Treatment of Sick Sinus Syndrome
F. DORTICÓS1, M.A. QUIÑONES1, F. TORNES1, Y. FAYAD1, R. ZAYAS1, J. CASTRO1, A. BARBETTA2, F. DIGREGORIO2
Introduction
Cardiac rate adaptation to changes in metabolic demand for blood supply is essential for the optimisation of exercise capacity and general well-being, especially for people inclined to an active life-style. Since patients affected by sick sinus syndrome often present with different forms of chronotropic incompetence [1], dual-chamber rate-responsive pacing is usually indicated in the electrical treatment of this disease. Sensors of various kind are cur- rently applied to regulate the pacing rate, but the ideal goal to precisely meet the physiological needs by an artificial control system has not yet been fully achieved [2]. Indeed, activity sensors, which are generally based on an accelerometer, are highly sensitive and quickly reactive during dynamic exercise, but they cannot detect conditions of isometric exercise, post-exer- cise recovery, or mental stress, which would normally entail cardiovascular compensation. In addition, the accelerometer indications are not specific, since the sensor can induce a rate increase even in response to passive move- ments. Sensors designed to record changes in physiological parameters indi- cating exercise or fatigue, such as minute ventilation, are more specific, but usually slow and less sensitive. Sensors of different manifestations of adren- ergic tone, e.g. Q–T interval, pre-ejection interval, unipolar ventricular impedance, and peak endocardial acceleration (PEA), generally provide a good approximation of the expected rate regulation [3–6], but may require complex hardware [7], can be affected by positive feedback from the pacing rate itself [8], or may be unreliable under particular conditions [9].
1Department of Arrhythmias and Cardiac Pacing, Institute of Cardiology and Cardio- vascular Surgery, La Havana, Cuba;2Medico Clinical Research, Rubano (Padua), Italy
A new and interesting advancement in sensor technology is the applica- tion of trans-valvular impedance (TVI) in the assessment of cardiac haemo- dynamics. TVI is the impedance recorded between the right atrium and ven- tricle with standard pacing electrodes that can be either in contact with the myocardium or floating in the blood [10, 11]. It is well-known that cardiac impedance changes in-phase with the cardiac cycle, in a fashion suggesting an inverse correlation with the ventricular volume. This relationship can be applied to infer relative modifications in end-diastolic volume (EDV), end- systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) from absolute impedance measurements [12, 13]. Simultaneous monitoring of SV and preload can account for the influence of intrinsic heart regulation on myocardial contraction, as predicted by Starling’s law. The fraction of SV changes that is not ascribed to the preload effect represents the adrenergic component of inotropic regulation [14–16], which can be correlated with the sinus rate in patients endowed with physiological chronotropic competence [17, 18]. Impedance measurement in trans-valvular configuration is especial- ly suitable for the practical implementation of this haemodynamic model, since the TVI signal is quite stable and allows reliable DC recording. The the- oretical expectation has been confirmed by previous experience demonstrat- ing that end-diastolic TVI decreases under conditions of increased preload and increases when preload is reduced, while end-systolic TVI and signal peak-to-peak amplitude are increased by adrenergic stimulation [15, 17–19].
In addition to the development of advanced novel sensors, the current strat- egy for rate-responsive pacing improvement is oriented toward matching dif- ferent sensors together, thus extending the sensitivity to a variety of different conditions and increasing the reliability of the system, thanks to sensor cross- checking [20, 21]. This principle has been applied in the design of a new dual- chamber rate-responsive pacemaker (Sophòs 100 by Medico) that is equipped with the TVI sensor integrated by an accelerometer. Pilot implantations of this device have been done in our center, with the aim of testing the effectiveness of rate adaptation in patients affected by sinus node disease.
Materials and Methods
The study was approved by the local Ethical Committee and the enrolled patients provided written informed consent. Seven patients presenting with sick sinus syn- drome, marked bradycardia at rest, and depressed chronotropic response were im- planted with the DDD-R pacemaker Sophòs 100 along with the atrial lead mod- el 366 and the ventricular lead model 340 (Medico, Padua, Italy), positioned in the right atrial appendage and the right ventricular apex, respectively. Both leads are tined bipolar and bear porous Ti electrodes coated with Pt.
