Disclosure: Dr. Machado serves on the scientific advisory board for Guidant Corporation, and is a consultant for Medtronic, Guidant and Biotronik.

Cardiac Resynchronization Therapy in Sinus Rhythm
       Patients with dilated cardiomyopathy and uncoordinated left ventricular (LV) wall motion due to intraventricular conduction delay are at increased risk for decompensated heart failure, arrhythmias, and have higher mortality rates.¹

       Infranodal conduction delay, most commonly in a left bundle branch block (LBBB) pattern, displays early activation of the septal wall. This is followed by delayed lateral contraction at higher stress and systolic stretch of the early-activated septum. The net result of reciprocal sloshing of blood from early- to late- to early-activated regions is a decline in systolic function and ejection fraction (EF).^2,3
       Clinical trials have shown that cardiac resynchronization therapy (CRT) with biventricular or left univentricular pacing in patients with severely depressed left ventricular function and LBBB or intraventricular conduction delay can resynchronize contraction. The major effect of pacing is to shift the phase of lateral contraction earlier.¹ The consequence of resynchronization is noted immediately, leading to initiation of more simultaneous ventricular shortening of the septum and lateral wall of the left ventricle, and improvement of hemodynamic parameters, such as the maximal rate of pressure rise (dP/dt max), arterial pulse pressure and net ejection fraction.⁴ After one month or more of pacing, both end-systolic and end-diastolic chamber volumes decline,⁵ an effect which was sustained even after transient suspension of pacing within three months of CRT, supporting a true remodeling effect.⁵ Overall it has been shown that CRT leads to improved left ventricular systolic function with a decline in myocardial oxygen consumption,⁶ New York Heart Association (NYHA) functional class, and inhibition or reversal left ventricular chamber dilation and remodeling.^7–11 In the recent COMPANION trial, it was shown that for patients with advanced heart failure and a prolonged QRS interval, CRT decreases the combined risk of death from any cause or first hospitalization, and in combination with an implantable defibrillator, survival is significantly improved.¹²

Atrial Fibrillation and Heart Failure
       Atrial arrhythmias are common in patients with heart failure, regardless of the underlying etiology.¹³ The prevalence of atrial fibrillation (AF) in patients with heart failure is between 10–40%, varying in part upon the severity of heart failure.^14–16 Atrial fibrillation has deleterious effects on myocardial function in three pathways: loss of atrial contribution, irregular rhythm, and rapid ventricular rate leading to rate-related ventricular cardiomyopathy.^17–19 Observational studies have demonstrated that the development of chronic AF in heart failure patients is associated with significant worsening of heart failure and myocardial function.²⁰ Thus, it is important to control atrial fibrillation in patients with heart failure. There are two main issues that must be addressed in the treatment of AF: choice between rhythm and rate control, and prevention of systemic embolization.^21,22 Both rate and rhythm control lead to improved left ventricular function.²³ Though recent data from the AFFIRM and RACE trials have demonstrated that both rate and rhythm control are acceptable options for long-term treatment of atrial fibrillation,^24,25 this may not be applicable for patients with systolic heart failure. There are an array of pharmacological and non-pharmacological therapies available for rate control. The U.S. Carvedilol Heart Failure Studies demonstrated that rate control in this group of patients can significantly decrease mortality and morbidity and lead to an increase in left ventricular ejection fraction.²⁶ One type of hybrid therapy combining septal pacing with the ventricular rate regularization feature also demonstrated to improve acute hemodynamics in a selected group of AF patients.²⁷
       Non-pharmacological therapies are reserved for chronic atrial fibrillation patients with a rapid ventricular conduction that is refractory to pharmacological treatment.²⁸ The most commonly utilized non-pharmacological method for rate control is AV nodal ablation (AVNA) using radiofrequency and permanent pacemaker placement. The Ablate and Pace Trial showed overall safety and efficacy of this therapy.²⁹ AVNA and permanent pacemaker implantation in this study were associated with improved NYHA functional class and quality of life in a highly symptomatic population of patients with refractory atrial fibrillation. The patients with reduced systolic function at baseline had the greatest improvement in left ventricular systolic function after 12 months of pacing.
       In another study it was noted that AVNA and right ventricular (RV) pacing improves ventricular function, symptoms and quality of life in patients with AF refractory to drug therapy for ventricular rate control.³⁰
       However, some patients may have persistent or progressive CHF symptoms after AVNA and RV pacing.³¹ One explanation may be that cardiac pacing from the RV apex leads to an abnormal left ventricular activation sequence with a LV conduction pattern similar to LBBB. It provides a non-physiologic dyssynchronous contraction and leads to paradoxical septal motion with reduction in ejection fraction and a detrimental effect on systolic pressure and cardiac output.³² In one study, performed in patients with otherwise normal hearts, the presence of LBBB was associated with a significant deterioration of cardiac function of about 10–20%.³³

