Anthony J. Minisi

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.

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

BackgroundLeft 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 ResultsIn 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 LADI+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 IAD 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. ConclusionsReflex 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. (Circulation 1991;84:357–367)

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

BackgroundStimulation 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 ResultsWe 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%o 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%o; IP intracoronary bradykinin, 88.8±17.3%). ConclusionsWe conclude that cardiac receptors with sympathetic afferents are distributed equally to the IP and anterior regions of the LV.

Regional left ventricular deafferentation increases baroreflex sensitivity following myocardial infarction

OBJECTIVE Depressed baroreflex sensitivity (BRS) has been observed following MI and has adverse prognostic implications. The mechanism for this finding is unknown. We tested the hypothesis that depressed BRS following myocardial infarction (MI) is related to augmented input from afferent receptors in the left ventricle. METHODS Conscious, chronically-instrumented dogs were trained to undergo BRS testing. This testing was performed before and 4 weeks after creation of experimental anterior MI. Animals were then randomized to undergo regional deafferentation or sham thoracotomy. One week later, BRS testing was repeated. RESULTS Animals with reduced BRS post-MI showed slight increases in sensitivity values after regional deafferentation. Following sham thoracotomy, animals with reduced BRS post-MI exhibited further decreases in sensitivity values. The differences in mean BRS values measured after regional or sham deafferentation were significant (17.4+/-2.0 ms/mmHg vs. 11.7+/-1.4 ms/mmHg; P<0.05). CONCLUSIONS In animals with reduced BRS post-MI, deafferentation of the infarcted region prevented the progressive decline in sensitivity values that was noted in the control group. These data suggest that depressed BRS following MI is related to augmented afferent input from left ventricular receptors.

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.

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.

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.

Photoacoustic fibrinolysis: Pulsed-wave, mid-infrared laser-clot interaction

ObjectivesThe purpose of this study was to determine whether a mid-infrared laser can induce selective fibrinolysis and to analyze the effect of altered fibrin structure (thin vs. thick fibers) on laser-clot interaction.BackgroundMechanical disruption of thrombus can be achieved with balloon angioplasty, sonication, and thermal energy. Thrombi avidly absorb light in the mid-infrared optical spectrum due to their high water content. This phenomenon provides a potential for mid-infrared lasers as a source for selective thrombolysis. As fibrin is the essential component of clot, a study of mid-infrared laser-fibrin interaction is warranted.MethodsClots of varying fibrin structure were lased in cuvettes with a solid-state, pulsed-wave, mid-infrared laser (2.1 micron, 500 mJ/pulse, 250 msec pulse length). Total pulse energies of 5 Joules (J), 10 J, 37.5 J, 75 J, and 112.5 J were tested. Protein content of the extruded fluid was measured by optical density absorbance at 280 nm. The amount of released material was studied as a function of lasing energy and clot structure. SDS-polyacrylamide gel electrophoresis was applied for analysis of protein bands in order to identify unique protein bands released by the selective effect of laser fibrinolysis.ResultsA threshold for mid-infrared laser induced fibrinolysis was found; application of up to 20 J of energy did not result in dissolution. As lasing energy was increased above 37.5 J, the structure of these gels was mechanically destroyed and 12.4 ± 6.7% (mean ± SEM) of the original content of protein was released. Electrophoresis revealed that lased gels did not release any unique protein band. Lased, thin fibers released significantly less protein than thick fibers, indicating that they are more resistant to the effect of this wavelength of energy.ConclusionsMid-infrared laser can induce in-vitro photoacoustic dissolution of fibrin clots. However, this wave-length laser achieves fibrinolysis by mechanical destruction of the target clot rather than by a selective effect, as induced by the pulsed-dye laser. A threshold exists for energy levels required. Thin fibrin fibers, with their high elastic modulus (i.e., gel rigidity) appear more resistant than thick fibers to the effect of lasing at this wavelength.

Comparison of effectiveness of excimer laser angioplasty in patients with acute coronary syndromes in those with versus those without normal left ventricular function

Depressed left ventricular (LV) ejection fraction (EF) adversely affects procedural outcome during percutaneous coronary revascularization. This study examined the acute results, effectiveness, and safety of excimer laser coronary angioplasty (ELCA) in patients with acute coronary ischemic syndromes whose LVEF was depressed (<40%) versus those with preserved LVEF. One hundred patients with acute coronary syndromes (51 with unstable angina and 49 with acute myocardial infarction) underwent ELCA. Twenty-five patients (group 1) (29 lesions; 72% thrombotic) had decreased LVEF (mean 28 +/- 6%) and 75 patients (group 2) (81 lesions; 60% thrombotic) had preserved LVEF (mean 53 +/- 8%). Group 1 had a higher incidence of 3-vessel disease, Q-wave acute myocardial infarction, cardiogenic shock, diabetes, and hypertension. High laser success (87% group 1 vs 93% group 2, p = NS) and procedural success (93% group 1 vs 98% group 2, p = NS) were achieved in both groups. Minimal luminal diameter in group 1 increased from 0.7 +/- 0.5 to 1.4 +/- 0.5 mm after the laser procedure and finally to 3.0 +/- 0.4 mm; in group 2, minimal luminal diameter increased from 0.7 +/- 0.4 to 1.3 +/- 0.5 mm after the procedure to a final of 3.0 +/- 0.5 mm. The laser energy vaporized 75% of thrombus burden from the target lesion in group 1 versus 79% in group 2 (p = NS). Thrombolysis In Myocardial Infarction flow in group 1 increased from 1.4 +/- 1.2 to 2.7 +/- 0.7 by laser and finally to 2.9 +/- 0.3, and in group 2 from 2.0 +/- 1.0 to 2.8 +/- 0.6 after the laser procedure to a final of 2.9 +/- 0.4. There were no deaths, emergency bypass surgeries, strokes, or acute vessel closures in either group. Thus, ELCA is a safe and feasible revascularization modality for patients with acute coronary syndromes whose LVEF is depressed. The laser energy vaporizes a large thrombus burden from the treated plaque. Angiographic intracoronary thrombus does not adversely affect device and procedural success in these select patients.

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

Abstract. 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 lasers 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/cm2)). (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.