The TVI measurement is obtained by the application of subthreshold square-current pulses of 125-μs duration and amplitude automatically adapted to the detected impedance, up to a maximum of 45 μA. With a dual- lead system, TVI can either be derived between the ring atrial electrode and the tip ventricular electrode (Ar-Vt configuration) or between the ring atrial electrode and the ring ventricular electrode (Ar-Vr configuration). The most appropriate recording configuration is chosen in each patient after evalua- tion of the TVI waveform transmitted by telemetry, selecting the signal with the most physiological timing (minimum TVI in telediastole and maximum peak at the end of the T wave) and the best signal-to-noise ratio are chosen.
The minimum and maximum TVI in each cardiac cycle are processed to get the current values and the reference resting values. The comparison of rest- ing and current parameters provides information on myocardial contractili- ty changes, which are expressed by the TVI inotropic index. Pacing rate changes above the basic rate are proportional to the inotropic index, with a slope specified by the individual rate-gain.
The rate-response profile of the accelerometric sensor corresponds to a dual-slope linear increase in pacing rate as a function of the acceleration detected in excess of a programmable threshold. The first slope is specified by the difference between the pacing rate associated with moderate activity (snap rate) and the basic rate, while the second slope results from the differ- ence between the sensor upper rate and the snap rate. In the Sophòs 100 rate- responsive system, the accelerometer and the TVI sensor are closely interde- pendent and sensor cross-checking is applied since at the early stages of the processing procedure, to cut down the risk of false-positive reactions. In addition, the indications provided by each of the two sensors can be blended in programmable proportion to obtain the final pacemaker rate.
The present study was designed to assess the effectiveness and reliability of the pacemaker sensors in daily living and during different types of physi- cal activity, including walking, biking, and stair climbing. The latest follow- up check was performed at 6, 4, and 2 months from the implantation in four, one, and two patients, respectively, and comprised technical tests of the pace- maker, physical stress tests under controlled conditions, and 24-h Holter monitoring. Data are presented as mean ± SD; the statistical significance of differences was evaluated by two-tailed paired Student t test.
Results
Regular pacemaker operation was confirmed throughout the observation period, although the entire patient group could be checked only at 2-months follow-up, due to the different implantation times. Pacing function was test-
ed in unipolar mode, while sensing was assessed in bipolar mode. Atrial and ventricular pacing threshold at 2 months averaged 2.0 ± 0.7 and 1.7 ± 0.8 V, respectively. Atrial and ventricular sensing threshold averaged 1.9 ± 1.3 and 5.3 ± 2.4 mV, respectively. Neither pacing nor sensing threshold was affected by turning on the pacemaker sensors.
The sensitivity of the accelerometric sensor was tested in standard con- figuration during a short (3-min) fast walk. The maximal rate indicated by the accelerometer under exercise conditions ranged from 88 to 138 bpm (mean 109 ± 17), with the average time-course shown in Fig. 1. With stan- dard kinetic regulation, the time taken to reach the maximal rate indicated by the accelerometer after exercise start and to return to the basic rate after exercise end was in the order of 90 s.
The response of the haemodynamic sensor was assessed by fast walking for 6–15 min, which entailed a clear-cut increase in end-systolic TVI and peak-to-peak amplitude of the TVI signal (Fig. 2). As a result, the TVI- derived inotropic index was significantly increased with respect to resting conditions (Fig. 3). The time-course of pacing rate adaptation in a represen- tative patient is shown in Fig. 4. In this case, the TVI sensor was in Ar-Vt configuration, with TVI rate gain set at 0.375 and standard kinetic regula- tion. Little changes in rate were induced by the transition from supine to standing up position, while the start of exercise triggered a quick rise in the TVI-indicated rate, which was completed in less than 2 min. This fast reac-
Fig. 1.Average accelerometer indicated rate (thick line) ± 1 standard deviation (thinner lines) in the entire patient group during fast walk. The activity started at 1 min and lasted for 3 min
Fig. 3.Group mean ± 1 standard deviation of the maximum inotropic index (Inx) recorded in the supine position, standing up at rest, and standing up at the end of a 6- to 15-min fast walk. The exercise induced increase in Inx is statistically significant (*P < 0.05)
Fig. 2.Pacemaker event markers and TVI waveform transmitted to the programmer by teleme- try. Upper panel DDD pacing with the patient standing up at rest; lower panel atrium-driven pacing with the patient stand- ing up still after walking for 15 min. Note the increase in maxi- mum TVI and signal peak-to- peak amplitude induced by physical stress
tion was followed by a slower rate increase as a function of exercise duration.
When the patient stopped exercising, the TVI-indicated rate remained ele- vated in the early recovery phase and progressively decreased thereafter, so that 50% of the maximal rate increase was removed in about 4 min.
