Integrative Cardiovascular Physiology and Pathophysiology Dynamic cerebral autoregulation is impaired during submaximal isometric handgrip in patients with heart failure

The incidence of neurological complications, including stroke and cognitive dysfunction, is elevated in patients with heart failure (HF) with reduced ejection fraction. We hypothesized that the cerebrovascular response to isometric handgrip (iHG) is altered in patients with HF. Adults with HF and healthy volunteers were included. Cerebral blood velocity (CBV; transcranial Doppler, middle cerebral artery) and arterial blood pressure (BP; Finometer) were continuously recorded supine for 6 min, corresponding to 1 min of baseline and 3 min of iHG exercise, at 30% maximum voluntary contraction, followed by 2 min of recovery. The resistance-area product was calculated from the instantaneous BP-CBV relationship. Dynamic cerebral autoregulation (dCA) was assessed with the time-varying autoregulation index estimated from the CBV step response derived by an autoregressive moving-average time-domain model. Forty patients with HF and 23 BP-matched healthy volunteers were studied. Median left ventricular ejection fraction was 38.5% (interquartile range: 0.075%) in the HF group. Compared with control subjects, patients with HF exhibited lower time-varying autoregulation index during iHG, indicating impaired dCA ( P < 0.025). During iHG, there were steep rises in CBV, BP, and heart rate in control subjects but with different temporal patterns in HF, which, together with the temporal evolution of resistance-area product, confirmed the disturbance in dCA in HF. Patients with HF were more likely to have impaired dCA during iHG compared with age-matched control subjects. Our results also suggest an impairment of myogenic, neurogenic, and metabolic control mechanisms in HF. The relationship between impaired dCA and neurological complications in patients with HF during exercise deserves further investigation. NEW & NOTEWORTHY Our findings provide the first direct evidence that cerebral blood flow regulatory mechanisms can be affected in patients with heart failure during isometric handgrip exercise. As a consequence, eventual blood pressure modulations are buffered less efficiently and metabolic demands may not be met during common daily activities. These deficits in cerebral autoregulation are compounded by limitations of the systemic response to isometric exercise, suggesting that patients with heart failure may be at greater risk for cerebral events during exercise.

[1]  M. Drazner,et al.  2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. , 2013, Circulation.

[2]  R. Panerai,et al.  The critical closing pressure of the cerebral circulation. , 2003, Medical engineering & physics.

[3]  R. Panerai Transcranial Doppler for evaluation of cerebral autoregulation , 2009, Clinical Autonomic Research.

[4]  A. Massaro,et al.  Transcranial Doppler assessment of cerebral blood flow: Effect of cardiac transplantation , 2006, Neurology.

[5]  Joseph A Fisher,et al.  Integrative regulation of human brain blood flow , 2014, The Journal of physiology.

[6]  W. Abraham,et al.  Hormones and hemodynamics in heart failure. , 1999, The New England journal of medicine.

[7]  N. Secher,et al.  Dynamic cerebral autoregulation during exhaustive exercise in humans. , 2005, American journal of physiology. Heart and circulatory physiology.

[8]  Farzaneh A. Sorond,et al.  Impaired Cardiac Function and Cognitive Brain Aging. , 2017, The Canadian journal of cardiology.

[9]  R. Aaslid,et al.  Cerebral autoregulation dynamics in humans. , 1989, Stroke.

[10]  R. Panerai,et al.  Cerebral blood flow autoregulation in ischemic heart failure. , 2017, American journal of physiology. Regulatory, integrative and comparative physiology.

[11]  M. Haykowsky,et al.  Resting and exercise cerebral blood flow in long-term heart transplant recipients. , 2012, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[12]  Javed Butler,et al.  The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. , 2009, Journal of the American College of Cardiology.

[13]  Farzaneh A. Sorond,et al.  Elderly Women Regulate Brain Blood Flow Better Than Men Do , 2011, Stroke.

[14]  Toshinari Akimoto,et al.  Dynamic cerebral autoregulation during and after handgrip exercise in humans. , 2010, Journal of applied physiology.

