Summary
The growing interest in dyssynchrony and cardiac resynchronization therapy has opened the field of cardiac stimulation to new haemodynamic indications. French investigators have played a key role in the formulation of new concepts, all arising from clinical observations, and the development (in collaboration with industry) and clinical evaluation of resynchronization devices. This review summarizes recent knowledge and perspectives pertaining to atrial, atrioventricular and ventricular dyssynchrony and resynchronization. Some of these concepts have been validated by robust clinical evidence, on the basis of which scientific recommendations have been formulated. Other concepts have been less successful but probably merit further attention.
Résumé
L’intérêt pour la désynchronisation et la resynchronisation cardiaque n’a cessé de croître, permettant d’élargir le champ de la stimulation à de nouvelles indications hémodynamiques. Les équipes françaises ont joué un rôle moteur dans la définition de ces concepts nouveaux, tous nés de l’observation clinique, dans la conception des outils de resynchronisation en lien avec l’industrie, et dans leur évaluation clinique. Cette revue se propose de faire la synthèse des connaissances récentes sur la désynchronisation et la resynchronisation cardiaque aux trois étages, atrial, atrioventriculaire et ventriculaire, et de dresser quelques perspectives d’avenir.
Atrioventricular dyssynchrony and resynchronization
The first cardiac pacemaker was implanted at Stockholm’s Karolinska hospital in 1958, for the treatment of syncope due to complete AV block. The 57-year-old recipient survived for 43 years thereafter, consumed 24 pulse generators, lived comfortably and remained active and free from HF, despite the ventricular dyssynchrony caused by single-chamber ventricular pacing. Other less fortunate patients have not tolerated the cardiac dyssynchrony due to ventricular pacing. Identification of patients prone to developing cardiac dysfunction after ventricular pacing remains an important challenge for clinical practice.
For a quarter of a century, the only indication for cardiac pacing was the management or prevention of symptoms due to bradycardia; its adverse effects on cardiac mechanical function, which could not be circumvented, were overlooked. At that time, the only pacing mode applicable was VVI, perpetuating AV dissociation and asynchronous ventricular contraction. The first attempts at cardiac resynchronization were made in the 1960s, with the advent of atrial synchronous pacemakers, followed, in 1981, by the first DDD pacing system. ‘Physiologic’ stimulation was born, which restored AV synchrony and chronotropic function.
Symptomatic, high-degree, atrioventricular block: the prime indication for cardiac pacing
Symptomatic, high-degree, AV block remains the most prevalent (> 40%) of all pacing indications. The mean age of French patients paced for this indication, usually due to degenerative disease, is 80 years . In the presence of normal sinus node function, a DDD pacemaker restores the atrial contribution to ventricular filling and preserves the physiological heart rate adaptation. An alternative choice is single-chamber VVIR pacing, which does not eliminate AV dyssynchrony, although it restores chronotropic function with rate-responsive sensors.
What is the true impact of atrioventricular resynchronization in clinical practice?
The long-debated question of clinical superiority of DDD pacing over VVIR pacing has been answered only recently. After a French controlled study failed because of lack of support from the medical community and its industrial partners, 20 years elapsed until the publication of the UK-PACE trial, which showed that, in older patients, ‘physiologic’ pacing conferred no benefit compared with VVI or VVIR pacing in terms of overall survival (primary criterion) or cardiovascular morbidity, including HF, cerebral vascular accidents, atrial fibrillation, etc. .
Furthermore, the risk/benefit ratio was unfavourable to DDD pacing, which was associated with an 8% rate of major, procedure-related complications versus 4% with VVI or VVIR pacing. Despite being the land of Descartes, France paid little attention to these observations and the proportion of DDD/DDDR pacing systems continued to increase steadily, reaching 75% of implants in 2009 !
Patients with a symptomatic long PR interval may benefit from atrioventricular resynchronization
A subgroup of highly incapacitated patients owe their disability and symptoms to a markedly prolonged PR interval, which, as a result of non-adaptation to exercise, causes left heart mechanical AV dyssynchrony, which increases proportionally to heart rate acceleration . A typical example at rest is illustrated in Fig. 1 . When properly selected, these patients derive a major functional benefit from DDD pacing, despite the ventricular dyssynchrony it creates. This haemodynamic indication has been included as a class IIa recommendation in the practice guidelines issued by international professional societies .
