Masaru Sugimachi

Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats

Background—Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Methods and Results—Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1±5.9 versus 23.5±4.2 mm Hg, P <0.05) and higher maximum dp/dt of left ventricular pressure (4152±237 versus 2987±192 mm Hg/s, P <0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75±0.25 versus 3.14±0.22 g/kg, P <0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P =0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death. Conclusions—Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.

Bionic technology revitalizes native baroreflex function in rats with baroreflex failure.

Background—We developed a bionic technology for the treatment of baroreflex failure and tested its efficacy in restoration of arterial pressure against head-up tilt (HUT) in rats with baroreflex failure. Methods and Results—The bionic baroreflex system (BBS) was a negative feedback system controlled by a computer, the artificial vasomotor center. It sensed systemic arterial pressure (SAP) through a micromanometer placed in the aortic arch and automatically computed the frequency of a pulse train to stimulate sympathetic efferent nerves. We selected the celiac ganglion as the sympathetic vasomotor interface. To make this system bionic, the operational rule of the artificial vasomotor center (HBRP→STM; BRP indicates baroreceptor pressure; STM, electrical stimulation) was actively matched to that of the native center. First, we identified the open-loop transfer functions of the native baroreflex control of SAP (HNative) and the response of SAP to electrical stimulation of the celiac ganglion (HSTM→SAP). We computed HBRP→STM from HNative/HSTM→SAP and transplanted the operational rule into the computer. In 10 rats with baroreflex failure, we evaluated the performance of the BBS during rapid hypotension induced by HUT. Abrupt HUT dropped SAP by 34±6 mm Hg in 2 seconds and by 52±5 mm Hg in 10 seconds. During real-time execution of the BBS, on the other hand, the fall in SAP was 21±5 mm Hg at 2 seconds and 15±6 mm Hg at 10 seconds after HUT. These arterial responses controlled by the BBS were indistinguishable from those by the native baroreflex. Conclusions—We concluded that the BBS revitalized the native baroreflex function in rats with baroreflex failure.

Structural Heterogeneity in the Ventricular Wall Plays a Significant Role in the Initiation of Stretch-Induced Arrhythmias in Perfused Rabbit Right Ventricular Tissues and Whole Heart Preparations

Rationale: Mechanical stress is known to alter the electrophysiological properties of the myocardium and may trigger fatal arrhythmias when an abnormal load is applied to the heart. Objective: We tested the hypothesis that the structural heterogeneity of the ventricular wall modulates globally applied stretches to create heterogeneous strain distributions that lead to the initiation of arrhythmias. Methods and Results: We applied global stretches to arterially perfused rabbit right ventricular tissue preparations. The distribution of strain (determined by marker tracking) and the transmembrane potential (measured by optical mapping) were simultaneously recorded while accounting for motion artifacts. The 3D structure of the preparations was also examined using a laser displacement meter. To examine whether such observations can be translated to the physiological condition, we performed similar measurements in whole heart preparations while applying volume pulses to the right ventricle. At the tissue level, larger stretches (≥20%) caused synchronous excitation of the entire preparation, whereas medium stretches (10% and 15%) induced focal excitation. We found a significant correlation between the local strain and the local thickness, and the probability for focal excitation was highest for medium stretches. In the whole heart preparations, we observed that such focal excitations developed into reentrant arrhythmias. Conclusions: Global stretches of intermediate strength, rather than intense stretches, created heterogeneous strain (excitation) distributions in the ventricular wall, which can trigger fatal arrhythmias.

Open-loop dynamic and static characteristics of the carotid sinus baroreflex in rats with chronic heart failure after myocardial infarction

We estimated open-loop dynamic characteristics of the carotid sinus baroreflex in normal control rats and chronic heart failure (CHF) rats after myocardial infarction. First, the neural arc transfer function from carotid sinus pressure to splanchnic sympathetic nerve activity (SNA) and its corresponding step response were examined. Although the steady-state response was attenuated in CHF, the negative peak response and the time to peak did not change significantly, suggesting preserved neural arc dynamic characteristics. Next, the peripheral arc transfer function from SNA to arterial pressure (AP) and its corresponding step response were examined. The steady-state response and the initial slope were reduced in CHF, suggesting impaired end-organ responses. In a simulation study based on the dynamic and static characteristics, the percent recovery of AP was reduced progressively as the size of disturbance increased in CHF, suggesting that a reserve for AP buffering is lost in CHF despite relatively maintained baseline AP.

