CrossTalk opposing view: Blood flow pulsatility in left ventricular assist device patients is not essential to maintain normal brain physiology

Circulatory support among advanced heart failure (HF) patients with continuous‐flow (CF) left ventricular assist devices (LVADs) is unique compared to any other patient population in that these individuals are chronically exposed to a non‐physiological pulse. In our experience, CF‐LVAD patients have a pulse pressure of ∼20 mmHg, which results from pulsatile delivery of blood from the left ventricle to the pump (Cornwell et al. 2015). Thus the question is less of whether or not a physiological pulse is necessary, but rather, how much of a pulse is necessary, and can the brain function normally when chronically exposed to a non‐physiological (i.e. reduced) pulse? Arterial flow naturally transitions from pulsatile flow in larger conductance vessels to continuous flow in arterioles and capillaries – thus, CF‐LVADs arguably do not alter arterial flow characteristics in the distal cerebral vasculature.

If we first look globally at outcomes among the CF‐LVAD population – specifically, neurocognitive performance and stroke – interesting trends emerge. In the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), neurocognition was stable in 45%, and improved in 35%, of individuals assessed at 3, 6 and 12 months following CF‐LVAD implantation (Fendler et al. 2015). Strokes, which affect 10% of patients in the first year alone (Kirklin et al. 2017), are clearly associated with – and often are precipitated by – other device‐associated comorbidities, such as gastrointestinal bleeding (Stulak et al. 2014), pump thrombosis (Kirklin et al. 2014), infection (Harvey et al. 2015) and atrial fibrillation (Enriquez et al. 2014). Thus, from a ‘bird's‐eye view’, adverse neurological events arguably are not the direct result of chronic exposure to a non‐physiological pulse, but rather as a consequence of other LVAD‐related complications.

Cerebral perfusion and autoregulation in the setting of a non‐physiological pulse

While it might be argued that strokes are the result of impaired cerebral autoregulation, we have previously demonstrated that dynamic cerebral autoregulation during a 0.05 Hz sit–stand manoeuvre (to force large changes in mean arterial pressure (MAP)) is intact among CF‐LVAD patients, with autoregulatory indices that are comparable to age‐matched healthy controls and importantly, HF patients with previous‐generation, pulsatile LVADs (Heartmate XVE) (Cornwell et al. 2014). The magnitude of change in MAP and middle cerebral arterial velocity (MCAV) was similar between CF‐LVADs and healthy controls during the sit–stand, and furthermore, the cerebrovascular resistance index was virtually identical for the three groups (2.0 ± 0.5, 2.2 ± 1.4 and 2.0 ± 0.6 mmHg s cm⁻¹ for healthy individuals, pulsatile LVADs and CF‐LVADs, respectively).

Regarding cerebral perfusion, brain blood flow is preserved during acute and chronic exposure to a non‐physiological pulse. During cardiopulmonary bypass (CPB), cerebral blood flow did not differ among anaesthetized rabbits randomized to 1 h of pulsatile vs. non‐pulsatile perfusion at 27°C (30 ± 4 vs. 32 ± 5 ml 100 g⁻¹ min⁻¹ for pulsatile vs. non‐pulsatile flow) (Hindman et al. 1994). Similar results were found in humans undergoing pulsatile vs. non‐pulsatile cardiopulmonary bypass during coronary arterial bypass grafting (CABG), with MCAV as an index of cerebral perfusion, of 20 ± 5 vs. 24 ± 5 cm s⁻¹ for non‐pulsatile vs. pulsatile flow, respectively (Kawahara et al. 1999). Our group found that CF‐LVAD patients, evaluated 3 ± 1 months after support with a CF‐LVAD, had an MCAV that was similar to healthy controls (43 ± 10 vs. 49 ± 12 cm s⁻¹ for CF‐LVAD and healthy individuals, respectively) (Cornwell et al. 2014).

Cerebral tissue oxygenation and metabolism

Cerebral tissue oxygenation, as measured by near infrared spectroscopy, is similarly unaffected by perfusion characteristics (Grubhofer et al. 2000). Among 14 patients undergoing CPB during CABG, periprocedural reductions in blood volume and oxygenated haemoglobin were observed, but importantly, the magnitude of the reduction was similar for both pulsatile and non‐pulsatile CPB (Grubhofer et al. 2000). In a similar study, fluctuations in cytochrome‐oxidase aa ₃ (a mitochondrial enzyme highly dependent on oxygen delivery and critical for production of cellular adenosine triphosphate; Hoshi et al. 1993; Ferrari et al. 1995) were unaffected by perfusion type, suggesting that the degree of oxygen delivery during non‐pulsatile flow is similar (and sufficient) to that observed during pulsatile cerebral perfusion (Grubhofer et al. 2000). Finally, among individuals undergoing CABG, those randomized to non‐pulsatile CPB had nearly identical levels of regional cerebral oxygenation (r$S_{{\mathrm{O}}_2}$) as those randomized to pulsatile CPB (r$S_{{\mathrm{O}}_2}$ values >65% throughout surgery for both flow types) (Kawahara et al. 1999).

