The Role of the Calcium and the Voltage Clocks in Sinoatrial Node Dysfunction

Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release) jointly regulate sinoatrial node (SAN) automaticity. However, the relative importance of the voltage clock and Ca2+ clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Cai) and membrane potentials of the normal intact SAN simultaneously using optical mapping in Langendorff-perfused canine right atrium. We demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with robust late diastolic Cai elevation (LDCAE) during beta-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca2+ release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca2+ clock of SAN was unresponsiveness to beta-adrenergic stimulation and caffeine. Ryanodine receptor 2 (RyR2) in SAN was down-regulated. Using the prolonged low dose isoproterenol together with funny current block, we produced a tachybradycardia model. In this model, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the right atrium, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Finally, if the LDCAE was too small to trigger an action potential, then it induced only delayed afterdepolarization (DAD)-like diastolic depolarization (DD). The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca2+ clock and the voltage clock are important in sick sinus syndrome.

Comparison between pre-prandial and post-prandial heart rate variability (HRV).

After food ingestion, peptides are released in GIT, which cause local vasodilatation. Therefore, after meals, redistribution of blood occurs because of shifting of large amounts of blood into GIT. In normal individuals, this is well compensated and does not lead to post-prandial hypotension. The mechanism of post-prandial hypotension is well known. We hypothesized that there may be a decrease in parasympathetic activity (tone) after meals to compensate for the change in blood distribution. We carried out the study to find out the changes in the autonomic tone before and after meals (lunch) in normal individuals, using Heart Rate Variability (HRV). From the series of RR intervals marked, the time domain and frequency domain measures of HRV were obtained using Nevrokard software (version 6.4). Continuous ECG was recorded in 15 healthy adult subjects (mean age 29.06 +/- 6.2; 13 males and 2 females). The ECG was recorded in pre-prandial and post-prandial state for a period of five minutes each as follows: (1) just before the subjects had lunch, (2) 15 minutes after lunch, (3) 1 hour after lunch, and (4) 2 hours after lunch. Time domain and frequency domain measures of HRV were compared between pre-prandial state and rest of post-prandial states. The autonomic tone parameters did not show a significant change between the pre-prandial state and the immediate post-prandial state. [Range, i.e., the difference between the maximum and minimum RR intervals (406 +/- 161.14 vs. 416.66 +/- 125), standard-deviation of normal to normal RR interval (56.33 +/- 22.72 vs. 67.63 +/- 26.50), RMSSD (55.02 +/- 35.85 vs. 63.87 +/- 32.60), NN50 (42.13 +/- 29.43 vs. 51.86 +/- 29.83), PNN50 (12.67 +/- 10.29 vs. 15.27 +/- 9.71), HF (49.53 +/- 15.10 vs. 47.07 +/- 16.88), LF (41.41 +/- 13.18 vs. 46.49 +/- 15.99), LF/HF (0.98 +/- 0.53 vs. 1.26 +/- 0.90), total power (148.27 +/- 37.78 vs. 137.61 +/- 37.10)]. No significant change was seen in the above parameters between the pre-prandial state and the later phases of post-prandial state. Since there is no significant decrease in the time domain measures and the HF value between the pre-prandial and the post-prandial states, we conclude that the parasympathetic tone is not altered. The parameters denoting sympathetic tone, ie, LF and LF/HF, also do not show a significant change. This indicates that the cardiovascular autonomic tone is not affected by ingestion of meals in normal individuals. Thus we refute our hypothesis. In conclusion, the HRV parameters do not alter significantly after meals in normal individuals.

Heart rate variability in athletes and nonathletes at rest and during head-up tilt

