Ischemia-induced regional wall motion abnormality is improved after coronary angioplasty: demonstration by dobutamine stress echocardiography.

OBJECTIVES: The purpose of this study was to examine whether dobutamine stress echocardiography can detect reversal of ischemia-induced left ventricular regional wall motion abnormality immediately after percutaneous transluminal coronary angioplasty. BACKGROUND: Although angioplasty is routinely performed as a means of coronary revascularization, at present there is a question whether this results in an immediate improvement in ischemia-induced left ventricular regional function. METHODS: Thirty-five patients underwent dobutamine stress echocardiography 24 h before and 24 to 48 h after angiographically successful coronary angioplasty. Only patients with normal wall motion at rest were included. Dobutamine infusion was begun at 5 micrograms/kg per min and increased at 5-min intervals (10, 20, 30, 40 micrograms/kg per min). Echocardiographic images were stored into cine loops and analyzed off line with simultaneous comparison of images acquired at baseline, 5 micrograms/kg per min, peak infusion and recovery. Echocardiographic images were interpreted independently, without knowledge of other data, by two experienced cardiologists using the 16-myocardial segment model. RESULTS: Before angioplasty, dobutamine stress echocardiography induced wall motion abnormalities in 31 patients (88%). Wall motion score at peak dobutamine infusion improved in 28 (90%) of the 31 patients after angioplasty. Wall motion score at peak dobutamine infusion for the group improved from 20 +/- 3 before angioplasty to 17 +/- 2 after angioplasty (p < 0.001). There was no change in the rate-pressure product achieved for the group before and after angioplasty (20,038 +/- 6,415 beats/min x mm Hg before versus 20,775 +/- 5,435 after angioplasty, p = NS). Before angioplasty, dobutamine stress echocardiography induced angina in 13 patients (37%), whereas angina occurred only once after angioplasty. Electrocardiographic changes diagnostic of ischemia occurred seven times, all before angioplasty. CONCLUSIONS: We conclude that dobutamine stress echocardiography is an excellent method to demonstrate an immediate improvement in stress-induced regional left ventricular dysfunction in the distribution of the vessel undergoing successful angioplasty.

Myocardial contrast echocardiography for the assessment of coronary blood flow reserve: validation in humans.

OBJECTIVES: The aim of this study was to validate the use of myocardial contrast echocardiography to determine coronary blood flow reserve in humans. BACKGROUND: Although myocardial contrast echocardiography has been used to accurately quantify coronary flow reserve in animals, validation for its use in humans to measure flow reserve is lacking. METHODS: We analyzed the time-intensity curve from the anteroseptal region of the left ventricular short axis produced after a left main coronary artery injection of sonicated albumin before and after intracoronary administration of papaverine in 16 patients without angiographically significant coronary artery disease. The ratio of half-time of video intensity disappearance from peak intensity, variable of curve width, area under the time-intensity curve and corrected peak contrast intensity after papaverine compared with baseline were correlated with coronary flow reserve measured simultaneously with an intracoronary Doppler probe in the left anterior descending coronary artery. RESULTS: There was a strong inverse correlation with half-time of contrast washout and coronary flow reserve (r = -0.76, p = 0.0007) and a strong positive correlation between the variable of curve width (which is inversely proportional to curve width) and coronary flow reserve (r = 0.71, p = 0.002). There was a weak but significant inverse correlation between area under the time-intensity curve and coronary flow reserve (r = -0.54, p = 0.03) but no correlation between corrected peak contrast intensity and coronary flow reserve (r = -0.36, p = NS). Despite the strong correlation for the ratios for half-time of contrast washout and variable of curve width and actual coronary flow reserve measured with intracoronary Doppler probe, the transit time ratios consistently underestimated coronary flow reserve. CONCLUSIONS: Myocardial contrast echocardiography performed with left main coronary artery injections of sonicated albumin can be utilized to measure coronary flow reserve in humans. Transit time variable ratios (half-time of contrast washout and variable of curve width) derived from the time-intensity curve correlate most strongly with coronary flow reserve.

Alterations of platelet aggregation kinetics with ultraviolet laser emission: the "stunned platelet" phenomenon.

