Oliver Monfredi

The anatomy and physiology of the sinoatrial node--a contemporary review.

The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a “wandering pacemaker” and concomitant changes in the P‐wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up‐to‐date summary of the current state of our appreciation of the above topics. (PACE 2010; 1392–1406)

Exercise training reduces resting heart rate via downregulation of the funny channel HCN4

Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training.

Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues.

It is now over 100years since the discovery of the cardiac conduction system, consisting of three main parts, the sinus node, the atrioventricular node and the His-Purkinje system. The system is vital for the initiation and coordination of the heartbeat. Over the last decade, immense strides have been made in our understanding of the cardiac conduction system and these recent developments are reviewed here. It has been shown that the system has a unique embryological origin, distinct from that of the working myocardium, and is more extensive than originally thought with additional structures: atrioventricular rings, a third node (so called retroaortic node) and pulmonary and aortic sleeves. It has been shown that the expression of ion channels, intracellular Ca(2+)-handling proteins and gap junction channels in the system is specialised (different from that in the ordinary working myocardium), but appropriate to explain the functioning of the system, although there is continued debate concerning the ionic basis of pacemaking. We are beginning to understand the mechanisms (fibrosis and remodelling of ion channels and related proteins) responsible for dysfunction of the system (bradycardia, heart block and bundle branch block) associated with atrial fibrillation and heart failure and even athletic training. Equally, we are beginning to appreciate how naturally occurring mutations in ion channels cause congenital cardiac conduction system dysfunction. Finally, current therapies, the status of a new therapeutic strategy (use of a specific heart rate lowering drug) and a potential new therapeutic strategy (biopacemaking) are reviewed.

Modern Concepts Concerning the Origin of the Heartbeat

Physiological processes governing the heart beat have been under investigation for several hundred years. Major advances have been made in the recent past. A review of the present paradigm is presented here, including a look back at important steps that led us to where we are today, alongside a glimpse into the exciting future of pacemaker research.

Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported ([7][1]). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The

Sick sinus syndrome and atrial fibrillation in older persons - A view from the sinoatrial nodal myocyte.

Sick sinus syndrome remains a highly relevant clinical entity, being responsible for the implantation of the majority of electronic pacemakers worldwide. It is an infinitely more complex disease than it was believed when first described in the mid part of the 20th century. It not only involves the innate leading pacemaker region of the heart, the sinoatrial node, but also the atrial myocardium, predisposing to atrial tachydysrhythmias. It remains controversial as to whether the dysfunction of the sinoatrial node directly causes the dysfunction of the atrial myocardium, or vice versa, or indeed whether these two aspects of the condition arise through some related underlying pathological mechanism, such as extracellular matrix remodeling, i.e., fibrosis. This review aims to shed new light on the myriad possible contributing factors in the development of sick sinus syndrome, with a particular focus on the sinoatrial nodal myocyte. This article is part of a Special Issue entitled CV Aging.

Efficacy and Safety of Bosentan for Pulmonary Arterial Hypertension in Adults With Congenital Heart Disease

The dual endothelin receptor antagonist, bosentan, has been shown to be well tolerated and effective in improving pulmonary arterial hypertension (PAH) symptoms in patients with Eisenmenger syndrome but data from longer-term studies are lacking. The aim of this study was to retrospectively analyze the long-term efficacy and safety of bosentan in adults with PAH secondary to congenital heart disease (PAH-CHD). Prospectively collected data from adult patients with PAH-CHD (with and without Down syndrome) initiated on bosentan from October 2007 through June 2010 were analyzed. Parameters measured before bosentan initiation (62.5 mg 2 times/day for 4 weeks titrated to 125 mg 2 times/day) and at each follow-up (1 month and 3, 6, 9, 12, 18, and 24 months) included exercise capacity (6-minute walk distance [6MWD]), pretest oxygen saturation, liver enzymes, and hemoglobin. Data were analyzed from 39 patients with PAH-CHD (10 with Down syndrome) who had received ≥ 1 dose of bosentan (mean duration of therapy 2.1 ± 1.5 years). A significant (p < 0.0001) average improvement in 6MWD of 54 m over a 2-year period in patients with PAH-CHD without Down syndrome was observed. Men patients had a 6MWD of 33 m greater than women (p < 0.01). In all patients, oxygen saturation, liver enzymes, and hemoglobin levels remained stable. There were no discontinuations from bosentan owing to adverse events. In conclusion, patients with PAH-CHD without Down syndrome gain long-term symptomatic benefits in exercise capacity after bosentan treatment. Men seem to benefit more on bosentan treatment. Bosentan appears to be well tolerated in patients with PAH-CHD with or without Down syndrome.

Stochastic vagal modulation of cardiac pacemaking may lead to erroneous identification of cardiac chaos

Fluctuations in the time interval between two consecutive R-waves of electrocardiogram during normal sinus rhythm may result from irregularities in the autonomic drive of the pacemaking sinoatrial node (SAN). We use a biophysically detailed mathematical model of the action potentials of rabbit SAN to quantify the effects of fluctuations in acetylcholine (ACh) on the pacemaker activity of the SAN and its variability. Fluctuations in ACh concentration model the effect of stochastic activity in the vagal parasympathetic fibers that innervate the SAN and produce varying rates of depolarization during the pacemaker potential, leading to fluctuations in cycle length (CL). Both the estimated maximal Lyapunov exponent and the noise limit of the resultant sequence of fluctuating CLs suggest chaotic dynamics. Apparently chaotic heart rate variability (HRV) seen in sinus rhythm can be produced by stochastic modulation of the SAN. The identification of HRV data as chaotic by use of time series measures such as a positive maximal Lyapunov exponent or positive noise limit requires both caution and a quantitative, predictive mechanistic model that is fully deterministic.

Inverse Correlation between Heart Rate Variability and Heart Rate Demonstrated by Linear and Nonlinear Analysis.

The dynamical fluctuations in the rhythms of biological systems provide valuable information about the underlying functioning of these systems. During the past few decades analysis of cardiac function based on the heart rate variability (HRV; variation in R wave to R wave intervals) has attracted great attention, resulting in more than 17000-publications (PubMed list). However, it is still controversial about the underling mechanisms of HRV. In this study, we performed both linear (time domain and frequency domain) and nonlinear analysis of HRV data acquired from humans and animals to identify the relationship between HRV and heart rate (HR). The HRV data consists of the following groups: (a) human normal sinus rhythm (n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cells (SANC; n = 67); (d) conscious rat (n = 11). In both human and animal data at variant pathological conditions, both linear and nonlinear analysis techniques showed an inverse correlation between HRV and HR, supporting the concept that HRV is dependent on HR, and therefore, HRV cannot be used in an ordinary manner to analyse autonomic nerve activity of a heart.

Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model.

Background Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension. Methods Three groups of rats were created (n = 12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration. Results The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15 m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p < 0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s2 vs MACI 17.30 ± 1.89 m/s2; p < 0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1 cm vs MACI 0.10 ± 0.1 cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p < 0.05). Survival benefit was not seen in the MACI group (p = 0.50). Conclusions Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.