Low Heart Rate Is Associated with Cerebral Pulsatility after TIA or Minor Stroke

Abstract

Beta-blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. Methods: Patients 4-6 weeks after TIA or non-disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat-to-beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA-PI) are reported as beta-coefficients from general linear models for each individual. Results: Across 759 patients, average MCA-PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (ΔMCA-PI per 10 bpm/mmHg: À0.02, À0.04, 0.03, all p < 0.001), with HR particularly associated with low end-diastolic cerebral velocity (0.86, p = 0.014). Beat-to-beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat-to-beat cerebral pulsatility (average ΔMCA-PI vs HR/DBP/SBP unadjusted: À0.062, À0.052, 0.0092; adjusted for concurrent BP: À0.039, À0.11, 0.041). The beat-to-beat association between HR and MCA-PI increased with age, beta-blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: À0.081 vs À0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: À0.087 vs À0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA-PI. Interpretation: Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target.

Circadian and Diurnal Regulation of Cerebral Blood Flow

“…50 In addition to increases in the mean blood pressure, the pulsatile arterial waveform is also dampened at points of impedance (eg, the carotid bifurcation) and regions of vessel tortuosity such as the carotid siphon in humans 48 and the rete mirabile in other mammals, 54 with further dampening of the waveform as the total area of the vascular system increases and resistance decreases with the transition to arterioles and capillaries. Finally, the pulsatility of the arterial waveform also depends on the length of the cardiac cycle, with increasing pulsatility at lower heart rates exacerbating transmission through stiff vessels to the brain 55 and potentially increasing the risk of chronic cerebrovascular disease in older patients. 56,57…”

“…50 In addition to increases in the mean blood pressure, the pulsatile arterial waveform is also dampened at points of impedance (eg, the carotid bifurcation) and regions of vessel tortuosity such as the carotid siphon in humans 48 and the rete mirabile in other mammals, 54 with further dampening of the waveform as the total area of the vascular system increases and resistance decreases with the transition to arterioles and capillaries. Finally, the pulsatility of the arterial waveform also depends on the length of the cardiac cycle, with increasing pulsatility at lower heart rates exacerbating transmission through stiff vessels to the brain 55 and potentially increasing the risk of chronic cerebrovascular disease in older patients. 56,57 Autoregulation aims to maintain stable CBF across a broad range of blood pressures although the classical formulation of cerebral autoregulation as constant blood flow across a wide range of blood pressure was defined in anesthetized animals [58][59][60] and may not accurately reflect the awake state in humans although it is a readily comprehensible formulation to understand cerebrovascular injury during hypotension 61 or hypertension.…”

“…87,88 Asynchrony between the endogenous cardiomyocyte rhythm and the autonomic nervous system is demonstrated by a model of human jet lag in which a rapid phase shift in light results in rapid synchronization of heart rate under the influence of the synchronized SCN and (diurnal) behaviors that affect heart rate but a more gradual resynchronization of the PR interval, reflective of the intrinsic cardiomyocyte clock. 6 This variation in heart rate may result in a differential effect on systolic and diastolic flow as the heart rate affects cerebral pulsatility, 55 with a reduced diastolic perfusing pressure at the end of the cardiac cycle. This may also have effects on glymphatic drainage of the brain, which is driven by arterial pulsatility, which demonstrates an important diurnal variation and relationship with sleep, 113 dealt with in another article within this compendium.…”

Measuring global cerebrovascular pulsatility transmission using 4D flow MRI

“…To support this, an increase in pulsatility has been observed with increasing severity of Alzheimer's disease 6 – 8 and is associated with increased cognitive impairment 3 . Originated from cardiac contraction, waves of pulsatile pressure travel from the heart to the vascular bed, where the amplitude, speed, and temporal profile strongly depend on the energy-absorbing Windkessel effect of the vessels 9 , the cardiac frequency 10 , the peripheral microvascular resistance 11 , and the cardiac contractility 12 . In the assumed healthy case, this pulsatility transmission is well dampened before reaching the small vessels 13 , although several factors can alter this pulsatility transmission including age 14 , sex 15 , cardiovascular factors (chronotropy, inotropy) 10 , nervous system function 16 , pathological influences such as hypertension 4 and potentially pathological alterations in peripheral vasculature 11 .…”

“…Originated from cardiac contraction, waves of pulsatile pressure travel from the heart to the vascular bed, where the amplitude, speed, and temporal profile strongly depend on the energy-absorbing Windkessel effect of the vessels 9 , the cardiac frequency 10 , the peripheral microvascular resistance 11 , and the cardiac contractility 12 . In the assumed healthy case, this pulsatility transmission is well dampened before reaching the small vessels 13 , although several factors can alter this pulsatility transmission including age 14 , sex 15 , cardiovascular factors (chronotropy, inotropy) 10 , nervous system function 16 , pathological influences such as hypertension 4 and potentially pathological alterations in peripheral vasculature 11 . These factors increase the variability of pulsatility transmission and can manifest pathological penetration of pulsatility into smaller vessels, where it is hypothesised that encephalopathy occurs with the adjacent parenchyma 5 , 13 .…”