The purpose of the present study was to determine if autonomic heart rate modulation, indicated by heart rate variability (HRV), differs during supine rest and head-up tilt (HUT) when sedentary and endurance-trained cyclists are compared. Eleven sedentary young men (S) and 10 trained cyclists (C) were studied. The volunteers were submitted to a dynamic ECG Holter to calculate HRV at rest and during a 70° HUT. The major aerobic capacity of athletes was expressed by higher values of VO2 at anaerobic threshold and peak conditions (P < 0.05). At rest the athletes had lower heart rates (P < 0.05) and higher values in the time domain of HRV compared with controls (SD of normal RR interval, SDNN, medians): 59.1 ms (S) vs 89.9 ms (C), P < 0.05. During tilt athletes also had higher values in the time domain of HRV compared with controls (SDNN, medians): 55.7 ms (S) vs 69.7 ms (C), P < 0.05. No differences in power spectral components of HRV at rest or during HUT were detected between groups. Based on the analysis of data by the frequency domain method, we conclude that in athletes the resting bradycardia seems to be much more related to changes in intrinsic mechanisms than to modifications in autonomic control. Also, HUT caused comparable changes in sympathetic and parasympathetic modulation of the sinus node in both groups.

Correlation between short-term heart rate variability indices and heart rate, blood pressure indices, pressor reactivity to isometric handgrip in healthy young male subjects.

The purpose of the present study was to determine whether readily measured blood pressure (BP) indices and, responses to autonomic reflex tests could be used as surrogates of short-term heart rate variability (HRV), which is an established marker of autonomic regulation of SA node. Therefore, we examined the correlation between short-term HRV and heart rate (HR), BP indices viz. systolic pressure, diastolic pressure, pulse pressure (PP), and rate-pressure product (RPP), during supine rest and head-up tilt in 17 young healthy normotensive subjects, aged 19.8 +/- 1 yr (mean +/- SD). Three classic autonomic indices viz. Valsalva ratio, HR response to deep breathing and pressor response to isometric handgrip were also determined. We noted two interesting and statistically significant (P < 0.05 in both cases) correlations viz. i) a positive correlation (r = 0.6) between change in RPP during tilt and change in low frequency (LF) RR spectral power expressed in normalized units (LF nu) during tilt, and ii) a negative correlation (r = -0.6) between change in PP during isometric handgrip and LF nu during tilt. The possible physiologic significance of these and other correlations is discussed in this paper. In conclusion, the presence of a statistically significant correlation between RPP, PP and spectral measures of short-term HRV supports a simplistic approach to autonomic assessment, in that, easily measurable BP indices could be used as surrogates of HRV when it is not feasible to determine HRV indices directly. However, the same have to be tested in healthy subjects belonging to various age groups and in patients with conditions known to be associated with autonomic dysregulation.

Características ultra-estruturais do nó sinoatrial de rato Wistar / Superstructural features of the wistar strain male rats' sinoatrial node (SAN)

As características ultra-estruturais do nó sinoatrial (NSA) de 5 ratos machos da variedade Wistar, com 3 meses de idade, foram estudadas por meio de microscopia eletrônica de transmissão (MET). Fragmento pequeno, contendo a região do NSA e área adjacente do átrio direito do coração, foi retirado e fixado em glutaraldeído 2,5 por cento e processado de acordo com técnica convencional para MET. A morfologia do nó sinoatrial de ratos é semelhante a de outros mamíferos. O NSA é uma estrutura anatômica independente do miocárdio atrial, constituído por células típicas (miócitos nodais, células de transição e, principalmente, células nodais) imersos em matriz extracelular, na qual predominam fibras colágenas, fibroblastos e nervos

Experimental study of assessment on ventricular activation origin and contraction sequence by Doppler tissue imaging / 华中科技大学学报（医学）（英德文版）

To evaluate the possibility and accuracy of Doppler tissue image (DTI) on assessment of normal and abnormal ventricular activation and contraction sequence, 9 open chest canine hearts were analyzed by acceleration mode, M-mode, and spectrum mode DTI. Our results showed that: (1) Acceleration mode DTI could show the origin of activation and conduction sequence on line; (2) M-mode DTI revealed that the activation in mid-interventricular septum was earlier than that in mid-left ventricular posterior wall at sinus activation; (3) Spectrum DTI showed the ventricular endocardium was activated earlier than the ventricular epicardium in all segments at sinus rhythm. The earliest site of activation of the normal ventricular wall was at middle interventricular septum; the latest site was at basal-posterior wall; the contraction sequence was different at the different walls; (4) During abnormal ventricular activation, mid-left ventricular posterior wall was activated earliest in accordance with the pacing sites. Abnormal ventricular activation was slower than sinus activation, and the contraction sequence varied at different sites of ventricular wall. It is concluded that DTI can be used to localize the origin of normal or abnormal myocardial activation and to assess the contraction sequence conveniently, accurately and non-invasively.