Platelets, a major constituent of thrombus, play a crucial role in the pathogenesis of acute ischemic coronary syndromes. The effect of ultraviolet laser emission on platelets within thrombi is unknown. The effects of increasing levels of laser energy on platelets in whole blood were investigated. Blood samples were obtained by aseptic venipuncture and anticoagulated with 3.8% sodium citrate. Samples were exposed to increased levels (0, 30, 45, 60 mJ/mm2; 25 Hz) of ultraviolet excimer laser fluence (308 nm wave-length) and then tested for ADP and collagen induced platelet aggregation, platelet concentration, and for platelet contractile force (PCF) development. Scanning electron microscopy was used to detect laser induced morphologic changes of platelets and by flow cytometric analysis to detect changes in expression of platelet surface antigens p-selectin (CD 62) and glycoprotein IIb/IIIa (CD 43). Exposure to excimer laser energy produced dose dependent suppression of platelet aggregation and force development ("stunned platelets"). ADP aggregation decreased from 8.0+/-1.1 Ohms (mean+/-SEM) to 3.7+/-0.8 Ohms (p<0.001) to 2.7+/-0.6 Ohms (p <0.001) and to 1.8+/-0.5 Ohms (p <0.001) as the laser energy increased from 0 to 30 to 45 to 60 mJ/mm2, respectively. Collagen induced aggregation decreased from 21.4+/-1.4 Ohms to 15.7+/-1.2 Ohms (p <0.001) to 11.7+/-1.1 Ohms (p <0.001) and to 9.9+/-1.0 Ohms (p <0.001), in response to the same incremental range of laser energy. Platelet contractile forces declined from 34,500+/-3700 to 27.800+/-2700 dynes as laser energy increased from 0 to 60 mJ/mm2 (p <0.03). Platelet concentration did not change with increasing laser energy. The expression of platelet surface antigen p-selectin (CD 62) remained stable through increasing levels of laser energy exposures while the percentage of CD 43 positive platelets significantly increased with exposure to laser energy, yet the level of expression did not exceed 0.5% of cells. Thus, aggregation kinetics are altered in platelets exposed to ultraviolet laser energy as manifested by decreased platelet aggregation and reduction in platelet force development capability. The response is dose dependent and most pronounced at higher energy levels such as 60 mJ/mm2.

Cardiac nociceptive reflexes after transmyocardial laser revascularization: implications for the neural hypothesis of angina relief.

OBJECTIVE: The mechanism by which transmyocardial laser revascularization relieves angina is not understood. One theory is that laser-induced thermal damage to cardiac nerves results in cardiac denervation. This study examined the acute effects of transmyocardial laser revascularization on reflex responses mediated by cardiac nociceptors, the left ventricular receptors with sympathetic afferent fibers that are thought to mediate anginal chest pain. METHODS: Experiments were performed in 13 chloralose-anesthetized dogs with sinoaortic denervation and vagotomy. Left ventricular receptors with sympathetic afferent fibers were activated by epicardial and intracoronary bradykinin before and 45 minutes after transmyocardial laser revascularization. Reflex responses elicited by bradykinin were quantitated by direct recording of efferent renal sympathetic nerve activity. Transmyocardial laser revascularization was performed in the open-chest model with a hand-held holmium:YAG laser (2.1-microm wavelength). RESULTS: An average of 44.5 +/- 1.0 channels were created. Before transmyocardial laser revascularization, reflex increases in renal sympathetic nerve activity were elicited by both epicardial and intracoronary bradykinin. After transmyocardial laser revascularization, there was no significant attenuation in the reflex responses to either epicardial (before, 66% +/- 8%; after, 100% +/- 24%; P =.19) or intracoronary (before, 124% +/- 37%; after, 108% +/- 25%; P =.44) bradykinin. CONCLUSIONS: Transmyocardial laser revascularization has no significant short-term effect on reflexes mediated by left ventricular receptors with sympathetic afferent fibers in anesthetized dogs. These results indicate that transmyocardial laser revascularization does not acutely interrupt the afferent nerves, which are believed to transmit the perception of anginal pain.

Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography.

Coronary artery disease has emerged as the leading cause of late morbidity and mortality in heart transplant recipients. The incidence of allograft coronary artery disease has been reported to be as high as 40% to 50% by 5 years. Coronary angiography remains the standard approach for surveillance of coronary artery disease in this patient population. However, the detection and surveillance of allograft coronary disease by noninvasive methods remains a challenge. The purpose of this study was to determine the value of dobutamine stress echocardiography as a noninvasive screening test to rule out the presence of anatomically significant allograft coronary artery disease and to assess its prognostic power. Dobutamine stress echocardiography was carried out according to a standard protocol in which dobutamine was infused at 5, 10, 20, 30, and 40 micrograms/kg/min intravenously at 5-minute stages with 12-lead electrocardiogram and blood pressure monitoring. Left ventricular wall motion was analyzed at baseline and at peak dobutamine dose. Mean age (+/- standard error of the mean) of the study population was 50.5 +/- 1.5 years, and mean duration (+/- standard error of the mean) since transplantation was 57 +/- 5 months. The sensitivity, specificity, and positive and negative predictive accuracy of dobutamine stress echocardiography were 95%, 55%, 69%, and 92%, respectively. In the 12-month follow-up study 12 patients with abnormal dobutamine stress echocardiographic findings had 15 major cardiac events whereas no event occurred in patients with normal dobutamine stress echocardiograms.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo effect of coronary laser angioplasty on atherosclerotic plaques: histopathologic analysis.

