To examine the effects of heart rate reduction on exercise capacity in control subjects and patients with chronic heart failure.

Original proposal: Does iatrogenic chronotropic incompetence lead to impaired exercise capacity in patients with CHF

Aim The aim of this proposal is to examine the effects of iatrogenic CI on exercise capacity in control subjects and patients with chronic heart failure.

Hypothesis Iatrogenic chronotropic incompetence does not contribute significantly to reductions in exercise capacity in patients with heart failure or control subjects with pacemakers.

Methods REDUCING HEART RATE AT REST AND EXERCISE In patients with sinus rhythm, the present proposal utilizes a heart failure medication called ivabradine. This agent, an If channel blocker, specifically targets the sinus node leading to a slower heart rate. The agent is approved and licensed for use in patients with heart failure at the doses proposed. Ivabradine slows the sinus rate with none of the peripheral effects of beta-blockers. Heart rate lowering with ivabradine improves cardiac function, and outcomes related to the degree of bradycardia achieved.

In patients with atrial fibrillation, the present proposal will recruit patients with CRT and atrial fibrillation that have undergone atrio-ventricular node (AVN) ablation to improve the efficacy of CRT. Patients who have undergone AVN ablation are dependent upon their pacemaker, and we can therefore control their heart rate accurately.

SUBJECT SELECTION Inclusion criteria We will only include patients able to give informed written consent, which will be obtained in all subjects, and those capable of performing a peak exercise test. Since we are performing the study on three groups of patients, further inclusion criteria for each group are outlined below.

Inclusion criteria - CRT-sinus rhythm group We will enrol 25 patients with severe CHF on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation therapy at least 3 months previously. These individuals will be on optimal medical therapy for their heart failure with no change in medication or exacerbation for the preceding 3 months. They will not currently be taking ivabradine.

Inclusion criteria - CRT-atrial fibrillation group We will enrol 25 patients with severe CHF on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation therapy at least 3 months previously. All patients will be previously pacemaker dependant or have 'blocked' atrial fibrillation either due to medical therapy or previous atrio-ventricular nodal ablation.

Inclusion criteria - control group The control subjects (n=25) will be recruited from the general pacemaker clinic. They will undergo echocardiography to exclude structural heart disease. They will have no contraindications to exercise testing or ivabradine.

Exclusion criteria We will exclude subjects with musculoskeletal disorders limiting exercise capacity, patients with peripheral vascular disease, those with inflammatory disorders such as rheumatoid arthritis, and airways disease. Other exclusions include contraindications to ivabradine use such as severe hepatic impairment, significant renal impairment (creatinine clearance <15ml.min-1), and long QT syndrome. We will only include patients able to give informed written consent, which will be obtained in all subjects.

ECHOCARDIOGRAPHY Each subject will undergo a full echocardiographic examination. The images will be stored on a commercially available database, (Echopac PC, GE-Vingmed, USA) and analysed offline. We will assess LV systolic and diastolic function variables, mitral regurgitation, and pulmonary artery pressure.

EXERCISE TESTING Patients will describe their own NYHA symptom class at the beginning of each exercise session. Each individual will be invited for a familiarization test once agreeing to the study. At least one week following the familiarization test, heart failure patients and controls will return to the exercise laboratory and will be randomised to either ivabradine (7.5mg) or placebo. The following week they will return for the second arm. The randomization will be carried out in pharmacy to ensure blinding of the subject, the technician and the investigator. After ingesting the capsule, the subject will be asked to wait for an hour before the exercise test commences.

Prior to the start of exercise, patients' devices will be programmed to a base rate of 40 bts/min and they will then be they will be randomised to have their device programmed to either rate response on or off. A screen will separate the electrocardiographic monitor, which will be observed by the unblinded technician, from the metabolic cart, which will be observed by the blinded physician. The following week the other mode will be activated. At the end of each test the device will be returned to its original setting.

For the treadmill tests we will use the Bruce protocol modified by the addition of a 'stage 0' at onset consisting of 3 minutes of exercise at 1.61km/hr (1mile/hour) with a 5% gradient. During each test, expired air will be collected continuously and metabolic gas exchange analysis performed (Vmax 29, Sensormedics, USA). The system will be recalibrated prior to each test. Subjects will be encouraged to exercise to exhaustion, and a respiratory exchange ratio (RER), (VCO2/VO2) greater than 1.1 will be taken to suggest a maximal effort. The anaerobic threshold for each test will be calculated using the VO2/VCO2 slope method. At the end of each stage and at peak exercise subjects will be asked to indicate their score for dyspnoea or fatigue on a scale from 0 (no symptoms) to 10 (maximal symptoms) using the standardised Borg scoring system. The slope relating symptom scores against ventilation (Borg/VE) for each subject can then be plotted. We will also examine other ventilatory variables such as tidal volume (VT) and frequency (f) of ventilation.

Inclusion criteria:

We will only include patients able to give informed written consent, which will be obtained in all subjects, and those capable of performing a peak exercise test. Since we are performing the study on three groups of patients, further inclusion criteria for each group are outlined below.

Inclusion criteria - CRT-sinus rhythm group We will enrol 25 patients with severe CHF on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation therapy at least 3 months previously. These individuals will be on optimal medical therapy for their heart failure with no change in medication or exacerbation for the preceding 3 months. They will not currently be taking ivabradine.

Inclusion criteria - CRT-atrial fibrillation group We will enrol 25 patients with severe CHF on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation therapy at least 3 months previously. All patients will be previously pacemaker dependant or have 'blocked' atrial fibrillation either due to medical therapy or previous atrio-ventricular nodal ablation.

Inclusion criteria - control group The control subjects (n=25) will be recruited from the general pacemaker clinic. They will undergo echocardiography to exclude structural heart disease. They will have no contraindications to exercise testing or ivabradine.

Exclusion Criteria:

We will exclude subjects with musculoskeletal disorders limiting exercise capacity, patients with peripheral vascular disease, those with inflammatory disorders such as rheumatoid arthritis, and airways disease. Other exclusions include contraindications to ivabradine use such as severe hepatic impairment, significant renal impairment (creatinine clearance <15ml.min-1), and long QT syndrome. We will only include patients able to give informed written consent, which will be obtained in all subjects.

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2 weeks: immediate/early complications post intervention

All-cause mortality, serious adverse events, non-serious/other adverse events