Intrapericardial Research Articles

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model.

The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.

Pharmacokinetic Advantage of ASD Device Promote Drug Absorption through the Epicardium.

Due to low therapeutic efficacy and severe adverse reaction of systemic administration for coronary heart disease (CHD) therapy, we designed a novel local target delivery system, called Active hydraulic ventricular Support Drug delivery system (ASD). This study aims to investigate the potential advantages of ASD compared to intrapericardial (IPC) injection and factorsaffecting drug absorption through epicardium. Liposoluble, water soluble and viscous solutions of cyanine 5 (Cy5) fluorescent dye were delivered individually through ASD and IPC in Sprague-Dawley (SD) rats and then tissues were isolated and observed by in vivo imaging system. Atria and ventricles of the heart were taken for the paraffin section and observed under a fluorescence microscope. The fluorescence intensity of Cy5 injected by ASD distributed in the heart was significantly higher than IPC injection. Whereas, the fluorescence signal spread in other tissues such as lung, liver, spleen, and kidney of ASD groups was much weaker. Moreover, when choosing liposoluble and viscous Cy5, the intensity of the heart turned stronger and fluorescence dye distributed in other tissues was lesser. The application ofASD devicemay provide a promising route of drug delivery for CHD. Furthermore, increasing viscosity of the solution and liposolublity of the drug was beneficial to facilitate drug absorption through theepicardium.

Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION) study: Results of a pilot study.

Cardiac surgery patients are at high risk for postoperative bleeding. Intravenous (IV) tranexamic acid (TxA) is a commonly used antifibrinolytic drug, but is associated with postoperative seizures. We conducted this pilot randomized controlled trial (RCT) to determine the feasibility of a larger trial that will be designed to investigate the impact of TxA administration route, intrapericardial (IP) vs IV, on postoperative bleeding and seizures. In this single-center, double-blinded, pilot RCT we enrolled adult patients undergoing nonemergent on-pump cardiac operations through a median sternotomy. Participants were randomized to IP or IV TxA groups. The primary outcomes were cumulative chest tube drainage, transfusion requirements, and incidence of postoperative seizures. A total of 97 participants were randomized to the intervention and control groups. Baseline characteristics were similar in both groups. Most participants underwent a CABG and/or aortic valve replacement. There was no statistical difference. The IP TxA group was found to have a tendency for less chest tube drainage in comparison to the IV TxA group, 500.5 (370.0-700.0) and 540.0 (420.0-700.0) mL, respectively, which was not statistically significant (P = 0.2854). Fewer participants in the IP TxA group with cardiac tamponade and/or required a reoperation for bleeding and fewer packed red blood cell transfusions. None of the IP TxA group developed seizure vs one from the IV TxA group. This is the first known pilot RCT to investigate the role of TxA route of administration in open cardiac surgery. Intrapericardial TxA shows promising results with decreased bleeding, transfusion requirements, reoperations, and postoperative seizures. A larger RCT is needed to confirm these results and lead to a change in practice.

DECREASING POSTOPERATIVE BLOOD LOSS BY TOPICAL VS. INTRAVENOUS TRANEXAMIC ACID IN OPEN CARDIAC SURGERY (DEPOSITION) STUDY: RESULTS OF A PILOT STUDY

Background Cardiac surgery patients are at high risk for postoperative bleeding. Intravenous (IV) tranexamic acid (TxA) is a commonly used antifibrinolytic drug, but is associated with postoperative seizures. We conducted this pilot randomized controlled trial (RCT) to determine the feasibility of a larger trial that will be designed to investigate the impact of TxA administration route, intrapericardial (IP) vs IV, on postoperative bleeding and seizures. Methods In this single-center, double-blinded, pilot RCT we enrolled adult patients undergoing nonemergent on-pump cardiac operations through a median sternotomy. Participants were randomized to IP or IV TxA groups. The primary outcomes were cumulative chest tube drainage, transfusion requirements, and incidence of postoperative seizures. Results A total of 97 participants were randomized to the intervention and control groups. Baseline characteristics were similar in both groups. Most participants underwent a CABG and/or aortic valve replacement. There was no statistical difference. The IP TxA group was found to have a tendency for less chest tube drainage in comparison to the IV TxA group, 500.5 (370.0-700.0) and 540.0 (420.0-700.0) mL, respectively, which was not statistically significant (P = 0.2854). Fewer participants in the IP TxA group with cardiac tamponade and/or required a reoperation for bleeding and fewer packed red blood cell transfusions. None of the IP TxA group developed seizure vs one from the IV TxA group. Conclusion This is the first known pilot RCT to investigate the role of TxA route of administration in open cardiac surgery. Intrapericardial TxA shows promising results with decreased bleeding, transfusion requirements, reoperations, and postoperative seizures. A larger RCT is needed to confirm these results and lead to a change in practice.

