Sinus Node Refractoriness Research Articles

Postoperative Sinus Node Dysfunction in the Transplanted Heart: Impaired Automaticity but Normal Refractoriness

We describe the use of the extrastimulus technique to define the range of sinus node (SN) effective refractoriness (SNERP) in the denervated transplanted human heart. SNERP could be successfully determined in 18 of 28 patients corresponding to 25 of 43 SN studies and ranged from 210 to 360 ms at a basic pacing cycle length of 500 ms (95 percent confidence limits: 252.5 to 296.2 ms), which is shorter than reported in the innervated native heart. Sixteen data sets in 12 patients showed normal SN function and nine sets of measurements in seven patients showed abnormal SN function (corrected SN recovery time greater than 520 ms). While recovery time was profoundly abnormal (279.7 +/- 94 vs 7,284.8 +/- 10,454, p less than 0.001), the SNERP did not differ significantly between the groups (274.3 +/- 40 vs 286 +/- 42 ms at 500 ms, p = 0.5) and was normal at a range of 220 to 340 ms even in those patients with grossly impaired SN recovery (SNERP in patients with normal SN function: 210 to 360 ms at 500 ms). This study demonstrates that SN refractoriness in the transplanted human heart is shorter than previously reported in innervated controls and suggests that posttransplantation SN dysfunction is characterized by impaired automaticity rather than impaired refractoriness.

Evidence suggesting time-dependent recovery of excitability in the in vivo human sinus node

The sinus node (SN) possesses the properties of automaticity and conduction. Automaticity arises in its dominant and latent pacemaker cells and results from both time and voltage-dependent ionic currents as shown by in vitro studies. 1,2 Conduction is required for propagation of the generated impulse. Both automaticity and conduction can be assessed in vivo by way of clinical electrophysiologic studies, as well as in vitro. 3,4 The SN also displays excitability; i.e., the ability for an action potential to be produced by an applied stimulatory current. 1,2 In the SN, in vitro studies have shown that the recovery of excitability, the ability of a cell to be reexcited by a subsequent application of current, is also both voltage-dependent, typical of all cardiac tissues, and time-dependent, characteristic of only “slow response” fibers. 1,2 Time-dependent recovery outlasts voltage-dependent recovery; thus, SN cells cannot be reexcited by a stimulatory current (are “refractory”) despite a return of membrane potential to baseline voltage until time-dependent recovery has also been achieved. 1,2 Unlike automaticity and conduction, recovery of SN excitability has not been directly studied in humans since clinical electrophysiologic studies have not encompassed the ability to directly stimulate the SN and verify such stimulation. Nevertheless, one might expect that similar mechanisms would be operative in vivo as in vitro. In the 1980s, 2 developments occurred which bear on the ability to assess excitability in vivo. The first was the recognition and verification that SN refractoriness could be studied through retrograde activation 5–8 (i.e., the responses to atrial premature stimuli can be analyzed to determine the coupling interval at which retrograde penetration of the SN is lost and the complexes become interpolated). Interpolation has been shown to occur when SN refractoriness is encountered. 5 The second was the development of SN electrography 9–12 and the documentation that the extracellular, transcatheter SN electrogram truly reflects the action potentials occurring in the underlying SN. We believe these 2 developments could be combined to indicate whether time-dependent recovery of SN excitability exists in vivo. If SN refractoriness outlasts the voltage excursions of the SN depolarization on the SN electrogram, time dependence of recovery of excitability is suggested.

Effects of acetylcholine, propranolol, and verapamil on sinus node refractoriness of the rabbit.

At a critical premature interval, atrial premature beats encounter sinus node refractoriness and are blocked on entering and fail to reset the sinus node, resulting in interpolation of the premature beat. The transition from reset to interpolated response has been used to define the effective refractory period of the sinus node (SNERP). In an in vitro preparation of rabbit sinus node, we evaluated the effects of acetylcholine, propranolol, and verapamil on SNERP. Results obtained in the control state were compared with those obtained during superfusion with drugs, all of which prolonged refractoriness: acetylcholine from 233 +/- 41 (SD) to 325 +/- 88 ms; propranolol from 215 +/- 60 to 241 +/- 67 ms; and verapamil from 192 +/- 69 to 254 +/- 79 ms (p less than 0.005 with all drugs). The site of block of premature beats was mapped between sinus node and crista terminalis with an intracellular microelectrode. All three drugs resulted in block of premature beats at sites farther from the primary pacemaker site. Thus, acetylcholine, propranolol, and verapamil prolong sinus node refractoriness.