[15]  G. ÓLaighin,et al.  The relationship between cardiac output and dynamic cerebral autoregulation in humans. , 2010, Journal of applied physiology.

[16]  R. Panerai,et al.  The Leicester cerebral haemodynamics database: normative values and the influence of age and sex , 2016, Physiological measurement.

[17]  R. Panerai,et al.  Dynamic Cerebral Autoregulation Changes during Sub-Maximal Handgrip Maneuver , 2013, PloS one.

[18]  M. Brys,et al.  Dynamic cerebral autoregulation remains stable during physical challenge in healthy persons. , 2003, American journal of physiology. Heart and circulatory physiology.

[19]  K. Schmieder,et al.  Dynamic Autoregulatory Response After Aneurysmal Subarachnoid Hemorrhage and Its Relation to Angiographic Vasospasm and Clinical Outcome , 2015, Neurocritical Care.

[20]  Biykem Bozkurt,et al.  2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. , 2013, Circulation.

[21]  P. Brassard,et al.  Exercise Intolerance in Heart Failure: Did We Forget the Brain? , 2016, Canadian Journal of Cardiology.

[22]  R. Panerai,et al.  Multivariate modeling of cognitive-motor stimulation on neurovascular coupling: transcranial Doppler used to characterize myogenic and metabolic influences. , 2012, American journal of physiology. Regulatory, integrative and comparative physiology.

[23]  Ronney B Panerai,et al.  Effects of cerebral ischemia on human neurovascular coupling, CO2 reactivity, and dynamic cerebral autoregulation. , 2015, Journal of applied physiology.

[24]  Y. Tzeng,et al.  Relationship Between Cerebral Blood Flow and Blood Pressure in Long-Term Heart Transplant Recipients , 2014, Hypertension.

[25]  D. Low,et al.  Dynamic cerebral autoregulation during passive heat stress in humans. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[26]  Philip Scheltens,et al.  Cognitive impairment in heart failure: A systematic review of the literature , 2007, European journal of heart failure.

[27]  R. McKelvie,et al.  Cerebral hypoperfusion is exaggerated with an upright posture in heart failure: impact of depressed cardiac output. , 2015, JACC. Heart failure.

[28]  Matthias Endres,et al.  Chronic Heart Failure and Ischemic Stroke , 2011, Stroke.

[29]  R. Panerai,et al.  Spontaneous fluctuations in cerebral blood flow regulation: contribution of PaCO2. , 2010, Journal of applied physiology.

[30]  J. Ravits Aaem minimonograph #48: Autonomic nervous system testing , 1997, Muscle & nerve.

[31]  Philip N. Ainslie,et al.  Blood pressure regulation IX: cerebral autoregulation under blood pressure challenges , 2013, European Journal of Applied Physiology.

[32]  S. Mandic,et al.  Effects of aerobic or aerobic and resistance training on cardiorespiratory and skeletal muscle function in heart failure: a randomized controlled pilot trial , 2009, Clinical rehabilitation.

[33]  D. Newell,et al.  Comparison of static and dynamic cerebral autoregulation measurements. , 1995, Stroke.

[34]  Y. Tzeng,et al.  Assessment of cerebral autoregulation: the quandary of quantification. , 2012, American journal of physiology. Heart and circulatory physiology.

[35]  S. Ogoh,et al.  Regulatory Mechanisms of Cerebral Blood Flow During Exercise: New Concepts , 2009, Exercise and sport sciences reviews.

[36]  T G Robinson,et al.  Continuous estimates of dynamic cerebral autoregulation during transient hypocapnia and hypercapnia. , 2010, Journal of applied physiology.

[37]  N. Secher,et al.  Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise. , 2007, American journal of physiology. Heart and circulatory physiology.

[38]  A. Gelb,et al.  Cardiac Output and Cerebral Blood Flow: The Integrated Regulation of Brain Perfusion in Adult Humans , 2015, Anesthesiology.