Intrapericardial Amiodarone for the Prevention of Postoperative Atrial Fibrillation.

Despite probably being the most effective prophylactic drug for postoperative atrial fibrillation (POAF), amiodarone is reserved as a second-line agent because of its potential systemic side effects. Herein, we review the available experimental and clinical trials examining the effectiveness of intrapericardial (IPC) amiodarone administration in preventing POAF which, if confirmed by future studies, can have a significant impact on cardiac surgery practice.

Cardiac Responses to the Intrapericardial Delivery of Metoprolol: Targeted Delivery Compared to Intravenous Administration

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Efficacy and safety of intrapericardial bleomycin for malignant pericardial effusion.

e19687 Background: Malignant pericardial effusion (MPE) is a relatively common complication of advanced malignancies including lung and breast cancer. Although pericardial drainage results in good palliation of symptoms, it is often inadequate to prevent recurrence of effusion. Intrapericardial (IP) sclerotherapy is associated to good results in terms of recurrence prevention. Absence of MPE at 30 days (d) after sclerosis can be observed in 70 to 90% of treated patients (pts). In comparison to tetracyclines and other agents used for IP sclerosis, bleomycin appears to be effective and safe. Methods: We retrospectively reviewed 18 pts with MPE who had been treated with IP bleomycin at our institution from July 2004 to July 2009. Our aim was to identify the number of MPE recurrences at 30 d and treatment-related morbidity. Results: Twelve men and 6 women with a median age of 62 years were included with diagnosis of lung cancer (67%), breast cancer (11%) and others (22%). They all presented clinical and/or radiological evidence of pericardial effusion. Cytology of the effusion was positive in 8 cases out of the 17 examined (47%). There were no deaths due to initial sclerosis failure or complication of procedure. MPE recurrence developed in 4 pts (22.2%), 3 of which (75%) did so after 30 d. Mild fever (37-37.5°C) occurred in 5 pts (27.8%). Three pts (16.7%) developed atrial fibrillation with rapid ventricular response reverting to sinus rhythm after intravenous administration of amiodarone. Retrosternal pain and infection of catheter were observed in one pt (5.5%). Conclusions: Our experience with MPE is consistent with that reported in literature, supporting the use of bleomycin as IP sclerosing agent to prevent the recurrence of MPE with generally controllable morbidity. No significant financial relationships to disclose.

Intrapericardial Ranolazine Prolongs Atrial Refractory Period and Markedly Reduces Atrial Fibrillation Inducibility in the Intact Porcine Heart

Extensive experimental studies and clinical evidence (Metabolic Efficiency with Ranzolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction-36 [MERLIN TIMI-36] trial) indicate potential antiarrhythmic efficacy of the antianginal agent ranolazine. Delivery of agents into the pericardial space allows high local concentrations to be maintained in close proximity to myocardial tissue while systemic effects are minimized. The effects of intrapericardial (IPC) administration of ranolazine (50-mg bolus) on right atrial and right ventricular effective refractory periods (ERP), atrial fibrillation threshold, and ventricular fibrillation threshold were determined in 17 closed-chest anesthetized pigs. IPC ranolazine increased atrial ERP in a time-dependent manner from 129 +/- 5.14 to 186 +/- 9.78 ms (P < 0.01, N = 7) but did not significantly affect ventricular ERP (from 188.3 +/- 4.6 to 201 +/- 4.3 ms (NS, N = 6). IPC ranolazine increased atrial fibrillation threshold from 4.8 +/- 0.8 to 28 +/- 2.3 mA (P < 0.03, N = 6) and ventricular fibrillation threshold (from 24 +/- 3.56 baseline to 29.33 +/- 2.04 mA at 10-20 minutes, P < 0.03, N = 6). No significant change in mean arterial pressure was observed (from 92.8 +/- 7.1 to 74.8 +/- 7.5 mm Hg, P < 0.125, N = 5, at 7 minutes). IPC ranolazine exhibits striking atrial antiarrhythmic actions as evidenced by increases in refractoriness and in fibrillation inducibility without significantly altering mean arterial blood pressure. Ranolazine's effects on the atria appear to be more potent than those on the ventricles.