Information from histopathologic examination of coronary arterial atherosclerotic plaques treated with in vivo laser energy is sparse. Directional atherectomy provides biopsies for study of tissue changes (injury) due to coronary arterial debulking devices, including laser. Sixteen patients who presented with acute ischemic coronary syndromes underwent debulking of a total of 17 obstructive intracoronary lesions with pulsed-wave holmium:YAG laser (2.1 microm wavelength). Laser was performed with the "pulse and retreat" technique which incorporates slow catheter advancement (0.5-1 mm/s) with controlled emission of energy. Immediately postlasing, directional atherectomy was utilized to obtain irradiated plaque tissue for pathologic examination. Extent of laser-induced tissue injury to plaques was graded as 0 (no tissue damage), 1 (small foci or charring and vacuoles), 2 (large amount of charring, edge disruption and vacuoles) and 3 (extensive tissue damage). Angiographically and clinically, all 17 lesions were successfully debulked with the laser energy (mean 47+/-25 pulses), with a reduction of target lesion percent diameter stenosis from 92+/-6% to 47+/-25%. Adjunct balloon dilations further reduced the target lesions to a final of 10+/-10% stenosis. The histopathologic examination of the lased specimens demonstrated that 13 lesions (76%) had no evidence of laser-induced injury (Grade 0). Four lesions had low-level injury (Grade 1), and none had evidence of Grade 2 or 3 laser-induced trauma. Therefore, a laser debulking technique, which incorporates slow catheter advancement with controlled emission of pulses, does not cause significant injurious effects to the irradiated plaque.

Vagal cardiopulmonary reflexes after total cardiac deafferentation.

BACKGROUND: There are conflicting data regarding whether the primary source of afferent input for the vagal cardiopulmonary reflex emanates from receptors located in the ventricles, atria, and/or lungs. This study evaluated the effects of total cardiac deafferentation on the reflex control of efferent renal sympathetic nerve activity (RSNA) in response to a stimulus that affected all vagal receptors in the cardiopulmonary region. METHODS AND RESULTS: Experiments were performed in 14 chloralose-anesthetized dogs with sinoaortic denervation. Reflex control of RSNA in response to blood volume expansion was measured before and after interruption of cardiac vagal afferents by pericardial lidocaine (PL). Reflex sensitivity (% change in RSNA/mm Hg change in left atrial pressure) was markedly attenuated after PL (pre, -10.9+/-2.2; post, -1.6+/-0. 6; P=0.002). RSNA responses to intracoronary nicotine and left atrial balloon inflation were abolished after PL, confirming that cardiac afferents were interrupted. RSNA responses to lung inflation were not affected by PL, indicating that pulmonary afferents remained intact. In 8 experiments, reflex sensitivity values returned to baseline levels after the effects of PL had worn off. CONCLUSIONS: These results indicate that the heart provides the primary source of afferent input for the control of sympathetic outflow by the vagal cardiopulmonary reflex during changes in thoracic blood volumes and pressures.

Activation of cardiac sympathetic afferents during coronary occlusion. Evidence for reflex activation of sympathetic nervous system during transmural myocardial ischemia in the dog.

