Yoshinori Murayama

Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity

It has been established that vagal nerve stimulation (VNS) benefits patients and/or animals with heart failure. However, the impact of VNS on sympathetic nerve activity (SNA) remains unknown. In this study, we investigated how vagal afferent stimulation (AVNS) impacts baroreflex control of SNA. In 12 anesthetized Sprague–Dawley rats, we controlled the pressure in isolated bilateral carotid sinuses (CSP), and measured splanchnic SNA and arterial pressure (AP). Under a constant CSP, increasing the voltage of AVNS dose dependently decreased SNA and AP. The averaged maximal inhibition of SNA was ‐28.0 ± 10.3%. To evaluate the dynamic impacts of AVNS on SNA, we performed random AVNS using binary white noise sequences, and identified the transfer function from AVNS to SNA and that from SNA to AP. We also identified transfer functions of the native baroreflex from CSP to SNA (neural arc) and from SNA to AP (peripheral arc). The transfer function from AVNS to SNA strikingly resembled the baroreflex neural arc and the transfer functions of SNA to AP were indistinguishable whether we perturbed ANVS or CSP, indicating that they likely share common central and peripheral neural mechanisms. To examine the impact of AVNS on baroreflex, we changed CSP stepwise and measured SNA and AP responses with or without AVNS. AVNS resets the sigmoidal neural arc downward, but did not affect the linear peripheral arc. In conclusion, AVNS resets the baroreflex neural arc and induces sympathoinhibition in the same manner as the control of SNA and AP by the native baroreflex.

Changes in Vascular Properties, Not Ventricular Properties, Predominantly Contribute to Baroreflex Regulation of Arterial Pressure

Baroreflex modulates both the ventricular and vascular properties and stabilizes arterial pressure (AP). However, how changes in those mechanical properties quantitatively impact the dynamic AP regulation remains unknown. We developed a framework of circulatory equilibrium, in which both venous return and cardiac output are expressed as functions of left ventricular (LV) end-systolic elastance (Ees), heart rate (HR), systemic vascular resistance (R), and stressed blood volume (V). We investigated the contribution of each mechanical property using the framework of circulatory equilibrium. In six anesthetized dogs, we vascularly isolated carotid sinuses and randomly changed carotid sinus pressure (CSP), while measuring the LV Ees, aortic flow, right and left atrial pressure, and AP for at least 60 min. We estimated transfer functions from CSP to Ees, HR, R, and V in each dog. We then predicted these parameters in response to changes in CSP from the transfer functions using a data set not used for identifying transfer functions and predicted changes in AP using the equilibrium framework. Predicted APs matched reasonably well with those measured (r2=0.85-0.96, P<0.001). Sensitivity analyses indicated that Ees and HR (ventricular properties) accounted for 14±4 and 4±2%, respectively, whereas R and V (vascular properties) accounted for 32±4 and 39±4%, respectively, of baroreflex-induced AP regulation. We concluded that baroreflex-induced dynamic AP changes can be accurately predicted by the transfer functions from CSP to mechanical properties using our framework of circulatory equilibrium. Changes in the vascular properties, not the ventricular properties, predominantly determine baroreflex-induced AP regulation.

Optimal Titration Is Important to Maximize the Beneficial Effects of Vagal Nerve Stimulation in Chronic Heart Failure

BACKGROUND Although vagal nerve stimulation (VNS) benefits patients with chronic heart failure (CHF), the optimal dose of VNS remains unknown. In clinical trials, adverse symptoms limited up-titration. In this study, we evaluated the impact of various voltages of VNS which were titrated below symptom threshold on cardiac function and CHF parameters in rat myocardial infarction (MI) models. METHODS AND RESULTS We randomly allocated MI rats to vagal (VNS; n = 41) and sham (Sham; n = 16) stimulation groups. We stimulated the right vagal nerve with 20 Hz at 3 different voltages for 4 weeks. We defined Max as the highest voltage that did not evoke any symptom, Half as one-half of Max, and Quarter as one-fourth of Max. All 3 VNS groups significantly reduced biventricular weight compared with Sham (P < .05). In contrast, only Half decreased left ventricular (LV) end-diastolic pressure (Half: 17.5 ± 2.0 mm Hg; Sham: 24.2 ± 1.2 mm Hg; P < .05) and increased LV ejection fraction (Half: 37.9 ± 3.1%; Sham: 28.4 ± 2.3%,-P < .05) and LV maximum +dP/dt (Half: 5918.6 ± 2.0 mm/Hg/s; Sham: 5001.2 ± 563.2 mm Hg/s; P < .05). The number of large vagal nerve fibers was reduced with Max (Max: 163.1 ± 43.0 counts/bundle; Sham: 360.0 ±61.6 counts/bundle; P < .05), indicating significant neural damage by VNS. CONCLUSION The optimal titration of VNS would maximize benefits for CHF and minimize adverse effects.