Estudio comparativo de los efectos de la dronedarona y la amiodarona sobre el automatismo del nódulo sinusal del conejo / Comparative study of the effects of dronedarone and amiodarone on automaticity of the sinus node of the rabbit

La amiodarona es un agente antiarrítmico de gran eficacia en el tratamiento de las arritmias supraventriculares y ventriculares. La dronedarona es un nuevo derivado de la amiodarona libre de yodo con un perfil farmacológico similar. En este estudio se comparan los efectos electrofisiológicos in vitro de la amiodarona y la dronedarona sobre preparados de nódulo sinusal del corazón de conejo. La amiodarona (30 µM) y la dronedarona (10µM) prolongaron la longitud del ciclo espontánea y disminuyeron la amplitud del potencial de acción y la pendiente de la fase 4. En este modelo, la presencia de dronedarona no modificó la intensidad de la respuesta automática ante la exposición a isoproterenol. La dronedarona, como la amiodarona, deprime el automatismo sinusal, debido probablemente a un mecanismo de bloqueo cálcico

Baroreflex control of sympathetic activity in experimental hypertension

The arterial baroreceptor reflex system is one of the most powerful and rapidly acting mechanisms for controlling arterial pressure. The purpose of the present review is to discuss data relating sympathetic activity to the baroreflex control of arterial pressure in two different experimental models: neurogenic hypertension by sinoaortic denervation (SAD) and high-renin hypertension by total aortic ligation between the renal arteries in the rat. SAD depresses baroreflex regulation of renal sympathetic activity in both the acute and chronic phases. However, increased sympathetic activity (100 percent) was found only in the acute phase of sinoaortic denervation. In the chronic phase of SAD average discharge normalized but the pattern of discharges was different from that found in controls. High-renin hypertensive rats showed overactivity of the renin angiotensin system and a great depression of the baroreflexes, comparable to the depression observed in chronic sinoaortic denervated rats. However, there were no differences in the average tonic sympathetic activity or changes in the pattern of discharges in high-renin rats. We suggest that the difference in the pattern of discharges may contribute to the increase in arterial pressure lability observed in chronic sinoaortic denervated rats.

Influence of stimulatory parameters on simus node recovery time: an in vitro study

The effects of pacing frequency, overdrive duration and stimulus amplitude on the sinus node recovery time (SNRT) were studied in the isolated right atrium of the rat. a positive relationship between pacing frequency and the SNRT was observed, whereas overdrive duration ans stimulus amplitude did not affect SNRT. There was no significant interaction among the factors studied. The effect of frequency upon SNRT probably does not involve neurotransmitter release due to stimulation, since in vitro pretreatment with atropine plus propranolol does change the SNRT - frequency relation

A modified technique for canine sinoatrial node autoperfusion

En el presente trabajo se propone un nuevo modelo experimental para la autoperfusión del nódulo sinusal canino, basado en el originalmente descripto por James y Nadeau, con modificaciones que, a nuestro juicio, lo hacen más ventajoso. Se realizó un cortocircuito entre las arterias mamaria interna y auricular dorsal derecha. Esta última, en un 82% de los perros, es la arteria dominante en la irrigación del nódulo. Midiendo la velocidad de avance del colorante se calculó el flujo sanguíneo del cortocircuito, que fue de 2.5ñ0.15 ml/m. Cuando se inyectaron en el "by-pass" tanto isoproterenol como verapamil, se produjeron rápidos cambios en la frecuencia cardíaca, sin que se observaran modificaciones apreciables en el comportamiento eléctrico del resto del miocardio. Ello se puede constatar a través del electrocardiograma y de los registros endocavitarios. Este modelo de autoperfusión sinusal deja la circulación coronaria intacta, a diferencia de James y Nadeau, que introduce el catéter en la arteria coronaria derecha. El cortocircuito intratorácico reduce la pérdida de calor y disminuye la posibilidad de aparición de coágulos dentro del catéter. El modelo es apropiado tambíen para estudios experimentales crónicos