BACKGROUND: Left ventricular sympathetic afferent nerves are located mainly in superficial epicardial layers. Reflex excitatory responses mediated by sympathetic afferent nerves have been observed during myocardial ischemia in cats and humans but not in dogs. Previous canine studies have induced ischemia by occlusion of a coronary artery. Extensive collateral circulation in the canine heart may limit ischemia of epicardial layers during simple coronary occlusion, resulting in little stimulation of sympathetic afferent nerves and minimal reflex excitatory responses. METHODS AND RESULTS: In anesthetized dogs with sinoaortic and vagal deafferentation, we determined whether reflex sympathoexcitatory responses mediated by sympathetic afferents occurred during transmural myocardial ischemia. Reflex sympathoexcitation was quantitated by direct recording from either efferent renal (n = 20) or cardiac (n = 5) sympathetic nerves. Responses of arterial pressure and efferent sympathetic nerve activity were measured during simple occlusion of the anterior descending artery (LAD alone) and during LAD occlusion with a circumflex stenosis (LAD + CIRC). This circumflex stenosis was adjusted to abolish coronary vasodilator reserve without reducing basal flow. We observed significantly greater reflex increases in renal (32 +/- 5%) and cardiac (58 +/- 15%) nerve activity during LAD + CIRC than during LAD alone (14 +/- 6% and 8 +/- 7%, respectively). Reflex changes in renal nerve activity during LAD + CIRC were abolished by interruption of cardiac sympathetic afferent pathways (n = 5). In eight experiments, myocardial blood flow was measured during the two coronary occlusions. These experiments confirmed that LAD + CIRC elicited more transmural ischemia in the LAD distribution than did LAD alone. However, these experiments also revealed that LAD + CIRC elicited endocardial ischemia in the circumflex distribution. In five additional experiments, regional sympathetic deafferentation of the posterior left ventricle by epicardial application of 88% phenol along the atrioventricular groove had no significant effect on renal nerve responses to LAD + CIRC (36 +/- 5% increase before phenol versus 31 +/- 3% increase after phenol). These results indicate that endocardial ischemia in the circumflex distribution did not contribute to the reflex increases in nerve activity that were noted during LAD + CIRC. CONCLUSIONS: Reflex sympathoexcitation mediated by cardiac sympathetic afferents can be elicited in dogs. However, these responses are significant only during ischemia that is transmural and involves the superficial epicardial layers of the left ventricle.

Distribution of left ventricular sympathetic afferents demonstrated by reflex responses to transmural myocardial ischemia and to intracoronary and epicardial bradykinin.

BACKGROUND: Stimulation of left ventricular (LV) receptors with sympathetic afferents generally results in reflex sympathoexcitatory responses. Stimulation of LV receptors with vagal afferents results in reflex sympathoinhibitory responses. Vagal afferents are known to be preferentially distributed to the inferoposterior (IP) wall of the LV. We tested the hypothesis that there is also a preferential distribution of LV sympathetic afferents. METHODS AND RESULTS: We measured reflex responses to stimulation of sympathetic afferents located in the anterior and IP LV: We used myocardial ischemia and chemical stimuli to increase the activity of the sensory endings in 15 chloralose-anesthetized, mechanically ventilated dogs with sinoaortic denervation and vagotomy. Reflex responses were assessed by direct recordings of efferent renal sympathetic nerve activity (RSNA). In nine dogs, maximal RSNA changes elicited by transmural anterior myocardial ischemia (22.6 +/- 3.9% increase from baseline nerve traffic) were not significantly different from maximal RSNA changes observed during transmural IP ischemia (27.1 +/- 4.4%). Similar changes in mean arterial and left atrial pressures were noted during transmural anterior and IP ischemia. In eight dogs, maximal changes of RSNA elicited by epicardial or intracoronary bradykinin to the anterior LV were not significantly different from those observed during bradykinin to the IP LV (anterior epicardial bradykinin, 76.7 +/- 11.7%; IP epicardial bradykinin, 72.2 +/- 10.0%; anterior intracoronary bradykinin, 84.6 +/- 21.0%; IP intracoronary bradykinin, 88.8 +/- 17.3%). CONCLUSIONS: We conclude that cardiac receptors with sympathetic afferents are distributed equally to the IP and anterior regions of the LV.

Reflex responses to myocardial ischemia and reperfusion. Role of prostaglandins.

Powerful vasodepressor and cardioinhibitory reflexes are activated in humans during inferior wall myocardial ischemia or infarction and during restoration of flow to the ischemic region. Experiments in dogs have demonstrated that these responses are due to stimulation of afferent vagal fibers that are located mainly in the inferior wall of the heart. Prostaglandins are released during myocardial ischemia and possibly during reperfusion. Prostaglandins stimulate chemosensitive but not mechanosensitive endings in the ventricles. Our studies determined whether blockade of prostaglandin synthesis with indomethacin or sodium meclofenamate decreased the reflex inhibitory responses to coronary occlusion and reperfusion. Experiments were done in alpha-chloralose-anesthetized dogs after sinoaortic baroreceptor denervation. Occlusion of the circumflex coronary artery for 5 minutes resulted in decreases in arterial pressure and in renal sympathetic nerve activity. During the first 5 minutes after release of the occlusion, renal nerve activity remained inhibited. After treatment with indomethacin (n = 6, 5 mg/kg i.v.) or sodium meclofenamate (n = 3, 4 mg/kg i.v.), coronary occlusion resulted in significantly less inhibition of renal nerve activity. Renal nerve activity returned to control during the first minute of reperfusion. In six additional experiments the responses to coronary occlusion and reperfusion were not altered by treatment with vehicle. Our data suggest that prostaglandins serve as the major stimulus to ventricular sensory endings during myocardial ischemia and reperfusion. Our data further suggest that reflex inhibitory responses during ischemia and reperfusion are due mainly to stimulation of chemosensitive endings.