Noninvasive transcutaneous bionic baroreflex system prevents severe orthostatic hypotension in patients with spinal cord injury

Central baroreflex failure in patients with spinal cord injury results in serious orthostatic hypotension. We examined if transcutaneous electrical stimulation regulates arterial pressure in those patients. We identified skin regions capable of increasing arterial pressure and determined respective transfer function. Using the transfer function, we designed the feedback regulator (i.e., bionic baroreflex system) to control arterial pressure. Orthostatic stress decreased arterial pressure profoundly. Activation of bionic regulator restored and maintained arterial pressure at pre-specified levels. We conclude that the transcutaneous bionic system is noninvasive and capable of stabilizing arterial pressure in patients with spinal cord injury.Central baroreflex failure in patients with spinal cord injury results in serious orthostatic hypotension. We examined if transcutaneous electrical stimulation regulates arterial pressure in those patients. We identified skin regions capable of increasing arterial pressure and determined respective transfer function. Using the transfer function, we designed the feedback regulator (i.e., bionic baroreflex system) to control arterial pressure. Orthostatic stress decreased arterial pressure profoundly. Activation of bionic regulator restored and maintained arterial pressure at pre-specified levels. We conclude that the transcutaneous bionic system is noninvasive and capable of stabilizing arterial pressure in patients with spinal cord injury.

Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expressions and pathway activation

The heart has remarkable capacity to adapt to mechanical load and to dramatically change its phenotype. The mechanism underlying such diverse phenotypic adaptations remains unknown. Since systolic overload induces wall thickening, while diastolic overload induces chamber enlargement, we hypothesized that cardiac phase-sensitive mechanisms govern the adaptation. We inserted a balloon into the left ventricle (LV) of a Langendorff perfused rat heart, and controlled LV volume (LVV) using a high performance servo-pump. We created isolated phasic systolic overload (SO) by isovolumic contraction (peak LV pressure >170mmHg) at unstressed diastolic LVV [end-diastolic pressure (EDP)=0mmHg]. We also created pure phasic diastolic overload (DO) by increasing diastolic LVV until EDP >40mmHg and unloading completely in systole. After 3hours under each condition, the myocardium was analyzed using DNA microarray. Gene expressions under SO and DO conditions were compared against unloaded control condition using gene ontology and pathway analysis (n=4 each). SO upregulated proliferation-related genes, whereas DO upregulated fibrosis-related genes (P<10(-5)). Both SO and DO upregulated genes related functionally to cardiac hypertrophy, although the gene profiles were totally different. Upstream regulators confirmed by Western blot indicated that SO activated extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, and Ca(2+)/calmodulin-dependent protein kinase II (3.2-, 2.0-, and 4.7-fold versus control, P<0.05, n=5), whereas DO activated p38 (2.9-fold, P<0.01), which was consistent with the downstream gene expressions. In conclusion, pure isolated systolic and diastolic overload permits elucidation of cardiac phase-sensitive gene regulation. The genomic responses indicate that mechanisms governing the cardiac phase-sensitive adaptations are different.

Artificial baroreflex system restores volume tolerance in the absence of native baroreflex

The arterial baroreflex stabilizes arterial pressure by modulating the mechanical properties of cardiovascular system. We previously demonstrated that the baroreflex impairment makes the circulatory system extremely sensitive to volume overload and predisposes to pulmonary edema irrespective of left ventricular systolic function. To overcome the volume intolerance, we developed an artificial baroreflex system by directly stimulating the carotid sinus nerves in response to changes in arterial pressure. The artificial baroreflex system precisely reproduced the native arterial pressure response and restored physiological volume buffering function. We conclude that the artificial baroreflex system would be an attractive tool in preventing pulmonary edema in patients with impaired baroreflex function.

Impact of baroreflex on venous return surface

Background: Although Guytons concept of venous return (VR) revolutionized circulatory physiology, the pulmonary circulation is invisible in its original framework. Since the pulmonary circulation is critical in left heart failure, we characterized the VR as a surface described by right (PRA) and left atrial (PLA) pressures and demonstrated that the VR surface was capable of representing mechanics of pulmonary as well as systemic circulation. However how baroreflex impacts the VR surface remains unknown. Methods/Results: In 8 dogs, we isolated the carotid sinuses and replaced both ventricles with pumps. We varied cardiac output, shifted blood distribution between the systemic and pulmonary circulation at carotid sinus pressures (CSP) of 100 or 140 mmHg. The coefficient of determination of the VR surface ranged 0.96–0.99 indicating how flat the surface is. Increasing CSP decreased maximum VR (233±27 vs. 216±33 ml/kg/min, p<0.05), whereas did not change the slopes of VR along PRA or PLA axes. Conclusions: Baroreflex parallel shifts the VR surface, thereby stressed volume, without changing its slopes.

INTRAVENOUS VAGAL NERVE STIMULATION IN ACUTE MYOCARDIAL INFARCTION (AMI) MARKEDLY IMPROVES CARDIAC FUNCTION AND PREVENTS CHRONIC HEART FAILURE

Although vagal nerve stimulation (VNS) in the acute phase of AMI has a powerful anti-ischemic effect, technical difficulties associated with VNS preclude its application under emergency clinical settings. Furthermore, how the acute phase VNS translates into the long term benefit remains unknown. In

How to quantitatively synthesize dynamic changes in arterial pressure from baroreflexly modulated ventricular and arterial properties

Baroreflex regulates arterial pressure by modulating ventricular and vascular properties. We investigated if the framework of circulatory equilibrium that we developed previously (Am J Physiol 2004, 2005) by extending the classic Guytons framework is capable of predicting baroreflex induced changes in arterial pressure. In animal experiments, we estimated open loop transfer functions of baroreflexly modulated ventricular and vascular properties, synthesized baroreflex induced dynamic changes in arterial pressure using the estimated transfer functions and compared the predicted responses with measured responses. We demonstrated that the predicted baroreflex induced changes in arterial pressure matched reasonable well with those measured. We conclude that the framework of circulatory equilibrium is generalizable under the condition where baroreflex dynamically changes arterial pressure.