Assessment of the Relationship Between Cerebral Blood Flow and Heart Rate

Background: Cerebral blood flow (CBF) is maintained at a relatively constant level by multiple overlapping auto-regulatory systems over a wide range of blood pressures. This ensures adequate oxygen delivery to the brain and is critical to ongoing brain function and consciousness. Patients with reduced CBF experience symptoms of presyncope (e.g. lightheadedness, dizziness, trouble concentrating) and may faint. In patients with postural tachycardia syndrome (POTS), these orthostatic symptoms are a chronic issue, but the underlying pathophysiology is poorly understood - there is both evidence for and against impaired cerebral auto-regulation in POTS patients.

Previous studies have demonstrated that increased cardiac output improves CBF independent of mean blood pressure. This is of particular interest in POTS patients, who display reduced cardiac output both during rest and orthostasis. This is due in part smaller heart size and reduced blood volume, which necessitate high heart rates to maintain cardiac output. The relationship between cardiac output and CBF has not been studied in POTS patients. Given the characteristic orthostatic tachycardia seen in these patients, the effects of heart rate on CBF are also of interest. The relationship between heart rate and CBF, to our knowledge, has not been studied.

The chronic orthostatic symptoms in POTS patients are largely unexplained, but contributed centrally to significantly reduced quality of life. These symptoms are thought to be caused in part by alterations in CBF. While POTS does not have a "cure", alleviation of orthostatic symptoms would likely improve patients' ability to engage with activities of daily living and may reduce overall disease burden. Gaining an improved understanding of the hemodynamic determinants of CBF is essential to achieving this goal.

Objectives: To assess the relationship between heart rate and middle cerebral artery (MCA) CBF. Additionally, to better understand the hemodynamic determinants of MCA CBF velocity by examining the relationships between heart rate, stroke volume, pulse pressure, and MCA CBF velocity.

Methods: This will be an open-label, single group study in otherwise healthy patients scheduled for elective electrophysiology studies prior to planned ablations for supraventricular tachycardia. The study will take place with the participant supine on the electrophysiology laboratory procedure table, with a temporary pacing catheter already placed in the high right atrium. Prior to beginning the study protocol, the participant will be instrumented with non-invasive (a) skin electrodes to continuously monitor heart rate and record an electrocardiogram; (b) a volume-clamp finger cuff to monitor beat-to-beat blood pressure, calibrated with intermittent brachial cuff measurements; and (c) a transcranial Doppler System to record CBF velocity. Estimates of stroke volume, cardiac output, and systemic vascular resistance will be obtained using Modelflow-based waveform analysis of the continuous blood pressure waveform. A clinically standard sinus node recovery time (SNRT) protocol will be performed whilst collecting CBF and hemodynamic responses. Pacing will occur at 600 ms (100 bpm), 500 ms (120 bpm), 400 ms (150 bpm), and 350 ms (171 bpm) cycles for 60 seconds each, with a rest period of at least 60 seconds between pacing runs. After these pacing runs, the study data collection will be complete and the extra blood pressure cuffs and transcranial doppler probes will be removed from the participant so that the clinical electrophysiology study may continue as planned. The investigators estimate that this study will add no more than 10-15 minutes to the overall procedure time.

In this exploratory "proof of concept" study, the investigators plan to enrol 20 participants.

• Change in MCA CBF velocity in response to high right atrial pacing at 600 ms (100 bpm) relative to baseline while in the supine position [Time frame: After 1 minute of pacing at 600 ms (100 bpm)]
• Change in MCA CBF velocity in response to high right atrial pacing at 350 ms (171 bpm) relative to baseline while in the supine position [Time frame: After 1 minute of pacing at 350 ms (171 bpm)]
• Change in MCA CBF velocity in response to high right atrial pacing at 400 ms (150 bpm) relative to pacing at the lowest rate (100 bpm) while in the supine position [Time frame: 10 minute electrophysiological pacing protocol]
• Change in MCA CBF velocity in response to high right atrial pacing at 350 ms (171 bpm) relative to pacing at the lowest rate (100 bpm) while in the supine position [Time frame: 10 minute electrophysiological pacing protocol]
• Change in stroke volume in response to high right atrial pacing at 400 ms (150 bpm) relative to baseline while in the supine position [Time frame: 10 minute electrophysiological pacing protocol]
• Change in cardiac output in response to high right atrial pacing at 400 ms (150 bpm) relative to baseline while in the supine position [Time frame: 10 minute electrophysiological pacing protocol]
• Change in pulse pressure in response to high right atrial pacing at 400 ms (150 bpm) relative to baseline while in the supine position [Time frame: 10 minute electrophysiological pacing protocol]