Vagal cardiopulmonary reflexes after left ventricular deafferentation.

BACKGROUND: Cardiac transplantation and chronic myocardial infarction interrupt vagal afferent nerve fibers, which originate mainly from the ventricles. Marked abnormalities of reflexes mediated by cardiopulmonary receptors with vagal afferent fibers have been demonstrated after both cardiac transplantation and chronic myocardial infarction. The relation between these reflex abnormalities and ventricular deafferentation is not known. METHODS AND RESULTS: To further assess this relation, we investigated the effects of left ventricular (LV) deafferentation on the control of renal sympathetic nerve activity (RSNA) by the vagal cardiopulmonary reflex in chloralose-anesthetized, mechanically ventilated dogs with sinoaortic denervation. Responses of left atrial pressure (LAP) and RSNA to hemorrhage and volume expansion were measured before and after application of 88% phenol to either the inferoposterior LV (n = 12) or the entire LV (n = 14). In control experiments, measurements were made before and after application of saline to the LV (n = 12). Reflex sensitivity (percent change in RSNA per mm Hg change in LAP) measured during volume expansion was mildly attenuated after both total (prephenol, -9.1 +/- 0.7; postphenol, -6.6 +/- 0.7; P < .05) and inferoposterior (pre, -12.5 +/- 1.8; post, -8.1 +/- 0.6; P = .055) LV deafferentation. Reflex sensitivity measured during hemorrhage was not significantly altered by inferoposterior or total LV deafferentation. Epicardial saline had no significant effect on reflex sensitivity values measured during either volume expansion or hemorrhage. Reflex inhibition of RSNA in response to intracoronary nicotine was abolished after phenol application, indicating adequate ventricular deafferentation. Phenol application had no significant effect on LAP-myocardial segment length relations measured by sonomicrometry (n = 6). CONCLUSIONS: Interruption of vagal afferent input from the LV has only modest effects on the control of RSNA by the vagal cardiopulmonary reflex. These data indicate that there is considerable redundancy in the vagal cardiopulmonary reflex such that receptors from the lungs and other cardiac chambers can largely compensate for the loss of afferent input from the LV.

Simultaneous cardiac and renal sympathetic neural responses to activation of left ventricular sympathetic afferents.

In separate sets of experiments, we observed that activation of left ventricular sympathetic afferents by transmural myocardial ischemia (TMI) appeared to elicit greater reflex increases in efferent sympathetic nerve activity (SNA) to the heart than to the kidney. To assess this observation more rigorously, we simultaneously measured changes in cardiac and renal SNA elicited by TMI and by epicardial and intracoronary bradykinin (BK). Experiments were performed in 19 chloralose-anesthetized dogs with sinoaortic denervation and vagotomy. TMI was created by a 2 min complete occlusion of the anterior descending coronary artery while a collateral flow limiting stenosis was present on the circumflex coronary artery. Epicardial BK was applied to small sponges (1 cm2) which were placed on the anterior wall of the left ventricle. Intracoronary BK was injected into a branch of the anterior descending artery. We observed that mean maximal reflex increases in SNA during TMI and intracoronary BK were significantly greater in cardiac than in renal nerves (TMI; 58 +/- 11% versus 36 +/- 9%, p = 0.01; intracoronary BK; 144 +/- 48% versus 77 +/- 26%, p = 0.05). Epicardial BK elicited reflex increases in cardiac and renal SNA which were not significantly different (167 +/- 44% versus 127 +/- 36%; p = 0.72). Our results indicate that activation of left ventricular sympathetic afferents by TMI and intracoronary BK elicits greater reflex increases in sympathetic outflow to the heart than to other end-organs such as the kidney. We speculate that these augmented excitatory responses are most likely related to engagement of cardio-cardiac spinal sympathetic reflexes during intense stimulation of sympathetic afferent endings.

Effect of chronic myocardial infarction on vagal cardiopulmonary baroreflex.