Intrapericardial Delivery of Amiodarone and Sotalol: Atrial Transmural Drug Distribution and Electrophysiological Effects

Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg.kg.h. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (-74% +/- 20% and -66% +/- 30%, respectively) compared with IV delivery (-11% +/- 17% and -17% +/- 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (-70% +/- 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.

Comparison of Elimination and Cardiovascular Effects of Adenine Nucleosides Administered Intrapericardially or Intravenously in Anesthetized Dog

Intrapericardial (IP) administration of certain cardioactive agents allows investigation of local pharmacological actions on the heart and may carry potential benefit to influence myocardial function. The cardioprotective adenosine (ADO) and inosine (INO) may be the most representative candidates. Elimination and cardiovascular effects of IP and intravenously (IV) applied ADO and INO were compared on anesthetized dogs. Their pericardial and systemic concentrations were measured after consecutive administration of increasing ADO and INO doses. In the case of IP administration at the end of the incubation period, pericardial concentrations of adenine nucleosides significantly exceeded the control values. However, the IV applied ADO and INO were rapidly metabolized in the systemic plasma. As characteristic hemodynamic effects, small but sustained decrease in heart rate (IP ADO) and increase in myocardial contractility (IP INO) were observed. During IV administration, ADO and INO exerted remarkable effects on all hemodynamic variables, which then gradually disappeared in 15 minutes. In summary, the elimination of ADO and INO was significantly slower in the pericardial fluid than in the plasma. Considering the balanced cardiac actions and lack of strong systemic hemodynamic effects, IP administration of adenine nucleosides may suggest a promising approach in the local treatment of the diseased heart.

Effects of Intrapericardial Sotalol and Flecainide on Transmural Atrial Electrophysiology and Atrial Fibrillation

Intrapericardial (IPC) delivery of antiarrhythmic agents is an appealing idea to increase the therapeutic width and reduce side effects of drugs, particularly in the thin atria. The aim of this study was to determine the effects of IPC versus intravenous (IV) d,l-sotalol and flecainide infusion on transmural atrial electrophysiology and sustained atrial fibrillation (AF) in the goat. Effects of IPC and IV sotalol and flecainide infusion on epi- and endocardial atrial electrophysiology, ECG, and tissue drug concentrations were studied in goats without and with persistent AF (>24 hours). Epicardial atrial refractory period (AERP, bcl 400 ms) increased after 120 minutes of 1 mg/kg/hour IPC sotalol with 61 +/- 8 ms (P = 0.02), whereas the endocardial AERP was not affected. One mg/kg/hour IPC flecainide increased the epicardial pacing threshold and the epicardial AERP with 4 +/- 0.5 mA (P = 0.003) and 33 +/- 11 ms (P = 0.05), respectively. Endocardial values were unchanged. Marked ST-elevations in the precordial ECG leads were observed after IPC flecainide. In the AF group, IPC drugs did not prolong AF cycle length to a greater extent than IV delivery. The number of cardioversions was not different between the two delivery routes. A steep transmural drug concentration gradient after IPC sotalol and flecainide was observed in all heart chambers. IPC sotalol and flecainide infusion in goats markedly affects epicardial atrial electrophysiology. IPC delivery, however, does not prolong AFCL or terminate AF to a greater extent than IV infusion. This suggests that the perpetuation of AF is not dominated by the epicardial and sub epicardial atrial layers.

