Pathophysiology of Physiologic Cardiac Pacing: Title and subTitle BreakAdvantages of Leaving Well Enough Alone

The implantable cardiac pacemaker was first introduced in 1960, with a primary goal of maintaining adequate heart rates in individuals with symptomatic bradycardia. In such patients, single-ventricle stimulation was effective even though it was suboptimal from a physiologic standpoint. However, with sustained bradyarrhythmia requiring frequent ventricular activation, problems with this approach became apparent. Ventricular pacing disrupted the normal temporal sequence of atrial-ventricular systole, resulting in AV-dissociation, mitral and tricuspid valvular regurgitation, and cardiac cycles with variable filling and thus systolic dysfunction. For patients in whom cardiac performance was compromised, loss of effective atrial contraction and elevated filling pressures worsened symptoms.

The first solution to this problem came in the late 1970s with development of dual-chamber pacing, whereby native atrial activation was either sensed or provided if it did not occur at a preset rate, and subsequent ventricular activation was then timed to maintain more physiologic coordination between the chambers. Now ventricular stimulation would be used only in patients with more distal conduction delay, whereas pure sinus bradyarrhythmia could be dealt with by atrial stimulation alone. Dual-chamber pacing, with better maintenance of normal-range atrial rates and atrioventricular timing, has been shown to reduce clinical symptoms of cardiac failure, enhance quality of life, and help prevent arrhythmias such as atrial fibrillation.^{1 - 2} These issues are important as the prevalence of bradyarrhythmias has increased with more patients living to advanced age and with more widespread use of β-blockers and antiarrhythmic agents.

One group of patients that has routinely received pacemakers even in the absence of bradycardia consists of those with severe ventricular arrhythmia requiring treatment with an implantable cardioverter defibrillator (ICD). These devices have long been coupled with pacemakers to deal with bradyarrhythmia that might occur immediately following any cardioversion and to provide minimum backup stimulation. While their effectiveness has largely been established with single-chamber backup pacing,^{3 - 4} most currently implanted ICDs come with dual-chamber devices, which has opened the window for more frequent pacing.⁵ But is this necessarily a good idea?

In this issue of THE JOURNAL, the DAVID Trial investigators addressed this question.⁶ They studied 506 patients with a primary or secondary indication for ICD therapy, none requiring pacing for bradyarrhythmia and all with evidence of ventricular dysfunction. Nearly 85% had ischemic heart disease and 70% had a prior myocardial infarction. All patients received a combined ICD/dual-chamber pacemaker and were randomly assigned to either ventricular-only backup pacing (VVI-40: 40/min lower rate) or dual-chamber rate-responsive pacing (DDDR-70: 70/min lower rate). The trial was terminated early when the data and safety monitoring board determined the conditional power to find dual-chamber pacing as superior fell below 10%, whereas the opposite outcome—that DDDR-70 was actually worse for patients—appeared to be the case. Hints for this result were evident early because the incidence of new or worsened congestive heart failure (CHF) was greater in the DDDR-70 group than in the VVI-40 group even before discharge from the initial hospitalization. At the 18-month follow-up, DDDR-70 patients had an approximately 60% higher relative probability of death or hospitalization for new or worsened CHF compared with VVI-40 patients (P≤.03). Component end points were just short of statistical significance, but trended similarly.

Why the unexpected findings? Important clues that might explain the study outcome derive from features of the patient population. None of the patients had a primary indication for bradycardia pacing, despite nearly 90% receiving β-blockers and 25% to 30% receiving antiarrhythmics (principally amiodarone). Thus, independent of the mode of pacing, the backup rate settings resulted in a marked disparity in the percentage of ventricularly paced beats. In the VVI-40 group, pacing accounted for approximately 1% of all beats, whereas in the DDDR-70 group nearly 60% of all beats were paced. Some DDDR-70 patients also received atrial pacing without subsequent ventricular activation (normal distal conduction). Also, only a minority of patients (<30%) had underlying bundle-branch block conduction delay.

