not precise, owing to subcellular compartmentation of indo-1; however, the instrument would allow full quantitation if indo-1 free acid was introduced by microinjection. Simultaneously, cell length is measured on-line from the bright-field image of the cell. Because fluorescence collection is time gated during the brief flash, and red light (650-750 nm) is used for the bright-field image, cell length and [Ca2+]i measurements are obtained simultaneously without cross talk. Membrane potential or current can be recorded simultaneously with indo-1 fluorescence and cell length via standard patch-clamping techniques.

Milrinone enhances cytosolic calcium transient and contraction in rat cardiac myocytes during beta-adrenergic stimulation.

We have investigated the mechanism that underlies the absence of a positive inotropic effect of milrinone on rat myocardium. The twitch characteristics of enzymatically dissociated left ventricular myocytes from the adult rat and guinea pig were assessed by edge tracking during field stimulation. In some rat myocytes loaded with the ester derivative of the Ca2+ probe Indo-1 we simultaneously measured changes in cell length and in the associated cytosolic Ca2+ (Cai) transient. Our results show that in guinea pig myocytes bathed in 0.5 mM [Ca2+] and field stimulated at 1 Hz, milrinone (10 microM) had a positive inotropic effect. In contrast milrinone had no effect on the contractile properties of rat myocytes studied under similar conditions and field stimulated at 0.2 Hz. In rat myocytes bathed in 0.5 mM [Ca2+] and stimulated at 0.2 Hz isoproterenol (1 nM) increased the amplitude and shortened the duration of the contraction and of the associated Cai transient; these effects of beta-adrenergic stimulation were further enhanced by the addition of milrinone (10 microM) in the presence of isoproterenol. Under conditions of higher cell Ca2+ loading achieved by raising bathing [Ca2+] to 1 mM and isoproterenol to 3 nM the positive inotropic effect of milrinone (10 microM) in rat myocytes saturated when spontaneous oscillatory Ca2+ release appeared in the diastolic intervals between electrically stimulated twitches. Our results suggest that an enhancement in the baseline beta-adrenergic stimulation is required for milrinone to exercise a positive inotropic action on rat myocardial tissue.

Extracellular ATP has a potent effect to enhance cytosolic calcium and contractility in single ventricular myocytes.

The effect of extracellular ATP on the contraction of single rat cardiac myocytes was investigated, together with the effect on the transient change in cytosolic Ca2+ (Cai) elicited by excitation and on the relationship between these two parameters. In unstimulated single myocytes, ATP caused a small increase in Cai (measured as the ratio of fluorescence of Indo-1 at 410 to that at 490 nm. In myocytes bathed in a medium containing 1.0 mM [Ca2+] at 23 degrees C and stimulated at 1 Hz, ATP (1 microM) resulted in a two-threefold increase in amplitude of contraction, as measured by video cinemicrographic techniques. The duration of the Cai-transient was not altered but its amplitude was markedly enhanced, as was the amplitude of contraction. The relation between Cai and contraction-amplitude was not altered by ATP, when measured over a range of extracellular [Ca2+], suggesting that ATP does not affect the myofilament-Ca2+ interaction. The primary site of action of ATP in increasing Cai is at the sarcolemma since the addition to suspensions of myocytes of caffeine (10 mM), which depletes the sarcoplasmic reticulum Ca2+ load, does not prevent the subsequent increase of Cai due to ATP. Further, lowering of the extracellular [Ca2+] to less than 1 microM with EGTA abolishes the response of Cai to ATP, though not the response to caffeine. Thus in rat cardiac myocytes ATP stimulates trans-sarcolemmal influx of Ca2+: ADP, AMP and adenosine are ineffective. ATP markedly augments the amplitude of the Cai transient elicited by electrical stimulation thus rendering it a potent inotropic agent.