BackgroundBradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption.ObjectivesThe purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia.MethodsWe assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the “funny” current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1–30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography).ResultsIn mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% ± 3% and 15% ± 2% at 3 and 10 µM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% ± 6%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% ± 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function.ConclusionsWe have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If.

Research into cardiac autonomic control has received an explosion of interest in the past 20 years, and we are now at a critical juncture with regard to the clinical translation of the experimental findings.There has been a rush to develop clinical interventions and implant a range of devices aimed at cardiac neuromodulation therapy. This interest has been driven by research, superimposed on commercial opportunities and perhaps the more relaxed regulatory framework governing implantable devices and interventions compared with that for pharmacotherapy. However, many of the results of the clinical trials into these therapies have been disappointing or conflicting. This lack of positive results is partly due to a scramble to find simple solutions for complex problems that we do not yet fully understand. Are there reasons to be optimistic? In this Review, we highlight areas in the field of cardiac autonomic control that we feel show most promise for clinical translation, and areas where our current range of blunt tools need to be refined to bring about long-term success in treating arrhythmia.

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Background - Low radiofrequency (RF) powers are commonly used on the posterior wall of the left atrium (LA) for atrial fibrillation (AF) ablation to prevent esophageal damage. Compared with higher powers, they require longer ablation durations to achieve a target lesion size index (LSI). Esophageal heating during ablation is the result of a time-dependent process of conductive heating produced by nearby RF delivery. This randomized study was conducted to compare risk of esophageal heating and acute procedure success of different LSI-guided ablation protocols combining higher or lower RF power and different target LSI values. Methods - Eighty consecutive patients were prospectively enrolled and randomized to one of 4 combinations of RF power and target LSI for ablation on the LA posterior wall (20W/LSI 4, 20W/LSI 5, 40W/LSI 4 and 40W/LSI 5). The primary endpoint of the study was the occurrence and number of esophageal temperature alerts (ETAs) per patient during ablation. Acute indicators of procedure success were considered as secondary end-points. Long term follow-up data were also collected for all patients. Results - Esophageal temperature alerts (ETAs) occurred in a similar proportion of patients in all groups. Significantly shorter RF durations were required to achieve the target LSI in the 40W groups. Less than 50% of the RF lesions reached the target LSI of 5 when using 20W despite a longer RF duration. A lower rate of first-pass Pulmonary Vein Isolation and a higher rate of acute Pulmonary Vein Reconnection were recorded in the group 20W/LSI 5. A lower AF recurrence rate was observed in the 40W groups compared to the 20W groups at 29 months follow-up. Conclusions - When guided by LSI, posterior wall ablation with 40W is associated with a similar rate of ETAs and a lower AF recurrence rate at follow-up if compared to 20W. These data will provide a basis to plan future randomized trials.

Aims The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. Methods and results Peripheral venous NPY levels were significantly higher in patients with STEMI ( n = 45) compared to acute coronary syndromes/stable angina ( n = 48) or with normal coronary arteries (NC, n = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated ( r = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y 1 receptor antagonist BIBO3304 (1 μM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y 1 receptors. Conclusion High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y 1 receptor, and antagonists may be a useful PPCI adjunct therapy.