Takeshi Tohyama

Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure

BACKGROUND Reducing myocardial damage is a prerequisite to prevent chronic heart failure after acute myocardial infarction (AMI). Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have potent anti-infarct effect, technical difficulties have precluded its clinical application. We developed a novel therapeutic strategy of intravenous VNS (iVNS) and examined whether iVNS administered prior to coronary reperfusion in a canine AMI model reduces infarct size and prevents heart failure. METHODS AND RESULTS In 35 mongrel dogs, we induced ischemia by ligating the left anterior descending coronary artery and then reperfused 3h later (I/R). We transvenously placed a catheter electrode in the superior vena cava and adjusted the stimulation intensity to a level that induced bradycardia but maintained stable hemodynamics (continuous, 5.1±2.1V, 10Hz). We administered iVNS from onset (iVNS-0, n=7) or 90min after onset (iVNS-90, n=7) of ischemia until one hour after reperfusion. Four weeks after ischemia-reperfusion, iVNS markedly reduced infarct size (iVNS-0: 2.4±2.1%, p<0.05 and iVNS-90: 4.5±4.5%, p<0.05) compared with I/R control (I/R: 13.3±2.5%), and improved cardiac performance and hemodynamics. Atrial pacing (n=7) to abolish iVNS-induced bradycardia significantly attenuated the beneficial effects of iVNS. CONCLUSIONS Short-term iVNS delivered prior to coronary reperfusion markedly reduced infarct size and preserved cardiac function one month after AMI. The bradycardic effect plays an important role in the beneficial effect of iVNS. How other mechanisms contribute to the reduction of infarct size remains to be studied.

Central chemoreflex activation induces sympatho‐excitation without altering static or dynamic baroreflex function in normal rats

Central chemoreflex activation induces sympatho‐excitation. However, how central chemoreflex interacts with baroreflex function remains unknown. This study aimed to examine the impact of central chemoreflex on the dynamic as well as static baroreflex functions under open‐loop conditions. In 15 anesthetized, vagotomized Sprague‐Dawley rats, we isolated bilateral carotid sinuses and controlled intra‐sinus pressure (CSP). We then recorded sympathetic nerve activity (SNA) at the celiac ganglia, and activated central chemoreflex by a gas mixture containing various concentrations of CO2. Under the baroreflex open‐loop condition (CSP = 100 mmHg), central chemoreflex activation linearly increased SNA and arterial pressure (AP). To examine the static baroreflex function, we increased CSP stepwise from 60 to 170 mmHg and measured steady‐state SNA responses to CSP (mechanoneural arc), and AP responses to SNA (neuromechanical arc). Central chemoreflex activation by inhaling 3% CO2 significantly increased SNA irrespective of CSP, indicating resetting of the mechanoneural arc, but did not change the neuromechanical arc. As a result, central chemoreflex activation did not change baroreflex maximum total loop gain significantly (−1.29 ± 0.27 vs. −1.68 ± 0.74, N.S.). To examine the dynamic baroreflex function, we randomly perturbed CSP and estimated transfer functions from 0.01 to 1.0 Hz. The transfer function of the mechanoneural arc approximated a high‐pass filter, while those of the neuromechanical arc and total (CSP‐AP relationship) arcs approximated a low‐pass filter. In conclusion, central chemoreflex activation did not alter the transfer function of the mechanoneural, neuromechanical, or total arcs. Central chemoreflex modifies hemodynamics via sympatho‐excitation without compromising dynamic or static baroreflex AP buffering function.

Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure

BACKGROUND Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. METHODS We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. RESULTS Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CONCLUSIONS CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure.

Estimation of nocturnal cardiac output by automated analysis of circulation time derived from polysomnography

To the Editors;Two-thirds of heart failure (HF) patients are reportedly accompa-niedbycomorbidsleepdisorderedbreathing(SDB)[1].Pulmonarycon-gestion, low cardiac output and enhanced ventilatory response tocarbondioxideinHFhavebeenobservedtocauseCheyne–Stokesrespi-ration [2,3].Asidefromtheabove,fluidaccumulationandnocturnalros-tral fluid shift may also predispose to obstructive sleep apnea in thisparticular group [4]. A community-based cohort study has shown thatcomorbid obstructive sleep apnea is associated with an increase in therisk of death in patients with HF [5]. Several existing non-randomizedstudies have suggested that treatment with continuous positive airwaypressure improved the prognosis of such patients [5,6].WiththespreadofawarenessofthesemutualrelationshipsbetweenSDB and HF, sleep study has become one of the most fundamental ex-aminations in current HF management [7] and a large number ofpolysomnography studies are carried out on HF patients every year forthis very reason. Among the data obtained in polysomnography study,the lag time from the start of re-breathing to the rising point of pulseoximetric saturation (SpO

The impact of volume loading-induced low pressure baroreflex activation on arterial baroreflex-controlled sympathetic arterial pressure regulation in normal rats

