For most of my clinical career, there were very established guidelines for who needed a pacemaker and who did not. Guidelines from the leading specialty society are still one of the most important reference works for a clinician. The American College of Cardiology, American Heart Association, and the Heart Rhythm Society jointly issue guidelines on pacemakers (available on the websites of these organizations). Back in the olden days, people with symptomatic bradycardia caused by sick sinus syndrome or advanced A-V block were the only pacing candidates. We also had pretty established ideas as to what a pacemaker did: it paced the right ventricle and, in dual-chamber systems, the right atrium as well. Pacemakers got smaller, longer-lasting, and more sophisticated in terms of the special features they offered, but they were pretty much devices that paced that right ventricle of people with sinus node dysfunction or heart block. The landmark randomized clinical trial MADIT II, published in 2002,1 demonstrated a survival benefit for myocardial infarction survivors with compromised left ventricular function when they received an implantable cardioverter-defibrillator (ICD). Interestingly, in a subgroup analysis, it was found that while ICD patients survived better, they had increased heart failure morbidity (as evidenced by hospitalizations for heart failure). The MADIT II substudy did not prove anything, but it was the first glimmer into something that some pacing experts had suspected, namely that pacing the RV apex in a patient with LV dysfunction can make the LV dysfunction worse. A large clinical trial known as the Mode Selection Trial (MOST) had previously found that there was no conclusive scientific evidence to issue a global recommendation for dual-chamber pacing over single-chamber pacing.2 In fact, evidence from randomized clinical trials as to which pacing mode worked best in which patients was very confusing.3 Then the DAVID Investigators found that dual-chamber pacing might actually be detrimental to ICD patients with a left ventricular ejection fraction (LVEF) of 40% or lower, and no standard pacing indication. In such patients, the rate of mortality and the rate of hospitalization for new or worsened congestive heart failure increased with DDDR pacing at 70 pulses per minute.4 Today there is a growing body of evidence that suggests that a conventional right ventricular (RV) pacing lead placed in the RV apex can have a negative impact on patients with LV dysfunction. For patients with good systolic function and standard pacing indications, this caveat does not seem to apply. The development of biventricular (BiV) pacemakers was a major technical achievement and a new way of thinking about pacing the heart. Instead of just trying to keep the heart going at a specific rate, these devices introduced cardiac resynchronization therapy (CRT). The biggest mistaken notion in CRT is that it is just about synchronizing the right and left sides of the heart. It s true that the BiV or CRT device has a right ventricular and a so-called left ventricular lead (which actually goes into a coronary vein by way of the coronary sinus), but one of the primary purposes of a CRT system is to improve left ventricular contraction. Many patients with LV dysfunction have a left ventricle which contracts in segments or waves rather than as a single unit. The result is an ineffective contraction and less-than-optimal pumping capability. The CRT system uses two leads to help the left ventricle contract more synchronously with the objective of achieving better pumping efficiency per depolarization. CRT is essentially pacing, that is, low-voltage stimulation to the heart. The technology quickly was adopted in ICDs (the CRT-D systems), but also exists in the form of CRT-P devices of CRT pacemakers. So why would anyone opt for a CRT-P device? First of all, the current guidelines for standard pacemakers that is, RV pacemakers have not changed. People who need bradycardia support should still get RV pacemakers, and that patient population is very well defined. It includes people with symptomatic bradycardia because of sinus node dysfunction and those with moderate to severe A-V block. However, CRT-P systems are now indicated in patients who have undergone an elective AV-nodal ablation to manage the rapid ventricular response to atrial fibrillation. It is estimated that about 37,000 patients had an AV-nodal ablation procedure in 2003, and that number is expected to reach about 75,000 by 2008.5 Since an AV nodal ablation induces complete heart block (the atria and the ventricle are disconnected when the AV node is ablated), patients require permanent pacing after the procedure. This procedure has been around since the 1980s which is long enough to get a nickname. These are known as ablate-and-pace procedures. A recent clinical study called PAVE found that ablate-and-pace patients who received a CRT-P device instead of a conventional pacemaker had significantly improved exercise capacity and significantly improved LVEF scores.6 In the PAVE study, the most pronounced benefits were seen in patients with the lowest LVEF scores. The PAVE findings make intuitive sense. People have an AV nodal ablation procedure because they have symptomatic, difficult-to-treat atrial fibrillation with a rapid ventricular response. This long-term ventricular tachyarrhythmia can induce cardiomyopathy, which impairs LV function. A conventional pacemaker serves the purpose of keeping the heart going, but probably would exacerbate the systolic dysfunction over the long term. A CRT system helps preserve systolic function. But what about patients with only LV dysfunction? The