Early Short-Term Vagal Nerve Stimulation Attenuates Cardiac Remodeling After Reperfused Myocardial Infarction

BACKGROUND Vagal nerve stimulation (VS) has been suggested to be an effective adjunct to reperfusion therapy in myocardial infarction (MI). However, the effect of VS on left ventricular (LV) remodeling after reperfused MI has not been examined. METHODS AND RESULTS We investigated the effects of early, brief VS on acute inflammatory reactions (study 1) and chronic LV remodeling (study 2) in a rabbit model of reperfused MI. In study 1, rabbits were subjected to 60-minute coronary artery occlusion followed by reperfusion alone (MI, n = 8) or treated with 24-hour VS (MI-VS, n = 8). At 24 hours after ischemia-reperfusion, MI-VS rabbits showed significantly decreased myocardial infiltration of neutrophils and reduced myocardial expressions of tumor necrosis factor-alpha and matrix metalloproteinase-8 and -9, compared with MI rabbits. Myocardial expression of interleukin-6 was not affected by VS. In study 2, rabbits were subjected to coronary occlusion and reperfusion alone (n = 16) or treated with VS for 3 days (n = 14). At 8 weeks after ischemia-reperfusion, MI-VS rabbits showed significantly improved LV dysfunction and dilatation, and significantly reduced infarct size, infarct wall thinning, and LV weight compared with MI rabbits. CONCLUSION Early, short-term VS attenuates LV remodeling after reperfused MI, which may be associated with suppression of acute inflammatory reactions.

Evaluation of the severity of mitral regurgitation by transesophageal Doppler flow echocardiography

The severity of mitral regurgitation (MR) was assessed by transesophageal Doppler flow echocardiography (TEE) using new criteria in 87 patients. The severity of MR assessed by TEE (TEE-MR) was compared with that obtained by left ventriculography (LVG-MR). Although the severity of TEE-MR has been evaluated by MR jet area, it is often difficult because the MR jet extends beyond a single frame image in severe MR. We found that (1) when the MR area was larger than 3 cm2, the severity of MR was more than second-degree by LVG; (2) there was systolic turning flow (STF) of the MR jet within the left atrial cavity in 27 of 30 patients with third- and fourth-degree LVG-MR; and (3) there was late systolic backward flow (SBF) in the pulmonary veins in 9 of 10 patients with fourth-degree LVG-MR. A new grading of the severity of MR by TEE was proposed, which combined the findings of STF, SBF, and the MR area. These new criteria of the severity of TEE-MR excellently correlated with that by LVG (y = 0.94x + 0.08; r = 0.95, p less than 0.01). The criteria for MR by TEE were also useful for assessment of MR in patients with prosthetic mitral valve dysfunction (y = 0.96x + 0.04; r = 0.97, p less than 0.01). We conclude from this study that the severity of MR can be accurately assessed with TEE by measuring the MR area and the specific flow patterns in the left atrium and pulmonary veins.

Muscle Sympathetic Nerve Activity Averaged Over 1 Minute Parallels Renal and Cardiac Sympathetic Nerve Activity in Response to a Forced Baroreceptor Pressure Change

Background—Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown. Method and Results—In experiment 1, muscle (microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits (n=6) while arterial pressure was changed by intravenous bolus injections of nitroprusside (3 &mgr;g/kg) followed by phenylephrine (3 &mgr;g/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits (n=10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal (r=0.96±0.01, mean±SE) and cardiac (r=0.96±0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal (r=0.97±0.01) and cardiac (r=0.97±0.01) SNAs in experiment 2 (baroreflex open-loop condition). Conclusions—Muscle SNA averaged over 1 minute parallels renal and cardiac SNAs in response to a forced baroreceptor pressure change.

Resetting of the arterial baroreflex increases orthostatic sympathetic activation and prevents postural hypotension in rabbits

Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic‐denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.

High-frequency dominant depression of peripheral vagal control of heart rate in rats with chronic heart failure.

To examine whether dynamic characteristics of the peripheral vagal control of heart rate (HR) are altered in chronic heart failure (CHF).

Detection of endogenous acetylcholine release during brief ischemia in the rabbit ventricle: A possible trigger for ischemic preconditioning

AIMS To examine endogenous acetylcholine (ACh) release in the rabbit left ventricle during acute ischemia, ischemic preconditioning and electrical vagal stimulation. MAIN METHODS We measured myocardial interstitial ACh levels in the rabbit left ventricle using a cardiac microdialysis technique. In Protocol 1 (n=6), the left circumflex coronary artery (LCX) was occluded for 30min and reperfused for 30min. In Protocol 2 (n=5), the LCX was temporarily occluded for 5min. Ten minutes later, the LCX was occluded for 30min and reperfused for 30min. In Protocol 3 (n=5), bilateral efferent vagal nerves were stimulated at 20Hz and 40Hz (10V, 1-ms pulse duration). KEY FINDINGS In Protocol 1, a 30-min coronary occlusion increased the ACh level from 0.39+/-0.15 to 7.0+/-2.2nM (mean+/-SE, P<0.01). In Protocol 2, a 5-min coronary occlusion increased the ACh level from 0.33+/-0.07 to 0.75+/-0.11nM (P<0.05). The ACh level returned to 0.48+/-0.10nM during the interval. After that, a 30-min coronary occlusion increased the ACh level to 2.4+/-0.49nM (P<0.01). In Protocol 3, vagal stimulation at 20Hz and 40Hz increased the ACh level from 0.29+/-0.06 to 1.23+/-0.48 (P<0.05) and 2.44+/-1.13nM (P<0.01), respectively. SIGNIFICANCE Acute ischemia significantly increased the ACh levels in the rabbit left ventricle, which appeared to exceed the vagal stimulation-induced ACh release. Brief ischemia as short as 5min can also increase the ACh level, suggesting that endogenous ACh release can be a trigger for ischemic preconditioning.