Sensory endings in the left ventricle are damaged by acute myocardial infarction. The goal of our experiments was to determine whether reflexes that originate in the heart are impaired by chronic myocardial infarction. Inferoposterior (n = 11) or anterior (n = 10) infarction was produced in dogs by ligation and intracoronary injection of rapidly hardening latex into either the proximal left anterior descending or left circumflex coronary arteries. Four weeks after infarction, the changes in renal sympathetic nerve activity induced by phenylephrine infusion, hemorrhage, and volume expansion were assessed before and after sinoaortic baroreceptor denervation. The results in infarct dogs were compared with the results in 11 sham-operated dogs. With arterial baroreceptors intact, baroreflex sensitivity (defined as the percent change in renal nerve activity per millimeter of mercury change in mean pulmonary artery wedge pressure) was similar in all groups of dogs. Following sinoaortic denervation, dogs with anterior and inferoposterior infarction had impaired responses to volume expansion. The responses during hemorrhage were abolished in dogs with inferoposterior infarction. We conclude that chronic myocardial infarction impairs reflexes that originate in the heart in response to changes in cardiac filling pressures.

Vagal cardiopulmonary baroreflex activation during phenylephrine infusion.

Phenylephrine infusion (PE) has been used to raise arterial pressure (BP) in order to investigate reflex responses mediated by sinoaortic baroreflexes (SAB). Increases in cardiac filling pressures have been reported during PE. Our experiments determined whether PE selectively activates SAB without activation of vagal cardiopulmonary baroreflexes (CPR). We measured changes in mean BP, mean pulmonary arterial pressure (PAP), and renal sympathetic nerve activity (RSNA) during PE in alpha-chloralose-anesthetized dogs before and after sinoaortic denervation (SAD; n = 10), selective vagotomy (n = 9), or SAD and vagotomy (n = 4). PE elevated both BP and PAP in all dogs studied. In dogs with SAB and CPR intact, RSNA was reflexively inhibited (% change RSNA: -76.3 +/- 4.7). In SAD dogs, inhibition of RSNA was significantly attenuated but not abolished (% change RSNA: -27.5 +/- 11.8). This inhibition after SAD correlated closely with increases in PAP. Small BP changes (10 mmHg) were associated with insignificant changes in PAP and RSNA. Volume expansion after SAD produced changes in PAP and RSNA similar to those produced by PE. After selective vagotomy, the sensitivity (% change RSNA/mmHg change BP) of the reflex elicited by PE was significantly decreased (-2.7 +/- 0.03 pre vs. -1.8 +/- 0.12 post; P = 0.01). PE failed to change RSNA after combined SAD and vagotomy. We conclude that vagal CPR contribute to reflex inhibition of RSNA during PE except when elevations of BP are small.

Renal sympathetic responses to conflicting baroreceptor inputs: rapid ventricular pacing in dogs.

1. Ventricular tachycardia generates complex changes in baroreceptor input to the central nervous system: arterial baroreceptors are unloaded while cardiopulmonary receptors are stimulated. In humans with heart diseases, muscle sympathetic nerve activity increases during ventricular tachycardia. This suggests that arterial baroreceptor-mediated sympathoexcitation overrides cardiopulmonary receptor-mediated sympathoinhibition. However, the relative roles of each reflex are difficult to determine in humans. 2. We measured efferent renal sympathetic neural responses to simulated ventricular tachycardia, to determine what pathophysiological mechanisms are invoked when inputs from different baroreceptive areas change in opposite directions. In alpha-chloralose anaesthetized, mechanically ventilated dogs, we recorded the electrocardiogram, mean left atrial and arterial pressures and multifibre efferent renal sympathetic nerve activity (RSNA) during 1 min of right ventricular pacing at 214 beats min-1. Pacing was repeated after either sinoaortic or vagal cardiopulmonary denervation and again after both sinoaortic and cardiopulmonary denervation. 3. With all afferent baroreceptor pathways intact, right ventricular pacing elicited transient sympathoinhibition (delta RSNA, -19 +/- 10%, mean +/- S.E.M.). After sinoaortic denervation (cardiopulmonary receptors intact), right ventricular pacing elicited abrupt and sustained sympathoinhibition (delta RSNA, -53 +/- 8%, P < 0.05 vs. intact). After vagal cardiopulmonary denervation (sinoaortic receptors intact), right ventricular pacing elicited abrupt and sustained sympathoexcitation (delta RSNA, + 56 +/- 19%, P < 0.05 vs. intact). After both sinoaortic and vagal cardiopulmonary denervation, right ventricular pacing elicited a gradual increase in sympathetic outflow (delta RSNA, + 16 +/- 6%, P < 0.05 vs. intact). 4. We conclude that interactions between vagal cardiopulmonary and arterial baroreflexes determine renal sympathetic outflow during simulated ventricular tachycardia. In healthy anaesthetized dogs, the balance of the two opposing reflexes is weighted towards vagal cardiopulmonary-mediated sympathoinhibition.