Although low pressure baroreflex (LPB) has been shown to elicit various cardiovascular responses, its impact on sympathetic nerve activity (SNA) and arterial baroreflex (ABR) function has not been fully elucidated. The aim of this study was to clarify how volume loading‐induced acute LPB activation impacts on SNA and ABR function in normal rats. In 20 anesthetized Sprague‐Dawley rats, we isolated bilateral carotid sinuses, controlled carotid sinus pressure (CSP), and measured central venous pressure (CVP), splanchnic SNA, and arterial pressure (AP). We infused blood stepwise (3 mL/kg/step) to activate volume loading‐induced LPB. Under the ABR open‐loop condition, stepwise volume loading markedly increased SNA by 76.8 ± 21.6% at CVP of 3.6 ± 0.2 mmHg. In contrast, further volume loading suppressed SNA toward the baseline condition. Bilateral vagotomy totally abolished the changes in SNA by volume loading. To assess the impact of LPB on ABR function, we changed CSP stepwise. Low volume loading (CVP = 3.6 ± 0.4 mmHg) significantly shifted the sigmoidal CSP–SNA relationship (central arc) upward from baseline, whereas high volume loading (CVP = 5.4 ± 0.4 mmHg) returned it to the baseline level. Volume loading shifted the linear SNA–AP relationship (peripheral arc) upward without significant changes in slope. In conclusions, volume loading‐induced acute LPB activation evoked two‐phase changes, an initial increase followed by decline from baseline value, in SNA via resetting of the ABR central arc. LPB may contribute greatly to stabilize AP in response to volume status.

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation

Background Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Methods Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. Results In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. Conclusions LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed peripheral arc determines SNA and hemodynamics in LPS-induced acute inflammation.

Pulmonary arterial input impedance reflects the mechanical properties of pulmonary arterial remodeling in rats with pulmonary hypertension

Aims: Although pulmonary arterial remolding in pulmonary hypertension (PH) changes the mechanical properties of the pulmonary artery, most clinical studies have focused on static mechanical properties (resistance), and dynamic mechanical properties (compliance) have not attracted much attention. As arterial compliance plays a significant role in determining afterload of the right ventricle, we evaluated how PH changes the dynamic mechanical properties of the pulmonary artery using high‐resolution, wideband input impedance (ZPA). We then examined how changes in ZPA account for arterial remodeling. Clarification of the relationship between arterial remodeling and ZPA could help evaluate arterial remodeling according to hemodynamics. Main methods: PH was induced in Sprague–Dawley rats with an injection of Sugen5416 (20mg/kg) and 3‐week exposure to hypoxia (10% oxygen) (SuHx). ZPA was evaluated from pulmonary artery pressure and flow under irregular pacing. Pulmonary histology was examined at baseline and 1, 3, and 8weeks (n=7, each) after Sugen5416 injection. Key findings: SuHx progressively increased pulmonary arterial pressure. ZPA findings indicated that SuHx progressively increased resistance (baseline: 9.3±3.6, SuHx1W: 20.7±7.9, SuHx3W: 48.8±6.9, SuHx8W: 62.9±17.8mmHg/mL/s, p<0.01) and decreased compliance (baseline: 11.9±2.1, SuHx1W: 5.3±1.7, SuHx3W: 2.1±0.7, SuHx8W: 1.9±0.6×10−3mL/mmHg, p<0.01). The time constant did not significantly change. The progressive reduction in compliance was closely associated with wall thickening of small pulmonary arteries. Significance: The finding that changes in resistance were reciprocally associated with those in compliance indicates that resistant and compliant vessels are anatomically inseparable. The analysis of ZPA might help evaluate arterial remodeling in PH according to hemodynamics.

Diabetes mellitus attenuates the pressure response against hypotensive stress by impairing the sympathetic regulation of the baroreflex afferent arc

Patients with diabetes mellitus (DM) often show arterial pressure (AP) lability associated with cardiovascular autonomic neuropathy. Because the arterial baroreflex tightly regulates AP via sympathetic nerve activity (SNA), we investigated the systematic baroreflex function, considering the control theory in DM by open-loop analysis. We used Zucker diabetic fatty (ZDF) rats as a type 2 DM model. Under general anesthesia, we isolated the carotid sinuses from the systemic circulation, changed intracarotid sinus pressure (CSP), and recorded SNA and AP responses. We compared CSP-AP (total loop), CSP-SNA (afferent arc), and SNA-AP (efferent arc) relationships between ZDF lean ( n = 8) and ZDF fatty rats ( n = 6). Although the total loop gain of baroreflex (ΔAP/ΔCSP) at the operating point did not differ between the two groups, the average gain in the lower CSP range was markedly reduced in ZDF fatty rats (0.03 ± 0.01 vs. 0.87 ± 0.10 mmHg/mmHg, P < 0.001). The afferent arc showed the same trend as the total loop, with a response threshold of 139.8 ± 1.0 mmHg in ZDF fatty rats. There were no significant differences in the gain of efferent arc between the two groups. Simulation experiments indicated a markedly higher AP fall and lower total loop gain of baroreflex in ZDF fatty rats than in ZDF lean rats against hypotensive stress because the efferent arc intersected with the afferent arc in the SNA unresponsive range. Thus, we concluded that impaired baroreflex sympathetic regulation in the lower AP range attenuates the pressure response against hypotensive stress and may partially contribute to AP lability in DM. NEW & NOTEWORTHY In this study, we investigated the open-loop baroreflex function, considering the control theory in type 2 diabetes mellitus model rats to address the systematic mechanism of arterial pressure (AP) lability in diabetes mellitus. The unresponsiveness of baroreflex sympathetic regulation in the lower AP range was observed in type 2 diabetic rats. It may attenuate the baroreflex pressure-stabilizing function and induce greater AP fall against hypotensive stress.