All patients also underwent a stair-climbing test (three storeys, repeated twice), which increased the inotropic index from 0.14 ± 0.10 (maximal value recorded at rest) to 0.85 ± 0.52 (P < 0.05). In some cases, an incre- mental stress test with the ergometric bicycle was also performed, increasing the exercise power in 25-W steps every 3 min. Under such conditions, the TVI inotropic index progressively increased as a function of time, with a response proportional to the exercise energy cost (Fig. 5).
The TVI- and accelerometer-indicated rate trends were recorded in each patient in 24 h of daily living. The indications of the two sensors were gen- erally consistent and allowed a clear discrimination of periods of rest and activity (Fig. 6). Sensor blending and cross-check further improved the specificity of the rate-responsive system (Fig. 7). Simultaneous Holter moni- toring did not show any evidence of tachycardia due to inappropriate pacing, thus both sensors were left permanently enabled with standard settings in all patients.
Fig. 4.Time-course of TVI-indicated rate in a patient undergoing a fast-walk test (same case as in Fig. 2). The patient was lying in supine position in the first 3 min, during which he was paced at the basic rate. In the next 3 min (interval between the first two arrows), the patient was standing upright without moving. Thereafter, he walked at his maximum speed for 15 min: the third arrow marks the exercise end. In the following recovery stage, the patient was standing up again with no motion. At the end of the stress, the acquisition was broken for few minutes to allow TVI waveform recording (Fig. 2, lower panel). See text for details and comments
Fig. 5.Inotropic index (Inx) as a function of time, during incremental stress test with the ergometric bicycle. The power was increased in 25-W steps every 3 min. The Inx trend is described by the regression line: Inx = 0.057*min – 0.028, with r2 = 0.76 and stan- dard error of the slope = 0.004
Fig. 6.Whole group mean ± standard deviation of the rate indicated by the TVI sensor, by the accelerometer sensor, and applied by the pacemaker (PM) after 50–50 sensor blending, in day-time (white bars) and night-time (grey bars). All differences between day-time and night-time rates are statistically significant (P < 0.01)
Discussion
Rate-responsive systems relying on haemodynamic sensors adapt the pac- ing rate following changes in inotropic tone, with the aim of restoring the correlation between cardiac rate and myocardial contractility, which is ensured by the extrinsic regulation of the heart under physiological condi- tions. Usually, haemodynamic sensors can detect different manifestations of the ventricular contraction strength, like the right ventricular dP/dt, the pre-ejection interval, the peak endocardial acceleration, and the unipolar ventricular impedance waveform [3, 22–25]. It is well-known, however, that contraction strength is not a univocal reflection of contractility modula- tion, since it is also heavily affected by ventricular preload, which can change independently of the autonomic nervous system input [14, 16]. TVI is the first sensor that takes into account the influence of cardiac intrinsic regulation on haemodynamic performance, by monitoring SV and preload at the same time [17–19]. This feature improves the specificity of the rate- responsive system, preventing undue pacing-rate modifications induced by postural changes [9]. Integration with the accelerometer makes the dual- sensor system even more sensitive and selective, as suggested for other haemodynamic sensors [26].
Our experience confirms that TVI sensor shows a physiological response to physical activity and is characterised by quick rate adaptation at exercise onset and additional modulation reflecting increasing fatigue. After the stress, the TVI-indicated rate decreases slowly, supporting the patient in the recovery phase [27]. In daily life, the pacemaker rate-responsive system effectively discriminates periods of rest and activity, avoiding at the same Fig. 7.Trends of the rate indicated by the accelerometer (open triangles) and the TVI sen- sor (open circles) in a 24-h observation of a representative patient. The rate actually applied by the pacemaker (PM) after sensor cross-checking and 50–50 blending is indi- cated by the marked curve
time high rate pacing. The activation of the TVI sensor, which implies the application of sub-threshold current pulses to allow impedance sampling, does not influence the basic pacemaker functions of pacing and sensing. As a result, the implanted device proved effective and reliable throughout the fol- low-up.
Haemodynamic monitoring may have several applications in permanent cardiac pacing besides rate regulation, including confirmation of ventricular activity, optimisation of pacemaker configuration, and assessment of the patient’s clinical condition and response to the therapy [19, 28]. These addi- tional features will be available in forthcoming devices of the Sophòs family, which promise to be a breakthrough in pacing technology and advanced new tools in the medical care of pacemaker patients.
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