Abstract 2861: Amiodarone, in Contrast to Sotalol, Equally Decreases Epicardial and Endocardial Atrial Fibrillation Inducibility, Despite a Steep Transmural Concentration Gradient

Background: Amiodarone causes less ventricular transmural dispersion of repolarization (TDR) and proarrhythmia than sotalol. Effects of both drugs on atrial TDR, however, have not yet been well defined. We applied intrapericardial (IPC) drug delivery to produce in vivo transmural concentration gradients. We assessed the hypotheses that IPC amiodarone causes less atrial TDR than IPC sotalol and that IPC amiodarone is more effective than IPC sotalol in lowering atrial fibrillation (AF) inducibility. Methods: Goats (n = 25) were randomised into 5 groups receiving either IPC dextrose, amiodarone (IV or IPC) or d,l-sotalol (IV or IPC). Drugs were infused for 3 hours at a constant rate of 2 mg/kg per hour. Quadripolar catheters were placed on the epi- and endocardial surfaces of the right atrium. Atrial effective refractory period (AERP) and AF inducibility were measured by single premature stimuli at 4 times the diastolic threshold. Atria were freeze-microtomed parallel to the epicardial surface and analysed by HPLC. Results: IPC drug delivery produced high epicardial concentrations (fig.1a ) with significantly decreased epicardial AF inducibility. A similar decrease in endocardial AF inducibility was only observed in the IPC amiodarone group (fig.1b ). TDR (defined as endo-minus epicardial AERP) became negative after IPC sotalol (from 13.0 ± 3.2 to -30.7 ± 7.3 ms, p &lt; 0.05). In the other groups TDR did not change significantly and remained positive. Conclusions: IPC delivery boosts epicardial drug concentration and efficacy. For amiodarone, this also increases endocardial efficacy. IPC sotalol, however, inverts TDR, which may explain its inferior endocardial efficacy. Figure 1a. Concentrations in right atrium (mean + SD) Figure 1b. Chang in AF inducibility (mean + SD)

Suppression of Calcium-Induced Repolarization Heterogeneity as a Mechanism of Nitroglycerin??s Antiarrhythmic Action

This study examined whether the antifibrillatory action of nitroglycerin (NTG) is attributable to reduction in calcium-induced heterogeneity of repolarization independent of autonomic and coronary vasodilatory influences. The effects of intrapericardial (IPC) NTG on coronary blood flow, contractility, repolarization, and arrhythmia susceptibility were measured in anesthetized pigs (N = 43). Autonomic influences were minimized by vagotomy and beta-adrenergic blockade (metoprolol, 1.25 mg/kg, intravenous). Electrophysiological parameters were tested at 30 min, a time when coronary hemodynamics had returned to baseline. Intracoronary calcium chloride (CaCl2, 50-mg bolus) injection augmented contractility (dP/dt(max), 1760 +/- 144 to 2769 +/- 274 mmHg/s, and following NTG, 1531 +/- 384 to 2138 +/- 242 mmHg/s, P < 0.0002), reflecting increased myocardial intracellular calcium. Calcium increased repolarization heterogeneity (interlead precordial T-wave heterogeneity, 95 +/- 15 to 264 +/- 33 microV, P < 0.006; T(peak)-T(end), an index of transmural dispersion of repolarization, 37 +/- 3 to 76 +/- 6 ms, P < 0.05) and lowered repetitive extrasystole threshold (RET; 24 +/- 2 to 13 +/- 1 mA, and following NTG, 32 +/- 4 to 18 +/- 1 mA, P < 0.0001). IPC NTG raised the RET from baseline by 33% and blunted calcium-induced contractility (dP/dt(max) by 23%, P < 0.05), repolarization changes (T-wave heterogeneity by 24%, P < 0.006; T(peak)-T(end) by 18%, P = 0.04), and arrhythmia vulnerability (RET by 39%, P < 0.003). Thus, the capacity of NTG to suppress calcium-induced repolarization heterogeneity is an important mechanism of its antiarrhythmic action, which is independent of autonomic and vasodilatory actions.

Role of epicardial and pericardial sensory nerves on spontaneous variations of blood pressure and heart rate in conscious rats