The problem with DDDR pacing is that what is achieved via improved rate response and atrial-ventricular synchrony is countered by the more frequent delivery of single-site ventricular stimulation. In patients with intrinsically normal distal conduction, single-chamber pacing generates conduction delay coupled with mechanical dyssynchrony and chamber dysfunction.⁷ The paced region displays early contraction at a time of low load, but then is stretched later in systole as the lateral wall finally contracts.⁸ The result is an increase in end-systolic volume and wall stress, reduced systolic function and cardiac output, and energetic inefficiency.^{9 - 10} The latter could be particularly troublesome in patients with coronary artery disease (>80% of the patients in the DAVID study) because the energy supply-demand balance is likely already compromised. The more frequent the pacing, the more likely cardiac performance is compromised. The DAVID Trial did not examine a group of patients in whom DDDR was also set to the lower backup rate of 40/min (eg, DDDR-40). However, because only a very small percentage of total beats were paced in these patients at the lower backup rate, one would expect little if any difference in clinical outcome between DDDR-40 and VVI-40.

The importance of cardiac mechanical dyssynchrony has been recognized recently in patients with CHF and has led to a novel treatment termed cardiac resynchronization.¹¹ This therapy typically involves placement of 2 ventricular leads (biventricular pacing), one in the mid-lateral wall via a cardiac vein and the other in the right ventricular apex or mid-septum. Atrial stimulation is generally sensed followed by premature stimulation of both lower chambers simultaneously or with a small interventricular delay. Resynchronization improves mechanoenergetic efficiency and systolic function and reduces systolic wall stress.^{12 - 14} Longer-term studies of cardiac resynchronization have revealed symptomatic and exertional improvements and reduction in rehospitalization for worsening heart failure.^{15 - 17}

This observation raises an interesting question—should patients receiving an ICD also receive biventricular pacing rather than single-chamber DDDR, or should native conduction be permitted as much as possible by simply lowering backup rates? On the basis of present data, it is difficult to argue for the former more complicated solution, particularly for patients in whom bradypacing is minimally required. Even if biventricular pacing at a rate of 70/min was better than DDDR-70, it would first have to reverse a substantial disadvantage found in the DAVID Trial of DDDR compared with VVI-40 pacing. It is far from clear that more frequent pacing at slightly higher than the native atrial rate is advantageous. Acute increases in heart rate alone typically do little to enhance cardiac output because they are concomitantly coupled with a slight decline in per-beat stroke volume.¹⁸ Furthermore, preexcitation of the ventricles requires a shortened AV delay, and while this can be beneficial in patients with a long intrinsic conduction delay (eg, >250 ms) by enhancing diastolic filling and reducing mitral regurgitation if present,¹⁹ it is detrimental to those with normal delays because it diminishes atrial pump action. Moreover, biventricular pacing is not a perfect substitute for native His-Purkinje stimulation because it involves intramyocardial and thus slower conduction.

Virtually all studies to date revealing benefits of biventricular pacing have focused on patients with severe heart failure (New York Heart Association [NYHA] class III-IV). While nearly 60% of the patients in the DAVID Trial had a clinical history of CHF and the mean ejection fraction was less than 30%, only 12% had NYHA class III-IV symptoms, and nearly half were minimally symptomatic (NYHA class I). It has been generally held that discoordinate contraction is particularly troublesome for patients with significant underlying cardiac dysfunction. The current data indicate that even patients with underlying dysfunction but minimal symptoms can be adversely influenced by discoordinated ventricular activity. The question is whether iatrogenic dyssynchrony should be treated with resynchronization pacing, or whether leaving well enough alone is preferred, by reducing the backup rate to pace the heart only if really needed. In an era of rapidly advancing and costly technology, the simpler solution is attractive. The latter can be supported only with clear evidence for its advantage but cannot be predicted from currently available data and will require more studies.