Heart failure (HF) is increasingly prevalent in Western countries. It is a major risk factor of life-threatening ventricular arrhythmias and sudden death, and an important risk factor for atrial fibrillation (AF)[1]. Poorly treated HF has a mortality rate at five years of about 60%[2]. Abnormalities in sinoatrial node (SAN) function are common in HF and may contribute to bradyarrythmic death[1]. However, detailed data concerning SAN remodelling in HF is limited. Patients with HF show electrophysiological remodelling of sinoatrial node (SAN) function and regulation. They show decreased heart rate and heart rate variability[3]. Severe HF patients also show internodal conduction slowing, dispersion in excitability and prolongation of the SAN recovery time[4]. In animal models, HF decreases intrinsic heart rate and circadian rhythmicity [5,6,7]. In rabbit, myocytes from within the SAN region demonstrate that the HF induced increase in cycle length, is caused by a reduction in diastolic depolarization rate[8]. HF impairs single sinus-node cell automaticity by downregulating the hyperpolarization-activated “pacemaker” current (If), without changing voltage dependence or kinetics. Other currents involved in pacemaking, the T-type and L-type calcium current, rapid and ultra-rapid delayed rectifier current, transient outward currents, and sodium-calcium exchange current are unaltered[8]. In a canine model in which congestive heart failure was induced by overdrive pacing, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits HCN2 and HCN4 underlying If, are downregulated. In the same model an upregulation of atrial HCN4 is observed which may help to promote atrial arrthymia formation[7]. Patients with heart failure produces complex endocrine changes, including alterations in atrial and brain natriuretic peptides, and changed concentrations of arginine vasopressin, angiotensin-II and aldosterone. Many of these changes could affect SAN function and need further investigation. In addition, heart failure is associated with profound changes in the balance of the autonomic nervous system, such as activation of the sympathetic nerve, parasympathetic withdrawal and increased catecholamine levels. Changes in adrenergic receptor number, function and stimulation also occur[9]. In animal models HF decreases intrinsic heart rate with a larger responsiveness to acetylcholine and a decreased circadian rhythmicity. The responsiveness of the SAN to beta-adrenergic stimulation with noradrenaline is not changed[5]. Only throughout the last decade, intracellular calcium (Ca²⁺_i) has been recognized as an additional mechanism through which beta-adrenergic stimulation exerts its positive chronotropic action. Beta-adrenergic stimulation increases Ca²⁺_i transients and augment spontaneous and triggered Ca²⁺ releases during diastolic depolarisation. This promotes Ca²⁺ transport across the sarcolemmal membrane by the sodium calcium exchanger (NCX), which delivers a depolarising current at diastolic potentials. In this way also INCX, albeit indirectly, is increased by beta-adrenergic stimulation and helps to accelerate pacemaker activity[10]. It is unknown to what extent ACh stimulation modulates Ca²⁺_i transients and Ca²⁺ releases during diastolic depolarisation in pacemaker cells. Moreover, the role of Ca²⁺_i to the negative chronotropic action of ACh in non-stimulated and beta-adrenergic stimulated nodal myocytes is still unclear. These questions in relation to the occurrence of heart failure will be addressed during the presentation.