Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy.

BACKGROUND: The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVES: This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM. METHODS: In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls. RESULTS: After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls. CONCLUSIONS: Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia.

Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy.

BACKGROUND: Premature ventricular contractions (PVCs) commonly coexist with cardiomyopathy. Recently, PVCs have been identified as a possible cause of cardiomyopathy. We developed a PVC-induced cardiomyopathy animal model using a novel premature pacing algorithm to assess timeframe and reversibility of this cardiomyopathy and examine the associated histopathologic abnormalities. METHODS AND RESULTS: Thirteen mongrel dogs were implanted with a specially programmed pacemaker capable of simulating ventricular extrasystoles. Animals were randomly assigned to either 12 weeks of bigeminal PVCs (n = 7) or no PVCs (control, n = 6). Continuous 24-hour Holter monitoring corroborated ventricular bigeminy in the PVC group (PVC, 49.8% versus control, < 0.01%; P<0.0001). After 12 weeks, only the PVC group had cardiomyopathy, with a significant reduction in left ventricular ejection fraction (PVC, 39.7 ± 5.4% versus control, 60.7 ± 3.8%; P < 0.0001) and an increase in left ventricular end-systolic dimension (PVC, 33.3 ± 3.5 mm versus control, 23.7 ± 3.6 mm; P < 0.001). Ventricular effective refractory period showed a trend to prolong in the PVC group. PVC-induced cardiomyopathy was resolved within 2 to 4 weeks after discontinuation of PVCs. No inflammation, fibrosis, or changes in apoptosis and mitochondrial oxidative phosphorylation were observed with PVC-induced cardiomyopathy. CONCLUSIONS: This novel PVC animal model demonstrates that frequent PVCs alone can induce a reversible form of cardiomyopathy in otherwise structurally normal hearts. PVC-induced cardiomyopathy lacks gross histopathologic and mitochondrial abnormalities seen in other canine models of cardiomyopathy.

Aspirin desensitization/challenge in 3 patients with unstable angina.

Aspirin sensitivity is relatively frequent and can be a major problem in patients who need percutaneous coronary intervention and stenting with subsequent dual antiplatelet therapy. Desensitization is often the therapy in these patients, but this can prolong the time to revascularization significantly. Rapid oral aspirin desensitization protocols have been described since 2000. However, data are lacking on the optimal strategy for aspirin desensitization and determining which patients are mostly benefited from this desensitization. The authors describe the use of a Wong-modified protocol in 3 patients who had known aspirin sensitivity and who had unstable angina and an indication for percutaneous coronary intervention.

Aortic baroreceptor function and depressed baroreflex sensitivity following myocardial infarction.

Depressed sinoaortic baroreflex control of heart rate following myocardial infarction (MI) is associated with increased morbidity and mortality. The etiology of this autonomic disturbance is unknown but could potentially occur at several levels of the reflex arc. The purpose of this study was to assess whether depressed baroreflex sensitivity (BRS) post-MI is associated with aortic baroreceptor dysfunction. BRS was measured before and 4-8 weeks after anterior MI in 17 chronically-instrumented, trained, conscious dogs. BRS (ms/mm Hg) was defined as the slope of the relationship between changes in systolic blood pressure (SBP) and heart period in response to a bolus dose of phenylephrine (PE). After the effects of MI on BRS were determined, the animals were anesthetized and the aortic depressor nerves (ADN) were isolated from the cervical vagi. Aortic baroreceptor function was measured by direct recording of ADN activity during gradual elevation of SBP induced by PE infusion. BRS was depressed following MI in 7 of these dogs and preserved in the remaining 10. Aortic baroreceptor sensitivity (ABS) defined as the slope of the relationship between changes in ADN activity and SBP was not significantly different between the dogs with depressed BRS compared to the dogs with preserved BRS post-MI. In conclusion, the response of the aortic baroreceptors to an increase in SBP is similar in dogs with and without depressed BRS post-MI. Based on these data, we conclude that depressed reflex control of heart rate following MI is not related to dysfunction of the afferent limb of the sinoaortic baroreflex.

Reflex control of sympathetic outflow and depressed baroreflex sensitivity following myocardial infarction.

Reflex control of heart rate is frequently impaired following myocardial infarction. This is referred to as depressed baroreflex sensitivity. The aim of these experiments was to assess the function of other autonomic reflexes in dogs with depressed baroreflex sensitivity. Comparisons were made to dogs in whom baroreflex sensitivity was preserved or unchanged after myocardial infarction. Under chloralose-barbiturate anesthesia, reflex control of sympathetic outflow by the sinoaortic baroreceptors was determined by measurement of changes in systolic arterial pressure and efferent renal sympathetic nerve activity during infusion of phenylephrine. Following sinoaortic denervation, reflex control of sympathetic outflow by cardiac receptors with vagal afferent fibers was determined by measurement of changes in pulmonary capillary wedge pressure and renal nerve activity during blood volume expansion. Reflex decreases in renal nerve activity in response to increases in arterial pressure were similar in the two groups of dogs. In contrast, elevation of pulmonary capillary wedge pressure elicited significantly greater reflex decreases in renal nerve activity in dogs with depressed baroreflex sensitivity following myocardial infarction compared to dogs with preserved baroreflex sensitivity. Hemodynamic parameters and infarct sizes were similar in each group. In conclusion, activation of cardiac receptors with vagal afferent fibers elicited greater reflex inhibition of sympathetic outflow in dogs with depressed baroreflex sensitivity following myocardial infarction. These data suggest that these receptors are "sensitized". These results provide additional support for the hypothesis that depressed reflex control of heart rate following myocardial infarction is related to augmented afferent input from the left ventricle.