[39]  F. McAlister,et al.  A meta-analysis of the effect of exercise training on left ventricular remodeling in heart failure patients: the benefit depends on the type of training performed. , 2007, Journal of the American College of Cardiology.

[40]  A. Voors,et al.  Dynamics of cerebral blood flow in patients with mild non‐ischaemic heart failure , 2017, European journal of heart failure.

[41]  L. Vianna,et al.  Muscle metaboreflex and cerebral blood flow regulation in humans: implications for exercise with blood flow restriction. , 2016, American journal of physiology. Heart and circulatory physiology.

[42]  N. Wahlgren,et al.  Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise. , 1996, Journal of applied physiology.

[43]  Vera Bittner,et al.  Validity and reliability of the NYHA classes for measuring research outcomes in patients with cardiac disease. , 2002, Heart & lung : the journal of critical care.

[44]  R. Panerai,et al.  Cerebral blood flow velocity during mental activation: interpretation with different models of the passive pressure-velocity relationship. , 2005, Journal of applied physiology.

[45]  R. Haley,et al.  Reflex sympathetic activation during static exercise is severely impaired in patients with myophosphorylase deficiency. , 2003, The Journal of physiology.

[46]  H. Middlekauff,et al.  Abnormal neurovascular control during exercise is linked to heart failure severity. , 2001, American journal of physiology. Heart and circulatory physiology.

[47]  Signal-to-noise ratio of bilateral nonimaging transcranial Doppler recordings of the middle cerebral artery is not affected by age and sex. , 2011, Ultrasound in medicine & biology.

[48]  J. Claassen,et al.  Cerebral Autoregulation: An Overview of Current Concepts and Methodology with Special Focus on the Elderly , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[49]  F. Giallauria,et al.  Clinical outcomes and cardiovascular responses to exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis. , 2015, Journal of applied physiology.

[50]  R. Panerai Assessment of cerebral pressure autoregulation in humans - a review of measurement methods , 1998, Physiological measurement.

[51]  L. Sinoway,et al.  Altered mechanisms of sympathetic activation during rhythmic forearm exercise in heart failure. , 1998, Journal of applied physiology.

[52]  M. van Buchem,et al.  Middle cerebral artery diameter changes during rhythmic handgrip exercise in humans , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[53]  R. Kloner,et al.  Heart Failure-Induced Brain Injury. , 2017, Journal of the American College of Cardiology.

[54]  L. Vianna,et al.  Impaired dynamic cerebral autoregulation at rest and during isometric exercise in type 2 diabetes patients. , 2015, American journal of physiology. Heart and circulatory physiology.

[55]  Gitte M. Knudsen,et al.  Cerebral Blood Flow in Patients With Chronic Heart Failure Before and After Heart Transplantation , 2001, Stroke.

[56]  Ronney B Panerai,et al.  Cerebral Autoregulation: From Models to Clinical Applications , 2008, Cardiovascular engineering.

[57]  O. Paulson,et al.  Effect of captopril on the cerebral circulation in chronic heart failure , 1986, European journal of clinical investigation.

[58]  P. Raven,et al.  Regulation of middle cerebral artery blood velocity during dynamic exercise in humans: influence of aging. , 2008, Journal of applied physiology.

[59]  Min-Seok Kim,et al.  Heart and brain interconnection - clinical implications of changes in brain function during heart failure. , 2015, Circulation journal : official journal of the Japanese Circulation Society.

[60]  R. Panerai,et al.  Reproducibility of cerebral and peripheral haemodynamic responses to active, passive and motor imagery paradigms in older healthy volunteers: A fTCD study , 2012, Journal of Neuroscience Methods.

[61]  M. Haykowsky,et al.  Exercise limitations in heart failure with reduced and preserved ejection fraction. , 2018, Journal of applied physiology.

[62]  Richard P. White,et al.  Grading of cerebral dynamic autoregulation from spontaneous fluctuations in arterial blood pressure. , 1998, Stroke.