Atrial dyssynchrony and resynchronization
Disorders that cause progressive left atrial dilatation, such as long-standing hypertrophic cardiomyopathy and hypertensive heart disease, are often associated, during sinus rhythm, with major intra-atrial conduction abnormalities. The most extreme form is complete interatrial block, with P waves more than 120 ms in duration, opposite axes of the initial vectors reflecting normal activation of the right atrium and late vectors reflecting retrograde and delayed activation of the left atrium ( Fig. 2 A). These patients are at high risk of atrial tachyarrhythmias – mainly left atrial flutter and HF . LV ejection fraction in usually preserved or only slightly impaired in these patients. This atrial dyssynchrony can be remedied by biatrial stimulation, which implies the implantation of a coronary sinus lead to stimulate the lateral or posterolateral wall of the left atrium . Atrial resynchronization devices have been built, along with an algorithm, to sense sinus activity in the right atrium and trigger synchronous left atrial stimulation ( Fig. 2 C). It became readily apparent that atrial resynchronization improves AV synchrony in the left heart as well as the global mechanical performance of hypertrophied and non-compliant left ventricles ( Fig. 3 ).
The clinical usefulness of atrial resynchronization has remained unproven despite results of long-term observational studies suggesting clinical benefit . The negative results of SYNBIAPACE – the only controlled, crossover study of atrial resynchronization conducted in the early 1990s – were never published. It should, however, probably be pursued. SYNBIAPACE was methodologically weak and used atrial fibrillation burden as a primary study endpoint, when the expected clinical benefit was haemodynamic instead of antiarrhythmic. We will follow with much interest the imminent revival of a controlled study by other French investigators, who will examine the effects of atrial resynchronization in HF in the presence of a preserved ejection fraction .
Ventricular dyssynchrony and resynchronization
Three different concepts will be discussed: prevention of ventricular dyssynchrony, deliberate ventricular dyssynchrony and ventricular resynchronization.
Prevention of ventricular dyssynchrony
Over 50% of approximately 60,000 pacemakers implanted annually in France are used to treat isolated sinus dysfunction or bradycardia-tachycardia syndrome . Nearly all of these patients are paced incessantly at the atrial level, either in single-chamber AAI-AAIR mode, if AV conduction is preserved, or in dual-chamber DDD-DDDR mode, which is considered safer but is associated with a risk of unnecessary and deleterious asynchronous ventricular pacing. In the early 1990s, two mechanistic studies compared the effects of DDD pacing with ventricular capture versus atrial pacing alone, in recipients of dual-chamber pacemakers implanted for sinus node dysfunction . These studies showed that asynchronous activation due to ventricular capture caused considerable degradation of global and septal LV function, accentuated by exercise.
Subsequent observational and controlled clinical studies confirmed the suspicion of long-term adverse effects and higher morbidity and mortality caused by ‘forced’ ventricular pacing . To prevent unnecessary ventricular capture, state-of-the art pacing systems incorporate specific algorithms that confine pacing to the atrial level, as long as intrinsic AV conduction is preserved. AAI SafeR, the first such algorithm, was developed in France. The clinical merit of one these algorithms was confirmed in a large controlled trial, which revealed a decreased incidence of atrial fibrillation in particular .
Deliberate ventricular dyssynchrony: the particular case of obstructive, hypertrophic cardiomyopathy
Obstructive, hypertrophic cardiomyopathy is the only cardiac disorder that might benefit from ventricular dyssynchrony. Original clinical observations were made in France by Gilgenkrantz et al. in the 1960s . Pre-excitation of the right ventricular apex reverses septal activation and delays the systolic thickening of the basal septum, decreasing or eliminating the systolic obstruction ( Fig. 4 ). This effect requires the coexistence of complete ventricular capture, manifest on the electrocardiogram by the widest paced QRS, and the preservation of normal AV synchrony in the left heart to promote optimal atrial contribution.