Failure of chronic transmyocardial laser revascularization to alter cardiac nociceptive reflexes: implications for the treatment of angina pectoris.

The aim of this study was to assess the delayed effects of transmyocardial laser revascularization (TMLR) on cardiac nociceptors. Experiments were performed in anesthetized dogs 1 month after thoracotomy with either TMLR (n = 17) or sham laser procedure (n = 17). All dogs underwent sinoaortic denervation and vagotomy to isolate the sympathetic afferent system. Left ventricular sympathetic afferents were stimulated by intracoronary bradykinin and transmural myocardial ischemia. Efferent responses were measured by direct recording of renal sympathetic nerve activity. Renal nerve responses to intracoronary bradykinin administered to the laser-treated anterior ventricular wall were not significantly different from those observed from the unlased posterior wall. Anterior transmural ischemia elicited similar renal nerve responses in laser-treated and sham groups. Pathologic analysis showed intact neural structures in the subepicardial regions both near and remote from the lased channels. We conclude that reflexes mediated by left ventricular sympathetic afferents are preserved after chronic TMLR. These findings do not support the neural hypothesis for angina relief.

Ventricular reflex interactions during transmural myocardial ischemia.

The role of left ventricular receptors with sympathetic afferent fibers in the reflex response to myocardial ischemia is controversial, particularly in the canine model. Previous experiments have shown that reflex excitatory responses mediated by left ventricular sympathetic afferents can be detected in sinoaortic denervated and vagotomized dogs during transmural myocardial ischemia. The purpose of these experiments was to determine if reflex excitatory responses occur in dogs with intact left ventricular vagal afferents. Experiments were performed in 27 chloralose-anesthetized dogs with sinoaortic denervation. Responses of efferent renal sympathetic nerve activity, arterial, and left atrial pressures to transmural and non-transmural inferoposterior myocardial ischemia were measured before and after interruption of left ventricular sympathetic afferents by stellectomy. The adequacy of sympathetic deafferentation was assessed by measurement of renal nerve responses to epicardial bradykinin. Prior to stellectomy, excitatory responses were observed in 10 animals and inhibitory responses in 9 animals. The remaining animals had no responses and were excluded from analysis. In the excitatory group, reflex increases in renal nerve activity during both transmural and non-transmural inferoposterior ischemia were abolished by stellectomy and not replaced by inhibitory responses. In the inhibitory group, non-transmural inferoposterior ischemia elicited greater reflex decreases in renal nerve activity when left ventricular sympathetic afferents were intact. After stellectomy, transmural ischemia elicited greater reflex inhibition of renal nerve activity. Renal nerve responses to epicardial bradykinin were abolished by stellectomy. These results indicate that reflex excitatory responses mediated by left ventricular receptors with sympathetic afferent fibers can be elicited in dogs with intact vagal afferents. These excitatory responses are most apparent during transmural myocardial ischemia. In dogs with inhibitory responses to coronary occlusion, activation of sympathetic afferents during transmural ischemia appears to attenuate reflex inhibitory responses mediated by left ventricular vagal afferents.

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.

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.

Patients with coronary artery disease who present with chest pain have significantly elevated platelet contractile force and clot elastic modulus.

Rapid laboratory markers that correlate with patient risk would facilitate the decision making regarding admission of patients with chest pain (CP). Platelet contractile force (PCF) and clot elastic modulus (CEM) are elevated in patients undergoing coronary bypass grafting. This study assessed PCF, CEM, and platelet aggregation in patients presenting to the emergency department with chest pain (CP). Results were compared with fifty normal controls. Both the total group of CP patients (n = 100) and the subset of patients (n = 36) with documented coronary artery disease (CAD) had significantly elevated PCF and CEM, and significantly decreased platelet aggregation relative to normal (p <0.001 for the total group, p

Relationship between dobutamine-induced regional wall motion abnormalities and coronary flow reserve in heart transplant patients without angiographic coronary artery disease.

BACKGROUND: Regional wall motion abnormalities (RWMA) demonstrated by dobutamine stress echocardiography (DSE) are a sensitive predictor of coronary artery disease (CAD) in heart transplant recipients. However, RWMA have been shown to occur in patients with angiographically "normal" coronary arteries. The reasons for this are unknown. We sought to determine if abnormal responses to dobutamine in this setting can be explained by microvascular dysfunction in the coronary circulation as detected by decreased coronary flow reserve (CFR). METHODS: Twenty-six consecutive heart transplant patients were evaluated prospectively. Five of 26 (19.2%) patients (seven coronary arteries) were excluded for poor acoustic windows on echocardiography. Another three patients were excluded for angiographically apparent CAD. CFR and wall motion score index (WMSI) derived from DSE were measured in the remaining 18 patients and formed the basis of this study. Patients were divided into two groups based on the absence (Group 1; n = 5) or presence (Group 2; n = 13) of RWMA on DSE. CFR was measured with the Doppler Flo-Wire in 34 coronary arteries (18 patients) and correlated with WMSI. RESULTS: In Group 1 patients, CFR measured in eight coronary arteries was normal (2.6 +/- 0.4). In Group 2 patients, CFR measured in 26 coronary arteries also was normal (2.2 +/- 0.6; p = NS vs Group 1). In Group 2, CFR was measured in 20 of 24 vessels assigned to segments that developed RWMA. Only 6 of these 20 vessels (30%) had abnormal CFR. Overall, there was no correlation between decreased CFR and the presence of RWMA induced by dobutamine. CONCLUSIONS: These data suggest that, in cardiac transplant patients with angiographically "normal" coronary arteries, inducible wall motion abnormalities during DSE cannot be attributed to coronary microvascular dysfunction as manifested by decreased CFR.