COMPANION trial implanted CRT systems (both CRT-D and CRT-P devices) in heart failure patients (NYHA Class III or IV) with an LVEF of 120 ms. These were symptomatic patients with impaired LV function. CRT reduced the risk of death or hospitalization for any cause by about 20% compared to drug therapy alone (this finding was not quite significant at p = 0.059); CRT also significantly reduced the risk of all-cause mortality compared to drug therapy alone.7 The COMPANION trial was not designed to make a head-to-head comparison of CRT-D to CRT-P devices. Thus, it is easy to wonder how much of the mortality benefit COMPANION turned up traced back to CRT, and how much was attributable to the rescue function of the defibrillator. The morbidity benefits of CRT were clear: COMPANION patients with CRT devices had fewer hospitalizations (for a cardiovascular cause, or specifically for a heart failure cause) than the patients receiving only drug therapy. Just this year, the CARE-HF study announced its results. Unlike COMPANION, which mixed CRT-P and CRT-D devices together in its study, CARE-HF evaluated strictly CRT-P devices. CARE-HF patients were similar to COMPANION patients: people with symptomatic heart failure (NYHA Class III or IV), depressed LV function (LVEF 120 ms). The CARE-HF investigators reported that CRT patients showed a significantly reduced risk (37%) of all-cause mortality or first unplanned hospitalization for a major CV cause (primary endpoint) compared to drugs-alone patients. In fact, CRT patients exhibited a 36% reduced risk of all-cause mortality versus the drug group, and a 46% reduced risk of all-cause mortality or first unplanned hospitalization for worsening heart failure.8 Since no patients in the CARE-HF study received a high-voltage device, none of this benefit came from the rescue function of defibrillation. Clearly, CRT alone was responsible for the difference. Although we do not completely understand what CRT does or why it works, evidence suggests it can hold back the clock on the progressive downward spiral of heart failure. CARE-HF Primary Investigator John G.F. Cleland stated in an interview with the website theheart.org what he thought of CRT: I think it s realistic to talk in terms of remission of heart failure. For people with symptomatic heart failure, compromised LV function (as evidenced by a low LVEF score), and some degree of ventricular dyssynchrony (as evidenced by a long QRS duration), CRT has been shown to offer morbidity and mortality benefits. By pacing the left ventricle into a more unified, homogenous contraction, pumping function is improved and the progression of heart failure is delayed. Bear in mind that the patients in the COMPANION trial and CARE-HF study did not have standard pacing indications. (In fact, in those studies, a standard pacing indication would have excluded them.) What does this mean for clinical practice? Right now, evidence-based medicine tells us the following about pacemakers: People undergoing the so-called ablate-and-pace procedure should receive CRT-P devices instead of conventional RV systems, regardless of whether they have LV dysfunction or not. People with other conventional pacing indications are probably well served by conventional (RV) devices. Symptomatic heart failure patients (NYHA Class III or IV) with LV dysfunction (LVEF 120 ms) should be considered for CRT systems, even if they do not have bradycardia or other standard pacing indications. Clinicians are wondering if we can expand that last description even further. For example, if CRT benefits NYHA Class III and IV patients, what about Class I and II? Would patients with normal or even narrow QRS durations benefit from CRT pacing? Studies are underway or proposed to explore these other populations. For clinicians familiar with programming conventional RV pacemakers, there are a few ways that CRT systems are different than conventional pacemakers: Conventional pacemakers should be programmed in such a way that allows the patient s natural rhythm to prevail as much as possible. The opposite is true of CRT, which only provides benefits when it is in control and pacing the heart. Therefore, you should program CRT pacemakers to pace as often as they can (100% is the goal). Conventional pacemakers are relatively easy to implant, but CRT systems require some expertise to position the LV lead in the coronary sinus. Unlike conventional pacemakers, which usually work in the patients for whom they are indicated, there is a large minority of patients who might be called CRT-non-responders. These are patients who appear to be good CRT candidates but who do not benefit from the therapy. Such CRT-non-responders can frequently be converted into responders through careful reprogramming of certain timing parameters. This technique is known as V-V timing or optimization. In the simplest terms, it allows the clinician to precisely time the two ventricular outputs to cause a unified ventricular contraction. (This requires the use of echocardiography.) AV delay adjustment has also proven to be a good optimization tactic for some patients. Thus, conventional pacemaker follow-up is fairly routine, but following a CRT may involve more advanced techniques to get the therapy exactly right. Pacemaker therapy is changing, and patient populations are changing along with it. While it may be challenging to keep up with the latest device-based therapy trials, it s exciting to be able to bring real benefits to new groups of cardiac patients. Not so very long ago, it could be discouraging to treat heart failure patients simply because we had so little to offer them. Today, things are changing, and that s exciting!