CRT in Patients with Atrial Fibrillation
       CRT, a left-sided pacing therapy for drug-refractory and highly symptomatic heart failure patients with ventricular conduction delay, is currently indicated in patients with preserved normal sinus rhythm (SR). CRT can be delivered in different fashions, either by simultaneous pacing of the RV and LV (referred to as biventricular pacing) or by pacing of the LV alone. CRT improves systolic function, quality of life, and exercise tolerance in patients with severe heart failure despite optimal medical therapy, left ventricular dysfunction and a wide QRS complex of >= 120 ms.³⁴ Most clinical trials of CRT have excluded patients with atrial fibrillation or chronic RV pacing. Only recently have trials been designed to specifically look at CRT in patients with heart failure and chronic atrial fibrillation with and without AV nodal ablation.
       In a study by Leclerq et al., patients with NYHA functional class III with left ventricular systolic dysfunction (EF < 35%) and chronic AF with slow ventricular response underwent biventricular pacemaker implantation. These patients had a wide RV-paced QRS complex of > 200 ms. Patients were treated for three months with conventional right univentricular pacing, and subsequently with biventricular pacing for three months.³³ In patients who completed the cross-over phases, it was noted that effective biventricular pacing improved exercise tolerance as well as peak oxygen uptake compared to conventional VVIR pacing. Leon et al. studied patients with an EF < 35%, prior AVNA and RV pacing, and chronic atrial fibrillation. They demonstrated that switching from RV pacing to biventricular pacing was associated with significant improvements in NYHA functional class, hospitalization frequency, quality of life, and left ventricular ejection fraction, and leads to reversed remodeling. These benefits were similar to those seen in patients in sinus rhythm in previous CRT trials, suggesting that benefits of biventricular pacing may result from resynchronization rather than optimization of AV nodal delay.³⁵
       In the most recent OPSITE Trial,³⁶ patients with permanent atrial fibrillation and drug-refractory, severely symptomatic, uncontrolled rapid ventricular rate were treated with AVNA and underwent biventricular pacemaker implantation. These patients also had drug-refractory heart failure and depressed LV function and/or LBBB. Univentricular RV pacing was compared to univentricular LV pacing in a prospective, randomized, cross-over study design. RV and LV pacing studies were performed during the same session in each patient. Compared to RV pacing, LV pacing resulted in significant increase in EF, decrease in mitral regurgitation, and reduction in QRS duration. Similarly beneficial results were seen in patients with normal or depressed cardiac function, and also in patients with or without LBBB in this study. LV pacing resulted in a statistically significant clinical advantage over RV pacing. The authors did not compare the effects of biventricular pacing, which may be more effective than LV pacing alone. This may be especially true in patients with previous AVNA, as pre-exitation of only the LV may create a delayed activation of the septum and RV, which may worsen overall LV systolic function, analogous to the negative effects generated by RV pacing only. The PAVE trial was presented by Rahul N. Dosh on behalf of the PAVE Study Group at the American College of Cardiology Annual Scientific Sessions in 2004. It represented the first prospective, randomized comparison of RV and biventricular pacing in 184 patients with chronic atrial fibrillation who underwent AVNA and pacemaker implantation. Inclusion criteria included chronic atrial fibrillation of >= 1 month, NYHA functional class I–III and a six-minute walking distance of under 450 m. Enrollment of patients was regardless of LV function and QRS duration. Improvement in six-minute walking distance was significantly more in the biventricular pacer group compared to the RV paced group of patients after six months of therapy (+ 82.5 m vs. + 56.8 m; p = 0.03). Also, exercise duration during cardiopulmonary testing, peak oxygen consumption, and quality of life significantly improved with biventricular pacing, compared to the group that was RV paced. At six months, LV ejection fraction remained stable, compared to baseline in the biventricular pacing group (45.6% vs. 46.0%; p = NS), whereas a deterioration was seen in the RV paced group (44.9% vs. 40.7%; p = 0.03). There was no difference in survival between the two groups.

Conclusion
       In conclusion, CRT with biventricular or univentricular LV pacing in patients with heart failure and chronic atrial fibrillation is safe and effective. Univentricular RV pacing may be associated with poorer outcomes, due to alteration of the natural sequence of electrical activation and discordinate mechanical contraction. Biventricular or univentricular LV pacing may provide a more physiologic correction of mechanical dyssynchrony, and results in significant and sustained improvements in functional capacity, LV ejection fraction, quality of life parameters, and QRS duration.