Epicardial and pericardial sensory nerves mediate cardiac inhibitory (Bezold-Jarisch reflex) as well as cardiac sympathoexcitatory reflexes. Although direct stimulation of cardiac sympathetic afferent nerves influences baroreflex control of blood pressure (BP), the contribution of these cardiac sensory nerves to blood pressure control under normal physiological conditions is not fully clear. In the present study we tested whether elimination of cardiac sympathetic reflexes by intrapericardial (IPC) administration of the neurotoxin resiniferatoxin (RTX) would affect spontaneous blood pressure (BPV) and heart rate variability (HRV) in conscious rats. To this end RTX (15 μg/kg) was administered IPC via a catheter implanted in the pericardial sac of Wistar rats. BP and HR were measured via an indwelling catheter placed in the femoral artery. Cardiac sympathetic deafferentation was verified by comparing the magnitude of pressor responses evoked by IPC applied bradykinin before and after RTX. Using immunohistochemistry the density of CGRP containing nerves in the pericard was compared in vehicle and RTX treated rats (n=3). Cardiac sensory deafferentation by RTX (n=7) did not alter steady state BP and HR as measured in the conscious resting state 3 days before and 3 days after RTX treatment. BPV and HRV were quantified by spectral analysis. The magnitude of the low-frequency and high-frequency components of BPV and HRV were not significantly altered after RTX. These data suggest that cardiac sympathetic afferents do not play a major role in determining BPV and HRV under normal physiological conditions.

Intrapericardial delivery enhances cardiac effects of sotalol and atenolol.

Targeting drugs to the heart by intrapericardial (i.p.c.) delivery may be a promising strategy to obtain higher drug efficiencies with lesser side effects. We examined whether i.p.c. delivery of sotalol and atenolol in rats offers advantages over intravenous (i.v.) application. Following sustained IPC infusion of sotalol or atenolol, pericardial fluid levels exceeded plasma levels 97 and 134 times respectively (P < 0.01) resulting in 3.8 and 4.7 times higher overall left ventricular tissue drug levels (P < 0.05). In a second experiment, the effects of the i.p.c. or i.v. beta-blocker infusions on nitroprusside-induced tachycardia were studied in conscious rats. For both drugs, i.p.c. infusion of 0.03 mg/kg.h produced similar antitachycardiac effects as the 1 mg/kg.h i.v. dose. In a third set of studies, dP/dt max challenged by dobutamine infusion was assessed to study ventricular contractile function after i.v. and i.p.c. sotalol in anesthetized rats. i.p.c. sotalol infusion attenuated the dobutamine response curve to a greater extent than i.v. (P < 0.01). In conclusion, i.p.c. infusion of sotalol and atenolol results in high cardiac tissue concentrations with low systemic drug levels. Similar antitachycardiac effects can be obtained at a 10- to 30-fold lower dose compared with i.v. delivery. Also, depression of ventricular contractility is acquired at a substantially lower i.p.c. sotalol dose. Thus, beta-blocking properties of sotalol and atenolol can be greatly enhanced by applying them i.p.c.

Intrapericardial paclitaxel delivery inhibits neointimal proliferation and promotes arterial enlargement after porcine coronary overstretch.

Catheter-based intrapericardial (IPC) delivery of therapeutic agents has recently been demonstrated. Paclitaxel is known to inhibit vascular smooth muscle cell proliferation. This study examined the effect of IPC instillation of paclitaxel on neointimal proliferation after balloon overstretch of porcine coronary arteries. Overstretch injury of coronary arteries was followed by IPC administration of micellar paclitaxel at low dose (LD, 10 mg; n=6) or high dose (HD, 50 mg; n=7) or of control micelles (50 mg, n=5). Animals were euthanized 28 days after balloon dilation. Arterial injury indices were no different among the groups. The neointimal area, maximal intimal thickness, and adventitial thickness were significantly reduced in both LD (0.47+/-0.04 mm(2), 0.43+/-0.03 mm, and 0.35+/-0.02 mm, respectively) and HD (0.51+/-0.06 mm(2), 0.42+/-0.03 mm, and 0. 38+/-0.03 mm, respectively) paclitaxel groups compared with the control group (0.79+/-0.07 mm(2), 0.56+/-0.02 mm, and 0.47+/-0.02 mm, respectively; P:<0.001). Meanwhile, the vessel circumference measured at the external elastic lamina of paclitaxel-treated vessels was significantly larger than the control circumference. Apoptotic cells were found in the neointima. The apoptotic cell percentage was not different between the control (1.72%) and LD (2. 31%) groups but was higher in the HD group (7.07%, P:<0.0001 versus control and LD groups). Immunostaining for matrix metalloproteinase-2 revealed concurrent reduction in the HD group compared with the control and LD groups. IPC space delivery of a single dose of paclitaxel significantly reduces vessel narrowing in this balloon-overstretch model. This effect is mediated by reduction of neointimal mass as well as positive vascular remodeling.