Labetalol by continuous intravenous infusion in severe hypertension.

This study documents our experience with labetalol administered by continuous intravenous infusion for severe hypertension. Infusions were performed in 14 hospitalized patients (15 infusions) with supine diastolic pressure greater than 125 mmHg or supine systolic pressure greater than 200 mmHg. Blood pressures were measured by intra-arterial recording or an Arteriosonde 1225 Doppler instrument standardized with a mercury sphygmomanometer. Patients initially received 2 mg/min continuous infusion; the infusion rate varied between 0.5 and 2.0 mg/min according to the protocol. The infusion was terminated when diastolic pressure decreased 30 mmHg or when 300 mg of the drug had been infused. Goal blood pressure was achieved in all but two infusions. Sedation was the most common adverse reaction, followed by nausea and diaphoresis. No patient required discontinuation or reduction in infusion rate secondary to side effects. We conclude that continuous intravenous infusion of labetalol offers an effective alternative to current parenteral therapy.

Evidence against reinnervation of cardiac vagal afferents after human orthotopic cardiac transplantation.

BACKGROUND: Orthotopic cardiac transplantation results in total cardiac denervation. Recent studies in humans suggest that reinnervation of cardiac sympathetic nerves (cardiac efferents) may occur after cardiac transplantation. We hypothesized that reinnervation of cardiac afferents may occur as well. To test this hypothesis, we investigated reflex responses produced by stimulation of ventricular chemosensory endings subserved by vagal afferents (cardiac depressor reflex). METHODS AND RESULTS: Two cardiac transplant groups were studied: an "early" group (n = 18, < 24 months after transplant) and a "late" group (n = 18, > 43 months after transplant); these groups were compared with a control group with intact innervation (n = 18). The reflex response of the recipient sinus node (RSN) in the remnant right atrium, which remains innervated after transplantation, was observed during selective right coronary artery (RCA) and left coronary artery (LCA) injection of the radiographic contrast agent meglumine diatrizoate, which is known to stimulate ventricular chemosensory endings. A decrease in the rate of the RSN was expected if reinnervation of chemosensory endings had occurred and the afferent limb of the cardiac depressor reflex was intact. With injection, the RSN rate of both transplant groups did not decrease but increased (early: LCA, 7.2 +/- 1.4 beats per minute; RCA, 6.3 +/- 1.3 beats per minute; late: LCA, 5.9 +/- 1.0 beats per minute; RCA, 6.0 +/- 0.9 beats per minute) compared with the expected decrease in control patients (LCA, -20.8 +/- 2.5 beats per minute; RCA, -18.0 +/- 4.0 beats per minute; P < .001 versus transplants). Decreases in mean arterial pressure in the transplant groups (early: LCA, -11.3 +/- 1.4 mm Hg; RCA, -10.0 +/- 1.6 mm Hg; late: LCA, -13.0 +/- 1.6 mm Hg; RCA, -9.1 +/- 1.5 mm Hg) were less than those observed in the control group (LCA, -19.8 +/- 2.2 mm Hg; RCA, -18.7 +/- 4.0 mm Hg; P < .05 versus transplants). CONCLUSIONS: The results suggest that reinnervation of ventricular chemosensory endings subserved by vagal afferents in cardiac transplant patients does not occur up to 74 months after transplantation.

Reflexes mediated by cardiac sympathetic afferents during myocardial ischaemia: role of adenosine.

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano- or chemosensitive, whereas sympathetic afferents may be mechano-, chemosensitive or both. 2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses. 3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate. 4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A1, but not adenosine A2 receptors. 5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.

Absence of parasympathetic control of heart rate after human orthotopic cardiac transplantation.

