Historical perspective

Cardiac Pacing in humans was originally described in the 1950's.(81, 82) Modern

percutaneous transvenous techniques have been developed and refined over the past thirty years. The concept of pacing in patients with heart failure has steadily evolved over this time period.

One of the initial pilot studies was performed by Derek Gibson in 1971. It demonstrated the acute effects of biventricular pacing.(83) Using six patients with Starr-Edwards aortic valve prostheses in the acute post-operative period, biventricular pacing using the surgical

epicardial leads was shown to reduce the surface QRS duration on the electrocardiogram (ECG). Using the stroke distance as calculated by the movement of the ball in the prosthesis itself, the authors also demonstrated that biventricular pacing resulted in improved ventricular work.

Other groups performed small limited pilot studies around this time period.(84, 85) but no further investigational work was performed in this area for the following thirty years. Though the large randomised controlled trials of heart failure pharmacotherapy started to report in the late 1980s and early 1990s, there was a large number of patients with symptomatic advanced disease. Hence a renewed focus was placed on pacing as a potential treatment for this cohort.

Hochleitner, in 1990, demonstrated, using conventional dual chamber pacing set in dual chamber pacing mode (DDD), a marked clinical and haemodynamic improvement in sixteen

patients with dilated cardiomyopathy (DCM).(86) All patients had advanced symptomatic disease and had proven dilated cardiomyopathy with normal coronary angiography and

myocardial biopsies. The severity of their disease meant that all 16 patients have been initially referred for cardiac transplantation with seven on the current transplant list. All patients were on the optimal tolerated medical therapy of the time (vasodilators, diuretics and digitalis). A total of seven patients had left bundle branch block (LBBB) on the surface electrocardiogram. (ECG) All patients underwent standardised implantation of a transvenous dual chamber system (right atrial and ventricular leads). Following the implantation of dual chamber pacemakers which were set at DDD mode with a ventricular rate of 50 beats per minute (BPM) with an atrioventricular (AV) delay of 100 milliseconds. The results demonstrated an improvement in clinical symptoms such as breathlessness, NYHA class improved from 3.6 ± 0.4 to 2.1 ± 0.5 (P<0.001), left ventricular dimensions improved, left ventricular end diastolic diameter improved from 74 ± 11 mm to 72 ±10 mm (P<0.05). All patients were discharged from hospital three weeks following their pacemaker implantation and after one year of clinical follow up, 4 patients had died, 12 individuals had persistent clinical improvement and subsequently a third of these patients received cardiac transplants. In three patients the impact of pacing was so marked that they were removed from the transplant list all together. This cohort was then subsequently followed up for an extended period of time. The effects of pacing seemed to persist after the acute period and the median survival for the cohort was 22 months. Three patients survived beyond the extended five year period of follow up.(87)

Following this initial work others evaluated the role of dual chamber pacing in patients with heart failure, particularly due to dilated cardiomyopathy. Brecker and colleagues, in 1992, investigated the effect of atrioventricular delay in patients with dual chamber pacing and dilated cardiomyopathy.(88) A cohort of twelve patients was identified with dilated

cardiomyopathy and concomitant mitral and tricuspid regurgitation. As a consequence of the regurgitation, all patients possessed shortened ventricular filling times. A shorter

atrioventricular delay resulted in improved biventricular filling times (65 (35-95) ms and 90 (60-120)ms, P<0.001). A shortened AV delay also resulted in an increased cardiac output (by 1.1 [0.8-1.4] l/min, p < 0.01) and rises in exercise capacity (104 [45-165] s, P < 0.05) and maximal oxygen demand (2.1 [1.5-2.7] ml kg-1 min-1, P< 0.05). Linde and colleagues replicated the experiment in a smaller cohort of similar patients in 1995.(89) A day after successful DDD permanent pacemaker implantation, AV delay was optimised using Doppler flows across the aortic valve. The cohort was then re-evaluated at one, three, and six month

intervals following pacemaker implantation. Clinical data was collected at these time points including NYHA class, stroke volume, left ventricular ejection fraction and cardiac output. The initial optimisation did induce a short term improvement in haemodynamics (Baseline stroke volume = 22 ± 7 ml, day 1 = 28 ± 12 ml; p = 0.03: Baseline cardiac output = 1.9 ± 0.6 L/min, day 1 = 2.2 ± 1.1 L/min; p = 0.10) however the authors found no longer term effect on any of the documented variables.

Whilst some work, as described previously, had evaluated the role of predominately right atrial and ventricular pacing in patients with dilated cardiomyopathy, other groups decided to revisit the potential of biventricular pacing. Initial reports of multisite pacing started to emerge around this time. Cazeau and colleagues issued one of the first case series in 1996.(90) This involved eight patients who had advanced symptomatic heart failure, a broadened QRS duration on the surface ECG and who had either been refused or had turned down a cardiac transplant. Using temporary pacing leads and a series of connectors and pacing boxes, multisite pacing (including biventricular pacing) was tested. Biventricular pacing increased the mean cardiac index (CI) by 25 percent (from a baseline of 1.83 +/- 0.30 L/min per m2, P < 0.006) and decreased pulmonary capillary wedge pressure by 17% (from a baseline of 31 +/- 10 mmHg, P < 0.01). Notably half (50 percent) of the patients suffered either intra-procedure or peri-procedural death but for the four survivors there was an

improvement in NYHA class. The remaining question about biventricular pacing was whether the effect on short term haemodynamics would translate into longer term clinical benefit and outcomes.

Bakker and her colleagues were the first to release data in this area in 2000.(91) A series of twelve patients with end stage heart failure and aetiologies comprising both ischaemic (33 percent) and non-ischaemic (67 percent) aetiologies with prolonged PR interval and QRS duration on their surface ECGs (PR interval 217 ± 20ms and QRS duration 194±21 ms). All patients had left bundle branch block (LBBB) on their surface ECG. They all had successful biventricular pacing systems implanted under general anaesthesia with a surgical epicardial left ventricular lead being implanted using a small left mini-thoracotomy. Clinical follow up was then performed at set intervals. The cumulative survival at one, two and three years was 66.7 percent [40.0,93.4] at 1 year and 50 percent [21.8, 78.2] respectively. The median NYHA class improved from IV to II at 1 year. (P=0.008). There were improvements in LVEF and end diastolic diameter at one year, though these were non-significant (P=0.10 and P=0.20

respectively). There were significant changes observed in dP/dt and stroke volume at one year (466±130 to 243 ± 113 (p=0.03)) and 37±9 to 42± 10 (P=0.05))).

The beneficial effects in these reports, led to further clinical trials, including randomised controlled trials. For the purpose of the rest of the thesis, atrio-biventricular pacing will be considered to be synonymous with cardiac resynchronisation therapy. (CRT)