Furosemide elicits nonuniform reflex responses via cardiac sympathetic afferents.

To examine whether furosemide elicits a cardiorenal reflex response via stimulation of cardiac afferents, furosemide was administered intrapericardially in sinoaortic denervated rats. The role of vagal afferents was evaluated by intrapericardial (IPC) administration of furosemide before and after bilateral vagotomy. The role of cardiac sympathetic afferents was examined by IPC administration of furosemide before and after IPC lidocaine blockade in rats with bilateral vagotomy. Low-dose furosemide (10 micrograms) elicited renal sympathoinhibition, whereas high-dose furosemide (1000 micrograms) produced a rapid and transient change in efferent renal sympathetic nerve activity of either inhibitory (19/49, or 39%) or excitatory (30/49, or 61%) nature. The responses were not affected by vagotomy but were abolished by IPC lidocaine blockade. In rats with a renal sympathoinhibitory response to IPC administration of 1000 micrograms furosemide, both the hypotensive and sympathoinhibitory responses were inhibited by indomethacin, whereas indomethacin did not affect reflex responses in rats showing a renal sympathoexcitatory response to IPC injection of 1000 micrograms furosemide. We conclude that furosemide elicits a nonuniform reflex response mediated via cardiac sympathetic afferents of which the renal sympathoinhibitory response is dependent on intact cyclooxygenase function.

Accelerated myocardial relaxation in conscious dogs during acute cardiac tamponade.

Eight chronically instrumented conscious dogs were used to test the hypothesis that left ventricular (LV) relaxation is accelerated during cardiac tamponade. The time constant of LV transmural pressure fall was measured before and during intrapericardial (IP) saline infusion (baseline) with and without beta-adrenergic blockade (propranolol 1 mg/kg iv). Heart rate was controlled by atrial pacing. Increasing IP pressure caused a progressive linear decrease in stroke volume before and during beta-blockade in each animal. The time constant of LV transmural pressure fall also decreased continuously with an increase in IP pressure from 26 +/- 7 ms during baseline to 18 +/- 5 ms during severe cardiac tamponade (P < 0.01) before beta-blockade. However, after beta-blockade, the time constant of LV transmural pressure fall was constant over a wide range of IP pressures despite a continuous decrease in LV end-diastolic volume. The time constant of LV transmural pressure fall was not altered by vena caval occlusions that caused the same decrease in LV preload observed during cardiac tamponade. We concluded that despite decreased pump function, LV relaxation was accelerated progressively during graded cardiac tamponade, and this change was dependent not on changes in loading conditions but on an intact beta-adrenergic influence.

Determinants of intrapericardial pressure in dogs

This study investigates factors that influence the pressure measured in the intrapericardial (IP) space. Seven dogs were studied after they were anesthetized with pentobarbital sodium. With the chest closed, intravascular volume expansion by dextran infusion from a mean left atrial (LA) transmural pressure of 8.4 +/- 1.2 (SD) to 15.5 +/- 1.6 Torr caused an increase in mean IP of from 2.6 +/- 1.2 to 3.9 +/- 1.7 Torr (P less than 0.01). This reflected a predominant increase in the influence of the cardiac fossa (CF), which accounted for 56% of the IP pressure after volume expansion. In the open-chest state an increase in mean LA transmural pressure from 9.5 +/- 2.5 to 16.4 +/- 0.6 Torr caused IP pressure to increase from 1.1 +/- 0.9 to 3.0 +/- 1.6 (P less than 0.005), representing the influence of the elastic pericardium alone. The use of positive end-expiratory pressure (PEEP) significantly increased the influence of the CF. Of note, the relation of LA to right atrial (RA) pressure was significantly different with and without the influence of the CF; the RA-to-LA ratio was higher with the chest open under each set of volume conditions with and without PEEP. In four dogs, acute transection of the pericardiodiaphragmatic ligaments led to a small (1-2 Torr) but distinct drop in IP pressure. Thus, IP pressure is affected by the intracardiac volume, the elastic pericardium, the CF, and the pericardiodiaphragmatic attachments, all of which must be considered in an analysis of diastolic properties of the heart in situ.