CHARACTERIZATION OF SINUS NODE REFRACTORINESS AND SINOATRIAL CONDUCTION DURING ACUTE HYPOXIA

Since hypoxia inhibits conduction & automaticity predominantly in tissues dependent on the slow (Ca-channel) current, sinus node (SN) function should be selectively depressed. The effects of acute, severe hypoxia (H) on SN refractoriness and sinoatrial conduction time (SACT) were studied using rabbit SN-right atrial preparations and standard micro-electrode techniques. True SN pacemaker cells were identified by intracellular action potentials having low amplitude (65±7mV) and Vmax (3.3±1.0 V/s), and rapid rates of spontaneous diastolic depolarization (51±15 mV/s). Spontaneous sinus cycle length (CL) (control = 460±58ms) increased by 36% with H. Retrograde SACT, measured from the crista terminalis to a true SN pacemaker cell, was rate dependent; increasing at shorter paced CL. SACT increased at all paced CL with H. At a CL of 400ms, SACT increased from 41±12 to 101±19ms (+146%). The minimum paced CL with 1:1 atrio-SN conduction (CLm) increased from 203±34 to 308±41ms (+52%) with H. SACT at CLm increased from 65±19 to 134±30ms (+105%). SN effective refractory period (ERP)(at a paced CL of 400ms) increased from 158±37 to 261±45ms (+66%). All changes in SN function related to H were significant (at least p<0.05). SN pacing from the crista terminalis was never limited by atrial muscle conduction (fast, Na-channel dependent) or refractoriness. Atrial ERP changed from 86±14 to 96±20ms (NS) with H. In summary, acute H adversely affects SN automaticity, conduction and refractoriness; presumably related to alterations in the Ca current. These changes may be responsible for many of the bradyarrhythmias seen clinically during severe H.

Effect of basic pacing cycle length on sinus node refractoriness in the rabbit

The effect of basic pacing cycle length on sinus node refractoriness was investigated. In 18 rabbit right atrial preparations, the sinus node effective refractory period (SNERP) was measured at multiple basic pacing cycle lengths. In 14 experiments SNERP was measured at basic pacing cycle lengths of 400, 350 and 300 ms. The mean SNERP (±standard deviation) prolonged from 168 ± 31 ms at 400 ms to 181 ± 37 ms at 350 ms to 196 ± 40 ms at 400 ms (p < 0.001). To rule out the possibility that rapid stimulation might release acetylcholine and thus prolong refractoriness, 4 more experiments were conducted in the presence of atropine (2 × 10 −6 M), and similar results were obtained. The spatial orientation of refractoriness was examined in 7 experiments. At the same premature interval, shorter basic pacing cycle lengths resulted in block of the premature impulse at a greater distance from the sinus node. Therefore, in sinus node tissue refractoriness increases with shortening of basic pacing cycle length, a response similar to that of the atrioventricular node.

The measurement of sinus node refractoriness in man.

We recently described a method for measuring sinus node refractoriness in the rabbit heart. Atrial premature beats either may result in reset return responses or may become interpolated because of encroachment on sinus node refractoriness. In previous studies with rabbits we defined the effective refractory period of the sinus node (SNERP) as the longest premature interval that is interpolated. This study presents results on the extension of this technique to the measurement of sinus node refractoriness in man. Out of 30 patients (12 with and 18 without sinus node dysfunction), SNERP could be measured in 26 at one or more basic cycle lengths. At a basic pacing cycle length of 600 msec, SNERP ranged from 250 to 380 msec (mean 325 +/- 39) in patients without sinus node dysfunction and from 500 to 550 msec (mean 522 +/- 20) in patients with sinus node dysfunction. This clear differentiation of patients with and without sinus node dysfunction by SNERP is in contrast to various results obtained by assessing sinus node function from sinus node recovery time and sinoatrial conduction time. Thus this study suggests the possible use of the measurement of SNERP in the assessment of sinus node function in man and its possible value in identifying patients with sinus node dysfunction.