BACKGROUND: Partial reinnervation of cardiac sympathetic nerves has been observed after heart transplantation; we hypothesized that parasympathetic control to the heart after transplantation may return as well. To test this hypothesis, we examined heart rate responses produced by two cardiovascular reflexes whose efferent limbs are subserved by vagal fibers to the heart: (1) trigeminal reflex (simulated diving reflex) and (2) arterial baroreflex with phenylephrine injection. METHODS AND RESULTS: An "early" group (n=31, <24 months after transplantation) and a "late group" (n=27, >45 months after transplantation) were studied and compared with a control group with intact cardiac innervation (n=32) and a renal transplant group with similar transplant immunosuppressive regimen (n=11). For trigeminal reflex testing, responses of the donor sinus node (DSN) (sinus node controlling heart rate) and recipient sinus node (RSN) in the innervated remnant right atrium in cardiac transplant patients were compared with heart rate responses in the control groups. For arterial baroreflex testing, baroreflex gains for the DSN and RSN in the cardiac transplant groups were compared with those of the control group. With engagement of the trigeminal reflex, the DSN rate of both transplant groups changed minimally (early, 1.2+/-1.2 bpm; late, 1.8+/-2.5 bpm) compared with the expected decrease in control subjects (-19.8+/-3.0 bpm) and renal transplant patients (-23.9+/-4.9 bpm) (P<.001 versus cardiac transplants). Changes in the RSN rate of both cardiac transplant groups (early, -13.0+/-4.0 bpm; late, -10.0+/-3.7 bpm) were similar to the control groups. Arterial baroreflex gains for the DSN were also depressed (early, 0.1+/-0.2 ms/mm Hg; late, 0.2+/-0.2 ms/mm Hg) compared with control (14.9+/-1.8 ms/mm Hg) and RSN (early, 9.9+/-1.3 ms/mm Hg; late, 10.9+/-1.3 ms/mm Hg; P<.001 versus DSN transplant). CONCLUSIONS: These data suggest that parasympathetic influences on donor heart rate are absent in the majority of patients up to 96 months after cardiac transplantation.

Enhancement of t-PA Induced Fibrinolysis with Laser Energy: In-Vitro Observations.

The solid-state, pulsed-wave, holmium:YAG laser operates within strong water absorption peaks at the mid-infrared optical wavelength. This laser has been shown to be capable of inducing a mechanical, photoacoustic dissolution of fibrin, a major constituent of thrombi. It is not known whether this laser's energy combined with pharmacologic therapy can enhance the rate of fibrinolysis. The aims of this study were (1) to test the hypothesis that mid-infrared laser emission can enhance tissue-type plasminogen-activator (t-PA) mediated fibrinolysis and (2) to test the combined effect of these two methods of fibrinolysis on fibrin clots varying in age.Three in vitro experimental protocols were used. (1) Fibrin clots were treated with 116 000 IU t-PA for 1, 6 and 12 h, respectively, and then exposed to mid-infrared laser energy (solid-state, pulsed-wave, holmium:YAG, 2.1 µm wavelength 250 ms pulse length, 5 Hz repetition rate, 500 mJ/pulse (33 J/cm(2))). (2) Fibrin gels layered with t-PA were exposed to either 25, 50, 75 or 100 J laser energy. t-PA was then allowed to interact with the lased gels for an additional 4 h. (3) The effects of varying clot age (1, 4 or 8 h) on laser (75 J) augmentation of t-PA induced fibrinolysis were tested. Each experimental protocol had control gels and following each experimental manoeuvre, 20 µl of the plasmin inhibitor ε-amino-n caproic acid was added and fibrin degradation products (FDPs), an indicator of fibrinolysis, were measured by latex agglutination.In fibrin clots exposed to t-PA for 6 h, the addition of laser energy significantly increased FDPs released (t-PA alone 40±0 µg/ml, laser plus t-PA 160±0 µg/ml, p<0.001). For gels exposed to t-PA for 12 h, addition of laser energy resulted in complete dissolution of the clot (FDPs with t-PA alone 160±0 µg/ml vs. laser plus t-PA>300 µg/ml, p=0.001). The rise in FDPs was significantly greater with 75 J of laser energy compared to 25 J (160±0 µg/ml vs. 80±0 µg/ml, p=0.0001), however, energy levels greater than 75 J did not further increase the amount of FDPs indicating a plateau phenomenon in dose-response relationship. t-PA had a decreased fibrinolytic effect on 4 and 8 h-old clots (FDPs of 60±20 µg/ml and 30±10 µg/ml, respectively). Laser energy reversed this trend and enhanced fibrinolysis in both 4 and 8 h-old clots. In 4 h-old clots, laser plus t-PA resulted in FDP release of 160±0 µg/ml compared to 60±20 µg/ml for t-PA alone (p=0.007). In 8 h-old clots, FDP release with laser plus t-PA was 160±0 µg/ml compared to 30±10 µg/ml with t-PA alone (p=0.0004).It was concluded that in vitro application of mid-infrared laser energy significantly enhances fibrinolysis in fibrin clots initially treated by t-PA. The in vitro interaction between mid-infrared laser and t-PA is energy dependent, however, at energy levels exceeding 75 J there is a plateau phenomenon in dose-response relationship. This wavelength photoacoustic energy also augments the decreased response of ageing clots to t-PA.