Sympathetic nerve activity and baroreceptor physiology

Chronic exposure to a non‐physiological pulse does lead to an increase autonomic tone through a baroreceptor‐mediated pathway (Markham et al. 2013; Cornwell et al. 2015). Among CF‐LVAD patients, muscle sympathetic nerve activity (MSNA) levels, assessed by microneurography of the peroneal nerve, were markedly elevated compared to levels observed among healthy controls (MSNA burst frequency of >40 bursts min⁻¹ among CF‐LVAD patients lying supine, vs. ∼30 bursts min⁻¹ among healthy individuals at a 60° head‐up tilt (Markham et al. 2013). Similarly, supine noradrenaline levels among CF‐LVAD patients (536 ± 333 pg ml⁻¹) markedly exceeded those of the healthy individuals (341 ± 131 pg ml⁻¹) and pulsatile LVAD patients (421 ± 40) at a 60° HUT (Markham et al. 2013).

However, it is unclear that the observed increase in sympathetic tone adversely affects normal brain physiology. First, it was demonstrated almost 100 years ago that provocative manoeuvres such as baroreceptor denervation, as well as sympathetic and vagal stimulation, had no adverse effect on cerebral autoregulation (Fog, 1939; Strandgaard & Sigurdsson, 2008). In fact, sympathoexcitation may even play a protective role over cerebral perfusion and the blood–brain barrier (BBB) (Heistad and Marcus, 1979). For example, during acute severe hypertension, brain blood flow increases, leading to increased permeability of the BBB (Johansson et al. 1970, Heistad & Marcus, 1979). However, in anaesthetized cats, electrical stimulation of the superior cervical ganglion during acute severe hypertension (induced by noradrenaline infusion), dramatically attenuated the increase in cerebral blood flow and BBB permeability (Heistad & Marcus, 1979). Among healthy volunteers, α‐adrenergic blockade with phentolamine increased transfer function gain and coherence between arterial pressure and MCAV at frequencies >0.05 Hz, suggesting that sympathetic blockade impaired cerebral autoregulatory processes (Hamner et al. 2010). It has been hypothesized that reductions in MCAV during orthostasis are the result of an increase in sympathetic tone causing arterial vasoconstriction and a reduction in brain blood flow (Levine et al. 1994). However, administration of trimethaphan (to block sympathetic ganglia) did not prevent reductions in MCAV that occur with low‐body negative pressure (Zhang & Levine, 2007). This finding suggests that factors other than sympathetic tone, such as local mediators like nitric oxide and endothelin‐1, contribute substantially to regulation of cerebral blood flow in humans (Rubanyi et al. 1986; Treib et al. 1996; White et al. 2000). In addition, myogenic mechanisms may contribute substantially to preservation of cerebral flow amidst changes in arterial perfusion pressure, since nitric oxide inhibition by N ^G‐monomethyl‐l‐arginine had no effect on dynamic cerebral autoregulation (Zhang et al. 2004). Thus, the hyperadrenergic environment, resulting from a baroreceptor‐mediated pathway in the setting of CF‐LVAD support, does not appear to adversely influence cerebral blood flow and normal brain physiology.

Conclusion

Collectively, available data suggest that chronic exposure of the brain to a non‐physiological pulse does not adversely influence cerebrovascular processes. In normal humans, arterial perfusion at the level of cerebral arterioles and capillaries is essentially non‐pulsatile – thus, brain blood flow in the distal cerebral vasculature among individuals supported with CF‐LVADs is not dissimilar to normal conditions. Cerebral autoregulation, perfusion, and cerebral tissue oxygenation and metabolism are all preserved. In addition, observed increases in sympathetic tone, which occur through a baroreceptor‐mediated pathway, do not appear to adversely influence brain physiology and may actually be protective.

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Additional information

Competing interests

None declared.

Author contributions

All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

W.K.C. is supported by an NIH/NHLBI Mentored Patient‐Oriented Research Career Development Award (No. 1K23HLI32048‐01), the Susie and Kurt Lochmiller Distinguished Heart Transplant Fund, and the Clinical Translational Science Institute at the University of Colorado Anschutz Medical Campus. A.V.A. is supported by a Scientist Development Grant from the American Heart Association and by the Boettcher Foundation's Webb‐Waring Biomedical Research Program. T.T. is supported by an NIH/NHLBI Pathway to Independence Award (5K99HL133449).

Biography

William K. Cornwell is an assistant professor of medicine–cardiology at the University of Colorado Anschutz Medical Campus in Aurora, CO, where he specializes in advanced heart failure, LVAD and cardiac transplant. His research interests include cardiac and cerebrovascular, autonomic and haemodynamic abnormalities in advanced heart failure, as well as exercise physiology in healthy and diseased populations.